CA2236007A1 - Antithrombotic diamines - Google Patents
Antithrombotic diamines Download PDFInfo
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- CA2236007A1 CA2236007A1 CA002236007A CA2236007A CA2236007A1 CA 2236007 A1 CA2236007 A1 CA 2236007A1 CA 002236007 A CA002236007 A CA 002236007A CA 2236007 A CA2236007 A CA 2236007A CA 2236007 A1 CA2236007 A1 CA 2236007A1
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/64—Oxygen atoms
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
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Abstract
This application relates to the use as thrombin inhibitors, coagulation inhibitors and thromboembolic disorder agents of diamines of formula (I) as defined herein. It also provides novel compounds of formula (I), processes and intermediates for their preparation, and pharmaceutical formulations comprising the novel compounds of formula (I).
Description
W O 97/25033 PCT~US96/17995 A~'l'l'l'~KOMBOTIC DI~INES
This invention relates to thrombin inhibitors which are useful anticoagulants in m~m~l S . In particular it relates to diamine derivatives having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new inhibitors of thrombin, pharmaceutical compositions cont~;n;ng the compounds as active ingredients, and the use of the compounds as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process. In addition, the diamine derivatives are useful as anticoagulants in in vitro applications.
The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the A~-~h~; n~ and the B~ ; n.~ of ~ibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation.
Anticoagulation currently is achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins.
W O 97/25033 PCT~US96/17995 Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin). Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ine~fective treatment. Because coagulation assays are believed to be associated with efficacy and with safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay). Coumarins impede the generation of thrombin by blocking the posttranslational gamma-carboxylation in the synthesis of prothrombin and other proteins of this type.
Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration.
Further, they are not selective anticoagulants. Coumarins also re~uire monitoring with coagulation assays (particularly the prothrombin time (PT) assay).
Recently, interest has grown in small synthetic molecules which demonstrate potent direct inhibition of thrombin. See, for example Robert M. Scarborough, Annual RePorts in Medicinal Chemistrv, (1995), 30, 71-80.
Although the heparins and coumarins are effective anticoagulants, no commercial drug has yet emerged from the small synthetic molecules; and despite the continuing promise for this class of compounds, there still exists a need ~or anticoagulants which act selectively on thrombin, and which, independent of antithrombin III, exert inhibitory action shortly after administration, preferably by an oral route, and do not interfere with lysis of blood clots, as required to maintain hemostasis.
The present invention is directed to the discovery that the compounds of the present invention, as defined below, are potent thrombin inhibitors that may have high bioavailability following oral ~mi n; stration.
According to the invention there is provided a method of inhibiting thrombin comprising using an effective W 0 97/25033 PCTAUSg6tl7995 amount of a thrombin inhibiting compound o~ ~ormula I (or a pharmaceutically acceptable salt thereo~) Xl-A3-X3-(CH2)g-(CXR3-CHR3)r-NRCRd l ~ A ~ A2-x2-~cH2)j-(c~R2)k-(cH2)m-NR R
wherein A is O, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical cont~; n; ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the
This invention relates to thrombin inhibitors which are useful anticoagulants in m~m~l S . In particular it relates to diamine derivatives having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new inhibitors of thrombin, pharmaceutical compositions cont~;n;ng the compounds as active ingredients, and the use of the compounds as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process. In addition, the diamine derivatives are useful as anticoagulants in in vitro applications.
The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the A~-~h~; n~ and the B~ ; n.~ of ~ibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation.
Anticoagulation currently is achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins.
W O 97/25033 PCT~US96/17995 Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin). Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ine~fective treatment. Because coagulation assays are believed to be associated with efficacy and with safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay). Coumarins impede the generation of thrombin by blocking the posttranslational gamma-carboxylation in the synthesis of prothrombin and other proteins of this type.
Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration.
Further, they are not selective anticoagulants. Coumarins also re~uire monitoring with coagulation assays (particularly the prothrombin time (PT) assay).
Recently, interest has grown in small synthetic molecules which demonstrate potent direct inhibition of thrombin. See, for example Robert M. Scarborough, Annual RePorts in Medicinal Chemistrv, (1995), 30, 71-80.
Although the heparins and coumarins are effective anticoagulants, no commercial drug has yet emerged from the small synthetic molecules; and despite the continuing promise for this class of compounds, there still exists a need ~or anticoagulants which act selectively on thrombin, and which, independent of antithrombin III, exert inhibitory action shortly after administration, preferably by an oral route, and do not interfere with lysis of blood clots, as required to maintain hemostasis.
The present invention is directed to the discovery that the compounds of the present invention, as defined below, are potent thrombin inhibitors that may have high bioavailability following oral ~mi n; stration.
According to the invention there is provided a method of inhibiting thrombin comprising using an effective W 0 97/25033 PCTAUSg6tl7995 amount of a thrombin inhibiting compound o~ ~ormula I (or a pharmaceutically acceptable salt thereo~) Xl-A3-X3-(CH2)g-(CXR3-CHR3)r-NRCRd l ~ A ~ A2-x2-~cH2)j-(c~R2)k-(cH2)m-NR R
wherein A is O, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical cont~; n; ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the
2,5- (or 3,5-) relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~in;ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~in;ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or
3,6- relationship, and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sul~ur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected ~rom (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)Rf or -NHS(O)2Rg in which Rf is hydrogen or .(1-2C)alkyl and Rg is (1-2C)alkyl or phenyl;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-1,1-diyl;
W O 97~5033 PCTAJS96/17995 (a) x2 is imino, a direct bond, methylene, O or S;
] is 0; k is Oi m is 1, 2, 3 or 4i provided that when m is 1, then x2 is a direct bondi and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, O or S; j is li k is 1; m is 1; R2 is hydroxyi and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, O or Si j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, O or Si j is 0, 1, 2 or 3; k is 1;
m is 0 or li provided that j and m are not both 0; R2 and Ra together form a diradical ~(CH2)n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(O)-; ] is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, O or S;
q is 0, 1 or 2; and r is 0 or 1; provided that ~ and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bondi each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-1,1-diyl;
W O 97~5033 PCTAJS96/17995 (a) x2 is imino, a direct bond, methylene, O or S;
] is 0; k is Oi m is 1, 2, 3 or 4i provided that when m is 1, then x2 is a direct bondi and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, O or S; j is li k is 1; m is 1; R2 is hydroxyi and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, O or Si j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, O or Si j is 0, 1, 2 or 3; k is 1;
m is 0 or li provided that j and m are not both 0; R2 and Ra together form a diradical ~(CH2)n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(O)-; ] is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, O or S;
q is 0, 1 or 2; and r is 0 or 1; provided that ~ and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bondi each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or
4; and Rc and Rd are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or (2) X3 is imino, O or S; ~ is Oi r is 1; one R3 group is (1-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently W O 97/25033 PCT~US96/17995 hydrogen or (l-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) x3 is -N(Rh)-i q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) x3 is -N(Rh)-i q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or
(5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
q is l; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethylen~; m; no.
One particular method of inhibiting thrombin comprises using an effective amount of a thrombin inhibiting compound of formula I, or a p~rm~ceutically acceptable salt thereof, wherein A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n~ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent (and more particularly, which divalent radical does not bear a substituent)i A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~'n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or W O 97/25033 PCT~US96117995 2 ring nitrogens in which heteroaromatic divalent radical the ~alences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (l-3C)alkyl, (1-2C)alkoxy or halo substituent ~and more particularly, which divalent radical may bear a (1-3C)alkyl or halo substituent);
Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyli x2 is a direct bond, methylene, O or Si j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyl~n~; m; no;
X3 is a direct bond, methylene, imino, ~ or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when g is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 ~roups together form a divalent radical -~CH2~S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A compound of formula I in which j and k are both 0 may be denoted as a compound of formula I'.
Xl-A3-X3-(CH2)q-(CHR3-CHR3)r-NR R
R~
A A2_X2-(CH2)m-NRaRb I' A particular aspect of the above method is one wherein said compound is a compound of formula I in which A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Ri ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to x2 (and more particularly, which divalent radical does not bear a substituent);
wa, 97/25033 PCTnUS96/17995 A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is oined to X3 (and more particularly, Re is (1-3)alkyl or halo)i R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is 0, S, methylene, carbonyl or ethene~ diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2i and r is O or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 2~ 4; and Rc and Rd are independently (1-3C)alkyl or the group MRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A more particular aspect of any of the above methods is one wherein said compound is a compound of formula Ia R ~ ~ ~ X3~-C~R3-CH~3 ~n~CRd D X -(CH2)2-NR R
wherein A is S, -CH=CH- or -CH2-CH2-;
~ D is CH, CRi or N in which Ri is methyl, hydroxy or methoxy (and more particularly D is CH or N);
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo (and more particularly E is CH, CRe or N
in which Re is (1-3C)alkyl or halo);
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2a is methylene or O; and Ra and Rb are independently hydrogen or (l-3C)alkyl or the group MRaRb is pyrrolidino or piperidino;
x3a is methylene, imino, O or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (l-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A particular method in which said compound is one of formula Ia is wherein A is S; D is CHi E is CRe in which Re is methoxyi R5 is hydrogeni R6 is hydroxy; Xl is methylene; x2a is O; and the group MRaRb is pyrrolidino; x3a is O; and the two R3 groups together form a divalent radical -(CH2)S- in which s is 4 and which ~orms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
It will be clear that a compound of formula Ia also may be expressed as a compound of formula I or as a compound of formula I'.
An additional particular aspect of the above method is one wherein said compound of formula I is one which may be denoted as a compound of formula Ib R~ Xl ~ CH2-NRCRd R6 A Ib G X2b-(CH2)2-NRaRb wherein A is S, -CH=CH- or -CH2-CH2-;
CA 02236007 l998-04-27 W~97/2~033 PCT~S96/]7995 G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene~ diyl;
x2b is a direct bond or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
A more particular method in which said compound is one of formula Ib is wherein A is S; G is CH or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; xl is methylene; x2b is a direct bond or O; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-l-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
A further particular aspect of any of the above methods is one wherein said compound is one in which Xl is methylene.
A further particular aspect of any of the above methods (in which the radical -(CH2)S- is present) is one wherein said compound is one in which s is 4.
Another particular aspect of any of the above methods is one wherein said compound is one in which A is S.
A further particular aspect of any of the above methods is one wherein said compound is a compound of formula I in which Rl denotes a hydroxy substituent at the position corresponding to the 6-position of a benzo[b]thiophene or a compound of formula Ia or of formula Ib in which R5 is hydrogen and R6 is hydroxy.
,~
W O 97/2S033 PCT~US96/17995 A selected aspect of the above methods is one in which said compound is a compound of formula Ia in which A is S, D is CH or N, E is CH or N, R5 is hydrogen, R6 is hydroxy, the group -X2a-(CH2)2-NRaRb is 2-(1-pyrrolidinyl)ethoxy, and the group -X3a-CHR3-CHR3-NRCRd is 3-(1-pyrrolidinyl)propyl 2-(1-pyrrolidinyl)ethoxy, trans-2-(l-pyrrolidinyl)cyclohexyloxy or trans-2~ piperidyl)cyclohexyloxy.
A preferred method of the invention includes one wherein said compound of formula I is one of those described herein at Examples 123, 124 and 164.
The present invention also provides a method of inhibiting coagulation in a m~mm~l comprising administering to a m~mm~ 1 in need of treatment, a coagulation inhibiting dose of a thrombin inhibiting compound of formula I having any of the above definitions.
The present invention further provides a method of inhibiting thrombin comprising ~m; n i~qtering to a m~mm~ 1 in need of treatment, a thrombin inhibiting dose of a thrombin inhibiting compound of formula I having any of the above definitions.
Further, the present invention provides a method of treating a thromboembolic disorder comprising ~mln; stering to a m~mm~l in need of treatment, an effective dose of a thrombin inhibiting compound of formula I having any of the above definitions.
In addition, there is provided the use of a thrombin inhibiting compound of formula I having any of the above definitions for the manufacture of a medicament for treatment of a thromboembolic disorders.
As a further aspect of the invention, there is provided a prodrug (or a ph~rm~ceutically acceptable salt thereof) of any of the above described thrombin inhibiting compounds of formula I which will form a prodrug. A compound of formula I (or formula Ia or ~ormula Ib) which will form a prodrug includes one in which Rl (or R5 or R6) or a substituent on A2 or ~3 is hydroxy, carbamoyl, aminomethyl or hydroxymethyl, or one in which one or both of Ra and Rb is W ~ 97/2~033 PCTAJS96/17995 hydrogen or the group MRaRb includes a hydroxymethyl group, or one in which R2 is hydroxy, or one in which one or both of c and Rd is hydrogen or the group NRCRd includes a hydroxymethyl group. Particular compounds of ~ormula I (or formula Ia) which will form a prodrug include those in which Rl (or R5 or R6) is hydroxy, carbamoyl, aminomethyl or hydroxymethyl or in which one or both of Ra and Rb is hydrogen. (It will be recognized that a thrombin inhibiting compound o~ formula I also may serve as a prodrug for a different thrombin inhibiting compound o~ formula I).
As an additional feature of the invention there is provided a pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a prodrug of a thrombin inhibiting compound of formula I (or of a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions.
Certain diamine compounds corresponding to formula I are included in the generic disclosure of United States Patent 4,133,814; issued to Jones et al., as antifertility agents. Weak antifertility activity is described therein for the compound 2-~4-(2-pyrrolidino-ethoxy)phenyl]-3-[4-(2-pyrrolidinoethoxy)benzoyl]-benzo[b]thiophene (isolated as its dicitrate salt). The r~m~;n;ng thrombin inhibiting compounds of formula I are believed to be novel and, thus, to constitute an additional aspect of the invention. Thus, according to the invention there is provided a novel compound of formula I (or a ~h~rm~ceutically acceptable salt thereof) Xl-A3-X3-(CH2)q~(CHR3-CHR3)~~NRCRd Rl ~ A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb wherein A is O, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-mem.bered ring CA 02236007 l998-04-27 heteroaromatic divalent radical cont~;n,ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical cont~inlng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (l-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~ln;ng 1 or 2 ring nitrogens in which the valences are in the l,4-~or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical contA-ning one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or ~wo substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)R~ or -NHS(O)2Rg in which Rf is hydrogen or (1-2~)alkyl and Rg is (1-2C)alkyl or phenyl;
Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydrox~methyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
(a) x2 is imino, a direct bond, methylene, 0 or Si j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-l-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-l-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, 0 or S; j is l; k is l; m is l; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3~)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or W O 97125033 PCT~US96/17995 (c) x2 is imino, O or S; j is l; k is l; m is Oi R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, O or S; j is 0, 1, 2 or 3i k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -~CH2) n- in which n is 2, 3 or 4 and the sum o~ m and n is 3 or 4i and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(O)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, O or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Ra are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, l-imidazolyl or 4,5-dihydro-l-imidazolyl; or (2) X3 is imino, O or S; q is 0; r is li one R3 group is (l-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (l-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyli or (4) X3 is -N(Rh)-; q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogeni and Rc and W O 97/2~033 PCT~US96/17995 Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
g is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; xl is carbonyl; x2 is Oi i and k are both 0, the group ~(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)~-(CHR3-CHR3)r- is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyl~n~imlno.
One particular novel compound of formula I, or a pharmaceutically acceptable salt thereof, is one wherein A is S, -C~-CH- or -CH2-CH2-;
~2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~; n; ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~in;n~ one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5~ or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent (and more particularly, which divalent radical does not bear a substituent);
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~i n i ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the W ~ 97/25033 PCTAUS96/17995 valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent (and more particularly, which divalent radical may bear a (1-3C~alkyl or halo substituent);
-~ 5 Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -~CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A particular novel compound of formula I as described above is one in which A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Ri ortho to the group x2 and Ri is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to x2 (and more particularly, which divalent radical does not hear a substituent);
A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 (and more particularly, Re is (1-3)alkyl or halo);
CA 02236007 l998-04-27 Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together ~orm a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A more particular novel compound of the invention is a compound of formula Ia R ~ A ~ X3~-cHR3-cHR3-~RcRd D X -(CH2)2-NR R
wherein A is S, -CH=CH- or -CH2-CH2-i D is CH, CRj or N in which Ri is methyl, hydroxy or methoxy (and more particularly D is CH or N);
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo (and more particularly E is CH, CRe or N
in which Re is (1-3C)alkyl or ha~o);
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
W O 97/25033 PCT~US96/17995 x2a is methylene or 0; and Ra and Rb are independently hydrogen or ~1-3C)alkyl or the group NRaRb is pyrrolidino or piperidinoi x3a is methylene, imino, O or S; and each R3 is hydrogen or the two R3 groups together ~orm a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethylenelmino or 1-imidazolyl;
provided that the compound is not one in which A is S; D is CH; E is CH; R5 is hydrogen, R6 is hydroge~, hydroxy or methoxy; Xl is carbonyl; x2a is 0; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; x3a is 0; each R3 is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethylene~ino.
A particular novel compound of formula Ia is one wherein A is S; D is CH; E is CRe in which Re is methoxy; R5 is hydrogen; R6 is hydroxy; Xl is methylene; x2a is 0; and the group NRaRb is pyrrolidino; X3a is 0; and the two R3 groups together form a divalent radical -(CH2)S- in which s is 4 and which forms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
An additional particular novel compound of formula I is one which may be denoted as a compound of ~ormula Ib RR ~ A ~ CH2 ~RCRd Ib G X2b-(CH2)2-NRaRb wherein A is S, -CH=CH- or -CH2-CH2-;
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
W O 97/25033 PCT~US96/17995 R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is 0, ~, methylene, carbonyl or ethene~ diyl;
x2b is a direct bond or 0; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently ~1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
A more particular novel compound is one of ~ormula Ib is wherein A is S; G is CH or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen;
R6 is hydroxyi X1 is methylene; x2b is a direct bond or 0;
the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
A further particular novel compound of the invention is any of the above novel compounds wherein X1 is methylene.
A further particular novel compound o~ the invention is any of the above novel compounds wherein s is 4.
Another particular novel compound of the invention is any of the above novel compounds wherein ~ is S.
A further particular novel compound of the invention is any of the above novel compounds wherein said compound is a compound of formula I in which R1 denotes a hydroxy substituent at the position corresponding to the
q is l; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethylen~; m; no.
One particular method of inhibiting thrombin comprises using an effective amount of a thrombin inhibiting compound of formula I, or a p~rm~ceutically acceptable salt thereof, wherein A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n~ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent (and more particularly, which divalent radical does not bear a substituent)i A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~'n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or W O 97/25033 PCT~US96117995 2 ring nitrogens in which heteroaromatic divalent radical the ~alences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (l-3C)alkyl, (1-2C)alkoxy or halo substituent ~and more particularly, which divalent radical may bear a (1-3C)alkyl or halo substituent);
Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyli x2 is a direct bond, methylene, O or Si j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyl~n~; m; no;
X3 is a direct bond, methylene, imino, ~ or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when g is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 ~roups together form a divalent radical -~CH2~S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A compound of formula I in which j and k are both 0 may be denoted as a compound of formula I'.
Xl-A3-X3-(CH2)q-(CHR3-CHR3)r-NR R
R~
A A2_X2-(CH2)m-NRaRb I' A particular aspect of the above method is one wherein said compound is a compound of formula I in which A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Ri ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to x2 (and more particularly, which divalent radical does not bear a substituent);
wa, 97/25033 PCTnUS96/17995 A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is oined to X3 (and more particularly, Re is (1-3)alkyl or halo)i R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is 0, S, methylene, carbonyl or ethene~ diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2i and r is O or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 2~ 4; and Rc and Rd are independently (1-3C)alkyl or the group MRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A more particular aspect of any of the above methods is one wherein said compound is a compound of formula Ia R ~ ~ ~ X3~-C~R3-CH~3 ~n~CRd D X -(CH2)2-NR R
wherein A is S, -CH=CH- or -CH2-CH2-;
~ D is CH, CRi or N in which Ri is methyl, hydroxy or methoxy (and more particularly D is CH or N);
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo (and more particularly E is CH, CRe or N
in which Re is (1-3C)alkyl or halo);
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2a is methylene or O; and Ra and Rb are independently hydrogen or (l-3C)alkyl or the group MRaRb is pyrrolidino or piperidino;
x3a is methylene, imino, O or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (l-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A particular method in which said compound is one of formula Ia is wherein A is S; D is CHi E is CRe in which Re is methoxyi R5 is hydrogeni R6 is hydroxy; Xl is methylene; x2a is O; and the group MRaRb is pyrrolidino; x3a is O; and the two R3 groups together form a divalent radical -(CH2)S- in which s is 4 and which ~orms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
It will be clear that a compound of formula Ia also may be expressed as a compound of formula I or as a compound of formula I'.
An additional particular aspect of the above method is one wherein said compound of formula I is one which may be denoted as a compound of formula Ib R~ Xl ~ CH2-NRCRd R6 A Ib G X2b-(CH2)2-NRaRb wherein A is S, -CH=CH- or -CH2-CH2-;
CA 02236007 l998-04-27 W~97/2~033 PCT~S96/]7995 G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene~ diyl;
x2b is a direct bond or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
A more particular method in which said compound is one of formula Ib is wherein A is S; G is CH or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; xl is methylene; x2b is a direct bond or O; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-l-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
A further particular aspect of any of the above methods is one wherein said compound is one in which Xl is methylene.
A further particular aspect of any of the above methods (in which the radical -(CH2)S- is present) is one wherein said compound is one in which s is 4.
Another particular aspect of any of the above methods is one wherein said compound is one in which A is S.
A further particular aspect of any of the above methods is one wherein said compound is a compound of formula I in which Rl denotes a hydroxy substituent at the position corresponding to the 6-position of a benzo[b]thiophene or a compound of formula Ia or of formula Ib in which R5 is hydrogen and R6 is hydroxy.
,~
W O 97/2S033 PCT~US96/17995 A selected aspect of the above methods is one in which said compound is a compound of formula Ia in which A is S, D is CH or N, E is CH or N, R5 is hydrogen, R6 is hydroxy, the group -X2a-(CH2)2-NRaRb is 2-(1-pyrrolidinyl)ethoxy, and the group -X3a-CHR3-CHR3-NRCRd is 3-(1-pyrrolidinyl)propyl 2-(1-pyrrolidinyl)ethoxy, trans-2-(l-pyrrolidinyl)cyclohexyloxy or trans-2~ piperidyl)cyclohexyloxy.
A preferred method of the invention includes one wherein said compound of formula I is one of those described herein at Examples 123, 124 and 164.
The present invention also provides a method of inhibiting coagulation in a m~mm~l comprising administering to a m~mm~ 1 in need of treatment, a coagulation inhibiting dose of a thrombin inhibiting compound of formula I having any of the above definitions.
The present invention further provides a method of inhibiting thrombin comprising ~m; n i~qtering to a m~mm~ 1 in need of treatment, a thrombin inhibiting dose of a thrombin inhibiting compound of formula I having any of the above definitions.
Further, the present invention provides a method of treating a thromboembolic disorder comprising ~mln; stering to a m~mm~l in need of treatment, an effective dose of a thrombin inhibiting compound of formula I having any of the above definitions.
In addition, there is provided the use of a thrombin inhibiting compound of formula I having any of the above definitions for the manufacture of a medicament for treatment of a thromboembolic disorders.
As a further aspect of the invention, there is provided a prodrug (or a ph~rm~ceutically acceptable salt thereof) of any of the above described thrombin inhibiting compounds of formula I which will form a prodrug. A compound of formula I (or formula Ia or ~ormula Ib) which will form a prodrug includes one in which Rl (or R5 or R6) or a substituent on A2 or ~3 is hydroxy, carbamoyl, aminomethyl or hydroxymethyl, or one in which one or both of Ra and Rb is W ~ 97/2~033 PCTAJS96/17995 hydrogen or the group MRaRb includes a hydroxymethyl group, or one in which R2 is hydroxy, or one in which one or both of c and Rd is hydrogen or the group NRCRd includes a hydroxymethyl group. Particular compounds of ~ormula I (or formula Ia) which will form a prodrug include those in which Rl (or R5 or R6) is hydroxy, carbamoyl, aminomethyl or hydroxymethyl or in which one or both of Ra and Rb is hydrogen. (It will be recognized that a thrombin inhibiting compound o~ formula I also may serve as a prodrug for a different thrombin inhibiting compound o~ formula I).
As an additional feature of the invention there is provided a pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a prodrug of a thrombin inhibiting compound of formula I (or of a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions.
Certain diamine compounds corresponding to formula I are included in the generic disclosure of United States Patent 4,133,814; issued to Jones et al., as antifertility agents. Weak antifertility activity is described therein for the compound 2-~4-(2-pyrrolidino-ethoxy)phenyl]-3-[4-(2-pyrrolidinoethoxy)benzoyl]-benzo[b]thiophene (isolated as its dicitrate salt). The r~m~;n;ng thrombin inhibiting compounds of formula I are believed to be novel and, thus, to constitute an additional aspect of the invention. Thus, according to the invention there is provided a novel compound of formula I (or a ~h~rm~ceutically acceptable salt thereof) Xl-A3-X3-(CH2)q~(CHR3-CHR3)~~NRCRd Rl ~ A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb wherein A is O, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-mem.bered ring CA 02236007 l998-04-27 heteroaromatic divalent radical cont~;n,ng 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical cont~inlng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (l-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~ln;ng 1 or 2 ring nitrogens in which the valences are in the l,4-~or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical contA-ning one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or ~wo substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)R~ or -NHS(O)2Rg in which Rf is hydrogen or (1-2~)alkyl and Rg is (1-2C)alkyl or phenyl;
Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydrox~methyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
(a) x2 is imino, a direct bond, methylene, 0 or Si j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-l-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-l-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, 0 or S; j is l; k is l; m is l; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3~)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or W O 97125033 PCT~US96/17995 (c) x2 is imino, O or S; j is l; k is l; m is Oi R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, O or S; j is 0, 1, 2 or 3i k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -~CH2) n- in which n is 2, 3 or 4 and the sum o~ m and n is 3 or 4i and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(O)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, O or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Ra are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, l-imidazolyl or 4,5-dihydro-l-imidazolyl; or (2) X3 is imino, O or S; q is 0; r is li one R3 group is (l-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (l-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyli or (4) X3 is -N(Rh)-; q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogeni and Rc and W O 97/2~033 PCT~US96/17995 Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
g is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; xl is carbonyl; x2 is Oi i and k are both 0, the group ~(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)~-(CHR3-CHR3)r- is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyl~n~imlno.
One particular novel compound of formula I, or a pharmaceutically acceptable salt thereof, is one wherein A is S, -C~-CH- or -CH2-CH2-;
~2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~; n; ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~in;n~ one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5~ or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent (and more particularly, which divalent radical does not bear a substituent);
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~i n i ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the W ~ 97/25033 PCTAUS96/17995 valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent (and more particularly, which divalent radical may bear a (1-3C~alkyl or halo substituent);
-~ 5 Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -~CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A particular novel compound of formula I as described above is one in which A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Ri ortho to the group x2 and Ri is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to x2 (and more particularly, which divalent radical does not hear a substituent);
A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 (and more particularly, Re is (1-3)alkyl or halo);
CA 02236007 l998-04-27 Rl denotes 0, 1 or 2 substituents on the benz-ring independently selected ~rom halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together ~orm a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or l-imidazolyl.
A more particular novel compound of the invention is a compound of formula Ia R ~ A ~ X3~-cHR3-cHR3-~RcRd D X -(CH2)2-NR R
wherein A is S, -CH=CH- or -CH2-CH2-i D is CH, CRj or N in which Ri is methyl, hydroxy or methoxy (and more particularly D is CH or N);
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo (and more particularly E is CH, CRe or N
in which Re is (1-3C)alkyl or ha~o);
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is O, S, methylene, carbonyl or ethene-l,l-diyl;
W O 97/25033 PCT~US96/17995 x2a is methylene or 0; and Ra and Rb are independently hydrogen or ~1-3C)alkyl or the group NRaRb is pyrrolidino or piperidinoi x3a is methylene, imino, O or S; and each R3 is hydrogen or the two R3 groups together ~orm a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethylenelmino or 1-imidazolyl;
provided that the compound is not one in which A is S; D is CH; E is CH; R5 is hydrogen, R6 is hydroge~, hydroxy or methoxy; Xl is carbonyl; x2a is 0; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; x3a is 0; each R3 is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethylene~ino.
A particular novel compound of formula Ia is one wherein A is S; D is CH; E is CRe in which Re is methoxy; R5 is hydrogen; R6 is hydroxy; Xl is methylene; x2a is 0; and the group NRaRb is pyrrolidino; X3a is 0; and the two R3 groups together form a divalent radical -(CH2)S- in which s is 4 and which forms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
An additional particular novel compound of formula I is one which may be denoted as a compound of ~ormula Ib RR ~ A ~ CH2 ~RCRd Ib G X2b-(CH2)2-NRaRb wherein A is S, -CH=CH- or -CH2-CH2-;
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
W O 97/25033 PCT~US96/17995 R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
xl is 0, ~, methylene, carbonyl or ethene~ diyl;
x2b is a direct bond or 0; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently ~1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
A more particular novel compound is one of ~ormula Ib is wherein A is S; G is CH or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen;
R6 is hydroxyi X1 is methylene; x2b is a direct bond or 0;
the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
A further particular novel compound of the invention is any of the above novel compounds wherein X1 is methylene.
A further particular novel compound o~ the invention is any of the above novel compounds wherein s is 4.
Another particular novel compound of the invention is any of the above novel compounds wherein ~ is S.
A further particular novel compound of the invention is any of the above novel compounds wherein said compound is a compound of formula I in which R1 denotes a hydroxy substituent at the position corresponding to the
6-position of a benzo[b]thiophene or a compound of ~ormula Ia or of formula Ib in which R5 is hydrogen and R6 is hydroxy.
A selected novel compound of the above novel compounds is a compound of formula Ia in which A is S, D is CH or N, E is CH or N, R5 is hydrogen, R6 is hydroxy, the group -X2a-(CH2)2-NRaRb is 2-(1-pyrrolidinyl)ethoxy, and the group -X3a-CHR3-CHR3-NRCRd is 3-(1-pyrrolidinyl)propyl, W O 97/25033 PCT~US96/17995 2-(1-pyrrolidinyl3ethoxy, trans-2-(1-pyrrolidinyl)-cyclohexyloxy or trans-2-(1-piperidyl)cyclohexyloxy.
A preferred novel compound of the invention includes one wherein said compound of formula I is one of those described herein at Examples 123, 124 and 164.
A pharmaceutically acceptable salt of an antithrombotic ~1 ~m; ne of the instant invention includes one which is an acid-addition salt made with an acid which provides a ph~rm~ceutically acceptable anion. Thus, an acid additon salt of a novel compound of formula I as provided above made with an acid which affords a ~h~rm~ceutically acceptable anion provides a particular aspect of the invention. Examples of such acids are provided hereinbelow.
As an additional aspect of the invention there is provided a ph~rm~ceutical formulation comprising in association with a ~rm~ceutically acceptable carrier, diluent or excipient, a novel compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions.
In this specification, the following definitions are used, unless otherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl" embraces only the straight chain ("normal") radical, a branched chain isomer such as "isopropyl" being specifically denoted.
It will be appreciated that certain compounds of formula I (or salts or prodrugs, etc.) (such as when R3 is not hydrogen) may exist in, and be isolated in, isomeric forms, including cis- or trans-isomers, as well as optically active, racemic, or diastereomeric forms. It is to be understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses inhibitory properties against thrombin, it being well known in the art how to prepare or isolate particular forms and how to determine inhibitory properties against thrombin by st~n~rd tests including those described below.
In addition, a compound of formula I (or salt or prodrug, etc.) may exhibit polymorphism or may form a solvate with water or an organic solvent. The present invention also encompasses any such polymorphic form, any solvate or any mixture thereo~.
Particular values are listed below for radicals, substituents, and ranges, for illustration only, and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A particular value for a (1-2C)alkyl group is methyl or ethyl; for a (1-3C)alkyl group is methyl, ethyl, propyl or isopropyl; for a (l-4C)alkyl group is methyl, ethyl, propyl, isopropyl or butyl; for a (l-5C)alkyl group is methyl, ethyl, propyl, isopropyl, butyl or pentyl; and for a (1-2C)alkoxy group is methoxy or ethoxy.
A particular value for A2 or A3 when it is a 6-membered ring heteroaromatic divalent radical is pyridin-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, or pyrimidin-2,5-diyl (and more particularly, pyridin-2,5-diyl or pyrazin-2,5-diyl; especially pyridin-2,5-diyl). A particular value for A2 or A3 when it is a 5-membered ring heteroaromatic divalent radical is furan-2,5-diyl, thiophen-2,5-diyl, oxazol-2,5-diyl, thiazol-2,5-diyl, isoxazol-3,5-diyl, isothiazol-3,5-diyl, 1,3,4-oxadiazol-2,5-diyl or 1,3,4-thiadiazol-2,5-diyl (and more particularly, isoxazol-3,5-diyl).
A compound of formula I may be made by processes which include processes known in the chemical art for the production of known compounds of formula I or of structurally analogous compounds or by a novel process described herein.
A process for a novel compound of formula I (or a ph~rm~ceutically acceptable salt thereof), novel processes for a compound of formula I and novel intermediates for the CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/~7995 manufacture of a compound of formula I as de~ined above provide further ~eatures of the invention and are illustrated by the following procedures in which the me~nings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of formula I in which a ~unctional group is protected using a conventional protecting group, then to remove the protecting yroup to provide the compound of formula I.
Thus, there is provided a process for preparing a novel compound of formula I (or a pharmaceutically acceptable salt thereo~) as provided in any of the above descriptions which is selected from:
(A) For a compound of formula I in which xl is ethene-l,l-diyl, methylenation of a corresponding compound of formula I in which xl is carbonyl. The methylenation conveniently is carried out using methylidenetriphenyl-phosphorane generated in situ from methylidenetriphenyl-phosphonium bromide and a strong base such as potassium tert-butoxide in an inert solvent such as tetrahydrofuran in a manner similar to that described in Example 12, Part A, for the preparation of an int~rme~l~te compound.
(B) For a compound of formula I (or formula Ia or formula Ib) in which xl is methylene, reductive removal of the hydroxy group of a corresponding alcohol of formula II
(or formula IIa or formula IIb).
Rl ~ ~ CH(OH)-A3-X3-(CH2)~-(CHR3-CHR3)r- ~ CRd A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb II
W O 97/25033 PCT~US96/17995 R CH(OH) ~ X3~ CHR3-CHR3-~nR'Rd R6 A ~ IIa D/~ X2a - ( CH 2 ) 2 _NRa Rb R~' CH ( OH ) Q CH2--NRC Rd R6 A ~ IIb X2b-(CH2)2- ~ aRb The reductive removal conveniently is carried out using sodium borohydride in trifluoroacetic acid in a manner similar to that described in Example 2, Part D, or using triethylsilane in trifluroracetic acid in a manner similar to that described in Example 3, Part E. An intermediate alcohol of formula II (or formula IIa or formula IIb) provides an additional feature of the inventioni it may be obtained by reducing the carbonyl group of a corresponding ketone of formula I (or formula Ia or formula Ib) in which xl is carbonyl, for example by using lithium aluminium hydride in tetrahydrofuran in a manner similar to that described in Example 2, Part D, or Example 3, Part E or by using diisobutylaluminium hydride in tetrahydrofuran in a manner similar to that described in Example 32, Part A.
(C) For a compound of formula I in which A is O or S and Xl is carbonyl, acylation of a corresponding compound of formula III
R1 ~ A ~1, A2_X2_(CH2) j - ( CHR2 ) k - ( CH2 ) m-~RaRb III
with an activated derivative of a corresponding acid of formula IV.
W O 97/25033 PCT~US96/I7995 HooC-A3-X3-(CH2)~-(CHR3-CHR3)r~NRCRd IV
Conveniently, the acylation is carried out using the hydrochloride salt of the acid chloride of the acid formula IV and a catalyst such as aluminium chloride in a manner s;m~l~r to that described in Example 1, Part C or titanium tetrachloride in a manner similar to that described in Example 2, Part C.
~ D) For a compound of formula I in which A is -CH=CH-, selective dehydrogenation of a corresponding compound in which A is -CH2-CH2-, for example using 2,3-dichloro-5,6-dicyano-1,4-benzo~uinone (DDQ) at 50 ~C to 100 ~C in an inert solvent such as dioxane.
(E) For a compound of formula I in which A is -CH2-CH2- and x2 is carbonyl, condensation o~ a corresponding compound of formula V
C ( O ) -A3 -X3 - ( CH2 ) q - ~ CHR3 -CHR3 ) r -NRCRd Rl 0~0PO (OC6H5 )2 V
with a corresponding reagent of formula VI;
Br-Mg-A2-X2-(CH2);-(CHR2)k-(CH2)m-NRaRb VI
for example, in an inert solvent such as tetrahydrofuran at about O ~C.
(F) For a compound of formula I in which Xl is 0, cross coupling a corresponding compound of formula VII
Rl ~ O A3--X3--( CH2 ) q - ( CHR3--C~IR3 ) r -NRCRd VII
with a corresponding boronic acid of formula VIII;
(H0)2B-A2-X2-(CH2)j-(CHR2)k-(CH2~m-NRaRb VIII
for example, using a similar procedure to that described in Example 11, Part D for the preparation of an int~rme~;ate compound in which A is S.
WO 97/2~033 PCT~US96/17995 (G) For a compound of formula I in which Xl is O
or S, treatment of a corresponding organolithium compound of formula IX Li Rl ~ ~ A ~ ( A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb IX
with a corresponding disulfide of formula X;
(-S-A3-X3-(CH2)q-(CHR3-CHR3)r-NRCRd)2 X
for example, using a similar procedure to that described in Example 10, Part B for the preparation of an intermediate compound in which A is S.
(H) For a compound of formula I in which Rl or a substituen~ on A2 or A3 is hydroxy, removal of the O-methyl group of a corresponding compound of formula I in which Rl or a substituent on A2 or A3 is methoxy. The removal may be carried out by any conventional manner consistent with the structure of the compound of formula I, for example, using aluminium chloride and ethanethiol in an inert solvent as described in Example 1, Part D.
(I) For a compound of formula I in which x2 is O
or S, alkylation at x2 of a corresponding compound of formula XI
Rl ~ ~ Xl-A3-X -(CH2)q~(CHR3~CHR~)~~NRCRd XI
in which x2 is O or S with a corresponding compound of formula XII
L-(CH2)j-(CHR2)k-(CH2)m-NRaRb XII
in which L denotes a leaving group. It may be preferred to generate the leaving group of the compound of formula XII in si tu from the corresponding hydroxy compound and perform the W O 97/25033 PCTrUS96/17995 alkylation under Mitsunobu conditions using triphenyl-phosphine and diethyl azodicarboxylate in an inert solvent, ~or example, as described in Example 4, Part B for the preparation of an int~rm~'ate compound. Alternatively, a compound o~ ~ormula XII in which L is chloro, bromo, iodo or a sulfonate, such as methanesul~onate or p-toluenesul~onate, may be used, preferably in conjunction with a base such as cesium carbonate, using a similar procedure to that described in Example 3, Part D, ~or example as described in Example 5, Part C.
(J) For a compound o~ ~ormula I in which X3 is O
or S, alkylation at X3 o~ a corresponding compound of formula XIII
Xl-A3-X3-H
Rl ~ A ~ A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XIII
in which X3 is O or S with a corresponding compound of formula XIV
L-(CH2)q-(CHR3-CHR3)r-~DRCRd XIV
in which L denotes a leaving group as defined above. It may be preferred to generate the leaving group of the compound o~
formula XIV from the corresponding hydroxy compound and to per~orm the alkylation under Mitsunobu conditions as described above. Alternatively, L may have any of the values described above for L, and the alkylation may be carried out using a similar procedure to that described in Example 3, Part D.
(K) For a compound o~ formula I in which x2 and X3 are O or ~ and in which -(CH2)j-(CHR2) k-(CH2)m-NRaR~ is the same as -(CH2)q-(CHR3-CHR3)r-NRCRb, dialkylation of a compound of formula XV
CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 xl-A3_X3_H
R1 ~ A~A2 _X2-H
with a compound of formula XII. The dialkylation may be t carried out as described above for the alkylation of a compound of formula XI or formula XIII, for example as 5 described in Example 8, Part D or Example 10, Part D.
(L) Eor a compound of formula I in which Rl is carbamoyl, aminolysis of a corresponding intermediate compound of formula I in which~Rl is a lower alkoxy-carbonyl group, such as a methoxy-carbonyl group. The aminolysis is 10 conveniently carried out using anhydrous ammonia in a lower alcohol under pressure, for example, as described in Example 30, Part E.
~M) For a compound of formula I in which Rl or a substituent on A3 or the value of -X3-(CH2)Ca-(CHR3-CHR3) r-15 NRCRb is aminomethyl, reduction of an int~rme~ate compound corresponding to a compound of formula I but in which Rl is cyano or of a corresponding compound of formula I in which a substituent on A3 is cyano or of an int~rmeAiate compound corresponding to a compound of formula I but in which -X3-(CH2)Ca-(CHR3-CHR3)r-NRCRb is cyano. The reduction conveniently is carried out using lithium aluminium hydride in tetrahydrofuran, for example as described in Example 31, Part D for the preparation of an intermediate alcohol of formula II in which Rl is aminomethyl or as described in Example 162.
(N~ For a compound of formula I in which Rl or R2 is hydroxymethyl, reduction of a corresponding intermediate compound of formula I in which Rl or R2 is a lower alkoxy-carbonyl group, such as a methoxy-carbonyl group. The reduction is conveniently carried out using diisobutyl-aluminium hydride in toluene and tetrahydrofuran, for example, as described in Example 32, Part A for the preparation of an intermediate alcohol of formula II in which Rl is hydroxymethyl or as described in Example 168.
W O 97/25033 PCT~US96/17995 (O) For a compound of ~ormula I in which A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 and X3 is 0, displacement of the leaving group L of a corresponding compound o~ ~ormula XVI, R1 ~A~A2 -X2-(CM2)j-~CHR2) k -(CH2)m-NRaRb ~I
in which L is defined as above, with an alkali metal alkoxide of an alcohol of formula XVII, HO-(CH2)q~(CHR3-CHR3)r-NRCRd XVII
for example with the sodium alkoxide. The reaction is conveniently carried out with a compound of formula XVI in which L is chloro and the sodium alkoxide derived from an alcohol of formula XVII using conditions described in Example 9, Part B and further illustrated in Example 33, Part B.
(P) For a compound of formula I in which A3 bears a (l-4C)alkyl substituent, substitution of the bromo group of a corresponding compound of formula I in which A3 bears a bromo substituent. The substitution is conveniently carried out using a tetralkyltin reagent and a palladium(O) catalyst in an inert solvent, for example as described in Example 8, Part B for the preparation of an int~rme~;ate compound.
(Q) For a compound of formula I in which xl is carbonyl, con~n.~ation of a corresponding organolithium compound of formula IX with a derivative of a corresponding acid of formula IV which will provide a ketone upon condensation. Derivatives of an acid of formula rv which will provide a ketone upon condensation include the lithium salt of the acid, corresponding amides such as the N-methoxy-N-methyl amide, and the corresponding nitrile. The condensation is typically carried out in an inert, aprotic solvent, for example tetrahydro~uran, at or below ambient temperature.
W O 97/2~033 PCT~US96/17995 (R) For a compound of formula I in which xl is carbonyl, condensation of a corresponding organolithium compound of formula XVIII
Li-A3-X3-(CH2)q-(CHR3-CHR3)r-NRCRd XVIII
with a derivative of a corresponding acid of formula XIX
COOH
Rl ~ A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XIX
which will provide a ketone upon condensation. Derivatives of an acid of formula XIX which will provide a ketone upon condensation include the lithium salt of the acid, corresponding amides such as the N-methoxy-N-methyl amide, and the corresponding nitrile. The reaction is typically carried out as described above in procedure (Q).
(S) For a compound of formula I in which A is -CH=CH- and xl is methylene, elimination of water from a corresponding compound of formula II in which A is -CH2-CH2-.
The elimination conveniently is effected using an acid catalyst, for example by heating the compound of formula II in a solution of anhydrous ethanolic HCl.
(T) For a compound of formula I in which A is S and xl is carbonyl, condensation of a compound of formula XXV
C(o)-A3-X3-(CH2)~-(CHR3-CHR3)r-NRCRd Rl ~ S N(CH3)2 XXV
with a corresponding reagent of formula VI. The condensation conveniently is carried out in an inert solvent such as tetrahydrofuran at about 0 ~C, for example as described in Example 34, Part B.
(U) Alkylation of an amine of formula HNRaRh with a compound of formula XXVI
wo 97/25033 PCT~US96/17995 Rl ~ Xl -A3--X 3 - ( CH 2 ) q--( CHR3 - CHR 3 ) r-NR CRd A2 _x2_ (CH2 ) j- (CHR2 ) k- (CH2 ) m-L XXVI
w]lerein L is a leaving group as defined above, or ~or a compound of formula I in which R2 is OH, wherein L and R2 form an epoxide. Conveniently, the alkylation is carried out by heating the reagents in a polar solvent, for example as described in Example 43, Part C or in Example 116, Part B.
(V) Alkylation of an amine of formula HNRCRd with a compound of formula XXVII
Rl ~ xl -A3-X3- (CH2 ) q- (CHR3-CHR3 ) r-L
A A2 _x2 _ ( CH 2 ~ j--( CHR2 ) k--( CH 2 ) m--NR aRl' XXVI I
wherein L is a leaving group as defined above. Conveniently, the alkylation is carried out by mixing the reagents in a polar solvent, for example as described in Example 129, Part C.
(W) For a compound of formula I in which X1 is carbonyl (particularly wherein A3 is unsubstituted or substituted para-phenylene) and X3 is imino, O, S or -N(Rh)-, substitution of the group Z wherein Z is fluoro or nitro (particularly wherein Z is fluoro) of a ketone of formula XXVIII
R1 ~ A ~-X2-(CH2)j- ( CHR2 ) k - ( CH2 ) m~NR R XXVIII
using a compound of formula XXIX, H-X3- (CH2 ) q- (CHR3-CHR3 ) r-NRCRd XXIX
or a metal salt thereof, pre~erably an alkali metal salt.
Conveniently, the substitution reaction is carried out by heating the reagents XXVIII and XXIX in dimethylformamide or tetrahydrofuran using sodium hydride or potassium carbonate, W O 97/2~033 PCTnJS96/17995 for example as illustrated in Example 59, Part B; in Example 121, Part B; in Example 145, Part C; in Example 147 or in Example 117, Part D for the preparation of an intermediate o~
formula XXV.
(X) For a compound of formula I in which a substituent on ~3 is amino, reduction of a corresponding compound of formula I in which a substituent on A3 is nitro.
The reduction may be carried out using a conventional method, for example by catalytic hydrogenation as described in Example ~7.
(Y) For a compound of formula I in which a substituent on A3 is -NHC(O)Rf or -NHS(O)2Rg, substitution of the amino group of a corresponding compound of formula I in which a substituent on A3 is amino using an activated derivative of an acid of formula HO~(O)Rf or HOS(O)2Rg.
Conveniently, the activated derivative is the acid anhydride or the acid chloride, and the substitution is carried out in a polar solvent, for example as in Example 111 or Example 113.
(Z) For a compound of formula I in which a substituent on A3 is -NHCH2Rf or a compound of formula I in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb t~rm; n~ tes in -CH2-NRaRb~
reduction of the amide of a corresponding compound of formula I
in which a substituent on A3 is -NHC(O)Rf or of an intermediate compound corresponding to a compound of formula I but in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb term; n~ tes in -C(O)NRaRb. The reduction conveniently is carried out using lithium alllm;n1lm hydride in tetrahydro~uran, ~or example as described in Example 112 or Example 166, Part E.
(AA) For a compound of formula I in which X3 is ethene-1,2-diyl, reduction of the triple bond of a corres-ponding compound of formula I in which X3 is ethyne-1,2-diyl.
For a compound of formula I in which the double bond is trans-, the reduction conveniently is effected using diisobutylall]m;nllm hydride as described in Example 130; ~or a compound of ~ormula I in which the double bond is cis-, the reduction conveniently is effected using hydrogenation over a Lindlar catalyst as ~escribed in Example 131.
W O 97/25033 PCT~US96/17995 (AB) For a compound of :Eormula I in which a substituent on A3 is cyano, substitution of the halo group of a - corresponding compound of formula I in which a substituent on A3 is bromo or iodo. The substitution conveniently is ef~ected by heating the compound with cuprous cyanide in a polar solvent such as l-methyl-2-pyrrolidinone as described in Example 161, Part A.
Whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group.
Wherea~ter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it may be obtained by reacting the basic form of such a compound of ~ormula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
A particular process of the invention is one selected from procedures (A)-(R) above for a novel compound of formula I wherein A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent;
W O 97/25033 PCT~US96/17995 R1 deno~es 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene~ diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; ~ is 0, 1 or 2; and r is ~ or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyl~ne; m; no or 1-imidazolyl;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; xl is carbonyl; ~2 is O; the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q-(CHR3-CHR3)r-is ethylene; and Rc and Rd are independently ~1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino whereafter, for any of the procedures (A)-(R), when a pharmaceutically acceptable salt of a compound of formula I
is re~uired, it is obtained by reacting ~he basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
As mentioned above, a compound corresponding to a compound of ~ormula I but in which a ~unctional group is protected may serve as an int~rm~;ate for a compound o~
formula I. Accordingly, such protected intermediates for a ~ novel compound of formula I provide further aspects of the invention. Thus, as one particular aspect of the invention, there is provided a compound corresponding to a novel compound of formula I as defined above and bearing at least one substiutent R1 which is hydroxy, but in which the corresponding substituent is -O~P in place of hydroxy, wherein RP is a phenol protecting group other than methyl.
Phenol protecting groups are well known in the art, for example as described in T.W Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis" (1991). Particular values of RP include, for example, benzyl (for example as described in Example 41 or Example 81) and allyl (for example as described in Example 88). Further, RP may denote a functionalized resin, for example as disclosed in H.V. Meyers, et al., Molecular Diversitv, (1995), 1, 13-20.
As mentioned above, the invention includes pharmaceutically acceptable salts of the thrombin inhibiting compounds defined by the above formula I. A particular ~1 ~m; ne of this invention possesses one or more sufficiently basic functional groups to react with any of a number of inorganic and organic acids affording a physiologically acceptable counterion to form a pharmaceutically acceptable salt. Acids c~onl y employed to form pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the li~e, and organic acids such as ~-toluene sulfonic, methanesulfonic acid, oxalic acid, ~-bromo phenyl sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid.
If not commercially available, the necessary starting materials for the preparation of a compound of formula I may be prepared by procedures which are selected from stAn~d techniques of organic chemistry, including aromatic and heteroaromatic substitution and transformation, from techniques which are analogous to the syntheses of known, structurally similar compounds, and techniques which are analogous to the above described procedures or procedures described in the Examples. It will be clear to one skilled in the art that a variety of sequences is available for the preparation of the starting materials. Starting materials which are novel provide another aspect of the invention.
As noted above in procedure (B), an intermediate alcohol of formula II may be obtained by reduction of a corresponding ketone of formula I. In addition, an alcohol of formula II may be obtained by condensation of an organolithium compound of formula IX with a corresponding aldehyde of formula XX
H-C(O)-A3-X3-(CH2)q~(CHR3-CHR3)r-NRCRd XX
using a procedure similar to that described in procedure (Q) or by condensing an organolithium compound of formula XVIII
with a corresponding aldehyde of formula XXI
W O 97/25033 PCT~US96/17995 CHO
R~
A ~ A2-X2-(CH2)~-(CHR2)k-(CH2)m-NRaR~ XXI
using a procedure similar to that described in procedure (R), particularly when j and k are both 0.
An int~rme~;ate of formula III may be prepared by any of a number of known procedures. A preferred method for a compound of formula III in which A is S, particularly when j and k are both 0, is the cross coupling of a boronic acid o~ formula XXII
Rl ~ S B(OH)2 XXII
with a reagent of ~ormula XXIII
X-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XXIII
in which X is, for example, bromo, iodo or trif~uoromethane-sulfonate, for example as described in Examples 1, 2, 4 and 16. For preparation of a compound of formula III in which A
is O, a preferred method is a copper mediated cross coupling of a compound of formula XXIII and a 2-metalated benzofuran, such as described in Example 119, Part A. It may be preferred to cross couple a species in which the side chain is not fully elaborated, then to complete the elaboration, for example as described in Example 14 and in Example 119.
Starting material acids of formula IV may be prepared by a number of st~n~rd procedures, a number of which are described in the Examples.
Starting material enol phosphates of formula V may be prepared and used by methods similar to those described in Jones et al., J. Med. Chem. (1992), 35~5), 931-938; and the correspon~;ng reagents of formula VI may be obtained by conventional methods from bromides of formula XXIII in which X is bromo.
W O 97/25033 PCT~US96/17995 A starting material iodide of formula VII in which A is S may be prepared in a manner similar to that described in Example 11, parts A and ~, and the boronic acid of ~ormula VIII may be obtained ~rom a compound o~ formula XXIII using a procedure similar to that of Example 11, part C.
An organolithium compound of formula IX may be prepared by transmetallation of the corresponding bromide, which itself may be obtained by bromination of the compound corresponding to formula IX, but with hydrogen in the place o~ lithium. For a compound in which A is S, the procedure may be carried out in a manner similar to that described in Example 10, parts A and B.
A starting material of formula XI in which x2 is O
or S may be obtained by deprotection of x2 o~ a corresponding compound in which x2 bears a protecting group. When x2 is O, it may be protected as a silyl ether, as described in Example 29, or as a methyl ether as described in several of the examples and cleaved by a variety of methods including by using pyridine hydrochloride (Example 5), all~m;nllm chloride and ethanethiol (Examples 9, 13, 15, 17, 18, 24, 26 and 28, part C), or boron tribromide (see below).
A starting material o~ ~ormula xIII in which X3 is O or S may be obtained by deprotection of X3 of a corresponding compound in which X3 bears a protecting group.
For example, when X3 is O, it may be protected as a methyl ether and liberated by treatment with sodium thioethoxide (Example 28, part A), aluminum chloride and ethanethiol, or pyridine hydrochloride, depending upon the groups present in other parts o~ the molecule.
A starting material o~ ~ormula XV in which x2 and X3 are O or S may be obtained by deprotection of x2 and X3 of a corresponding compound in which x2 and X3 bear protecting groups. ~or example, when x2 and X3 are both O, they may both be protected as methyl ethers and simultaneously deprotected by treatment with alllminl~m chloride and ethane-thiol (Example 3) with boron tribromide (Examples 8 and 10) or with pyridine hydrochloride (Examples 11 and 12).
-W O 97/25033 PCT~US96/1799 A starting material compound of formula XXV
typically is prepared by acylation of a compound of formula XXIV
Rl ~ S ~ N(CH3)2 XXIV
with an activated derivative of an acid of formula VI, conveniently the acid chloride, for example as described in Example 39, Part B.
Selective methods of protection and deprotection are well known in the art for preparation of compounds such as those of formula XI, XIII and XV discussed above. Selective methods for cleavage of methyl ethers, as described in the examples, are discussed in Jones, et al , J. Med. Chem., (1~84), 27, 1057-1066. For example, the diether 3-(4-methoxybenzoyl)-2-(4-methoxyphenyl)benzo[b]thiophene described at Example 3, part B, may be treated with boron tribromide in dichloromethane at -10 ~C (1 hour) to afford the monoether 2-(4-hydroxyphenyl)-3-(4-methoxybenzoyl)benzo[b]thiophene, whereas treatment with sodium thioethoxide (Example 28, part A) affords the isomeric monoether 3-(4-hydroxybenzoyl)-2-(4-methoxyphenyl)benzo[b]-thiophene. Treatment with boron tribromide under less mildconditions (0~, 6 hours, see Example 8, part C) or with aluminum chloride and ethanethiol cleaves both ethers (Example 3, part C).
The compounds of the invention are isolated best in the form of acid addition salts. Salts of the compounds of formula I formed with acids such as those mentioned above are useful as pharmaceutically acceptable salts for administration of the antithrombotic agents and for preparation of formulations of these agents. Other acid addition salts may be prepared and used in the isolation and purification of the compounds.
As noted above, the optically active isomers and diastereomers of the compounds of formula I are also considered part of this invention. Such optically active W O 97~5033 PCTAJS96/17995 isomers may be prepared ~rom their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by st~n~rd methods affords substantially optically pure isomers of the compounds of the present invention or their precursors. Further details regarding resolutions can be obtained in Jac~ues, et al., ~n~ntiomerS, Racemates, and Resolutions, John Wiley & Sons, 1981.
The compounds of the invention are believed to selectively inhibit thrombin over other proteinases and nonenzyme proteins involved in blood coagulation without appreciable interference with the body's natural clot lysing ability (the compounds have a low inhibitory effect on fibrinolysis). Further, such selectivity is believed to permit use with thrombolytic agents without substantial interference with thrombolysis and fibrinolysis.
The invention in one of its aspects provides a method of inhibiting thrombin in m~mm~l S comprising ~m;ni stering to a m~mm~l in need of treatment an effective (thrombin inhibiting) dose of a compound of formula I.
In another of its aspects, the invention provides a method of treating a thromboembolic disorder comprising administering to a m~mm~l in need of treatment an effective (thromboembolic disorder therapeutic and/or prophylactic amount) dose of a compound of formula I.
The invention in another of its aspects provides a method of inhibiting coagulation in m~mm~l s comprising administering to a m~mm~l in need o~ treatment an effective (coagulation inhibiting) dose of a compound of formula I.
The thrombin inhibition, coagulation inhibition and thromboembolic disorder treatment contemplated by the present method includes both medical therapeutic and/or prophylactic treatment as appropriate.
W O 97/25033 PCT~US96/17995 In a further embodiment the invention relates to treatment, in a hum~an or animal, of conditions where inhibition of thrombin is required. The compounds of the invention are expected to be useful in ~n;m~l s, including man, in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility are in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility, in treatment and/or prophylaxis, include venous thrombosis and pulmonary embolism, arterial thrombosis, such as in myocardial ischemia, myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis. Further, the compounds have expected utility in the treatment or prophylaxis of atherosclerotic disorders (diseases) such as coronary arterial disease, cerebral arterial disease and peripheral arterial disease. Further, the compounds are expected to be useful together with thrombolytics in myocardial infarction. Further, the compounds have expected utility in prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations. Further, the compounds have expected utility in prevention of rethrombosis after microsurgery. Further, the compounds are expected to ~e use~ul in anticoagulant treatment in connection with artificial organs and cardiac valves.
Further, the compounds have expected utility in anticoagulant treatment in hemodialysis and disseminated intravascular coagulation. A further expected utility is in rinsing of catheters and m~ n;cal devices used in patients in vivo, and as an anticoagulant for preservation of blood, plasma and other blood products in vitro. Still further, the compounds have expected utility in other diseases where blood coagulation could be a flln~m~ntal contributing process or a source of secondary pathology, such as cancer, including metastasis, inflammatory diseases, including arthritis, and diabetes. The anti-coagulant compound is a~in;stered orally or parenterally, e.g. by intravenous infusion (iv), intramuscular injection (im) or subcutaneously (sc).
The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound ~m;n;stered, the rate of ~m;n;stration, the route of A~m;n;stration, and the condition being treated.
A typical daily dose for each of the above utilities is between about 0.01 mg/kg and about 1000 mg/kg.
The dose regimen may vary e.g. for prophylactic use a single daily dose may be administered or multiple doses such as 3 or 5 times daily may be appropriate. In critical care situations a compound of the invention is administered by iv infusion at a rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferably between about 0.1 mg/kg/h and about 5 mg/kg/h.
The method of this invention also is practiced in conjunction with a clot lysing agent e.g. tissue pl ~-~m; nogen activator (t-PA), modified t-PA, streptokinase or urokinase.
In cases when clot formation has occurred and an artery or vein is blocked, either partially or totally, a clot lysing agent is usually employed. A compound of the invention can be ~m; n; stered prior to or along with the lysing agent or subsequent to its use, and preferably further is administered along with aspirin to prevent the reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with a platelet glycoprotein receptor (IIb/IIIa) antagonist, that inhibits platelet aggregation. A compound o~ the invention can be ~dm;n;stered prior to or along with the IIb/IIIa antagonist or subsequent to its use to prevent the occurrence or reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with aspirin. A compound of the invention can be A~ml n; stered prior to or along with aspirin or subsequent to WO 9712S033 PCT~US96~17995 its use to prevent the occurrence or reoccurrence of clot formation. As stated above, preferably a compound of the present invention is administered in coniunction with a clot lysing agent and aspirin.
This invention also provides ph~rm~ceutical formulations for use in the above described therapeutic method. Pharmaceutical formulations of the invention comprise an effective thrombin inhibiting amount of a compound of formula I in association with a ph~rm~ceutically acceptable carrler, excipient or diluent. For oral administration the antithrombotic compound is formulated in gelatin capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like.
For parenteral administration the antithrombotic is formulated in a pharmaceutically acceptable diluent e.g.
physiological saline (0.9 percent), 5 percent dextrose, Ringer's solution and the like.
The compound of the present invention can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg. Preferably the compound is in the form of a pharmaceutically acceptable salt such as for example the sulfate salt, acetate salt or a phosphate salt. An example of a unit dosage formulation comprises 5 mg of a compound of the present invention as a ~rm~ceutically acceptable salt in a 10 ml sterile glass ampoule. Another examp~e of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a ph~rm~ceutically acceptable salt in 20 ml of isotonic saline contained in a sterile ampoule.
The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds of the present invention are preferably formulated prior to administration. Another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a novel compound of formula I or a pharmaceutically acceptable salt or solvate thereof in association with a ph~rmAceutically acceptable carrier, diluent or excipient therefor.
The active ingredient in such formulations comprises ~rom 0.1 percent to 99.9 percent by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients o~ the formulation and not deleterious to the recipient thereof.
The present ~rm~ceutical formulations are prepared by known procedures using well known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form o~ a capsule, sachet, paper or other cont~; ner . When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
The following formulation examples are illustrative only and are not intended to llmit the scope of the invention in any way. "Active ingredient," of course, means a compound according to Formula I or a ~hArmAceutically acceptable salt or solvate thereof.
Formulation 1: Hard gelatin capsules are prepared using the following ingredients:
W O 97/2~033 PC~US96/17995 Quantity (mq/ca~sule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Formulation 2: A tablet is prepared using the ingredients below:
Quantity (ma/tablet) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.
Formulation 3: An aerosol solution is prepared cont~;n;ng the following components:
Weiaht Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)70.00 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 ~C and transferred to a filling device. The re~uired amount is then fed to a stainless steel container and diluted with the r~m~;n~er of the propellant. The valve units are then fitted to the container.
Formulation 4: Tablets, each cont~;n;ng 60 mg of active ingredient, are made as follows:
Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10 % solution in water~ 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 ma Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution cont~;n;n~ polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50 ~C and passed through a No. 18 mesh U.S.
Sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation 5: ~apsules, each cont~;n;ng 80 mg of active ingredient, are made as follows:
Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnes iUm.~ S tearate2 mq Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Formulation 6: Suppositories, each cont~;n;ng 225 mg of active ingredient, are made as ~ollows:
Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mq Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the m;n;mllm heat necessary. The mixture is then poured into a suppository mold of nomi n;31 2 g capacity and allowed to cool.
W O 97/25033 PCT~US96/1799 Formlllation 7: Suspensions, each cont~;n;ng 50 mg of active ingredient per 5 ml dose, are made as follows:
Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg ~ Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.
Color q.v.
Puri~ied water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to ~orm a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
Formulat;on 8: An intravenous ~ormulation may be prepared as ~ollows:
Active ingredient 100 mg Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate o~ 1 ml per minute.
The ability of the compounds of the present invention to be an ef~ective and orally active thrombin inhibitor are evaluated in one or more of the following assays.
The compounds provided by the invention (formula I) selectively inhibit the action of thrombin in m~mm~ls~ The inhibition of thrombin is demonstrated by in vitro inhibition of the amidase activity of thrombin as measured in an assay in which thrombin hydxolyzes the chromogenic substrate, N-benzoyl-L-phenylalanyl-L-valyl-L-arginyl-p-nitroanilide, N-benzoyl-L-Phe-L-Val-L-Arg-p-nitroanilide.
The assay is carried out by mixing 50 ~l buf~er (0.03M Tris, 0.15M NaCl, pH 7.4) with 25 ~l o~ human thrombin solution ~purified human thrombin, Enzyme Research Laboratories, South Bend, Indiana~ at 8 NIH units/ml) and 25 WO 97125033 PCT~US96/17995 ~l of test compound in a solvent (50% aqueous methanol (v:v)). Then 150 ~l of an aqueous solution of the chromogenic substate (at 0.25 mg/ml) are added and the rates of hydrolysis of the substrate are measured by monitoring the reactions at 405 nm for the release of p-nitroaniline.
Standard curves are constructed by plotting free thrombin concentration against hydrolysis rate. The hydrolysis rates observed with test compounds are then converted to "free thrombin" values in the respective assays by use of the standard curves. The bound thrombin (bound to test compound) is calculated by subtracting the amount of free thrombin observed in each assay from the known initial amount of thrombin used in the assay. The amount of free inhibitor in each assay is calculated by subtracting the number of moles of bound thrombin from the number of moles of added inhibitor (test compound).
The Kass value is the hypothetical e~uilibrium constant for the reaction between thrombin and the test compound (I).
Thrombin + I ' Thrombin-I
Kass= ~Thrombin-I]
t(Thrombin) x (I)]
Kass is calculated for a range of concentrations of test compounds and the mean value reported in units of liter per mole. In general, a thrombin inhibiting compound of f~rmllla I
of the instant insertion exhibits a Kass of 0.03 X 106 L/mole or much greater. For example, the compound of Example 3 was found to have a Kass of 5.0 X 106 L/mole, and the compound of Example 164 was found to have a Kass of 526 X 106 L/mole.
By substantially following the procedures described above for human thrombin, and using other human blood coagulation system serine proteases and using fibrinolytic system serine proteases, with the appropriate chromogenic substrates, identified below, the selectivity of the compounds of the present invention with respect to the coagulation factor serine proteases and to the fibronolytic , W O 97/25033 PCT~US96/1799 serine proteases are evaluated as well as their substantial lack of interference with human plasma clot fibrinolysis.
~ Human factors X, Xa, IXa, XIa, and XIIa are purchased from Enzyme Research Laboratories, South Bend, - 5 Indiana; human urokinase from Leo Pharmaceuticals, Denmark;
and recombinant activated Protein C (aPC) is prepared at Eli Lilly and Co. substantially according to U.S. Patent 4,981,952. Chromogenic substrates: N-Benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide (for factor Xa); N-Cbz-D-Arg-Gly-Arg-p-nitroanilide (for factor IXa assay as the factor Xasubstrate); Pyroglutamyl-Pro-Arg-p-nitroanilide (for Factor XIa and for aPC); H-D-Pro-Phe-Arg-p-nitroanilide (for factor XIIa); and Pyroglutamyl-Gly-Arg-p-nitroanilide (for urokinase); are purchased from Kabi Vitrum, Stockholm, Sweden, or from Midwest Biotech, Fishers, Indiana. Bovine trypsin is purchased from Worthington Biochemicals, Freehold, New Jersey, and human plasma kallikrein from Kabi Vitrum, Stockholm, Sweden. Chromogenic substrate H-D-Pro-Phe-Arg-p-nitroanilide for plasma kallikrein is purchased from Kabi Vitrum, Stockholm, Sweden. N-Benzoyl-Phe-Val-Arg-p-nitroanilide, the substrate for human thrombin and for trypsin, is synthesized according to procedures described above for the compounds of the present invention, using known methods of peptide coupling from commercially available reactants, or purchased from Midwest Biotech, Fishers, Trl~; ~n;~ .
Human plasmin is purchased from Boehringer Mannheim, In~;~nApolis, Indiana; nt-PA is purchased as single chain activity reference from American Diagnostica, Greenwich, Connecticut; modified-t-PA6 (mt-PA6) is prepared at Eli Lil~y and Company by procedure known in the art (See, Burck, et al., J. Biol. Chem., 265, 5120-5177 (1990).
Plasmin chromogenic substrate H-D-Val-Leu-Lys-p-nitroanilide and tissue pl~m;nogen activator (t-PA) substrate H-D-Ile-Pro-Arg-p-nitroanilide are purchased from Kabi Vitrum, Stockholm, Sweden.
W O 97/25033 PCT~US96/17995 In the chromogenic substrates described above the three-letter symbols Ile, Glu, Gly, Pro, Arg, Phe, Val, ~eu and Lys are used to indicate the corresponding amino acid group isoleucine, glutamic acid, glycine, proline, arginine, phenylalanine, valine, leucine and lysine, respectively.
Thrombin inhibitors preferably should spare ~ibrinolysis induced by urokinase, tissue plasminogen activator (t-PA) and steptokinase. This would be important to the therapeutic use o~ such agents as an adjunct to streptokinase, t-PA or urokinase thrombolytic therapy and to the use o~ such agents as an endogenous fibrinolysis-sparing (with respect to t-PA and urokinase) antithrom~otic agents.
In addition to the lack o~ interference with the amidase activity of the ~ibrinolytic proteases, such fibrinolytic system sparing can be studied by the use of human plasma clots and their lysis by the respective fibrinolytic plasminogen activators.
Materi~1s Dog plasma is obtained from conscious mixed-breed hounds (either sex Hazelton-LRE, ~ m~7.oo/ Michigan, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from fresh dog plasma and human fibrinogen is prepared ~rom in-date ACD human blood at the fraction I-2 according to previous procedures and specifications. Smith, Biochem ~., 185, 1-11 (1980); and Smith, et al., R;och~m;strv, 11, 2g58-2~67, (1972). Human ~ibrinogen (98 percent pure/plasmin ~ree) is from American Diagnostica, Greenwich, Connecticut. Radiolabeling o~ fibrinogen I-2 preparations is per~ormed as previously reported. Smith, et al., Biochemistry, 11, 2958-2967, (1972~. Urokinase is purchased ~rom Leo Pharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase is purchased from Hoechst-Roussel Pharmaceuticals, Somerville, New Jersey.
W O 97~5033 PCT~US96/17995 Methods - Ef~cts on Lvsis of Human Plasma Clots bv t-PA
Human plasma clots are formed in micro test tubes by adding 50 ~L thrombin (73 NIH unit/mL~ to 100 ~L human plasma which contains 0.0229 ~i 125-iodine labeled fibrinogen. Clot lysis is studied by overlaying the clots with 50 ~L of urokinase or streptokinase (50, 100, or 1000 unit/mL) and incubating for 20 hours at room temperature. After incubation the tubes are centrifuged in a Beckman Microfuge.
25 ~L of supernate is added into 1.O mL volume of 0.03 M
tris/0.15 M NaCl buffer for gamma counting. Counting controls 100 percent lysis are obtained by omitting thrombin (and substituting buf~er). The thrombin inhibitors are evaluated for possible interference with fibrinolysis by including the compounds in the overlay solutions at 1, 5, and 10 ~gJmL concentrations. Rough approximations of ICso values are estimated by linear extrapolations from data points to a value which would represent 50 percent of lysis for that particular concentration of fibrinolytic agent.
Anticoaaulant Activitv ~aterials Dog plasma and rat plasma are obtained from conscious mixed-breed hounds (either sex, hazelton-LRE, Kalamazoo, Michigan, U.S.A.) or from anesthetized male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis, Indiana, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from in-date ACD human blood as the fraction I-2 according to previous procedures and specifications. Smith, Blochem. J., 185, 1-11 (1980); and Smith, et al , Bioch~;strv, 11, 2958-2967 (1972). Human fibrinogen is also purchased as 98 percent pure/plasmin free from American Diagnostica, Greenwich, Connecticut. Coagulation reagents Actin, Thromboplastin, Innovin and Human plasma are from Baxter Healthcare Corp., Dade Division, Miami, Florida.
Bovine thrombin from Parke-Davis (Detroit, Michigan) is used for coagulation assays in plasma.
W O 97/25033 PCT~US96/17995 Methods ~ntiCoaqulation Determinations Coagulation assay procedures are as previously described.
Smith, et al., Thrombosis Research, 50, 163-174 (1988). A
CoAScreener coagulation instrument (American LABor, Inc.) is used for all coagulation assay measurements. The prothrombin time (PT) is measured by adding Q. 05 mL saline and 0. 05 mL
Thromboplastin-C reagent or recombinant human tissue ~actor reagent (Innovin) to 0.05 mL test plasma. The activated partial thromboplastin time (APTT) is measured by incubation of 0.05 mL test plasma with 0.05 mL Actin reagent for 120 seconds ~ollowed by 0.05 mL CaC12 (0.02 M). The thrombin time (TT) is measured by adding 0.05 mL saline and 0.05 mL
thrombin (10 NIH units/m~) to 0.05 mL test plasma. The compounds o~ formula I are added to human or ~n;m~l plasma over a wide range o~ concentrations to determine prolongation effects on the APTT, PT, and TT assays. Linear extrapolations are per~ormed to estimate the concentrations re~uired to double the clotting time for each assay. For preferred compounds of the instant invention, a concentration of 30 ng/mL or less typically is su~ficient to double the TT.
~nim;~l S
Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc., Indianapolis, IN) are anesthetized with xylazine (20 mg/kg, s.c.) and ketamine (120 mg/kg, s.c.) and maintained on a heated water blanket (37 ~C). The ~ugular vein(s) is cannulated to allow for infusions.
Arterio-Venous shunt ~odel The le~t jugular vein and right carotid artery are cannulated with 20 cm lengths of polyethylene PE 60 tubing. A 6 cm center section o~ larger tubing (PE 190) with a cotton thread (5 cm) in the lumen, is ~riction ~itted between the longer sections to complete the arterio-venous shunt circuit. Blood is circulated through the shunt ~or 15 min be~ore the thread is care~ully removed and weighed. The weight o~ a wet thread CA 02236007 l998-04-27 W O 97125033 PCT~US96/17995 is subtracted from the total weight of the thread and thrombus (see J.R. Smith, Br J Pharmacol, 77:29, 1982). In - this model preferred compounds of the instant invention reduce the net clot weight to approximately 25-30% of - 5 control, or even lower, at an i.v. dose of 33.176 ~mol/kg/h.
FeC13 model of arterial iniurv The carotid arteries are isolated via a midline ventral cervical incision. A thermocouple is placed under each artery and vessel temperature is recorded continuously on a strip chart recorder. A cu~f of tubing (0.058 ID x 0.077 OD
x 4 mm, Baxter Med. Grade Silicone), cut longitl~;n~lly, is placea around each carotid directly above the thermocouple.
FeCl3 hexahydrate is dissolved in water and the concentration (20 percent) is expressed in terms of the actual weight of FeC13 only. To injure the artery and induce thrombosis, 2.85 ~L is pipetted into the cuff to bathe the artery above the thermocouple probe. Arterial occlusion is indicated by a rapid drop in temperature. The time to occlusion is reported in minutes and represents the elapsed time between application of FeCl3 and the rapid drop in vessel temperature (see K.D. Kurz, Thromb. Res., 60:269, 1990).
Spontaneous thrombolvsis model In vi tro data suggests that thrombin inhibitors inhibit thrombin and, at higher concentrations, may inhibit other serine proteases, such as plasmin and tissue plasminogen activator. To assess if the compounds inhibit fibrinolysis in vivo, the rate of spontaneous thrombolysis is determined by implanting a labeled whole blood clot into the pulmonary circulation. Rat blood (1 mL) is mixed rapidly with bovine thrombin (4 IU, Parke Davis) and 125I human Fibrogen (5 ~Ci, ICN), immediately drawn into silastic tubing and incubated at 37 ~C for 1 hour. The aged thrombus is expelled from the tubing, cut into 1 cm segments, washed 3X in normal saline and each segment is counted in a gamma counter. A segment with known counts is aspirated into a catheter that is WO 97/25033 PCT~US96/17995 subsequently implanted into the jugular vein. The catheter tip is advanced to the ~icinity of the right atrium and the clot is expelled to float into the pulmonary circulation.
One hour after implant, the heart and lungs are harvested and counted separately. Thrombolysis is expressed as a percentage where:
% Thrombolysis = (iniected cPm - luna c~m) x 100 injected cpm The fibrinolytic dissolution of the implanted clot occurs time-dependently (see J.P. Clozel, ~ardiovas. Pharmacol., 12:520, 1988).
Coaaulation ~arameters Plasma thrombin time (TT) and activated partial thromboplastin time (APTT) are measured with a fibrometer.
Blood is sampled from a jugular catheter and collected in syringe containing sodium citrate (3.8 percent, 1 part to 9 parts blood). To measure TT, rat plasma (0.1 mL) is mixed with saline (0.1 mL) and bovine thrombin (0.1 mL, 30 U/mL in TRIS buffer; Parke Davis) at 37 ~C. For APTT, plasma (0.1 mL) and APTT solution (O.1 mL, Organon Teknika) are incubated for 5 minutes (37 ~C) and ~aCl2 (0.1 mL, 0.025 M) is added to start coagulation. Assays are done in duplicate and averaged.
Tn~ex of ~ioavailabilitv For a measure of bioactivity, plasma thrombin time (TT) serves as a substitute for the assay of parent compound on the assumption that observed increments in TT resulted from thrombin inhibition by parent only. The time course of the effect of the thrombin inhibitor upon TT is determined after i.v bolus ~m;nl stration to anesthetized rats and after oral treatment of fasted conscious rats. Due to limitations of blood volume and the number of points re~uired to determine the time course from time of treatment to the time when the response returns to pretreatment values, two populations of rats are used. Each sample population represents alternating W O 97/25033 PCT~US96/17995 sequential time points. The average TT over the time course is used to calculate area under the curve (AUC). The index ~ of bioavailability is calculated by the ~ormula shown below and is expressed as percent relative activity.
- 5 The area under the curve (AUC) of the plasma TT
time course is determined and adjusted for the dose. This index of bioavailability is termed ~I% Relative Activity~ and is calculated as '~Relative Activity = C PA X Do X100 Com~ounds Compound solutions are prepared fresh daily in normal saline and are lnjected as a bolus or are infused starting 15 minutes before and continuing throughout the experimental perturbation which is 15 minutes in the arteriovenous shunt model and 60 minutes in the FeCl3 model of arterial injury and in the spontaneous thrombolysis model. Bolus injection volume is 1 mL/kg for i.v., and 5 mL/kg for p.o., and infusion volume is 3 mL/hr.
S~atistics Results are expressed as means +/- SEM. One-way analysis of variance is used to detect statistically significant differences and then Dunnett's test is applied to determine which means are different. Significance level for rejection of the null hypothesis of equal means is P~0.05.
~n;m~1s Male dogs ~Beagles; 18 months - 2 years; 12-13 kg, Marshall Farms, North Rose, New York 14516) are fasted overnight and fed Purina certified Prescription Diet (Purina Mills, St.
Louis, Missouri) 240 minutes after dosing. Water is available ad libi tum. The room temperature is maintained between 66-74 ~F; 45-50 percent relative humidity; and lighted from 0600-1800 hours.
~
W O 97/25033 PCT~US96/17995 ph~rmacokinetic model.
Test compound is formulated immediately prior to dosing by dissolving in sterile 0.9 percent saline to a 5 mg/mL
preparation. Dogs are given a single 2 mg/kg dose o~ test compound by oral gavage. Blood samples (4.5 mL) are taken from the cephalic vein at 0.25, 0.5, 0. 75, 1, 2, 3, 4 and 6 hours after dosing. Samples are collected in citrated Vacutainer tubes and kept on ice prior to reduction to plasma by centrifugation. Plasma samples are analyzed by HPLC MS.
Plasma concentration of test compound is recorded and used to calculate the pharmacokinetic parameters: elimination rate constant, Ke; total clearance, Clt; volume of distribution, VD; time of maximum plasma test compound concentration, Tmax;
maximum concentration of test compound of Tmax, Cmax; plasma hal~-life, to.5; and area under the curve, A.U.C.; fraction of test compound absorbed, F.
~n;ne Model of Coronarv Arterv Thrombosls Surgical preparation and instrumentation of the dogs are as described in Jackson, et al., Circulation, 82, 930-940 (1990). Mixed-breed hounds (aged 6-7 months, either sex, Hazelton-LRE, ~ m~oo, MI, U.S.A.) are anesthetized with sodium pentobarbital (30 mg/kg intravenously, i.v.), intubated, and ventilated with room air. Tidal volume and respiratory rates are adjusted to maintain blood PO2, PCO2, and pH within normal limits. Sub~erm~l needle electrodes are inserted for the recording of a lead II ECG.
The left jugular vein and common carotid artery are isolated through a left mediolateral neck incision. Arterial blood pressure (ABP) is measured continuously with a precalibrated Millar transducer (model (MPC-500, Millar Instruments, Houston, TX, U.S.A.) inserted into the carotid artery. The ~ugular vein is cannulated for blood sampling during the experiment. In addition, the femoral veins o~ both hindlegs are cannulated for administration of test compound.
-CA 02236007 l998-04-27 W O 97/25033 PCT~US96/1~995 A left thoracotomy is performed at the fifth intercostal space, and the heart is suspended in a pericardial cradle. A
- 1- to 2-cm segment of the left circum~lex coronary artery ~LCX) is isolated proximal to the first major diagonal~ 5 ventricular branch. A 26-gauge needle-tipped wire anodal electrode (Teflon-coated, 30-gauge silverplated copper wire) 3-4 mm long is inserted into the LCX and placed in contact with the intimal surface of the artery (confirmed at the end o~ the experiment). The stimulating circuit is completed by placing the cathode in a subcutaneous (s.c.) site. An adjustable plastic occluder is placed around the LCX, over the region of the electrode. A precalibrated electromagnetic flow probe (Carolina Medical Electronics, King, NC, U.S.A.) is placed around the LCX proximal to the anode for measurement of coronary blood flow (CBF). The occluder is adjusted to produce a 40-50 percent inhibition of the hyperemic blood flow response observed a~ter 10-s mechanical occlusion of the LCX. All hemodynamic and ECG measurements are recorded and analyzed with a data ac~uisition system (model M3000, Modular Instruments, Malvern, PA. U.S.A.).
Thrombus Formation and Compound ~m;n;stration Reaimens Electrolytic injury of the intima of the LCX is produced by applying 100-~A direct current (DC) to the anode. The current is maintained for 60 min and then discontinued whether the vessel has occluded or not. Thrombus formation proceeds spontaneously until the LCX is totally occluded (determined as zero CBF and an increase in the S-T segment).
Compound ~m; n; stration is started after the occluding thrombus is allowed to age for 1 hour. A 2-hour infusion of the compounds of the present invention at doses of 0.5 and 1 mg/kg/hour is begun simultaneously with an infusion of thrombolytic agent (e.g. tissue plasminogen activator, streptokinase, APSAC). Reperfusion is followed for 3 hour after ~m;n~stration of test compound. Reocclusion of coronary arteries after successful thrombolysis is defined as ~ zero CBF which persisted for ~ 30 minutes.
Hematolo~Y and tem~late bleedinq time determina~ion.~
Whole blood cell counts, hemoglobin, and hematocrit values are determined on a 40-~l sample o~ citrated (3.8 percent) blood (1 part citrate:9 parts blood) with a hematology analyzer (~ell-Dyn 900, Sequoia-Turner. Mount View, CA, U.S.A.). Gingival template bleeding times are determined with a Simplate II bleeding time device (Organon Teknika Durham, N.C., U.S.A.). The device is used to make 2 horizontal incisions in the gingiva of either the upper or lower left jaw of the dog. Each incision is 3 mm wide x 2 mm deep. The incisions are made, and a stopwatch is used to determine how long bleeding occurs. A cotton swab is used to soak up the blood as it oozes from the incision. Template bleeding time is the time from incision to stoppage of bleeding. Bleeding times are taken just before ~Am;n;stration of test compound (0 min), 60 min into infusion, at conclusion of ~m;nistration of the test compound (120 min), and at the end of the experiment.
All data are analyzed by one-way analysis of variance (ANOVA) followed by Student-Neuman-Kuels post hoc t test to determine the level o~ significance. Repeated-measures AMOVA are used to determine significant differences between time points during the experiments. Values are determined to be statistically different at least at the level of pc0.05. All values are mean i SEM. All studies are conducted in accordance with the guiding principles of the American Physiological Society. Further details regarding the procedures are described in Jackson, et al., J. Cardiovasc.
ph~rm~col., (1993), 21, 587-599.
The following Examples are provided to further describe the invention and are not to be construed as limitations thereof.
The abbreviations, symbols and terms used in the examples have the following meanings.
W ~ 97/2S033 PCT~US96/17995 Ac = acetyl AIBN = azobisisobutyronitrile ~ Anal. = elemental analysis Bu = butyl - 5 n-BuLi = butyllithium calcd = calculated DIBAL-H = diisobutyl all]minllm hydride ~MF = dimethylformamide DMSO = dimethylsulfoxide Et = ethyl EtOAc = ethyl acetate Et3N = triethylamine Et2O = diethyl ether EtOH = ethanol EtSH = ethanethiol FAB = Fast Atom Bombardment (Mass Spectrascopy) FDMS = field desorption mass spectrum Hex = hexanes HPLC = High Performance Liquid Chromatography HRMS = high resolution mass spectrum i-PrOH = isopropanol IR = Infrared Spectrum LAH = lithium aluminum hydride Me = methyl MeI = methyl iodide MeOH = methanol MPLC = Medium Pressure Liquid Chromatography NBS = N-bromosuccinimide NMR = Nuclear Magnetic Resonance Ph = phenyl PPA = polyphosphoric acid i-Pr = isopropyl Rochelle's Salt = potassium sodium tartrate RPHPLC = Reversed Phase High Performance Liquid Chromatography SiO2 = silica gel ~ SM = starting material TEA = triethylamine Temp. = temperature TFA = trifluoroacetic acid THF = tetrahydrofuran TIPS = triisopropylsilyl TLC = thin layer chromatography triflic acid = trifluoromethanesulfonic acid Unless otherwise stated, pH adjustments and work up are with aqueous acid or base solutions. PrepLC indicates preparative liquid chromatography using "Prep Pak (TM)"
silica cartridgesi radial chromatography indicates preparative chromatography using a "Chromatotron (TM)~
instrument.
CA 02236007 l998-04-27 W O 97/Z5033 PCT~US96tl7995 ~ .x~le 1 Preparation o~ 6-Hydroxy-2-t4-~2-(1-~1 olidinyl)-ethoxylphQnyl]benzolb]thiophen-3-yl 4-~2-(1-Pyrro-lidinyl)ethoxy]phenyl Ketone Dioxalate.
0 ~ ,~_,N ~
HO ~ "x~_,M ~ 2 C2H2O4 Part A. 6-Methoxybenzo[b~thiophene-2-boronic Acid.
MeO/ ~ B(OH)2 To a solution of 6-methoxybenzo Ib] thiophene (Graham, S. L., et al. J. Med. Chem. 1989, 32, 2548-2554)(18.13 g, 0.111 mol) in 150 mL of anhydrous THF at -60 ~C was added n-BuLi ~76.2 mL, 0.122 mol, 1.6 M solution in hexanes), dropwise via syringe. After stirring for 30 min, triisopropyl borate (28.2 mL, 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 0 ~C and then partitioned between 1.0 N HCl and EtOAc (300 mL each). The layers were separated, and the organic phase was dried over Na2SO4. Concentration in vacuo produced a white solid that was triturated from Et2O/hexanes.
Filtration provided 16.4 g (71~) of 6-methoxybenzo~b]thio-phene-2-boronic acid as a white solid.
mp 200 ~C (dec)i FDMS 208 (M+; 100); lH NMR (DMSO-d6) ~ 8.36 (br s), 7.86-7.75 (m, 2H), 7.53 (dd, J = 8.1 and 2.0 Hz, lH), 6.98 (m, lH), 3.82 (s, 3H).
Part B. 6-Methoxy-2-[4-~2-(1-pyrrolidinyl)ethoxy~-phenyl]benzo[blthiophene.
MeO
CA 02236007 l998-04-27 To a slurry of 6-methoxybenzo[b]thiophene-2-boronic acid (Example 1, Part A) (6.43 g, 30.9 mmol) in 310 mL of benzene was added l-(2-(4-bromophenoxy)ethyl)pyrrolidine (5.80 mL, 28.1 mmol). Upon addition the reaction mixture turned to a yellow homogeneous solution. The reaction ~lask was then co~ered with aluminum foil to keep out light. To this was added 1.07 g (0.92 mmol~ of tetrakis(triphenylphosphine)-palladium(O), followed by 30 mL of 2.0 N sodium carbonate solution. The biphasic mixture was heated at 85 C ~or 3 h with vigorous stirring. The mixture was cooled to 0 C and 175 mL of brine solution was added. The layers were sepa-rated and the a~ueous layer was extracted with 1.0 L of EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure The residue was purified by PrepLC (53:35:2 THF-hexanes-TEA) to afford 5.42 g (15.3 mmol, 55%) of an off-white solid.
mp 151-154 ~C; lH NMR (CDC13) ~ 7.61 (d, J = 8.8 Hz, lH),
A selected novel compound of the above novel compounds is a compound of formula Ia in which A is S, D is CH or N, E is CH or N, R5 is hydrogen, R6 is hydroxy, the group -X2a-(CH2)2-NRaRb is 2-(1-pyrrolidinyl)ethoxy, and the group -X3a-CHR3-CHR3-NRCRd is 3-(1-pyrrolidinyl)propyl, W O 97/25033 PCT~US96/17995 2-(1-pyrrolidinyl3ethoxy, trans-2-(1-pyrrolidinyl)-cyclohexyloxy or trans-2-(1-piperidyl)cyclohexyloxy.
A preferred novel compound of the invention includes one wherein said compound of formula I is one of those described herein at Examples 123, 124 and 164.
A pharmaceutically acceptable salt of an antithrombotic ~1 ~m; ne of the instant invention includes one which is an acid-addition salt made with an acid which provides a ph~rm~ceutically acceptable anion. Thus, an acid additon salt of a novel compound of formula I as provided above made with an acid which affords a ~h~rm~ceutically acceptable anion provides a particular aspect of the invention. Examples of such acids are provided hereinbelow.
As an additional aspect of the invention there is provided a ph~rm~ceutical formulation comprising in association with a ~rm~ceutically acceptable carrier, diluent or excipient, a novel compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions.
In this specification, the following definitions are used, unless otherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl" embraces only the straight chain ("normal") radical, a branched chain isomer such as "isopropyl" being specifically denoted.
It will be appreciated that certain compounds of formula I (or salts or prodrugs, etc.) (such as when R3 is not hydrogen) may exist in, and be isolated in, isomeric forms, including cis- or trans-isomers, as well as optically active, racemic, or diastereomeric forms. It is to be understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses inhibitory properties against thrombin, it being well known in the art how to prepare or isolate particular forms and how to determine inhibitory properties against thrombin by st~n~rd tests including those described below.
In addition, a compound of formula I (or salt or prodrug, etc.) may exhibit polymorphism or may form a solvate with water or an organic solvent. The present invention also encompasses any such polymorphic form, any solvate or any mixture thereo~.
Particular values are listed below for radicals, substituents, and ranges, for illustration only, and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A particular value for a (1-2C)alkyl group is methyl or ethyl; for a (1-3C)alkyl group is methyl, ethyl, propyl or isopropyl; for a (l-4C)alkyl group is methyl, ethyl, propyl, isopropyl or butyl; for a (l-5C)alkyl group is methyl, ethyl, propyl, isopropyl, butyl or pentyl; and for a (1-2C)alkoxy group is methoxy or ethoxy.
A particular value for A2 or A3 when it is a 6-membered ring heteroaromatic divalent radical is pyridin-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, or pyrimidin-2,5-diyl (and more particularly, pyridin-2,5-diyl or pyrazin-2,5-diyl; especially pyridin-2,5-diyl). A particular value for A2 or A3 when it is a 5-membered ring heteroaromatic divalent radical is furan-2,5-diyl, thiophen-2,5-diyl, oxazol-2,5-diyl, thiazol-2,5-diyl, isoxazol-3,5-diyl, isothiazol-3,5-diyl, 1,3,4-oxadiazol-2,5-diyl or 1,3,4-thiadiazol-2,5-diyl (and more particularly, isoxazol-3,5-diyl).
A compound of formula I may be made by processes which include processes known in the chemical art for the production of known compounds of formula I or of structurally analogous compounds or by a novel process described herein.
A process for a novel compound of formula I (or a ph~rm~ceutically acceptable salt thereof), novel processes for a compound of formula I and novel intermediates for the CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/~7995 manufacture of a compound of formula I as de~ined above provide further ~eatures of the invention and are illustrated by the following procedures in which the me~nings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of formula I in which a ~unctional group is protected using a conventional protecting group, then to remove the protecting yroup to provide the compound of formula I.
Thus, there is provided a process for preparing a novel compound of formula I (or a pharmaceutically acceptable salt thereo~) as provided in any of the above descriptions which is selected from:
(A) For a compound of formula I in which xl is ethene-l,l-diyl, methylenation of a corresponding compound of formula I in which xl is carbonyl. The methylenation conveniently is carried out using methylidenetriphenyl-phosphorane generated in situ from methylidenetriphenyl-phosphonium bromide and a strong base such as potassium tert-butoxide in an inert solvent such as tetrahydrofuran in a manner similar to that described in Example 12, Part A, for the preparation of an int~rme~l~te compound.
(B) For a compound of formula I (or formula Ia or formula Ib) in which xl is methylene, reductive removal of the hydroxy group of a corresponding alcohol of formula II
(or formula IIa or formula IIb).
Rl ~ ~ CH(OH)-A3-X3-(CH2)~-(CHR3-CHR3)r- ~ CRd A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb II
W O 97/25033 PCT~US96/17995 R CH(OH) ~ X3~ CHR3-CHR3-~nR'Rd R6 A ~ IIa D/~ X2a - ( CH 2 ) 2 _NRa Rb R~' CH ( OH ) Q CH2--NRC Rd R6 A ~ IIb X2b-(CH2)2- ~ aRb The reductive removal conveniently is carried out using sodium borohydride in trifluoroacetic acid in a manner similar to that described in Example 2, Part D, or using triethylsilane in trifluroracetic acid in a manner similar to that described in Example 3, Part E. An intermediate alcohol of formula II (or formula IIa or formula IIb) provides an additional feature of the inventioni it may be obtained by reducing the carbonyl group of a corresponding ketone of formula I (or formula Ia or formula Ib) in which xl is carbonyl, for example by using lithium aluminium hydride in tetrahydrofuran in a manner similar to that described in Example 2, Part D, or Example 3, Part E or by using diisobutylaluminium hydride in tetrahydrofuran in a manner similar to that described in Example 32, Part A.
(C) For a compound of formula I in which A is O or S and Xl is carbonyl, acylation of a corresponding compound of formula III
R1 ~ A ~1, A2_X2_(CH2) j - ( CHR2 ) k - ( CH2 ) m-~RaRb III
with an activated derivative of a corresponding acid of formula IV.
W O 97/25033 PCT~US96/I7995 HooC-A3-X3-(CH2)~-(CHR3-CHR3)r~NRCRd IV
Conveniently, the acylation is carried out using the hydrochloride salt of the acid chloride of the acid formula IV and a catalyst such as aluminium chloride in a manner s;m~l~r to that described in Example 1, Part C or titanium tetrachloride in a manner similar to that described in Example 2, Part C.
~ D) For a compound of formula I in which A is -CH=CH-, selective dehydrogenation of a corresponding compound in which A is -CH2-CH2-, for example using 2,3-dichloro-5,6-dicyano-1,4-benzo~uinone (DDQ) at 50 ~C to 100 ~C in an inert solvent such as dioxane.
(E) For a compound of formula I in which A is -CH2-CH2- and x2 is carbonyl, condensation o~ a corresponding compound of formula V
C ( O ) -A3 -X3 - ( CH2 ) q - ~ CHR3 -CHR3 ) r -NRCRd Rl 0~0PO (OC6H5 )2 V
with a corresponding reagent of formula VI;
Br-Mg-A2-X2-(CH2);-(CHR2)k-(CH2)m-NRaRb VI
for example, in an inert solvent such as tetrahydrofuran at about O ~C.
(F) For a compound of formula I in which Xl is 0, cross coupling a corresponding compound of formula VII
Rl ~ O A3--X3--( CH2 ) q - ( CHR3--C~IR3 ) r -NRCRd VII
with a corresponding boronic acid of formula VIII;
(H0)2B-A2-X2-(CH2)j-(CHR2)k-(CH2~m-NRaRb VIII
for example, using a similar procedure to that described in Example 11, Part D for the preparation of an int~rme~;ate compound in which A is S.
WO 97/2~033 PCT~US96/17995 (G) For a compound of formula I in which Xl is O
or S, treatment of a corresponding organolithium compound of formula IX Li Rl ~ ~ A ~ ( A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb IX
with a corresponding disulfide of formula X;
(-S-A3-X3-(CH2)q-(CHR3-CHR3)r-NRCRd)2 X
for example, using a similar procedure to that described in Example 10, Part B for the preparation of an intermediate compound in which A is S.
(H) For a compound of formula I in which Rl or a substituen~ on A2 or A3 is hydroxy, removal of the O-methyl group of a corresponding compound of formula I in which Rl or a substituent on A2 or A3 is methoxy. The removal may be carried out by any conventional manner consistent with the structure of the compound of formula I, for example, using aluminium chloride and ethanethiol in an inert solvent as described in Example 1, Part D.
(I) For a compound of formula I in which x2 is O
or S, alkylation at x2 of a corresponding compound of formula XI
Rl ~ ~ Xl-A3-X -(CH2)q~(CHR3~CHR~)~~NRCRd XI
in which x2 is O or S with a corresponding compound of formula XII
L-(CH2)j-(CHR2)k-(CH2)m-NRaRb XII
in which L denotes a leaving group. It may be preferred to generate the leaving group of the compound of formula XII in si tu from the corresponding hydroxy compound and perform the W O 97/25033 PCTrUS96/17995 alkylation under Mitsunobu conditions using triphenyl-phosphine and diethyl azodicarboxylate in an inert solvent, ~or example, as described in Example 4, Part B for the preparation of an int~rm~'ate compound. Alternatively, a compound o~ ~ormula XII in which L is chloro, bromo, iodo or a sulfonate, such as methanesul~onate or p-toluenesul~onate, may be used, preferably in conjunction with a base such as cesium carbonate, using a similar procedure to that described in Example 3, Part D, ~or example as described in Example 5, Part C.
(J) For a compound o~ ~ormula I in which X3 is O
or S, alkylation at X3 o~ a corresponding compound of formula XIII
Xl-A3-X3-H
Rl ~ A ~ A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XIII
in which X3 is O or S with a corresponding compound of formula XIV
L-(CH2)q-(CHR3-CHR3)r-~DRCRd XIV
in which L denotes a leaving group as defined above. It may be preferred to generate the leaving group of the compound o~
formula XIV from the corresponding hydroxy compound and to per~orm the alkylation under Mitsunobu conditions as described above. Alternatively, L may have any of the values described above for L, and the alkylation may be carried out using a similar procedure to that described in Example 3, Part D.
(K) For a compound o~ formula I in which x2 and X3 are O or ~ and in which -(CH2)j-(CHR2) k-(CH2)m-NRaR~ is the same as -(CH2)q-(CHR3-CHR3)r-NRCRb, dialkylation of a compound of formula XV
CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 xl-A3_X3_H
R1 ~ A~A2 _X2-H
with a compound of formula XII. The dialkylation may be t carried out as described above for the alkylation of a compound of formula XI or formula XIII, for example as 5 described in Example 8, Part D or Example 10, Part D.
(L) Eor a compound of formula I in which Rl is carbamoyl, aminolysis of a corresponding intermediate compound of formula I in which~Rl is a lower alkoxy-carbonyl group, such as a methoxy-carbonyl group. The aminolysis is 10 conveniently carried out using anhydrous ammonia in a lower alcohol under pressure, for example, as described in Example 30, Part E.
~M) For a compound of formula I in which Rl or a substituent on A3 or the value of -X3-(CH2)Ca-(CHR3-CHR3) r-15 NRCRb is aminomethyl, reduction of an int~rme~ate compound corresponding to a compound of formula I but in which Rl is cyano or of a corresponding compound of formula I in which a substituent on A3 is cyano or of an int~rmeAiate compound corresponding to a compound of formula I but in which -X3-(CH2)Ca-(CHR3-CHR3)r-NRCRb is cyano. The reduction conveniently is carried out using lithium aluminium hydride in tetrahydrofuran, for example as described in Example 31, Part D for the preparation of an intermediate alcohol of formula II in which Rl is aminomethyl or as described in Example 162.
(N~ For a compound of formula I in which Rl or R2 is hydroxymethyl, reduction of a corresponding intermediate compound of formula I in which Rl or R2 is a lower alkoxy-carbonyl group, such as a methoxy-carbonyl group. The reduction is conveniently carried out using diisobutyl-aluminium hydride in toluene and tetrahydrofuran, for example, as described in Example 32, Part A for the preparation of an intermediate alcohol of formula II in which Rl is hydroxymethyl or as described in Example 168.
W O 97/25033 PCT~US96/17995 (O) For a compound of ~ormula I in which A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 and X3 is 0, displacement of the leaving group L of a corresponding compound o~ ~ormula XVI, R1 ~A~A2 -X2-(CM2)j-~CHR2) k -(CH2)m-NRaRb ~I
in which L is defined as above, with an alkali metal alkoxide of an alcohol of formula XVII, HO-(CH2)q~(CHR3-CHR3)r-NRCRd XVII
for example with the sodium alkoxide. The reaction is conveniently carried out with a compound of formula XVI in which L is chloro and the sodium alkoxide derived from an alcohol of formula XVII using conditions described in Example 9, Part B and further illustrated in Example 33, Part B.
(P) For a compound of formula I in which A3 bears a (l-4C)alkyl substituent, substitution of the bromo group of a corresponding compound of formula I in which A3 bears a bromo substituent. The substitution is conveniently carried out using a tetralkyltin reagent and a palladium(O) catalyst in an inert solvent, for example as described in Example 8, Part B for the preparation of an int~rme~;ate compound.
(Q) For a compound of formula I in which xl is carbonyl, con~n.~ation of a corresponding organolithium compound of formula IX with a derivative of a corresponding acid of formula IV which will provide a ketone upon condensation. Derivatives of an acid of formula rv which will provide a ketone upon condensation include the lithium salt of the acid, corresponding amides such as the N-methoxy-N-methyl amide, and the corresponding nitrile. The condensation is typically carried out in an inert, aprotic solvent, for example tetrahydro~uran, at or below ambient temperature.
W O 97/2~033 PCT~US96/17995 (R) For a compound of formula I in which xl is carbonyl, condensation of a corresponding organolithium compound of formula XVIII
Li-A3-X3-(CH2)q-(CHR3-CHR3)r-NRCRd XVIII
with a derivative of a corresponding acid of formula XIX
COOH
Rl ~ A A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XIX
which will provide a ketone upon condensation. Derivatives of an acid of formula XIX which will provide a ketone upon condensation include the lithium salt of the acid, corresponding amides such as the N-methoxy-N-methyl amide, and the corresponding nitrile. The reaction is typically carried out as described above in procedure (Q).
(S) For a compound of formula I in which A is -CH=CH- and xl is methylene, elimination of water from a corresponding compound of formula II in which A is -CH2-CH2-.
The elimination conveniently is effected using an acid catalyst, for example by heating the compound of formula II in a solution of anhydrous ethanolic HCl.
(T) For a compound of formula I in which A is S and xl is carbonyl, condensation of a compound of formula XXV
C(o)-A3-X3-(CH2)~-(CHR3-CHR3)r-NRCRd Rl ~ S N(CH3)2 XXV
with a corresponding reagent of formula VI. The condensation conveniently is carried out in an inert solvent such as tetrahydrofuran at about 0 ~C, for example as described in Example 34, Part B.
(U) Alkylation of an amine of formula HNRaRh with a compound of formula XXVI
wo 97/25033 PCT~US96/17995 Rl ~ Xl -A3--X 3 - ( CH 2 ) q--( CHR3 - CHR 3 ) r-NR CRd A2 _x2_ (CH2 ) j- (CHR2 ) k- (CH2 ) m-L XXVI
w]lerein L is a leaving group as defined above, or ~or a compound of formula I in which R2 is OH, wherein L and R2 form an epoxide. Conveniently, the alkylation is carried out by heating the reagents in a polar solvent, for example as described in Example 43, Part C or in Example 116, Part B.
(V) Alkylation of an amine of formula HNRCRd with a compound of formula XXVII
Rl ~ xl -A3-X3- (CH2 ) q- (CHR3-CHR3 ) r-L
A A2 _x2 _ ( CH 2 ~ j--( CHR2 ) k--( CH 2 ) m--NR aRl' XXVI I
wherein L is a leaving group as defined above. Conveniently, the alkylation is carried out by mixing the reagents in a polar solvent, for example as described in Example 129, Part C.
(W) For a compound of formula I in which X1 is carbonyl (particularly wherein A3 is unsubstituted or substituted para-phenylene) and X3 is imino, O, S or -N(Rh)-, substitution of the group Z wherein Z is fluoro or nitro (particularly wherein Z is fluoro) of a ketone of formula XXVIII
R1 ~ A ~-X2-(CH2)j- ( CHR2 ) k - ( CH2 ) m~NR R XXVIII
using a compound of formula XXIX, H-X3- (CH2 ) q- (CHR3-CHR3 ) r-NRCRd XXIX
or a metal salt thereof, pre~erably an alkali metal salt.
Conveniently, the substitution reaction is carried out by heating the reagents XXVIII and XXIX in dimethylformamide or tetrahydrofuran using sodium hydride or potassium carbonate, W O 97/2~033 PCTnJS96/17995 for example as illustrated in Example 59, Part B; in Example 121, Part B; in Example 145, Part C; in Example 147 or in Example 117, Part D for the preparation of an intermediate o~
formula XXV.
(X) For a compound of formula I in which a substituent on ~3 is amino, reduction of a corresponding compound of formula I in which a substituent on A3 is nitro.
The reduction may be carried out using a conventional method, for example by catalytic hydrogenation as described in Example ~7.
(Y) For a compound of formula I in which a substituent on A3 is -NHC(O)Rf or -NHS(O)2Rg, substitution of the amino group of a corresponding compound of formula I in which a substituent on A3 is amino using an activated derivative of an acid of formula HO~(O)Rf or HOS(O)2Rg.
Conveniently, the activated derivative is the acid anhydride or the acid chloride, and the substitution is carried out in a polar solvent, for example as in Example 111 or Example 113.
(Z) For a compound of formula I in which a substituent on A3 is -NHCH2Rf or a compound of formula I in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb t~rm; n~ tes in -CH2-NRaRb~
reduction of the amide of a corresponding compound of formula I
in which a substituent on A3 is -NHC(O)Rf or of an intermediate compound corresponding to a compound of formula I but in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb term; n~ tes in -C(O)NRaRb. The reduction conveniently is carried out using lithium alllm;n1lm hydride in tetrahydro~uran, ~or example as described in Example 112 or Example 166, Part E.
(AA) For a compound of formula I in which X3 is ethene-1,2-diyl, reduction of the triple bond of a corres-ponding compound of formula I in which X3 is ethyne-1,2-diyl.
For a compound of formula I in which the double bond is trans-, the reduction conveniently is effected using diisobutylall]m;nllm hydride as described in Example 130; ~or a compound of ~ormula I in which the double bond is cis-, the reduction conveniently is effected using hydrogenation over a Lindlar catalyst as ~escribed in Example 131.
W O 97/25033 PCT~US96/17995 (AB) For a compound of :Eormula I in which a substituent on A3 is cyano, substitution of the halo group of a - corresponding compound of formula I in which a substituent on A3 is bromo or iodo. The substitution conveniently is ef~ected by heating the compound with cuprous cyanide in a polar solvent such as l-methyl-2-pyrrolidinone as described in Example 161, Part A.
Whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group.
Wherea~ter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it may be obtained by reacting the basic form of such a compound of ~ormula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
A particular process of the invention is one selected from procedures (A)-(R) above for a novel compound of formula I wherein A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical cont~;n;ng 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical cont~;n;ng one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent;
W O 97/25033 PCT~US96/17995 R1 deno~es 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
xl is O, S, methylene, carbonyl or ethene~ diyl;
x2 is a direct bond, methylene, O or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; ~ is 0, 1 or 2; and r is ~ or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyl~ne; m; no or 1-imidazolyl;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; xl is carbonyl; ~2 is O; the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q-(CHR3-CHR3)r-is ethylene; and Rc and Rd are independently ~1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino whereafter, for any of the procedures (A)-(R), when a pharmaceutically acceptable salt of a compound of formula I
is re~uired, it is obtained by reacting ~he basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
As mentioned above, a compound corresponding to a compound of ~ormula I but in which a ~unctional group is protected may serve as an int~rm~;ate for a compound o~
formula I. Accordingly, such protected intermediates for a ~ novel compound of formula I provide further aspects of the invention. Thus, as one particular aspect of the invention, there is provided a compound corresponding to a novel compound of formula I as defined above and bearing at least one substiutent R1 which is hydroxy, but in which the corresponding substituent is -O~P in place of hydroxy, wherein RP is a phenol protecting group other than methyl.
Phenol protecting groups are well known in the art, for example as described in T.W Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis" (1991). Particular values of RP include, for example, benzyl (for example as described in Example 41 or Example 81) and allyl (for example as described in Example 88). Further, RP may denote a functionalized resin, for example as disclosed in H.V. Meyers, et al., Molecular Diversitv, (1995), 1, 13-20.
As mentioned above, the invention includes pharmaceutically acceptable salts of the thrombin inhibiting compounds defined by the above formula I. A particular ~1 ~m; ne of this invention possesses one or more sufficiently basic functional groups to react with any of a number of inorganic and organic acids affording a physiologically acceptable counterion to form a pharmaceutically acceptable salt. Acids c~onl y employed to form pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the li~e, and organic acids such as ~-toluene sulfonic, methanesulfonic acid, oxalic acid, ~-bromo phenyl sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid.
If not commercially available, the necessary starting materials for the preparation of a compound of formula I may be prepared by procedures which are selected from stAn~d techniques of organic chemistry, including aromatic and heteroaromatic substitution and transformation, from techniques which are analogous to the syntheses of known, structurally similar compounds, and techniques which are analogous to the above described procedures or procedures described in the Examples. It will be clear to one skilled in the art that a variety of sequences is available for the preparation of the starting materials. Starting materials which are novel provide another aspect of the invention.
As noted above in procedure (B), an intermediate alcohol of formula II may be obtained by reduction of a corresponding ketone of formula I. In addition, an alcohol of formula II may be obtained by condensation of an organolithium compound of formula IX with a corresponding aldehyde of formula XX
H-C(O)-A3-X3-(CH2)q~(CHR3-CHR3)r-NRCRd XX
using a procedure similar to that described in procedure (Q) or by condensing an organolithium compound of formula XVIII
with a corresponding aldehyde of formula XXI
W O 97/25033 PCT~US96/17995 CHO
R~
A ~ A2-X2-(CH2)~-(CHR2)k-(CH2)m-NRaR~ XXI
using a procedure similar to that described in procedure (R), particularly when j and k are both 0.
An int~rme~;ate of formula III may be prepared by any of a number of known procedures. A preferred method for a compound of formula III in which A is S, particularly when j and k are both 0, is the cross coupling of a boronic acid o~ formula XXII
Rl ~ S B(OH)2 XXII
with a reagent of ~ormula XXIII
X-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb XXIII
in which X is, for example, bromo, iodo or trif~uoromethane-sulfonate, for example as described in Examples 1, 2, 4 and 16. For preparation of a compound of formula III in which A
is O, a preferred method is a copper mediated cross coupling of a compound of formula XXIII and a 2-metalated benzofuran, such as described in Example 119, Part A. It may be preferred to cross couple a species in which the side chain is not fully elaborated, then to complete the elaboration, for example as described in Example 14 and in Example 119.
Starting material acids of formula IV may be prepared by a number of st~n~rd procedures, a number of which are described in the Examples.
Starting material enol phosphates of formula V may be prepared and used by methods similar to those described in Jones et al., J. Med. Chem. (1992), 35~5), 931-938; and the correspon~;ng reagents of formula VI may be obtained by conventional methods from bromides of formula XXIII in which X is bromo.
W O 97/25033 PCT~US96/17995 A starting material iodide of formula VII in which A is S may be prepared in a manner similar to that described in Example 11, parts A and ~, and the boronic acid of ~ormula VIII may be obtained ~rom a compound o~ formula XXIII using a procedure similar to that of Example 11, part C.
An organolithium compound of formula IX may be prepared by transmetallation of the corresponding bromide, which itself may be obtained by bromination of the compound corresponding to formula IX, but with hydrogen in the place o~ lithium. For a compound in which A is S, the procedure may be carried out in a manner similar to that described in Example 10, parts A and B.
A starting material of formula XI in which x2 is O
or S may be obtained by deprotection of x2 o~ a corresponding compound in which x2 bears a protecting group. When x2 is O, it may be protected as a silyl ether, as described in Example 29, or as a methyl ether as described in several of the examples and cleaved by a variety of methods including by using pyridine hydrochloride (Example 5), all~m;nllm chloride and ethanethiol (Examples 9, 13, 15, 17, 18, 24, 26 and 28, part C), or boron tribromide (see below).
A starting material o~ ~ormula xIII in which X3 is O or S may be obtained by deprotection of X3 of a corresponding compound in which X3 bears a protecting group.
For example, when X3 is O, it may be protected as a methyl ether and liberated by treatment with sodium thioethoxide (Example 28, part A), aluminum chloride and ethanethiol, or pyridine hydrochloride, depending upon the groups present in other parts o~ the molecule.
A starting material o~ ~ormula XV in which x2 and X3 are O or S may be obtained by deprotection of x2 and X3 of a corresponding compound in which x2 and X3 bear protecting groups. ~or example, when x2 and X3 are both O, they may both be protected as methyl ethers and simultaneously deprotected by treatment with alllminl~m chloride and ethane-thiol (Example 3) with boron tribromide (Examples 8 and 10) or with pyridine hydrochloride (Examples 11 and 12).
-W O 97/25033 PCT~US96/1799 A starting material compound of formula XXV
typically is prepared by acylation of a compound of formula XXIV
Rl ~ S ~ N(CH3)2 XXIV
with an activated derivative of an acid of formula VI, conveniently the acid chloride, for example as described in Example 39, Part B.
Selective methods of protection and deprotection are well known in the art for preparation of compounds such as those of formula XI, XIII and XV discussed above. Selective methods for cleavage of methyl ethers, as described in the examples, are discussed in Jones, et al , J. Med. Chem., (1~84), 27, 1057-1066. For example, the diether 3-(4-methoxybenzoyl)-2-(4-methoxyphenyl)benzo[b]thiophene described at Example 3, part B, may be treated with boron tribromide in dichloromethane at -10 ~C (1 hour) to afford the monoether 2-(4-hydroxyphenyl)-3-(4-methoxybenzoyl)benzo[b]thiophene, whereas treatment with sodium thioethoxide (Example 28, part A) affords the isomeric monoether 3-(4-hydroxybenzoyl)-2-(4-methoxyphenyl)benzo[b]-thiophene. Treatment with boron tribromide under less mildconditions (0~, 6 hours, see Example 8, part C) or with aluminum chloride and ethanethiol cleaves both ethers (Example 3, part C).
The compounds of the invention are isolated best in the form of acid addition salts. Salts of the compounds of formula I formed with acids such as those mentioned above are useful as pharmaceutically acceptable salts for administration of the antithrombotic agents and for preparation of formulations of these agents. Other acid addition salts may be prepared and used in the isolation and purification of the compounds.
As noted above, the optically active isomers and diastereomers of the compounds of formula I are also considered part of this invention. Such optically active W O 97~5033 PCTAJS96/17995 isomers may be prepared ~rom their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by st~n~rd methods affords substantially optically pure isomers of the compounds of the present invention or their precursors. Further details regarding resolutions can be obtained in Jac~ues, et al., ~n~ntiomerS, Racemates, and Resolutions, John Wiley & Sons, 1981.
The compounds of the invention are believed to selectively inhibit thrombin over other proteinases and nonenzyme proteins involved in blood coagulation without appreciable interference with the body's natural clot lysing ability (the compounds have a low inhibitory effect on fibrinolysis). Further, such selectivity is believed to permit use with thrombolytic agents without substantial interference with thrombolysis and fibrinolysis.
The invention in one of its aspects provides a method of inhibiting thrombin in m~mm~l S comprising ~m;ni stering to a m~mm~l in need of treatment an effective (thrombin inhibiting) dose of a compound of formula I.
In another of its aspects, the invention provides a method of treating a thromboembolic disorder comprising administering to a m~mm~l in need of treatment an effective (thromboembolic disorder therapeutic and/or prophylactic amount) dose of a compound of formula I.
The invention in another of its aspects provides a method of inhibiting coagulation in m~mm~l s comprising administering to a m~mm~l in need o~ treatment an effective (coagulation inhibiting) dose of a compound of formula I.
The thrombin inhibition, coagulation inhibition and thromboembolic disorder treatment contemplated by the present method includes both medical therapeutic and/or prophylactic treatment as appropriate.
W O 97/25033 PCT~US96/17995 In a further embodiment the invention relates to treatment, in a hum~an or animal, of conditions where inhibition of thrombin is required. The compounds of the invention are expected to be useful in ~n;m~l s, including man, in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility are in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility, in treatment and/or prophylaxis, include venous thrombosis and pulmonary embolism, arterial thrombosis, such as in myocardial ischemia, myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis. Further, the compounds have expected utility in the treatment or prophylaxis of atherosclerotic disorders (diseases) such as coronary arterial disease, cerebral arterial disease and peripheral arterial disease. Further, the compounds are expected to be useful together with thrombolytics in myocardial infarction. Further, the compounds have expected utility in prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations. Further, the compounds have expected utility in prevention of rethrombosis after microsurgery. Further, the compounds are expected to ~e use~ul in anticoagulant treatment in connection with artificial organs and cardiac valves.
Further, the compounds have expected utility in anticoagulant treatment in hemodialysis and disseminated intravascular coagulation. A further expected utility is in rinsing of catheters and m~ n;cal devices used in patients in vivo, and as an anticoagulant for preservation of blood, plasma and other blood products in vitro. Still further, the compounds have expected utility in other diseases where blood coagulation could be a flln~m~ntal contributing process or a source of secondary pathology, such as cancer, including metastasis, inflammatory diseases, including arthritis, and diabetes. The anti-coagulant compound is a~in;stered orally or parenterally, e.g. by intravenous infusion (iv), intramuscular injection (im) or subcutaneously (sc).
The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound ~m;n;stered, the rate of ~m;n;stration, the route of A~m;n;stration, and the condition being treated.
A typical daily dose for each of the above utilities is between about 0.01 mg/kg and about 1000 mg/kg.
The dose regimen may vary e.g. for prophylactic use a single daily dose may be administered or multiple doses such as 3 or 5 times daily may be appropriate. In critical care situations a compound of the invention is administered by iv infusion at a rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferably between about 0.1 mg/kg/h and about 5 mg/kg/h.
The method of this invention also is practiced in conjunction with a clot lysing agent e.g. tissue pl ~-~m; nogen activator (t-PA), modified t-PA, streptokinase or urokinase.
In cases when clot formation has occurred and an artery or vein is blocked, either partially or totally, a clot lysing agent is usually employed. A compound of the invention can be ~m; n; stered prior to or along with the lysing agent or subsequent to its use, and preferably further is administered along with aspirin to prevent the reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with a platelet glycoprotein receptor (IIb/IIIa) antagonist, that inhibits platelet aggregation. A compound o~ the invention can be ~dm;n;stered prior to or along with the IIb/IIIa antagonist or subsequent to its use to prevent the occurrence or reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with aspirin. A compound of the invention can be A~ml n; stered prior to or along with aspirin or subsequent to WO 9712S033 PCT~US96~17995 its use to prevent the occurrence or reoccurrence of clot formation. As stated above, preferably a compound of the present invention is administered in coniunction with a clot lysing agent and aspirin.
This invention also provides ph~rm~ceutical formulations for use in the above described therapeutic method. Pharmaceutical formulations of the invention comprise an effective thrombin inhibiting amount of a compound of formula I in association with a ph~rm~ceutically acceptable carrler, excipient or diluent. For oral administration the antithrombotic compound is formulated in gelatin capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like.
For parenteral administration the antithrombotic is formulated in a pharmaceutically acceptable diluent e.g.
physiological saline (0.9 percent), 5 percent dextrose, Ringer's solution and the like.
The compound of the present invention can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg. Preferably the compound is in the form of a pharmaceutically acceptable salt such as for example the sulfate salt, acetate salt or a phosphate salt. An example of a unit dosage formulation comprises 5 mg of a compound of the present invention as a ~rm~ceutically acceptable salt in a 10 ml sterile glass ampoule. Another examp~e of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a ph~rm~ceutically acceptable salt in 20 ml of isotonic saline contained in a sterile ampoule.
The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds of the present invention are preferably formulated prior to administration. Another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a novel compound of formula I or a pharmaceutically acceptable salt or solvate thereof in association with a ph~rmAceutically acceptable carrier, diluent or excipient therefor.
The active ingredient in such formulations comprises ~rom 0.1 percent to 99.9 percent by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients o~ the formulation and not deleterious to the recipient thereof.
The present ~rm~ceutical formulations are prepared by known procedures using well known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form o~ a capsule, sachet, paper or other cont~; ner . When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
The following formulation examples are illustrative only and are not intended to llmit the scope of the invention in any way. "Active ingredient," of course, means a compound according to Formula I or a ~hArmAceutically acceptable salt or solvate thereof.
Formulation 1: Hard gelatin capsules are prepared using the following ingredients:
W O 97/2~033 PC~US96/17995 Quantity (mq/ca~sule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Formulation 2: A tablet is prepared using the ingredients below:
Quantity (ma/tablet) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.
Formulation 3: An aerosol solution is prepared cont~;n;ng the following components:
Weiaht Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)70.00 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 ~C and transferred to a filling device. The re~uired amount is then fed to a stainless steel container and diluted with the r~m~;n~er of the propellant. The valve units are then fitted to the container.
Formulation 4: Tablets, each cont~;n;ng 60 mg of active ingredient, are made as follows:
Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10 % solution in water~ 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 ma Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution cont~;n;n~ polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50 ~C and passed through a No. 18 mesh U.S.
Sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation 5: ~apsules, each cont~;n;ng 80 mg of active ingredient, are made as follows:
Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnes iUm.~ S tearate2 mq Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Formulation 6: Suppositories, each cont~;n;ng 225 mg of active ingredient, are made as ~ollows:
Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mq Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the m;n;mllm heat necessary. The mixture is then poured into a suppository mold of nomi n;31 2 g capacity and allowed to cool.
W O 97/25033 PCT~US96/1799 Formlllation 7: Suspensions, each cont~;n;ng 50 mg of active ingredient per 5 ml dose, are made as follows:
Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg ~ Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.
Color q.v.
Puri~ied water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to ~orm a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
Formulat;on 8: An intravenous ~ormulation may be prepared as ~ollows:
Active ingredient 100 mg Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate o~ 1 ml per minute.
The ability of the compounds of the present invention to be an ef~ective and orally active thrombin inhibitor are evaluated in one or more of the following assays.
The compounds provided by the invention (formula I) selectively inhibit the action of thrombin in m~mm~ls~ The inhibition of thrombin is demonstrated by in vitro inhibition of the amidase activity of thrombin as measured in an assay in which thrombin hydxolyzes the chromogenic substrate, N-benzoyl-L-phenylalanyl-L-valyl-L-arginyl-p-nitroanilide, N-benzoyl-L-Phe-L-Val-L-Arg-p-nitroanilide.
The assay is carried out by mixing 50 ~l buf~er (0.03M Tris, 0.15M NaCl, pH 7.4) with 25 ~l o~ human thrombin solution ~purified human thrombin, Enzyme Research Laboratories, South Bend, Indiana~ at 8 NIH units/ml) and 25 WO 97125033 PCT~US96/17995 ~l of test compound in a solvent (50% aqueous methanol (v:v)). Then 150 ~l of an aqueous solution of the chromogenic substate (at 0.25 mg/ml) are added and the rates of hydrolysis of the substrate are measured by monitoring the reactions at 405 nm for the release of p-nitroaniline.
Standard curves are constructed by plotting free thrombin concentration against hydrolysis rate. The hydrolysis rates observed with test compounds are then converted to "free thrombin" values in the respective assays by use of the standard curves. The bound thrombin (bound to test compound) is calculated by subtracting the amount of free thrombin observed in each assay from the known initial amount of thrombin used in the assay. The amount of free inhibitor in each assay is calculated by subtracting the number of moles of bound thrombin from the number of moles of added inhibitor (test compound).
The Kass value is the hypothetical e~uilibrium constant for the reaction between thrombin and the test compound (I).
Thrombin + I ' Thrombin-I
Kass= ~Thrombin-I]
t(Thrombin) x (I)]
Kass is calculated for a range of concentrations of test compounds and the mean value reported in units of liter per mole. In general, a thrombin inhibiting compound of f~rmllla I
of the instant insertion exhibits a Kass of 0.03 X 106 L/mole or much greater. For example, the compound of Example 3 was found to have a Kass of 5.0 X 106 L/mole, and the compound of Example 164 was found to have a Kass of 526 X 106 L/mole.
By substantially following the procedures described above for human thrombin, and using other human blood coagulation system serine proteases and using fibrinolytic system serine proteases, with the appropriate chromogenic substrates, identified below, the selectivity of the compounds of the present invention with respect to the coagulation factor serine proteases and to the fibronolytic , W O 97/25033 PCT~US96/1799 serine proteases are evaluated as well as their substantial lack of interference with human plasma clot fibrinolysis.
~ Human factors X, Xa, IXa, XIa, and XIIa are purchased from Enzyme Research Laboratories, South Bend, - 5 Indiana; human urokinase from Leo Pharmaceuticals, Denmark;
and recombinant activated Protein C (aPC) is prepared at Eli Lilly and Co. substantially according to U.S. Patent 4,981,952. Chromogenic substrates: N-Benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide (for factor Xa); N-Cbz-D-Arg-Gly-Arg-p-nitroanilide (for factor IXa assay as the factor Xasubstrate); Pyroglutamyl-Pro-Arg-p-nitroanilide (for Factor XIa and for aPC); H-D-Pro-Phe-Arg-p-nitroanilide (for factor XIIa); and Pyroglutamyl-Gly-Arg-p-nitroanilide (for urokinase); are purchased from Kabi Vitrum, Stockholm, Sweden, or from Midwest Biotech, Fishers, Indiana. Bovine trypsin is purchased from Worthington Biochemicals, Freehold, New Jersey, and human plasma kallikrein from Kabi Vitrum, Stockholm, Sweden. Chromogenic substrate H-D-Pro-Phe-Arg-p-nitroanilide for plasma kallikrein is purchased from Kabi Vitrum, Stockholm, Sweden. N-Benzoyl-Phe-Val-Arg-p-nitroanilide, the substrate for human thrombin and for trypsin, is synthesized according to procedures described above for the compounds of the present invention, using known methods of peptide coupling from commercially available reactants, or purchased from Midwest Biotech, Fishers, Trl~; ~n;~ .
Human plasmin is purchased from Boehringer Mannheim, In~;~nApolis, Indiana; nt-PA is purchased as single chain activity reference from American Diagnostica, Greenwich, Connecticut; modified-t-PA6 (mt-PA6) is prepared at Eli Lil~y and Company by procedure known in the art (See, Burck, et al., J. Biol. Chem., 265, 5120-5177 (1990).
Plasmin chromogenic substrate H-D-Val-Leu-Lys-p-nitroanilide and tissue pl~m;nogen activator (t-PA) substrate H-D-Ile-Pro-Arg-p-nitroanilide are purchased from Kabi Vitrum, Stockholm, Sweden.
W O 97/25033 PCT~US96/17995 In the chromogenic substrates described above the three-letter symbols Ile, Glu, Gly, Pro, Arg, Phe, Val, ~eu and Lys are used to indicate the corresponding amino acid group isoleucine, glutamic acid, glycine, proline, arginine, phenylalanine, valine, leucine and lysine, respectively.
Thrombin inhibitors preferably should spare ~ibrinolysis induced by urokinase, tissue plasminogen activator (t-PA) and steptokinase. This would be important to the therapeutic use o~ such agents as an adjunct to streptokinase, t-PA or urokinase thrombolytic therapy and to the use o~ such agents as an endogenous fibrinolysis-sparing (with respect to t-PA and urokinase) antithrom~otic agents.
In addition to the lack o~ interference with the amidase activity of the ~ibrinolytic proteases, such fibrinolytic system sparing can be studied by the use of human plasma clots and their lysis by the respective fibrinolytic plasminogen activators.
Materi~1s Dog plasma is obtained from conscious mixed-breed hounds (either sex Hazelton-LRE, ~ m~7.oo/ Michigan, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from fresh dog plasma and human fibrinogen is prepared ~rom in-date ACD human blood at the fraction I-2 according to previous procedures and specifications. Smith, Biochem ~., 185, 1-11 (1980); and Smith, et al., R;och~m;strv, 11, 2g58-2~67, (1972). Human ~ibrinogen (98 percent pure/plasmin ~ree) is from American Diagnostica, Greenwich, Connecticut. Radiolabeling o~ fibrinogen I-2 preparations is per~ormed as previously reported. Smith, et al., Biochemistry, 11, 2958-2967, (1972~. Urokinase is purchased ~rom Leo Pharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase is purchased from Hoechst-Roussel Pharmaceuticals, Somerville, New Jersey.
W O 97~5033 PCT~US96/17995 Methods - Ef~cts on Lvsis of Human Plasma Clots bv t-PA
Human plasma clots are formed in micro test tubes by adding 50 ~L thrombin (73 NIH unit/mL~ to 100 ~L human plasma which contains 0.0229 ~i 125-iodine labeled fibrinogen. Clot lysis is studied by overlaying the clots with 50 ~L of urokinase or streptokinase (50, 100, or 1000 unit/mL) and incubating for 20 hours at room temperature. After incubation the tubes are centrifuged in a Beckman Microfuge.
25 ~L of supernate is added into 1.O mL volume of 0.03 M
tris/0.15 M NaCl buffer for gamma counting. Counting controls 100 percent lysis are obtained by omitting thrombin (and substituting buf~er). The thrombin inhibitors are evaluated for possible interference with fibrinolysis by including the compounds in the overlay solutions at 1, 5, and 10 ~gJmL concentrations. Rough approximations of ICso values are estimated by linear extrapolations from data points to a value which would represent 50 percent of lysis for that particular concentration of fibrinolytic agent.
Anticoaaulant Activitv ~aterials Dog plasma and rat plasma are obtained from conscious mixed-breed hounds (either sex, hazelton-LRE, Kalamazoo, Michigan, U.S.A.) or from anesthetized male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis, Indiana, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from in-date ACD human blood as the fraction I-2 according to previous procedures and specifications. Smith, Blochem. J., 185, 1-11 (1980); and Smith, et al , Bioch~;strv, 11, 2958-2967 (1972). Human fibrinogen is also purchased as 98 percent pure/plasmin free from American Diagnostica, Greenwich, Connecticut. Coagulation reagents Actin, Thromboplastin, Innovin and Human plasma are from Baxter Healthcare Corp., Dade Division, Miami, Florida.
Bovine thrombin from Parke-Davis (Detroit, Michigan) is used for coagulation assays in plasma.
W O 97/25033 PCT~US96/17995 Methods ~ntiCoaqulation Determinations Coagulation assay procedures are as previously described.
Smith, et al., Thrombosis Research, 50, 163-174 (1988). A
CoAScreener coagulation instrument (American LABor, Inc.) is used for all coagulation assay measurements. The prothrombin time (PT) is measured by adding Q. 05 mL saline and 0. 05 mL
Thromboplastin-C reagent or recombinant human tissue ~actor reagent (Innovin) to 0.05 mL test plasma. The activated partial thromboplastin time (APTT) is measured by incubation of 0.05 mL test plasma with 0.05 mL Actin reagent for 120 seconds ~ollowed by 0.05 mL CaC12 (0.02 M). The thrombin time (TT) is measured by adding 0.05 mL saline and 0.05 mL
thrombin (10 NIH units/m~) to 0.05 mL test plasma. The compounds o~ formula I are added to human or ~n;m~l plasma over a wide range o~ concentrations to determine prolongation effects on the APTT, PT, and TT assays. Linear extrapolations are per~ormed to estimate the concentrations re~uired to double the clotting time for each assay. For preferred compounds of the instant invention, a concentration of 30 ng/mL or less typically is su~ficient to double the TT.
~nim;~l S
Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc., Indianapolis, IN) are anesthetized with xylazine (20 mg/kg, s.c.) and ketamine (120 mg/kg, s.c.) and maintained on a heated water blanket (37 ~C). The ~ugular vein(s) is cannulated to allow for infusions.
Arterio-Venous shunt ~odel The le~t jugular vein and right carotid artery are cannulated with 20 cm lengths of polyethylene PE 60 tubing. A 6 cm center section o~ larger tubing (PE 190) with a cotton thread (5 cm) in the lumen, is ~riction ~itted between the longer sections to complete the arterio-venous shunt circuit. Blood is circulated through the shunt ~or 15 min be~ore the thread is care~ully removed and weighed. The weight o~ a wet thread CA 02236007 l998-04-27 W O 97125033 PCT~US96/17995 is subtracted from the total weight of the thread and thrombus (see J.R. Smith, Br J Pharmacol, 77:29, 1982). In - this model preferred compounds of the instant invention reduce the net clot weight to approximately 25-30% of - 5 control, or even lower, at an i.v. dose of 33.176 ~mol/kg/h.
FeC13 model of arterial iniurv The carotid arteries are isolated via a midline ventral cervical incision. A thermocouple is placed under each artery and vessel temperature is recorded continuously on a strip chart recorder. A cu~f of tubing (0.058 ID x 0.077 OD
x 4 mm, Baxter Med. Grade Silicone), cut longitl~;n~lly, is placea around each carotid directly above the thermocouple.
FeCl3 hexahydrate is dissolved in water and the concentration (20 percent) is expressed in terms of the actual weight of FeC13 only. To injure the artery and induce thrombosis, 2.85 ~L is pipetted into the cuff to bathe the artery above the thermocouple probe. Arterial occlusion is indicated by a rapid drop in temperature. The time to occlusion is reported in minutes and represents the elapsed time between application of FeCl3 and the rapid drop in vessel temperature (see K.D. Kurz, Thromb. Res., 60:269, 1990).
Spontaneous thrombolvsis model In vi tro data suggests that thrombin inhibitors inhibit thrombin and, at higher concentrations, may inhibit other serine proteases, such as plasmin and tissue plasminogen activator. To assess if the compounds inhibit fibrinolysis in vivo, the rate of spontaneous thrombolysis is determined by implanting a labeled whole blood clot into the pulmonary circulation. Rat blood (1 mL) is mixed rapidly with bovine thrombin (4 IU, Parke Davis) and 125I human Fibrogen (5 ~Ci, ICN), immediately drawn into silastic tubing and incubated at 37 ~C for 1 hour. The aged thrombus is expelled from the tubing, cut into 1 cm segments, washed 3X in normal saline and each segment is counted in a gamma counter. A segment with known counts is aspirated into a catheter that is WO 97/25033 PCT~US96/17995 subsequently implanted into the jugular vein. The catheter tip is advanced to the ~icinity of the right atrium and the clot is expelled to float into the pulmonary circulation.
One hour after implant, the heart and lungs are harvested and counted separately. Thrombolysis is expressed as a percentage where:
% Thrombolysis = (iniected cPm - luna c~m) x 100 injected cpm The fibrinolytic dissolution of the implanted clot occurs time-dependently (see J.P. Clozel, ~ardiovas. Pharmacol., 12:520, 1988).
Coaaulation ~arameters Plasma thrombin time (TT) and activated partial thromboplastin time (APTT) are measured with a fibrometer.
Blood is sampled from a jugular catheter and collected in syringe containing sodium citrate (3.8 percent, 1 part to 9 parts blood). To measure TT, rat plasma (0.1 mL) is mixed with saline (0.1 mL) and bovine thrombin (0.1 mL, 30 U/mL in TRIS buffer; Parke Davis) at 37 ~C. For APTT, plasma (0.1 mL) and APTT solution (O.1 mL, Organon Teknika) are incubated for 5 minutes (37 ~C) and ~aCl2 (0.1 mL, 0.025 M) is added to start coagulation. Assays are done in duplicate and averaged.
Tn~ex of ~ioavailabilitv For a measure of bioactivity, plasma thrombin time (TT) serves as a substitute for the assay of parent compound on the assumption that observed increments in TT resulted from thrombin inhibition by parent only. The time course of the effect of the thrombin inhibitor upon TT is determined after i.v bolus ~m;nl stration to anesthetized rats and after oral treatment of fasted conscious rats. Due to limitations of blood volume and the number of points re~uired to determine the time course from time of treatment to the time when the response returns to pretreatment values, two populations of rats are used. Each sample population represents alternating W O 97/25033 PCT~US96/17995 sequential time points. The average TT over the time course is used to calculate area under the curve (AUC). The index ~ of bioavailability is calculated by the ~ormula shown below and is expressed as percent relative activity.
- 5 The area under the curve (AUC) of the plasma TT
time course is determined and adjusted for the dose. This index of bioavailability is termed ~I% Relative Activity~ and is calculated as '~Relative Activity = C PA X Do X100 Com~ounds Compound solutions are prepared fresh daily in normal saline and are lnjected as a bolus or are infused starting 15 minutes before and continuing throughout the experimental perturbation which is 15 minutes in the arteriovenous shunt model and 60 minutes in the FeCl3 model of arterial injury and in the spontaneous thrombolysis model. Bolus injection volume is 1 mL/kg for i.v., and 5 mL/kg for p.o., and infusion volume is 3 mL/hr.
S~atistics Results are expressed as means +/- SEM. One-way analysis of variance is used to detect statistically significant differences and then Dunnett's test is applied to determine which means are different. Significance level for rejection of the null hypothesis of equal means is P~0.05.
~n;m~1s Male dogs ~Beagles; 18 months - 2 years; 12-13 kg, Marshall Farms, North Rose, New York 14516) are fasted overnight and fed Purina certified Prescription Diet (Purina Mills, St.
Louis, Missouri) 240 minutes after dosing. Water is available ad libi tum. The room temperature is maintained between 66-74 ~F; 45-50 percent relative humidity; and lighted from 0600-1800 hours.
~
W O 97/25033 PCT~US96/17995 ph~rmacokinetic model.
Test compound is formulated immediately prior to dosing by dissolving in sterile 0.9 percent saline to a 5 mg/mL
preparation. Dogs are given a single 2 mg/kg dose o~ test compound by oral gavage. Blood samples (4.5 mL) are taken from the cephalic vein at 0.25, 0.5, 0. 75, 1, 2, 3, 4 and 6 hours after dosing. Samples are collected in citrated Vacutainer tubes and kept on ice prior to reduction to plasma by centrifugation. Plasma samples are analyzed by HPLC MS.
Plasma concentration of test compound is recorded and used to calculate the pharmacokinetic parameters: elimination rate constant, Ke; total clearance, Clt; volume of distribution, VD; time of maximum plasma test compound concentration, Tmax;
maximum concentration of test compound of Tmax, Cmax; plasma hal~-life, to.5; and area under the curve, A.U.C.; fraction of test compound absorbed, F.
~n;ne Model of Coronarv Arterv Thrombosls Surgical preparation and instrumentation of the dogs are as described in Jackson, et al., Circulation, 82, 930-940 (1990). Mixed-breed hounds (aged 6-7 months, either sex, Hazelton-LRE, ~ m~oo, MI, U.S.A.) are anesthetized with sodium pentobarbital (30 mg/kg intravenously, i.v.), intubated, and ventilated with room air. Tidal volume and respiratory rates are adjusted to maintain blood PO2, PCO2, and pH within normal limits. Sub~erm~l needle electrodes are inserted for the recording of a lead II ECG.
The left jugular vein and common carotid artery are isolated through a left mediolateral neck incision. Arterial blood pressure (ABP) is measured continuously with a precalibrated Millar transducer (model (MPC-500, Millar Instruments, Houston, TX, U.S.A.) inserted into the carotid artery. The ~ugular vein is cannulated for blood sampling during the experiment. In addition, the femoral veins o~ both hindlegs are cannulated for administration of test compound.
-CA 02236007 l998-04-27 W O 97/25033 PCT~US96/1~995 A left thoracotomy is performed at the fifth intercostal space, and the heart is suspended in a pericardial cradle. A
- 1- to 2-cm segment of the left circum~lex coronary artery ~LCX) is isolated proximal to the first major diagonal~ 5 ventricular branch. A 26-gauge needle-tipped wire anodal electrode (Teflon-coated, 30-gauge silverplated copper wire) 3-4 mm long is inserted into the LCX and placed in contact with the intimal surface of the artery (confirmed at the end o~ the experiment). The stimulating circuit is completed by placing the cathode in a subcutaneous (s.c.) site. An adjustable plastic occluder is placed around the LCX, over the region of the electrode. A precalibrated electromagnetic flow probe (Carolina Medical Electronics, King, NC, U.S.A.) is placed around the LCX proximal to the anode for measurement of coronary blood flow (CBF). The occluder is adjusted to produce a 40-50 percent inhibition of the hyperemic blood flow response observed a~ter 10-s mechanical occlusion of the LCX. All hemodynamic and ECG measurements are recorded and analyzed with a data ac~uisition system (model M3000, Modular Instruments, Malvern, PA. U.S.A.).
Thrombus Formation and Compound ~m;n;stration Reaimens Electrolytic injury of the intima of the LCX is produced by applying 100-~A direct current (DC) to the anode. The current is maintained for 60 min and then discontinued whether the vessel has occluded or not. Thrombus formation proceeds spontaneously until the LCX is totally occluded (determined as zero CBF and an increase in the S-T segment).
Compound ~m; n; stration is started after the occluding thrombus is allowed to age for 1 hour. A 2-hour infusion of the compounds of the present invention at doses of 0.5 and 1 mg/kg/hour is begun simultaneously with an infusion of thrombolytic agent (e.g. tissue plasminogen activator, streptokinase, APSAC). Reperfusion is followed for 3 hour after ~m;n~stration of test compound. Reocclusion of coronary arteries after successful thrombolysis is defined as ~ zero CBF which persisted for ~ 30 minutes.
Hematolo~Y and tem~late bleedinq time determina~ion.~
Whole blood cell counts, hemoglobin, and hematocrit values are determined on a 40-~l sample o~ citrated (3.8 percent) blood (1 part citrate:9 parts blood) with a hematology analyzer (~ell-Dyn 900, Sequoia-Turner. Mount View, CA, U.S.A.). Gingival template bleeding times are determined with a Simplate II bleeding time device (Organon Teknika Durham, N.C., U.S.A.). The device is used to make 2 horizontal incisions in the gingiva of either the upper or lower left jaw of the dog. Each incision is 3 mm wide x 2 mm deep. The incisions are made, and a stopwatch is used to determine how long bleeding occurs. A cotton swab is used to soak up the blood as it oozes from the incision. Template bleeding time is the time from incision to stoppage of bleeding. Bleeding times are taken just before ~Am;n;stration of test compound (0 min), 60 min into infusion, at conclusion of ~m;nistration of the test compound (120 min), and at the end of the experiment.
All data are analyzed by one-way analysis of variance (ANOVA) followed by Student-Neuman-Kuels post hoc t test to determine the level o~ significance. Repeated-measures AMOVA are used to determine significant differences between time points during the experiments. Values are determined to be statistically different at least at the level of pc0.05. All values are mean i SEM. All studies are conducted in accordance with the guiding principles of the American Physiological Society. Further details regarding the procedures are described in Jackson, et al., J. Cardiovasc.
ph~rm~col., (1993), 21, 587-599.
The following Examples are provided to further describe the invention and are not to be construed as limitations thereof.
The abbreviations, symbols and terms used in the examples have the following meanings.
W ~ 97/2S033 PCT~US96/17995 Ac = acetyl AIBN = azobisisobutyronitrile ~ Anal. = elemental analysis Bu = butyl - 5 n-BuLi = butyllithium calcd = calculated DIBAL-H = diisobutyl all]minllm hydride ~MF = dimethylformamide DMSO = dimethylsulfoxide Et = ethyl EtOAc = ethyl acetate Et3N = triethylamine Et2O = diethyl ether EtOH = ethanol EtSH = ethanethiol FAB = Fast Atom Bombardment (Mass Spectrascopy) FDMS = field desorption mass spectrum Hex = hexanes HPLC = High Performance Liquid Chromatography HRMS = high resolution mass spectrum i-PrOH = isopropanol IR = Infrared Spectrum LAH = lithium aluminum hydride Me = methyl MeI = methyl iodide MeOH = methanol MPLC = Medium Pressure Liquid Chromatography NBS = N-bromosuccinimide NMR = Nuclear Magnetic Resonance Ph = phenyl PPA = polyphosphoric acid i-Pr = isopropyl Rochelle's Salt = potassium sodium tartrate RPHPLC = Reversed Phase High Performance Liquid Chromatography SiO2 = silica gel ~ SM = starting material TEA = triethylamine Temp. = temperature TFA = trifluoroacetic acid THF = tetrahydrofuran TIPS = triisopropylsilyl TLC = thin layer chromatography triflic acid = trifluoromethanesulfonic acid Unless otherwise stated, pH adjustments and work up are with aqueous acid or base solutions. PrepLC indicates preparative liquid chromatography using "Prep Pak (TM)"
silica cartridgesi radial chromatography indicates preparative chromatography using a "Chromatotron (TM)~
instrument.
CA 02236007 l998-04-27 W O 97/Z5033 PCT~US96tl7995 ~ .x~le 1 Preparation o~ 6-Hydroxy-2-t4-~2-(1-~1 olidinyl)-ethoxylphQnyl]benzolb]thiophen-3-yl 4-~2-(1-Pyrro-lidinyl)ethoxy]phenyl Ketone Dioxalate.
0 ~ ,~_,N ~
HO ~ "x~_,M ~ 2 C2H2O4 Part A. 6-Methoxybenzo[b~thiophene-2-boronic Acid.
MeO/ ~ B(OH)2 To a solution of 6-methoxybenzo Ib] thiophene (Graham, S. L., et al. J. Med. Chem. 1989, 32, 2548-2554)(18.13 g, 0.111 mol) in 150 mL of anhydrous THF at -60 ~C was added n-BuLi ~76.2 mL, 0.122 mol, 1.6 M solution in hexanes), dropwise via syringe. After stirring for 30 min, triisopropyl borate (28.2 mL, 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 0 ~C and then partitioned between 1.0 N HCl and EtOAc (300 mL each). The layers were separated, and the organic phase was dried over Na2SO4. Concentration in vacuo produced a white solid that was triturated from Et2O/hexanes.
Filtration provided 16.4 g (71~) of 6-methoxybenzo~b]thio-phene-2-boronic acid as a white solid.
mp 200 ~C (dec)i FDMS 208 (M+; 100); lH NMR (DMSO-d6) ~ 8.36 (br s), 7.86-7.75 (m, 2H), 7.53 (dd, J = 8.1 and 2.0 Hz, lH), 6.98 (m, lH), 3.82 (s, 3H).
Part B. 6-Methoxy-2-[4-~2-(1-pyrrolidinyl)ethoxy~-phenyl]benzo[blthiophene.
MeO
CA 02236007 l998-04-27 To a slurry of 6-methoxybenzo[b]thiophene-2-boronic acid (Example 1, Part A) (6.43 g, 30.9 mmol) in 310 mL of benzene was added l-(2-(4-bromophenoxy)ethyl)pyrrolidine (5.80 mL, 28.1 mmol). Upon addition the reaction mixture turned to a yellow homogeneous solution. The reaction ~lask was then co~ered with aluminum foil to keep out light. To this was added 1.07 g (0.92 mmol~ of tetrakis(triphenylphosphine)-palladium(O), followed by 30 mL of 2.0 N sodium carbonate solution. The biphasic mixture was heated at 85 C ~or 3 h with vigorous stirring. The mixture was cooled to 0 C and 175 mL of brine solution was added. The layers were sepa-rated and the a~ueous layer was extracted with 1.0 L of EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure The residue was purified by PrepLC (53:35:2 THF-hexanes-TEA) to afford 5.42 g (15.3 mmol, 55%) of an off-white solid.
mp 151-154 ~C; lH NMR (CDC13) ~ 7.61 (d, J = 8.8 Hz, lH),
7.58 (d, J = 8.8 Hz, 2H), 7.33 (s, lH), 7.29 (d, ~ = 2.3 Hz, lH), 6.95 (d, ~ = 8.7 Hz, 3~), 4.18 (t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 2.97 (t, J = 5.9 Hz, 2H), 2.71 (br t, 4H), 1.85 (m, 4H); FDMS: 353 (Mt); Anal. Calcd for C21H23NO2S: C, 71.36 H, 6.56; N, 3.96. Found: C, 71.58; H, 6.35; N, 3.91.
Part C~. 6-Methoxy-2-~4-[2-(1~ olidinyl)-ethoxy~h~nyllbenzo~b]thiophen-3-yl 4-~2-(1-Pyrro-lidinyl)ethoxy]~henyl Ketone Dioxalat~.
0 ~ , ~ ,N ~
MeO ~ "~ ,N ~ 2 C2H2O4 A slurry of 600 mg (2.20 mmol) of 4-[2~ pyrro-lidinyl)ethoxy]benzoic acid hydrochloride in 20 mL of 1,2-dichloroethane and 2 drops of DMF was treated with 0.8 mL
(11.0 mmol) of SOCl2 and the mixture was heated to mild CA 02236007 l998-04-27 W O 97/2S033 PCT~US96/17995 reflux ~or 2 h. The clear solution was evaporated in vacuo, the residue was re-suspended in 20 mL of 1,2-dichloroethane, ~ and the mixture was re-concentrated. The solid was suspended in 20 mL o~ 1,2-dichloroethane and the mixture cooled to - 5 0 ~C. 1-[2-[4-(6-Methoxybenzo[~]thiophen-2-yl)phenoxy]-ethyl]pyrrolidine (part B; 650 mg, 1.97 mmol) was added to the acid chloride solution, followed by 2.10 g (15.7 mmol) of AlCl3 in two portions. The mixture was stirred at 0 ~C for 5 h at which time it was carefully poured into 200 mL of a 0 ~C solution of saturated a~ NaHCO3. The mixture was extracted with EtOAc (4 x 100 mL). The combined organic ex-tracts were dried over K2CO3 and evaporated in vacuo to ~ive 735 mg of an oil. Puri~ication by radial chromatography (sio2i 10% MeOH in CH2Cl2) afforded 330 mg (0.58 mmol; 26%) of the title compound as a viscous oil. A sample o~ the pure product (70 mg; 0.12 mmol) in 5 mL of EtOAc was treated with a solution of 25 mg (0.28 mmol; 2.3 eq) of oxalic acid in 3.0 mL EtOAc. The resulting solid was filtered, dried and characterized.
FDMS 571 (M+l); Anal. Calcd ~or C34H38N2O4S 2~2H2o4-H2o: C, 59.37; H, 5.77; N, 3.64. Found: C, 59.67; H, 5.56; N, 3.73.
Part D. 6-Hydroxy-2-[4-t2-(1-pyrrolidinyl)ethoxy~-phenyl~b~nzolb~thiophen-3-yl 4-12-(1-Pyrr~lidinyl)-Qthoxy~honyl Ketone Dioxalat~.
A 0 ~C solution of 250 mg (0.45 mmol) of 6-methoxy~2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl 4-[2-(l-pyrrolidinyl)ethoxy]phenyl ketone (Part C) in 10 mL o~
1,2-dichloroethane was treated with 360 mg (2.7 mmol) of AlC13, followed by 0.28 mL (3.8 mmol) of ethanethiol. The cold bath was removed and the reaction was stirred at room temperature for 10 h. The reaction mixture was poured into 200 mL o~ a 1:1 mixture of EtOAc and saturated aq NaHCO3 with 10 mL MeOH rinse. The two layers were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined EtOAc layers were dried over Na2S04 and evaporated to give 325 mg of an oil. Purification by radial chromatography (sio2i gradient o~ 10% MeOH in CH2C12 to 20% MeOH and 1~ TEA
in CH2Cl2) afforded 130 mg (0.23 mmol, 52~) of an amorphous solid. The solid was converted to the dioxalate salt according to the conditions outlined in Example 1, Part C.
lH NMR (DMSO-d6) ~ 9.77 (s, lH), 7.63 (dd, J = 8.8, 1.7 Hz, 2H), 7.31 (d, J = 2.1 Hz, lH), 7.24 (d, J = 8.7 Hz, 2H), 7.19 (s, lH), 6.95-6.79 (m, 5H) 4.05 (t, J = 6.0 Hz, 2H), 3.98 (t, ~ = 5.6 Hz, 2H), 2.78-2.63 (m, 4H), 2.53-2.37 (m, 8H) 1.66-1.57 (m, 8H); FDMS 557 (M+1; 100); Anal. Calcd for: C, 60.32i H, 5.47i N, 3.80. Found: C, 60.21; H, 5.63; N, 3.69.
Example 2 PreE)aration of 1- ~2-~4-t[5-Methyl-2-~4- ~2-(1-~yrrolidinyl)ethoxy]phenyl]bonzo~b]thiophen-3-yl]-methyll~henoxy]ethyllpyrroliaine Dioxalate.
~3C I ~ Z C~04 Part A. 5-Methylbenzolblthiorh~-2-boronic Acid.
2 0 1~ B ( OH ) 2 The title compound was prepared from 5-methyl-benzo[b]thiophene as a white solid in 51% yield by essentially following the procedure described in Example 1, Part A.
mp > 250 ~C; FDMS: 192 (M+~.
P~rt B. 5-Methyl-2-~4-~2~ r olidinyl)ethoxy~- r phenyllbenzo~b~thiophene~
CA 02236007 l998-04-27 W O 97/~5033 PCT~US96/17995 H3C ~ "_~" N ~
- The title compound was prepared from 5-methyl-benzo[b]thiophene-2-boronic acid as a light yellow solid in a 44% yield by essentially following the procedure described in Example 1, Part B.
mp 149.5-151.0 ~Ci FD3!![S 337 (M+; 100); Anal. Calcd for C2lH23NOS: C, 74 74; H, 6.87i N, 4.15. Found: C, 74.94; H, 6.82; N, 4.31.
Part C. 5-Methyl-2-~4-~2-(1-pyrrolidinyl)ethoxy~-phenyl~b~nzo~b]thiophen-3-yl ~4-~2-(1-Pyrrolidi~yl)-ethoxy~phenyl Ketone Dioxalate.
H3C ~ 2 C2H2O4 A slurry of 665 mg (2.45 mmol) of 4-[2-(1-pyrro-lidinyl)ethoxy]benzoic acid hydrochloride in 20 mL of 1,2-dichloroethane and 2 drops of DMF was treated with 0.90 mL
(12.3 mmol) of SOC12 and the mixture was heated to gentle reflux for 2.5 h. The resulting solution was evaporated in vacuo, the residue was re-suspended in 20 mL of 1,2-dichloro-ethane, and the mixture was re-concentrated. The solid was suspended in 20 mL of 1,2-dichloroethane and to this was added at 0 ~C 5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy)-phenyl]benzo[b]thiophene (part B; 750 mg, 2.22 mmol). The reaction was protected from light and 1.2 mL (10.9 mmol) TiC14 was added dropwise. The reaction was stirred at 0 ~C
for 3 h at which time it was quenched by the care~ul addition of 25 mL of saturated aq NaHC03. The mixture was filtered - through diatomaceous earth, and the two layers were W O 97/25033 PCTAUS96~17995 separated. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 1.34 g o~ crude product which was purified by radial chromatography (sio2; 10% MeOH in CH2C12) to a~ford 980 mg (1.77 mmol; 80%) of the title compound as a viscous oil. A 210 mg sample of this material was converted to the dioxalate salt according to the methods described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.98 (d, J = 8.2 Hz, lH), 7.75 (d, J = 8.6 Hz, 2H), 7.40 (d, ~ - 8.5 Hz, 2H). 7.34-7.24 (m, 2H), 7.06-6.94 (m, 4H), 4.38-4 21 (m, 4H), 3.59-3.46 (m, 4H), 3.36-3.22 (m, 8H), 2.36 (s, 3H), 1.98-1.84 (m, 8H); FDMS 555 (M~1); 645 (M+91; 100); Anal. Calcd for C34H3gN2O3S-2C2H2O4-0.5H2O: C, 61.36; H, 5.83; N, 3.77. Found: C, 61.35; H, 6.04; N, 3.97.
Part D. 1-~2-~4-[[5-Methyl-2-~4-~2-(1-~1lolidinyl)-ethoxy]phenyl~b~nzo~b3thio~hen-3-yl]methyl]phenox~]-ethyl]pyrroliaine Dioxalate.
A slurry of 160 mg (4.20 mmol) of T;~4 in 20 mL THF at 0 ~C was treated with a solution of 750 mg (1.35 mmol) of 5-methyl-2-~4-~2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b3-thiophen-3-yl [4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Example 2, Part C) in 10 mL THF. The reaction was stirred at 0 ~C for 2.5 h and was quenched by the sequential addition of 6 mL of H20, 6 mL o~ 2.0 N aq NaOH, and 6 mL o~ H20. The mixture was filtered, the THF was evaporated in vacuo, and the resulting aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over K2C03 and concentrated in vacuo. The residue was taken up in 5 mL o~
trifluoroacetic acid (TFA) and the mixture was cooled to 0 ~C. Sodium borohydride (100 mg; 2.91 mmol) was carefully added and the reaction stirred for 2 h. The mixture was evaporated in vacuo, the residue was taken up in 100 mL
EtOAc, and the mixture was washed with saturated aq NaHC03 (3 x 50 mL). The organic layer was dried over K2C03 and evaporated in vacuo to give 675 mg o~ an oil. Purification W O 97125033 PCT~US96/17995 by radial chromatography (sio2i 10~ MeOH/0.1% TEA in CH2C12) afforded 550 mg of the title compound as a light yellow oil which was converted to the dioxalate salt according the methods described in Example 1, Part C.
S
H NMR (DMSO-d6) ~ 7.85 (d, J = 8.2 Hz, lH), 7.48-7.36 (m, 3H), 7.19 (d, J = 8.2 Hz, lH). 7.10-6.96 (m, 3H), 6.91-6.80 (m, 3H), 4.17 (s, 2H), 4.11 (t, J = 5.8 Hz, 2H), 3.98 (t, J =
5.8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.75 (t, ~ = 5.8 Hz, 2H), 2.36 (s, 3H), 2.58-2.44 (m, 8H), 1.78-1.60 (m, 8H); FDMS
541 (M+1; 100)i Anal. Calcd for C34H4ON2o2s-2c2H2o4-o~5H2o: C, 62.54i H, 6.21; N, 3.84. Found: C, 62.27i H, 6.16; N, 3.93.
~YA '1~ 3 Preparation of 1-12-14-[[2- r4- [2-(1-Pyrrolidinyl)-~thoxy]~henyl]benzo[b]thiophen-3-yl]methyl]phenoxy]-ethyl]pyrrolidine Dioxalate.
'~~'M ~
Part A. 2-(4-N~thoxxphenyl)benzo[b]thiophene.
OMe The title compound was prepared in 91% yield from benzo[b]thiophene-2-boronic acid and 4-bromoanisole by essentially following the procedure detailed Example 1, Part B.
mp 188-191 ~C; lH NMR ~DMSO-d6) ~ 7.94 (d, J = 8.0 Hz, lH), 7.81 (d, J = 7.0 Hz, lH), 7.73 (m, 2H). 7.71 (s, lH), 7.35 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H); FDMS 240 W O 97/25033 PCT~US96/17995 (M+; 100); Anal. Calcd for C~lH23NO2S: C, 71.36; H, 6.56i N, 3 86. Found: C, 71.46; H, 6.60; N, 3.86.
Part B. 2-(4-Methoxyphenyl)bQnzolb]thiophQn-3-yl 4-M~thoxyphQnyl KetonQ.
O-le The title compound was prepared from 4-anisoyl chloride and 2-(4-methoxyphenyl)benzo[b]thiophene (Part A) as a tan solid in 90~ yield following recrystallization from THF-hexanes.
FDMS 375 (M+l; 100).
Part C. 2-(4-Hydroxyphenyl)benzo[blthio~hen-3-yl 4-Hydroxyphenyl ~Ketone.
~ ~
By essentially ~ollowing the procedure outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxyphenyl ketone (Part B) as a yellow solid in 93% yield following radial chromatography (SiO2; gradient of 20-40% EtOAc in hexanes).
FDMS 347 (M+l; 100); Anal. Calcd for C2lHl4O3S: C, 72.81; H, 4.07. Found: C, 72.57; H, 4.17.
Part D. 2-t4-12-(1-~y ~olidinyl)ethoxylphQnyllb~nzo-lb]thiophon-3-yl 4-[2-(1-Pyrrolidinyl~ethoxy]phenyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 _O~ ~
S ~ 2 c2H2O4 0 ~
A solution of 300 mg (0 87 mmol) of 2-(4-hydroxyphenyl)-benzo~b] thiophen-3-yl 4-hydroxyphenyl ketone (Part C) in 20 mL of DMF was treated with 880 mg (5.2 mmol) of 1-(2-5 chloroethyl)pyrrolidine hydrochloride followed by 2.26 g (6.94 mmol) of Cs2CO3. The mixture was heated to 80 ~C for 6 h at which time it was cooled and filtered. The mother liquor was concentrated in vacuo and the residue was partitioned between H2O (25 mL) and EtOAc (25 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over K2CO3 and evaporated to give 516 mg of an oil which was purified by radial chromatography (sio2; 60:35:5 hexanes-THF-TEA) to a~ord 371 mg ~0.69 mmol; 79%) of an oil. The oil was converted to the dioxalate salt according to the procedure detailed in Example 1, Part C.
FDMS 541 (M+1), 631 (M+91; 100); Anal. Calcd for C33H36N2O3S 2c2H2o4 0.1H20: C, 61.50; H, 5.60; N, 3.88.
Found: C, 61.21; H, 5.60; N, 3.91.
Part E. 1-12-14-112-14-[2-(1-Pyrroli~inyl)ethoxy}-phenyl~benzo[blthiophen-3-yl]methyl]phenoxy]ethyl]-pyrroli~ine Dioxalate.
A slurry of 45 mg of LiAlH4 in 10 mL of THF was cooled to 0 ~C and was treated with a solution of 200 mg (0.37 mmol) of 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-- yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) in 5 mL
of THF. The reaction was stirred at 0 ~C for 2 h and was ~u~nche~ by the se~uential addition of 1 mL of H2O, 1 mL of 2 N a~ NaOH, and 1 mL of H2O. The two layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL).
The combined organic layers were washed with 25 mL of brine, dried over K2CO3, and evaporated in vacuo. The residue was taken up in 10 mL o~ CH2C12, cooled to 0 ~C, and treated with 0.47 mL (2.94 mmol) of triethylsilane. A~ter stirrin~ at 0 ~C for 6 h, the reaction was treated with 0.3 mL (3.9 mmol) of TFA, followed by an additional 16 h o~ stirring at 0 ~C.
The reaction mixture was poured into 10 mL saturated aq NaHC03 and the two layers were separated. The a~ueous layer was extracted with CH2C12 (2 x 10 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 233 mg of an oil which was puri~ied by radial chromatography (sio2; gradient 2-10% MeOH in CH2Cl2) to a~ord 158 mg (0.30 mmoli 81%) of the title compound as the free base.
Conversion to the dioxalate salt was effected by the procedure detailed in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.99 (d, J = 7.8 Hz, lH), 7.59 (d, J = 8.5 Hz, lH), 7.50 (d, J = 8.2 Hz, 2H), 7.43-7.30 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H). 7.06 (d, J = 8.3 Hz, 2H), 6.89 (d, J =
Part C~. 6-Methoxy-2-~4-[2-(1~ olidinyl)-ethoxy~h~nyllbenzo~b]thiophen-3-yl 4-~2-(1-Pyrro-lidinyl)ethoxy]~henyl Ketone Dioxalat~.
0 ~ , ~ ,N ~
MeO ~ "~ ,N ~ 2 C2H2O4 A slurry of 600 mg (2.20 mmol) of 4-[2~ pyrro-lidinyl)ethoxy]benzoic acid hydrochloride in 20 mL of 1,2-dichloroethane and 2 drops of DMF was treated with 0.8 mL
(11.0 mmol) of SOCl2 and the mixture was heated to mild CA 02236007 l998-04-27 W O 97/2S033 PCT~US96/17995 reflux ~or 2 h. The clear solution was evaporated in vacuo, the residue was re-suspended in 20 mL of 1,2-dichloroethane, ~ and the mixture was re-concentrated. The solid was suspended in 20 mL o~ 1,2-dichloroethane and the mixture cooled to - 5 0 ~C. 1-[2-[4-(6-Methoxybenzo[~]thiophen-2-yl)phenoxy]-ethyl]pyrrolidine (part B; 650 mg, 1.97 mmol) was added to the acid chloride solution, followed by 2.10 g (15.7 mmol) of AlCl3 in two portions. The mixture was stirred at 0 ~C for 5 h at which time it was carefully poured into 200 mL of a 0 ~C solution of saturated a~ NaHCO3. The mixture was extracted with EtOAc (4 x 100 mL). The combined organic ex-tracts were dried over K2CO3 and evaporated in vacuo to ~ive 735 mg of an oil. Puri~ication by radial chromatography (sio2i 10% MeOH in CH2Cl2) afforded 330 mg (0.58 mmol; 26%) of the title compound as a viscous oil. A sample o~ the pure product (70 mg; 0.12 mmol) in 5 mL of EtOAc was treated with a solution of 25 mg (0.28 mmol; 2.3 eq) of oxalic acid in 3.0 mL EtOAc. The resulting solid was filtered, dried and characterized.
FDMS 571 (M+l); Anal. Calcd ~or C34H38N2O4S 2~2H2o4-H2o: C, 59.37; H, 5.77; N, 3.64. Found: C, 59.67; H, 5.56; N, 3.73.
Part D. 6-Hydroxy-2-[4-t2-(1-pyrrolidinyl)ethoxy~-phenyl~b~nzolb~thiophen-3-yl 4-12-(1-Pyrr~lidinyl)-Qthoxy~honyl Ketone Dioxalat~.
A 0 ~C solution of 250 mg (0.45 mmol) of 6-methoxy~2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl 4-[2-(l-pyrrolidinyl)ethoxy]phenyl ketone (Part C) in 10 mL o~
1,2-dichloroethane was treated with 360 mg (2.7 mmol) of AlC13, followed by 0.28 mL (3.8 mmol) of ethanethiol. The cold bath was removed and the reaction was stirred at room temperature for 10 h. The reaction mixture was poured into 200 mL o~ a 1:1 mixture of EtOAc and saturated aq NaHCO3 with 10 mL MeOH rinse. The two layers were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined EtOAc layers were dried over Na2S04 and evaporated to give 325 mg of an oil. Purification by radial chromatography (sio2i gradient o~ 10% MeOH in CH2C12 to 20% MeOH and 1~ TEA
in CH2Cl2) afforded 130 mg (0.23 mmol, 52~) of an amorphous solid. The solid was converted to the dioxalate salt according to the conditions outlined in Example 1, Part C.
lH NMR (DMSO-d6) ~ 9.77 (s, lH), 7.63 (dd, J = 8.8, 1.7 Hz, 2H), 7.31 (d, J = 2.1 Hz, lH), 7.24 (d, J = 8.7 Hz, 2H), 7.19 (s, lH), 6.95-6.79 (m, 5H) 4.05 (t, J = 6.0 Hz, 2H), 3.98 (t, ~ = 5.6 Hz, 2H), 2.78-2.63 (m, 4H), 2.53-2.37 (m, 8H) 1.66-1.57 (m, 8H); FDMS 557 (M+1; 100); Anal. Calcd for: C, 60.32i H, 5.47i N, 3.80. Found: C, 60.21; H, 5.63; N, 3.69.
Example 2 PreE)aration of 1- ~2-~4-t[5-Methyl-2-~4- ~2-(1-~yrrolidinyl)ethoxy]phenyl]bonzo~b]thiophen-3-yl]-methyll~henoxy]ethyllpyrroliaine Dioxalate.
~3C I ~ Z C~04 Part A. 5-Methylbenzolblthiorh~-2-boronic Acid.
2 0 1~ B ( OH ) 2 The title compound was prepared from 5-methyl-benzo[b]thiophene as a white solid in 51% yield by essentially following the procedure described in Example 1, Part A.
mp > 250 ~C; FDMS: 192 (M+~.
P~rt B. 5-Methyl-2-~4-~2~ r olidinyl)ethoxy~- r phenyllbenzo~b~thiophene~
CA 02236007 l998-04-27 W O 97/~5033 PCT~US96/17995 H3C ~ "_~" N ~
- The title compound was prepared from 5-methyl-benzo[b]thiophene-2-boronic acid as a light yellow solid in a 44% yield by essentially following the procedure described in Example 1, Part B.
mp 149.5-151.0 ~Ci FD3!![S 337 (M+; 100); Anal. Calcd for C2lH23NOS: C, 74 74; H, 6.87i N, 4.15. Found: C, 74.94; H, 6.82; N, 4.31.
Part C. 5-Methyl-2-~4-~2-(1-pyrrolidinyl)ethoxy~-phenyl~b~nzo~b]thiophen-3-yl ~4-~2-(1-Pyrrolidi~yl)-ethoxy~phenyl Ketone Dioxalate.
H3C ~ 2 C2H2O4 A slurry of 665 mg (2.45 mmol) of 4-[2-(1-pyrro-lidinyl)ethoxy]benzoic acid hydrochloride in 20 mL of 1,2-dichloroethane and 2 drops of DMF was treated with 0.90 mL
(12.3 mmol) of SOC12 and the mixture was heated to gentle reflux for 2.5 h. The resulting solution was evaporated in vacuo, the residue was re-suspended in 20 mL of 1,2-dichloro-ethane, and the mixture was re-concentrated. The solid was suspended in 20 mL of 1,2-dichloroethane and to this was added at 0 ~C 5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy)-phenyl]benzo[b]thiophene (part B; 750 mg, 2.22 mmol). The reaction was protected from light and 1.2 mL (10.9 mmol) TiC14 was added dropwise. The reaction was stirred at 0 ~C
for 3 h at which time it was quenched by the care~ul addition of 25 mL of saturated aq NaHC03. The mixture was filtered - through diatomaceous earth, and the two layers were W O 97/25033 PCTAUS96~17995 separated. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 1.34 g o~ crude product which was purified by radial chromatography (sio2; 10% MeOH in CH2C12) to a~ford 980 mg (1.77 mmol; 80%) of the title compound as a viscous oil. A 210 mg sample of this material was converted to the dioxalate salt according to the methods described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.98 (d, J = 8.2 Hz, lH), 7.75 (d, J = 8.6 Hz, 2H), 7.40 (d, ~ - 8.5 Hz, 2H). 7.34-7.24 (m, 2H), 7.06-6.94 (m, 4H), 4.38-4 21 (m, 4H), 3.59-3.46 (m, 4H), 3.36-3.22 (m, 8H), 2.36 (s, 3H), 1.98-1.84 (m, 8H); FDMS 555 (M~1); 645 (M+91; 100); Anal. Calcd for C34H3gN2O3S-2C2H2O4-0.5H2O: C, 61.36; H, 5.83; N, 3.77. Found: C, 61.35; H, 6.04; N, 3.97.
Part D. 1-~2-~4-[[5-Methyl-2-~4-~2-(1-~1lolidinyl)-ethoxy]phenyl~b~nzo~b3thio~hen-3-yl]methyl]phenox~]-ethyl]pyrroliaine Dioxalate.
A slurry of 160 mg (4.20 mmol) of T;~4 in 20 mL THF at 0 ~C was treated with a solution of 750 mg (1.35 mmol) of 5-methyl-2-~4-~2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b3-thiophen-3-yl [4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Example 2, Part C) in 10 mL THF. The reaction was stirred at 0 ~C for 2.5 h and was quenched by the sequential addition of 6 mL of H20, 6 mL o~ 2.0 N aq NaOH, and 6 mL o~ H20. The mixture was filtered, the THF was evaporated in vacuo, and the resulting aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over K2C03 and concentrated in vacuo. The residue was taken up in 5 mL o~
trifluoroacetic acid (TFA) and the mixture was cooled to 0 ~C. Sodium borohydride (100 mg; 2.91 mmol) was carefully added and the reaction stirred for 2 h. The mixture was evaporated in vacuo, the residue was taken up in 100 mL
EtOAc, and the mixture was washed with saturated aq NaHC03 (3 x 50 mL). The organic layer was dried over K2C03 and evaporated in vacuo to give 675 mg o~ an oil. Purification W O 97125033 PCT~US96/17995 by radial chromatography (sio2i 10~ MeOH/0.1% TEA in CH2C12) afforded 550 mg of the title compound as a light yellow oil which was converted to the dioxalate salt according the methods described in Example 1, Part C.
S
H NMR (DMSO-d6) ~ 7.85 (d, J = 8.2 Hz, lH), 7.48-7.36 (m, 3H), 7.19 (d, J = 8.2 Hz, lH). 7.10-6.96 (m, 3H), 6.91-6.80 (m, 3H), 4.17 (s, 2H), 4.11 (t, J = 5.8 Hz, 2H), 3.98 (t, J =
5.8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.75 (t, ~ = 5.8 Hz, 2H), 2.36 (s, 3H), 2.58-2.44 (m, 8H), 1.78-1.60 (m, 8H); FDMS
541 (M+1; 100)i Anal. Calcd for C34H4ON2o2s-2c2H2o4-o~5H2o: C, 62.54i H, 6.21; N, 3.84. Found: C, 62.27i H, 6.16; N, 3.93.
~YA '1~ 3 Preparation of 1-12-14-[[2- r4- [2-(1-Pyrrolidinyl)-~thoxy]~henyl]benzo[b]thiophen-3-yl]methyl]phenoxy]-ethyl]pyrrolidine Dioxalate.
'~~'M ~
Part A. 2-(4-N~thoxxphenyl)benzo[b]thiophene.
OMe The title compound was prepared in 91% yield from benzo[b]thiophene-2-boronic acid and 4-bromoanisole by essentially following the procedure detailed Example 1, Part B.
mp 188-191 ~C; lH NMR ~DMSO-d6) ~ 7.94 (d, J = 8.0 Hz, lH), 7.81 (d, J = 7.0 Hz, lH), 7.73 (m, 2H). 7.71 (s, lH), 7.35 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H); FDMS 240 W O 97/25033 PCT~US96/17995 (M+; 100); Anal. Calcd for C~lH23NO2S: C, 71.36; H, 6.56i N, 3 86. Found: C, 71.46; H, 6.60; N, 3.86.
Part B. 2-(4-Methoxyphenyl)bQnzolb]thiophQn-3-yl 4-M~thoxyphQnyl KetonQ.
O-le The title compound was prepared from 4-anisoyl chloride and 2-(4-methoxyphenyl)benzo[b]thiophene (Part A) as a tan solid in 90~ yield following recrystallization from THF-hexanes.
FDMS 375 (M+l; 100).
Part C. 2-(4-Hydroxyphenyl)benzo[blthio~hen-3-yl 4-Hydroxyphenyl ~Ketone.
~ ~
By essentially ~ollowing the procedure outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxyphenyl ketone (Part B) as a yellow solid in 93% yield following radial chromatography (SiO2; gradient of 20-40% EtOAc in hexanes).
FDMS 347 (M+l; 100); Anal. Calcd for C2lHl4O3S: C, 72.81; H, 4.07. Found: C, 72.57; H, 4.17.
Part D. 2-t4-12-(1-~y ~olidinyl)ethoxylphQnyllb~nzo-lb]thiophon-3-yl 4-[2-(1-Pyrrolidinyl~ethoxy]phenyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 _O~ ~
S ~ 2 c2H2O4 0 ~
A solution of 300 mg (0 87 mmol) of 2-(4-hydroxyphenyl)-benzo~b] thiophen-3-yl 4-hydroxyphenyl ketone (Part C) in 20 mL of DMF was treated with 880 mg (5.2 mmol) of 1-(2-5 chloroethyl)pyrrolidine hydrochloride followed by 2.26 g (6.94 mmol) of Cs2CO3. The mixture was heated to 80 ~C for 6 h at which time it was cooled and filtered. The mother liquor was concentrated in vacuo and the residue was partitioned between H2O (25 mL) and EtOAc (25 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over K2CO3 and evaporated to give 516 mg of an oil which was purified by radial chromatography (sio2; 60:35:5 hexanes-THF-TEA) to a~ord 371 mg ~0.69 mmol; 79%) of an oil. The oil was converted to the dioxalate salt according to the procedure detailed in Example 1, Part C.
FDMS 541 (M+1), 631 (M+91; 100); Anal. Calcd for C33H36N2O3S 2c2H2o4 0.1H20: C, 61.50; H, 5.60; N, 3.88.
Found: C, 61.21; H, 5.60; N, 3.91.
Part E. 1-12-14-112-14-[2-(1-Pyrroli~inyl)ethoxy}-phenyl~benzo[blthiophen-3-yl]methyl]phenoxy]ethyl]-pyrroli~ine Dioxalate.
A slurry of 45 mg of LiAlH4 in 10 mL of THF was cooled to 0 ~C and was treated with a solution of 200 mg (0.37 mmol) of 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-- yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) in 5 mL
of THF. The reaction was stirred at 0 ~C for 2 h and was ~u~nche~ by the se~uential addition of 1 mL of H2O, 1 mL of 2 N a~ NaOH, and 1 mL of H2O. The two layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL).
The combined organic layers were washed with 25 mL of brine, dried over K2CO3, and evaporated in vacuo. The residue was taken up in 10 mL o~ CH2C12, cooled to 0 ~C, and treated with 0.47 mL (2.94 mmol) of triethylsilane. A~ter stirrin~ at 0 ~C for 6 h, the reaction was treated with 0.3 mL (3.9 mmol) of TFA, followed by an additional 16 h o~ stirring at 0 ~C.
The reaction mixture was poured into 10 mL saturated aq NaHC03 and the two layers were separated. The a~ueous layer was extracted with CH2C12 (2 x 10 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 233 mg of an oil which was puri~ied by radial chromatography (sio2; gradient 2-10% MeOH in CH2Cl2) to a~ord 158 mg (0.30 mmoli 81%) of the title compound as the free base.
Conversion to the dioxalate salt was effected by the procedure detailed in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.99 (d, J = 7.8 Hz, lH), 7.59 (d, J = 8.5 Hz, lH), 7.50 (d, J = 8.2 Hz, 2H), 7.43-7.30 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H). 7.06 (d, J = 8.3 Hz, 2H), 6.89 (d, J =
8.1 Hz, 2H), 4.17 (s, 2H), 4.11 (t, J = 5.8 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.36 (s, 3H), 2.58-2.44 (m, 8H), 1.78-1.60 (m, 8H);
FDMS 527 (M+l, 100).
Exam~le 4 Preparation of 2-~4-12-(1-Pyrrolidinyl)ethoxy]phenyl3-benzo[b]thiophen-3-yl 4-13-(l-PYrrolidinyl)pr phenyl Ketone Dioxalat~.
WO 97/25033 PCT~US96/17995 O ~ N ~ ~ C2H2~4 O'-- "--'N~
:eart A. 1-12-[4-(Benzolb]thio~hen-2-yl)phenoxy]-~ethyl~pyrrolidine.
~5 ~
~ ~ ~--~N
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-[2-(4-bromophenoxy)-ethyl]pyrrolidine in 76% yield as a white solid following flash chromatography (sio2; 36:4:60 THF-TEA-hexanes).
FDMS 324 (M+1; 100).
Part B. Methyl 4-~3-(1-Pyrrolidinyl)plG~o~y]benzoate.
MeO2C
O~ "'~_,N ~
A solution of 6.25 g (23.8 mmol) of triphenylphosphine, 3.30 g (21.7 mmol) of methyl 4-hydroxybenzoate, and 2.80 g ~21.7 mmol) of 1-(3-hydroxypropyl)pyrrolidine in 100 mL of CH2Cl2 was treated with 3.80 mL (24.1 mmol) of diethyl azodicarboxylate in a dropwise m~nn~r . The reaction was stirred at ambient temperature for 16 h and was quenched by the addition of 20 mL of brine. The two layers were separated, and the organic layer was dried over K2CO3 and W O 97/25033 PCT~US96/17995 concentrated to give 6.10 g of an oily solid which was purified by flash chromatography (sio2i 0-5% MeOH in CH2Cl2) to afford 2.46 g (9.34 mmol; 43%) of the desired product.
FDMS 263 (M+; 100)i HRMS Calcd for C1sH21NO3: 264.1600.
Found: 264.1609.
Part C. 4-l3~ ~Y~olidinYl)Propoxy]bQnzoic Acid ~ydrochlorid~.
HO2C~
~ O~ "~_,N ~ HC1 A solution of 2.0 g (7. 6 ~mnol) oE the methyl 4-[3-(1-pyrrolidinyl)propoxy]benzoate (Part B) in 90 mL of THF was treated with 90 mL of 0.1 N aq LioH ~or 48 h. The THF was evaporated in vacuo. The aqueous phase was adjusted to pH 11 with 1.0 N aq HC1 and was applied to column of Biorad AG1-X8 Resin (100-200 mesh; acetate ~orm) which had been prewashed with 2 L of 2.0 N aq NaOH. The column was sequentially eluted with 1 L of H2O, 1 L of 50% THF in E2O, 1 L of H2O and 2 L of 3.0 N aq AcOH. The acidic fraction was evaporated in vacuo, the residue was reconstituted in 20 mL o~ 1.0 N ag HCl and the mixture was frozen Lyophilization afforded 1.50 g (3.g mmol; 51%) of the desired product as a white powder.
FDMS 249 (M+; 100); Anal. Calcd ~or C14H1gNO3 HC1: C, 58.84;
H, 7.05; N, 4.90. Found: C, 58.58; H, 6.85; N, 5.13.
Part D. 2-~4-12-(1-Pyrrolidinyl)~thoxy]phenyl]-benzo~blthiophen-3-yl 4-~3-(l-Pyrrolidinyl)pro~oxyl phenyl Ketone Dioxalate.
The title compound was prepared from 4-[3-~1-pyrro-lidinyl)propoxy]benzoic acid hydrochloride (Part C) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Part A) in 55% yield by essentially following the procedure outlined in Example 2, Part C.
CA 02236007 l998-04-27 w 097nso33 PCT~USs6/l7sss lH N~R (DMSO-d6) ~ 8.11 (d, ~ = 7.5 Hz, lH), 7.74 (d, ~ = 8.7 - Hz, 2H), 7.48-7.33 (m, 5H), 7.01 (d, ~ = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.30 (t, J = 3.8 Hz, 2H), 4.11 (t, ~ =
5.2 Hz, 2H), 3.S4 (t, ~ = 4.2 Hz, 2H), 3.43-3.15 (m, 8H), 2.18-2.05 (m, 2H), 2.02-1.85 (m, lOH); FDMS 555 (M+l; 100);
Anal. Calcd ~or C34H3gN2O3S 2C2H2O4: C, 62.11; H, 5.76; M, 3.81. Found: C, 62.08; H, 5.76; N, 3.84.
~.Yr _ 1Q 5 Preparation o~ 2-t4-~2-(l-pyrrolidinyl)ethoxy~phQn benzo~b~-thiophen-3-yl 4-~3 (l-Pyrrolidi~yl)propyll phenyl Ketone Dioxalate.
N~
" "'" N ~
Part A. 2-(4-Methoxyl?henyl)benzo~b~thiophen-3-yl 4-~3-(1-~y lolidinyl)propyl~henyl Ketono.
O~_~N/~
~ OMe By essentially ~ollowing the procedure outlined in Example 2, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3i Part A) and 4-[3-(l-pyrrolidinyl)propyl]benzoic acid hydrochloride in 33%
yield as a viscous oil.
FDMS 456 (M+l; 100~; Anal. Calcd :Eor C2gH2gNO2S: C, 76.45; H, 6.42; N, 3.07. Found: C, 76.21; H, 6.39i N, 3.14.
W O 97/25033 PCT~US96/17995 Part B. 2-(4-Hydroxynphenyl)benzo~bJthiophen-3-yl 4-~3-(1-Pyrrolidinyl)prO~yl~phenyl Ketone.
N
~1~
A 100 mL round bottom flask cont~;n'ng 300 mg (0.66 mmol) of 2-( 4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part A) was filled with 20 g of pyridine hydrochloride. The flask was heated to 160 ~C
to melt the solid. After 16 h, the reaction was cooled to warm temperature, diluted with 50 mL of H20, and transferred to separatory funnel cont~n'ng 50 mL H20 and 50 mL of EtOAc.
The two layers were separated and the a~ueous layer was extracted with EtOAc (2 x 50 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo to give 325 mg o~ a yellow oil. Purification by radial chromatography (sio2i gradient of 2-10% MeOH in CH2Cl2) afforded 200 mg (0.45 mmol; 69~) of the title compound as a viscous yellow oil.
FDMS 441 (M+; 100); Anal. Calcd for C2gH27NO2S: C, 76.16; H, 6.16; N, 3.17. Found: C, 76.59; H, 6.27; N, 3.07.
P~rt C. 2-~4-~2-(1-Pyl oliainyl)ethoxylphenyll-benzolblthiophen-3-yl 4- t3- (l-Pyrrolidinyl)propyl~-phenyl Ketone Dioxalat~a.
By essentially following the procedure outlined in Example 3, Part D, the free base of the title compound was prepared from 2-(4-hydroxyphenyl)benzo~b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 36% yield as a viscous oil following radial chromatography (sio2; gradient of 5-15% MeOH in CH2Cl2). The free base was converted to the W ~ 97/25033 PCTAUS96117995 dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.12 (d, ~ = 7.8 Hz, lH), 7.69 (d, ~ = 7.9 Hz, 2H), 7.45-7.34 (m, 7H), 7.30 (d, J = 8.0 Hz, 2H), 6.99 (d, ~ = 8.4 Hz, 2H), 4.32-4.21 (m, 2H), 3.57-3.43 (m, 2H), 3.35-3.12 (m, 8H), 3.07 (t, ~ = 6.2 Hz, 2H), 2.66 (t, ~ =
6.5 Hz, 2H), 2.04-1.80 (m, 10H); FDMS 539 (M+l; 66); Anal.
Calcd for C3gH3gN2O2S 2C2H2O4: C, 63.50; H, 5.89i N, 3.90.
Found: C, 63.75; H, 6.12; N, 3.85.
~ ple 6 2-[4-~2-(1-Pyrrolidinyl)Qthoxy~phQnyl]benzo[b~thio-phen-3-yl 4-[(1-~y~liainyl)methyl]phenyl Ketone Dioxalate.
''~--'N ~
Part A. Methyl 4-l(l-~y 7 ,~ Linyl)methyl~benzoate.
~ ~ OMe A solution of 6.20 mL (44.5 mmol) of TEA and 4.70 g (21.8 mmol) of 4-carboxybenzyl bromide in 50 mL of DMF was treated with 2.10 mL (25.2 mmol) of pyrrolidine at 50 ~C for 3 h. The reaction mixture was cooled, evaporated in vacuo, and the residue was taken up in 50 mL of MeOH. The solution was treated with a rapid stream of HCl (g) for 15 min, the reaction vessel was sealed and the reaction stirred at ambient temperature for 16 h. Evaporation of the solvent afforded 2.56 g of an oil which was purified by radial W O 97/25033 PCTnUS96/17995 chromatography (sio2; 80:18:2 hexanes-THF-TEA) to afford 2.30 g (10.5 mmoli 48%) o~ the title compound as an oil.
FDMS 219 (M~; 100) Part B. 4~ y~Lolidinyl)m~th~llbenzoic Acid Hydrochloride.
o ~ ~ OH
By essentially following the procedure outlined in Example 4, Part C, the title compound was prepared from methyl 4-[(1-pyrrolidinyl)methyl]benzoate in 22% yield as a white solid ~ollowing ion exchange chromatography.
FDMS 206 (M+1; 100)i Anal. Calcd ~or C12H1sNO2 HCl. 0-2 H2O:
C, 58.75; H, 6.74; N, 5.71. Found: C, 58.95; H, 6.56; N, 5.54.
Part C. 2-t4-~2-(1-Pyrroli~inyl) ethoxyl~henyl~-benzo~b~thioph~n-3-yl 4-~(1-Pyrroliainyl)methyl3phenyl Kotonc Dioxalate.
By essentially ~ollowing the procedure outlined in Example 2, Part C, the ~ree base o~ the title compound was prepared ~rom 4-[(1-pyrrolidinyl)methyl]benzoic acid hydrochloride (Part B) and 1-[2- L4- (~enzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 44%
yield. The ~ree base was conver~ed to the dioxalate salt according to the conditions described in Example 1, Part C.
lH MMR (DMSO-d6) ~ 8.10 (dd, J = 6.5, 1.8 Hz, lH), 7.68 (d, = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, lH), 7.52-7.36 (m, 4H), 7.32 (d, ~ = 8.7 Hz, 2H), 6.90 (d, ~ = 8.7 Hz, 2H), 4.27-4.15 (m, 4H), 3.53-3.43 (m, 2H), 3.34-3.20 (m, 4H), 3.20-2.94 (m, 4H), 1.96-1.80 (m, 8H); FDMS 510 (M+; 100); Anal. Calcd ~or C32H34N2O2S 2C2H2O4: C, 62.60; H, 5.54; N, 4.06. Found: C, 62. 79; H, 5.56; N, 4.00.
~rle 7 - 5 Preparation of 2-t4-[2-(1-Pyrrolidinyl)ethoxy]phenyl~-benzo~b]thiophen-3-yl 4-12-(l-Pyrroli~inyl)Qthyl3 ~henyl Ketone Dioxalate.
_ N ~ 2 ~2H2O4 ~ ~N ~
Part A. Methyl 4-t2-(1-~Y lolidinyl)ethyllbenzoate.
~ OMe lo G
By essentially following the procedure detailed in Example 6, Part A, the title compound was prepared from 4- [2-bromoethyl)benzoic acid and pyrrolidine in 39% yield as an oil following radial chromatography (SiO2; 89:9:2 hexanes-THF-TEA).
FDMS 234 (M+1; 100) Par~ B. 4-t2-(l-Pyrrolidinyl)ethyl]benzoic Acid Hydrochloride.
~ N HCl W O 97/25033 PCT~US96/17995 By essentially ~ollowing the procedure outlined in Example 4, Part C, the title compound was prepared from methyl 4-~2-(1-pyrrolidinyl)ethyl]benzoate (Part A) in 24%
yield as a white solid ~ollowing ion exchange chromatography.
FDMS 220 (M+l; 100); Anal. Calcd for Cl3Hl7NO2-HCl-O.lH2O: C, 60.63i H, 7.12; N, 5.44. Found: C, 60.48; H, 7.08; N, 5.32.
Part C. 2-14-12-(1-1y~ olidinyl)Qthoxylphenyll-benzo~blthiophen-3-yl 4-[2-(1-Pyrrolidinyl)ethyl]-ph~nyl Ketone Dioxalate.
By essentially following the procedure outlined in Example 2, Part C, the free base of the title compound was prepared from 4-[2-(1-pyrrolidinyl)ethyl]benzoic acid hydrochloride (Part B) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 45~
yield. The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.10 (dd, J = 6.4, 2.0 Hz, lH), 7.72-7.61 (m, 3H), 7.45-7.39 (m, 4H), 7.31 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.27-4.04 (m, 4H), 3.53-3.40 (m, 2H), 3.31-3.17 (m, 4H), 3.10-2.92 (m, 2H), 2.87-2.64 (m, 2H), 1.99-1.72 (m, 8H), 1.55-1.40 (m, 2H); FDMS 524 (M+; 100);
Anal. Calcd for C33H36N2O2S-2C2H2O4: C, 63.06; H, 5.72; N, 3.97. Found: C, 63.33; H, 5.67; N, 3.90.
~r rle 8 Preparation of 1-[2-12-Methyl-4-[2-[4-[2-(1-pyrro-lidinyl)~thoxy~phenyllbQnzolb]thiophQn-3-ylmethyl~l-phenoxy]ethyl]~yrrolidine Dioxalate.
Me ~ ~o~ N~3 2 C2H2~4 ~ N~
Part A. 2-(4-Methoxyphenyl)bQnzol~]thioph~n-3 3-Bromo-4-methoxyphQnyl Ketone.
Br ~Oe 5 The title compound was prepared in 76% yield :Erom 2-(4-metho~Z7phenyl)]benzo[b]thi0phene (Example 3, Part A) and 3-bromo-4-methoxybenzoic acid by essentially following the procedures detailed in Example 2, Part C.
10 lH NMR (DMSO-d6) ~ 8.12 (d, J = 7.3 Hz, lH), 7.91 (s, lH), 7.69 (dd, .:T = 8.7, 1.8 Hz, lH), 7.56 (d, J = 8.2 Hz, lH), 7.52-7.41 (m, 2H~, 7.37 (d, ~ = 8.6 Hz, 2H), 7.05 (d, ~ = 8.7 Hz, lH), 6.94 (d, ~J = 8.6 Hz, 2H), 3.89 (s, 3H), 3.75 (s, 3H); FDMS 452 (M-l), 454 (M~l).
Part B. 2-(4-Methoxyphenyl)bQnzo r~] thioFhen-3-yl 3-Methyl-4-methoxyph~nyl Ketone.
Me ~ OMe A slurry of 750 mg (1.65 mmol) of 2-(4-methoxyphenyl)-20 benzo[b]thiophen-3-yl 3-bromo-4-methoxyphenyl }cetone (Part A) in 15 mL of toluene was treated with 75 mg (O.07 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0. 54 mL (3.9 mmol) of tetrabutyltin. The tube was sealed and the contents were heated at 130 ~C for 15 h. The reaction was cooled, evaporated in vacuo, and the residue was taken up in 75 mL of Et20. Saturated a~ KF (75 mL) was added and the mixture was stirred vigorously for 6 h. The two layers were separated and the organic layer was washed with H2O (3 x 75 mL). The organic phase was dried over Na2SO~ and evaporated in vacuo to give 934 mg of an oil which was purified by radial chromatography (sio2; 25% EtOAc in hexanes) to af~ord 602 mg (1.55 mmol; 94%) of the title compound as a white solid.
FDMS 388 (M+), 389 (M~1); HRMS calcd for C24H21O3S, 389.1211.
Found 389.1180.
Part C. 2-(4-Hydroxyphenyl)benzo[b]thiophen-3-yl 3-Methyl-4-hydroxyphenyl Ketone.
Me ~ H
A 0 ~C solution of 700 mg (1.80 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-methoxyphenyl ketone (Part B) in 25 mL of CH2Cl2 was treated with 7.2 mL of BBr3 (1.0 M in CH2C12). The reaction was stirred at 0 ~C for 6 h, then cooled to -78 ~C, and was treated carefully with 50 mL of MeOH. The mixture was allowed to warm to room tem-perature over 1.5 h, and the volatiles were evaporated in vacuo. The dark red residue (monomethyl ether) was taken up in 75 mL dichloroethane and was treated with AlC13 and ethanethiol according to the conditions of Example 1, Part D
to afford 675 mg of an oil. Purification by radial chromatography (sio2i gradient of 20-30~ EtOAc in hexanes) WO 97/25033 PCT~US96/17995 afforded 410 mg (1.14 mmol; 63%) of the title compound as an orange solid.
.
FDMS 360 (M+); Anal. Calcd ~or C22H1603S: C, 73.31i H, 4.47.
Found: C, 73.57; H, 4.66.
Part D. 2-~4-12-(1-~y~ olidinyl)ethoxy]phenyl]-benzolb~thiophen-3-yl 3-Methyl-4-l2-(l-pyrroli~inyl) ethoxylphenyl Ketone Dioxalate.
e ~
~'"--'N
By essentially ~ollowing the procedure detailed in Example 3, Part D, the ~ree base o~ the title compound was prepared from 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-hydroxyphenyl ketone (Part C) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 83% yield as an oilfollowing radial chromatography (sio2; 10~ MeOH and 0.5% TEA
in CH2Cl2). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.10 (d, ~ = 7.8 Hz, lH), 7.64 (s, lH), 7.56-7.34 (m, 6H), 7.00-6.92 (m, 3H). 4.13 (t, ~ = 5.4 Hz, 2H), 4.08 (t, J = 5.7 Hz 2H), 2.95-2.78 (m, 4H) 2.68-2.56 (m, 8H), 2.12 (s, 3H), 1.78-1.64 (m, 8H); FDMS 555 (M+; 100) HRMS C34H3gN2O3S: 555.2681. Found: 555.2706.
Part E. 1-[2-12-Methyl-4-[2-14-12-(1-pyl-rolidinyl)-ethoxy~phenyll~enzo~blthiophen-3-ylmethyl]phenoxy}-~thyl~pyrrolidine Dioxalata.
By essentially following the conditions detailed in Example 2; Part D, the ~ree base o~ the title compound was CA 02236007 l998-04-27 W097/25033 PCT~US96/17995 prepared from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophen-3-yl 3-methyl-4-[ 2-( l-pyrrolidinyl)ethoxy:lphenyl ketone (Par~ D) in 88% yield as an oil :Eollowing radial chromatography (sio2; 10~ MeOH and 0.5% TEA in CH2Cl~). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
H NMR (DMSO-d6) ~ 8.04-7 .95 (m, lH), 7.64-7.56 (m, lH), 7.51 (d, ~ = 8.1 Hz, 2H), 7.42-7.32 (m, 2H). 7.14 (d, ~ = 8.2 Hz, 10 2H), 6.97 (s, lH), 6.92-6.80 (m, 2H), 4.36 (t, .J = 4.8 Hz, 2H), 4.22 (t, .J = 5.0 Hz 2H), 4.18 (s, 2H), 2.95-2.78 (m, 4H) 2.68-2.56 (m, 8H), 2.12 (s, 3H), 1.78-1.64 (m, 8H); FDMS 541 (M+; 100), 631 (M+ + ~2H2O4); Anal. Calcd for C34H~oN2O2S 2C2H2O4 1.9H2O: C, 63.78; H, 6.20; N, 3.93.
15 Found: C, 63.81; H, 6.47; N, 3.82.
RY~ _ le 9 Preparation o~ 2-14-r2-(1-Pyrrolidinyl)ethoxy~phQnyl]-benzo~b~thio~hen-3-yl 6-t2-(l-pyrrolidinyl)eth ~yrid-3-yl Ketone Dioxalate.
" " ~' N ~
Part A. 2-(4-Methoxyphenyl)benzo[b~thiophen-3-yl 6-Chloro-pyrid-3-yl Ketone.
?, ~1 By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared ~rom 6-CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/17995 chloronicotinic acid and 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 31% yield as a yellow solid following ~lash chromatographY (SiO2; CH2C12).
FDMS 379 (M+, 100), 381; Anal. Calcd ~or C21H14ClNO2S: C, 66.40; H, 3.71; N, 3.69 Found: C, 66.20; H, 3.71i N, 3.79.
Part B. 2-(4-Methoxy~henyl)benzolb]thiophen-3-yl 6-12-(1-Pyrroli~inyl)ethoxy]pyria-3-yl Ketone.
0 ~ "~ ,N
OMe A solution o~ 0.50 mL (4.30 mmol) of 1-(2-hydroxyethyl)-pyrrolidine in 10 mL o~ xylenes was treated with 50 mg (2.20 mmol) of Na. The mixture was heated to 50 ~C until all the Na had disappeared, cooled to room temperature, and then treated with a solution of 420 mg (1.10 mmol) of 2-~4-methoxyphenyl)benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) in 5 mL o~ xylenes. The reaction was heated to 50 ~C for 2 h and was evaporated in vacuo. The residue was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 810 mg of a yellow solid. Purification by radial chromatography (sio2; gradient of 1-5% MeOH in CH2Cl2) gave 525 mg (1.09 mmol; 99%) of the title compound as an amber oll .
FDMS 459 (M+; 100); Anal. Calcd ~or C27H26N2O3S: C, 70.72; H, 5.71; N, 6.11. Found: C, 70.43i H, 5.60; M, 6.02.
Part C. 2-(4-Hyd vxy~henyl)benzo[b]thiophen-3-yl 6-[2-(1-Pyrrolidinyl)ethoxy)pyrid-3-yl Ketone.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 ~~~ ~
OH ~
By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-[ 2-(1-pyrrolidinyl)-ethoxy]pyrid-3-yl ketone (Part B) in 89% yield as a yellow solid ~ollowing radial chromatography (sio2~ 5% MeOH in CH2Cl2 ) -FDMS 445 (M+l; lOO)i HRMS calcd for C26H2sN203S: 445.1586.
Found: 445.1569.
Part D. 2-t4-~2-(1-Pyrrolidinyl)ethoxy]phenyl~-benzolbl thiophen-3 -yl 6- ~2- ( 1-~y~ lolidinyl)ethoxy~-pyri~- 3 -yl Ketone Dioxalate.
By essentially following the procedure detailed in Example 3, Part D, the free base of the title compound was prepared from 2-(4 -hydroxyphenyl)benzo[b]thiophen-3-yl 6-[2-(1-pyrrolidinyl)ethoxy)pyrid-3-yl ketone (Part C) and 1-( 2-chloroethyl)pyrrolidine hydrochloride in 84% yield as an oil following radial chromatography (sio2; gradient of 5-20% MeOH
in THF). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
FDMS 542 (M+1); Anal. Calcd for C32H3sN303S-2C2H204 1.5H20: C, 57.74i H, 5.65; N, 5.61. Found: C, 57.68; H, 5.42; N, 5.49.
Example 10 Preparation of 1-~2-14-~[2-~4-[2-(1-Pyrroli~inyl)-ethoxy]~henyl]benzo[b~thiophen-3-yl]thio]phenoxy~-othyl~pyr~olidine Dioxalate.
W O 97/25033 PCT~US96/17995 o~ Nl3 ~~
Part A. 3-Bromo-2-(4-methoxyphenyl)benzo~b]thiophene.
A slurry of 5.0 g (20.8 mmol) of 2-(4-methoxyphenyl)-benzo[b]thiophene (Example 3, Part A) in 400 mL o:E CHCl3 at 0 ~C was treated slowly with 1.6 mL of Br2, resulting in a yellow solution. The reaction was stirred at 0 ~C ~or 1 h and then washed sec~uentially with 200 mL o:E 1.0 N aq Na2S2O3, 200 mL of 1.O N aq NaHC03, and 200 mL of H2O- A~ter drying over Na2SO4, evaporation of the solvent in vacuo gave 6. 24 g (19.5 ~nol; 94%) o~ an off-white solid which was clean by thin layer chromatography.
mp 84.5-86.5 ~C; lH NMR (CDCl3) ~i 7.86 (d, J = 7.9 Hz, lH), 15 7.80 (d, J = 7.9 Hz, lH), 7.72 (d, J = 8.7 Hz, 2H), 7.50-7.37 (m, 2H), 7.02 ( d, J = 8.7 Hz, 2H), 3.88 (s, 3H); FDMS 318 (100), 320 (M+l); Anal. Calcd For ClsHllBrOS: C, 56.44; H, 3.47. Found: C, 56.25; H, 3.38.
Part B. Methyl 4-[~2-(4-Methoxyphenyl)benzo[b]thio-~h~n-3-yl~thio3phQnyl Ether.
To a solution of 1.O g (3.1 mmol) of 3-bromo-2-(4-methoxyphenyl)benzo[b]thiophene (Part A~ in 20 mL of THF was added dropwise 2.9 mL of 1.6 M n-BuLi in hexanes (4.7 mmol) at -70 ~C. The mixture was stirred at -70 ~C for 10 min and then treated with 0.87 g (3.13 mmol) of solid bis(4-methoxyphenyl)disulfide. Stirring was continued at -70 ~C
for 0.5 h and then the reaction was allowed to warm slowly to room temperature. The reaction was ~uenched with 1 mL of saturated aq NH4Cl and 1 mL of MeOH and was concentrated in vacuo. The residue was partitioned between 100 mL of EtOAc and 100 mL of H20. The organic layer was separated, dried over MgSO4, and concentrated in vacuo to afford an oily solid which was subjected to flash chromatography (SiO2; gradient of 1-5% EtOAc in hexanes) to afford 0.82 g of the title compound as an oil.
FDMS 378 (M+l; 100).
Part C. 4-[~2-(4-Hy~roxyph~nyl)benzo~b3thiophen-3-yl]thiol~henol.
S~O~
OH
A solution of 0.82 g (2.2 mmol) of methyl 4-[[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]thio~phenyl ether (Part B) in 50 mL of dichloroethane was treated with 1.2 mL (3.3 g;
13 mmol) of BBr3 at 0 ~C for 5 h. The reaction was ~uenched by the careful addition of 15 mL of MeOH. Evaporation o~ the solvent in vacuo gave a residue which was subjected to flash chromatography (sio2i 1~ MeOH in CHCl3) to afford 0.47 g of the desired product as a solid.
FDMS 350 (M+; 100); Anal. Calcd For C20Hl4o2s2 0~5MeOH: C, 67.19; ~, 4.40. Found: C, 67.04; H, 4.25.
Part D. l-12-[4-1l2-14-t2-(l-~yllolidinyl)ethoxy]-ph~nyl]benzolblthioph~n-3-yl~thio~phonoxy~ethyl]-pyrrolidine Dioxalate.
By essentially following the procedure detailed in Example 4, Part B, except using 1-(2-hydroxyethyl)-pyrrolidine, the ~ree base of the title compound was prepared ~rom 4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]thio]phenol (Part C) and 1-(2-hydroxyethyl)pyrrolidlne in 43% yield as an oil following radial chromatography (sio2; 3% TEA and 37% THF
in hexanes). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.12-8.00 (m, lH), 7.76-7.65 (m, 3H), 7.47-7.38 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 4.36 (t, ~ = 5.0 Hz, 2H), 4.19 (d, J = 5.1 Hz, 2H), 3.56 tt, J = 4.8 Hz, 2H), 3.47 (t, ~ =
4.9 Hz, 2H), 3.42-3.18 (m, 8H), 2.03-1.82 (m, 8H); FDMS 545 (M+l), 636 (M+91, 100); Anal. Calcd For C32H36N2O2S2-2C2H2O4-0.4H2O: C, 59.07; H, 5.62; M, 3.83.
Found: C, 59.02; H, 5.49; N, 4.22.
RY~mple 11 ~reparation o~ 2-[4-[3-[4-[2-(l-Pyrrolidinyl)-ethoxyJphenoxy~benzo[b~thiopllen-2-yl]phenoxyl~thyl~-oli~ine Dioxalate.
~ o~ ~N ~ 2 C2H204 ~~ ~>
Part A. Benzolb~thiophen-3-yl 4-Methoxyph~nyl Ether.
W O 97/25033 PCTnUS96/1799S
O ~ OMe A mixture of 4.00 g (19.7 mmol~ of 3-bromobenzo[b]-thiophene, 4. 96 g (40 mmol) of 4-methoxyphenol, 5.52 g (40 mmol) of K2CO3, and 0.20 g (1.0 mmol) of CuI was heated to 140 ~C and sonicated at this temperature for 2 h. The reaction was allowed to cool, taken up in CH2Cl2, and the mixture was washed several times with 0.5 N NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo to an oil that was sub]ected to chromatography (sio2; gradient of 0-5~ EtOAc in hexanes). The fractions cont~ln;ng the desired product were combined, evaporated in vacuo, and the residue was recrystallized from hexanes to afford 500 mg (1.95 mmol; 10%) of the title compound as a white solid.
Anal. Calcd For ClsH21O2S: C, 70.29; H, 4.72. Found: C, 70.56; H, 4.88.
Part B. 2-Iodobenzotb]thioph~n-3-yl 4-Methoxyphenyl Ether.
O ~ OMe A solution of 133 mg (0.52 mmol) of 3-(4-methoxy-phenoxy)benzo[b]thiophene (Part A) in 3 mL of THF was treated with 0.33 mL of 1.6 M n-BuLi in hexanes (0.54 mmol) at -78 ~C
for 15 min and then treated with 138 mg (0.54 mmol) of I2 in 3 m~ of THF. The reaction was allowed to gradually warm to room temperature and then partitioned between brine and EtOAc/hexanes. The two phases were separated, the organic phase was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from hexanes to CA 02236007 l998-04-27 afford 143 mg (O.37 mmol; 7296) of the title compound as a solid.
Anal. Calcd For ClsH20Io2s: C, 47.14; H, 2.90. Found: C, 47.21; H, 2. 98.
Part C. (4-MethoxyphQnyl)~oronic Aci~.
MeO ~ B(OH)2 By essentially following the procedure detailed in Example 1, Part A, the title compound was prepared from 4-iodoanisole.
Part D. 2-(4-Methoxyphenyl)bQnzo~b]thiophen-3-yl 4-Methoxyphenyl Ethor.
~ ; OMe OMe By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from 2-iodo-3-(4-methoxyphenoxy)benzo[b]thiophene (Part B) and (4-methoxyphenyl)boronic acid (Part C) in 70% yield ~ollowing chromatography (sio2i 5% EtOAc in hexanes).
Anal. Calcd For C22HlgO3S: C, 72.90; H, 5.01. Eound: C, 72.82; H, 5.12.
Part E. 4-1[2-(4-Hyd.roxyph~nyl)bonzolb]thiophen-3-yl]oxy~phenol.
W O 97/25033 PCT~US96/17995 By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from 2-(4-methoxyphenyl)-3-(4-methoxyphenoxy)benzo[b]thiophene (Part D) in 87% yield following radial chromatography (sio2i 25% EtOAc in hexanes).
FDMS 334 (M+, 100); Anal. Calcd For C20H14O3S: C, 71.84; H, 4.22. Found: C, 71.94; H, 4.35.
Part F. 1-~2-[4-t3-t4-~2-(l-~y olidinyl)ethoxy]-phenoxy~b~nzo[b]thio~hen-2-yl~phQnoxy~ethyl~-pyrrolidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part D the ~ree base of the title compound was prepared from 4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl~oxy]phenol (Part E) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 52% yield following radial chromatography (SiO2; gradient o~ 2-10~ MeOH in CH2Cl2). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.96 (d, J = 8.0 Hz, lH), 7.68 (d, J = 8.5 Hz, 2H), 7.40-7.23 (m, 3H), 7.04 (d, ~ = 8.5 Hz, 2H), 6.91-6.80 (m, 4H), 4.38-4.13 (m, 4H), 3.55-3.41 (m, 4H), 3.36-3.14 (m, 8H), 1.97-1.78 (m, 8H); FDMS 529 (M+1; 100); Anal. Calcd For C32H36N2O3S-2C2H2O4: C, 61.00; H, 5.69; N, 3.95. Found:
C, 61.06; H, 5.86i N, 4.17.
Example 12 Preparation of 1-~2-~4-~1-12-~4-[2-(1-Pyrrolidinyl)-ethoxy~henyl]benzo~b~thiophen-3-yl~ethenyl]phenoxy~-~thyl~pyrrolidine Dioxalate.
~~V
Part A. Methyl 4- r 1 - [2-(4-Methoxyphenyl)benzo[b]-thiophen-3-ylJQthenyllphenyl Ether.
~ O
A solution of 1.20 g (3.36 mmol) of methyltriphenyl-phosphonium bromide in 50 mL of THF was treated with 0.45 g (4.01 mmol) of potassium tert-butoxide and the mixture stirred at room temperature for 0.5 h. To this was added dropwise 0.80 g (2.14 mmol) o~ 2-(4-methoxyphenyl)benzo[b]-thiophen-3-yl 4-methoxyphenyl ketone (Example 3, Part B) in 10 mL of THF and the reaction was stirred at room temperature for 18 h and then heated at gentle reflux ~or 48 h. The reaction was quenched by 100 mL of brine. The two layers were separated and the organic layer was dried over Na2SO4.
Concentration in vacuo gave 1.36 g of an oil which was pu-rified by radial chromatography (SiO2; 10% EtOAc in hexanes) to afford 0.610 g (1.64 mmol; 77~) of the desired product as an oil.
FDMS 372 ~M+; 100).
Part B. 4-~1-[2-(4-~ydroxylahenyl)benzo[bJthiophen-3-yl]ethenyl~phenol.
., By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from methyl 4-[1-[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]-ethenyl]phenyl ether (Part A) in 67% yield as a yellow solidfollowing radial chromatography (sio2; gradient of 20-40 EtOAc in hexanes).
FDMS 344 (M+; 100).
Part C. 1-~2-[4-~ 2-14-r2-(1-~ L~lidin~l)ethoxy~-phenyl]b~nzotb]thiophen-3-yl]ethenyl]ph~noxy]ethyl]-~rrolidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part D, the free base of the title compound was prepared from 4-[1-[2-(4-hydroxyphenyl)benzoLb]thiophen-3-yl]ethenyl]phenol (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 67% yield as an oil following radial chromatography (Sio2i gradient of 2-10% MeOH in CH2Cl2). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.95 (d, J = 7.5 Hz, lH), 7.49 (d, J = 8.0 Hz, 2H), 7.38-7.16 (m, 5H), 6.95 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 5.99 (s, lH), 5.14 (s, lH), 4.32-4.10 (m, 4H), 3.54-3.36 (m, 4H), 3.29-3.12 (m, 8H), 1.98-1.72 (m, 8H); FDMS 539 (M+l; 100)i Anal- Calcd For C34H38N2O2S-2C2H2O4:
C, 63.49; H, 5.89: N, 3.90. Found: C, 63.78i H, 6.14i N, 4.10.
W O 97/25033 PCT~US96~17995 ~m~l~ 13 Preparation of 4-[2-(Hexahydro-lH-azopin-l-yl)ethoxy]-; ~henyl 2-t4-t2-(1-Pyrrolidinyl)ethoxy]phenyl]-benzo[blthiophen-3-yl Ketone DioxalatQ.
0 ~ ,~~ ,N ~
~N ~
Part A. 4- r2- (H~xahy~ro-lH-azepin-l-yl)ethoxy~ph 2-(4-Nethoxyphenyl)b~nzoIb]thiophen-3-yl Ketone.
O ~
By essentially ~ollowing the procedure detailed in Example 1, Part C, the title compound was prepared ~rom 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[2-(hexahydro-lH-azepin-l-yl)ethoxy]benzoic acid hydrochloride in 35~ yield as an oil following radial chromatography (sio2i gradient of 1-10% isopropanol in CH2Cl2)-FDMS 485 (M+; 100).
Part B. 4-~2-(Hexahydro-lH-azepin-l-yl)ethoxy]phenyl 2-[4-t2-(1-Pyrrolidinyl)ethoxy~phenyllbenzoIb]thio-phen-3-yl Ketone Dioxalate.
Deprotection of the 4-[2-(hexahydro-lH-azepin-l-yl)-ethoxy]phenyl] 2-(4-methoxyphenyl)benzoIb]thiophen-3-yl ketone (Part A) was effected according to the conditions described in Example 1, Part D. The resulting phenol was W O 97/25033 PCT~US96/17995 alkylated with 1-(2-chloroethyljpyrrolidine hydrochloride according to the procedure detailed in Example 3, Part D to afford the free base of title compound which was converted to the dioxalate salt according to the methods described in 5 Example 1, Part C.
FDMS 569 (M+; 100); Anal. Calcd For C3sH3gN2O3S 2C2H2O4 H2O: C, 60.37i H, 6.10; N, 3.61. Found: C, 60.05; H, 5.71; N, 3.84 HRMS Calcd for C3sH40N2o3s: 568.2838. Found: 568.2869.
~ le 14 Preparation of 4-~2-(1-~y~ olidinyl)ethoxy]phenyl 2-~4-~3-(1-Pyrrolidinyl)propyl]~hQnyl]benzolb]thio-phen-3-yl Ketone Dioxalate.
0 ~ ,~_,N ~
M~ 2 C2H204 Part ~. :L- (tran~-4 -Bromoci~namoyl) pyrrolidine .
Br ~N~
A mixture of 5.0 g (22.0 mmol) oi~ 4-bromocinn~m;c acid, 6 rnL of oxalyl chloride and 3 drops of DMF in 40 mL of CH2C12 was heated to gentle reElux until gas evolution ceased. The volatiles were removed in vacuo and the residue was taken up in 50 mL oi~ CH2C12. Pyrrolidine (10 rnL; 120 Im[Lol) was added and the mixture was stirred overnight at room temperature.
The reaction mixture was evaporated in vacuo and chromatographed to a:E~ord 5.36 g rl9.1 mmol; 8796) o~ the title compound.
FDMS 279 (M-1), 281 (M+1); Anal. Calcd For C13H14BrNO: C, 55.73; H, 5.04i M, 5.00. Found: C, 56.00; H, 5.06; N, 5.04.
CA 02236007 l998-04-27 Part B. 1-[trans-4-(Benzolb]thiophen-2-yl)cinn~moyl]-pyrroli~ine.
¢~1 N~>
b-By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-(trans-4-bromo-c;nn~moyl)pyrrolidine (Part A) in 43% yield following chromatography.
FDMS 333 (Mt), 334 (M+13.
Part C. 1-13-[4-(Benzo[b]thlophen-Z-yl)phenyl]-propyl]pyrrolidine.
~ N ~
A solution of 1.2 g (3.6 mmol) of 1-[trans-4-(benzo[b]thiophen-2-yl)cinn~moyl]pyrrolidine (Part B) in 15 mL of THF was treated with 75 mg (2.0 mmol) of LiAlH4 at -15 ~C. After complete consumption of starting material, the reaction was cautiously ~uenched with H2O. The mixture was extracted with EtOAc and the combined organic layers were evaporated in vacuo . Chromatography afforded 600 mg (1.9 mmol; 52% yield) of the desired product.
FDM~ 320 (M-1).
Part D. 4-12-(1-Pyrrolidinyl)ethoxy~phenyl 2-14-13-(1-Pyrroli~inyl)propyl~phe~yl]benzo~b]thiophen-3-yl ~etone Dioxalate.
By essentially following the procedure outlined in Example 1, Part C, the free base of the title compound was W O 97/2~033 PCTAJS96/17995 prepared from l-[3-[4-(benzo[b]thiophen-2-yl)phenyl]propyl]-pyrrolidine (Part C) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 11% yield. Conversion to the dioxalate salt followed from the procedure described in Example 1, Part C.
mp 105 - 112 ~C; FDMS 536 (M+l; 100); Anal. Calcd For C32H3gN2O2S 3C2H2O4: C, 58.16; H, 5.65; N, 3.57. Found: C, 58.06; H, 5.15; N, 3.93.
... ple 15 Prcparation of 4-[2-(1-Pyrroli~inyl)ethoxy]phenyl 2-~4-[3-(1-Pyrrol idinyl ) propoxy~ph~nyl~benzo[b]thio~
phen-3-yl Kotone Dioxalate.
0~ ,N ~ 2 C2H
O'--" "~'N
Part A. 2-(4-Methoxyphenyl)benzoCblthiophen-3 4-C2-(l-Pyrrolidinyl)ethoxy]phenyl Ketone.
, ~ ,N
OMe By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b3thiophene (Example 3, Part A) and 4-C2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59%
yield as an oil following radial chromatography (sio2;
gradient of 2-5% MeOH in CH2Cl2).
Part B. 2-(4-Hyd~y~henyl)bonzo[b]thiophen-3-yl W O 97~033 PCTAUS96/17995 4-[2-(1-Pyrrolidinyl)ethoxylphenyl Ketone.
0 ~ ,~ ,N
~ OH
By essentially following the procedure detailed in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo~b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl ketone (Part A) in 33% yield as an oil ~ol-lowing radial chromatography (sio2; gradient of 2-10~ MeOH in CH2Cl2 ) FDMS 443 (M+; 100); Anal. Calcd For C27H2sNO3S: C, 73.11; H, 5.68; N, 3.16. Found: C, 73.11; H, 5.89; N, 3.20.
Part C. 4-~2-(1-1y ~ in~l)ethoxy~phenyl 2-[4-t3-(1-Pyrroli~inyl)propoxylphanyl~benzo~blthiophen-3-yl Ketone Dioxalat~.
By essentially following the procedure detailed in Example 3, Part D, the ~ree base o~ the title compound was prepared ~rom 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(l-pyrrolidinyl)ethoxylphenyl ketone (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 69% yield followingradial chromatography (sio2i gradient o~ 5-10% MeOH in CH2C12). The product was converted to the dioxalate salt according to the conditions o~ Example 1, Part C.
lH NMR ~DMSO-d6) ~ 8.04 (d, J = 8.8 Hz, lH), 7.68 (d, J = 8.7 Hz, 2H), 7.42-7.29 (m, 5H), 6.95 (d, J = 8.7 Hz, 2H), 6.89 ~ (d, J = 8.6 Hz, 2H), 4.35-4.23 (m, 2H), 3.98 (t, J = 5.5 Hz, 2H), 3.58-3.42 (m, 2H), 3.34-3.09 (m, 10H), 2.13-1.99 (m, 2H), 1.95-1.76 (m, 8H); FDMS 555 (M+l; 100); Anal. Calcd For C34H3gN2O3S 2C2H2O4 1.5H2O: C, 59.91; H, 5.95i N, 3.68. Found:
C, 59.72; H, 5.70i N, 3.48.
~ v~ le 16 Pre~aration of 4-~2-(1-Pyrrolidinyl)ethoxy]phenyl 2-[6-[2-(1-Pyrrolidinyl)ethoxy] pyrid-3 -yl 3benzo[b3-thiophen- 3 -yl Ketone Dioxalate.
O ~ N ~
S ~ 2 C2H2O4 N O~-~-'N ~
Part A. 5-8romo~yrid-2-yl 2-(1-~y olidinyl)ethyl Ether.
Br ~ N,~~_,O N
A solution of 8.00 g (69.6 mmol) of N-(2-hydroxyethyl)-pyrrolidine in 150 mL of xylenes was treated with 534 mg (23.2 mmol) of Na and the mixture was heated to 80 ~C until all the Na had disappeared. The reaction was cooled to 23 ~C
and 5.50 g (23.2 mmol) of 2,5-dibromopyridine was added. The mixture was stirred at room temperature for 2.25 h and was concentrated in vacuo. Purification by flash chromatography (sio2i gradient of 50-70% EtOAc in hexanes) af~orded 3.53 g (13.0 mmol; 56%) of the title compound.
Part B. 5-(Benzo~b]thiophen-2-yl)pyrid-2-yl 2-(1-Pyrroli~inyl)ethyl Ether.
~ N
~ ;
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from CA 02236007 l998-04-27 Wo 97/25033 PCT/US96/17995 benzo[b~thiophene-2-boronic acid and 5-bromopyrid-2-yl 2 pyrrolidinyl)ethyl ether (Part A) in 68% yield as an oil :Eollowing :Elash chromatography (sio2; gradient of 0-4~6 MeOH
in CHCl3).
FDMS 324 (M+; 100).
Part C. 4-~2-(1-Pyrrolidinyl)ethoxy]ph~nyl 2-[6-12-(l-Pyrrolidinyl)~thoxy]pyrid-3-yl]benzo~b]thiophen-3-yl Ketone Dioxalate.
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 5-(benzo[~]thiophen-2-yl)pyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part B) and 4-[2-(1-pyrrolidinyl)-ethoxy]benzoic acid hydrochloride in 30% yield as a solid following flash chromatography (sio2; 5% MeOH in CHC13) The free base was converted to the dioxalate salt according to the conditions outlined in Example 1, Part C.
FDMS 543 (M+2; 100); Anal. Calcd For C32H3sN3o3s 2c2H2o4: C, 59.91; H, 5.45; N, 5.82. Found: C, 59.80; H, 5.67; N, 5.61.
~Y~ _le 17 Preparation of 4-~2-(4-Morpholinyl)ethoxy]phenyl 2-[4-[2-(1-Pyrroliainyl)ethoxy]phQnyl]benzo~b~thio~hen-3-yl Ketone Dioxalate.
~ ~0~O
Part A. 2-(4-Methoxyphenyl)benzo~b]thiophen-3-yl 4-~2-(4-Morpholinyl)ethoxy]phenyl Ketone.
~1 W O 97/25033 PCT~US96/17995 ~ OMe ~ o By essentially following the procedure outlined in Example 3, part D, the title compound was prepared in 96 yield from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzo[b]-thiophen-3-yl ketone (Example 28, Part A) to yield an off-white foam following column chromatography (sio2i gradient 0-5% MeOH in EtOAc).
1H NMR (CDC13) ~ 7.86-7.83 (m, lH), 7.77 (d, ~ = 8.8 Hz, 2H), 7.65-7.62 (m, lH), 7.39-7.32 (m, 4H), 6.76 (d, J = 8.8 Hz, 4H), 4.08 (t, 3 = 5.6 Hz, 2H), 3.75 (s, 3H), 3.71 (t, J = 4.7 Hz, 4H), 2.77 (t, J = 5.6 Hz, 2H), 2.54 (t, J = 4.5 Hz, 4H).
Part B. 2-(4-Hydroxyphenyl)benzo~b]thio~hen-3-yl 4-~2-(4-D~orpholinyl)ethoxy~phenyl Ketone.
~ OH ~ O
Following the procedure outlined in Example 1, part D, the title compound was prepared in 91% yield from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[2-(4-morpholinyl)-ethoxy]phenyl ketone ~Part A). The desired compound wasisolated as a white solid after flash chromatography (sio2;
gradient 0-10% MeOH in EtOAc) and recrystallization from THF-hexanes.
mp 188-189 ~C; IR (KBr) 1598 cm 1; FDMS 459 (M~); Anal. Calcd for C27H2sNO4S: C, 70.57; H, 5.48; N, 3.05. Found C, 70.58;
H, 5.57; N, 3.35.
_99_ Part C. 4-12-~4-~orpholinyl)ethoxylph~nyl 2-~4-~2-(l-Pyrrolidinyl)ethoxy]phenyllbenzo~b~thiophen-3-yl ICetone Dioxalate.
Followin~ Example 3, part D, the title compound was prepared from 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(4-morpholinyl)ethoxy]phenyl ketone (Part B) i~ 78% yield as a light oil a~ter ~lash chromatography [sio2i gradient 0-12%
(1:2 TEA-i-PrOH) in THF]. Conversion to the dioxalate salt was carried out as detailed in Example 1, part C.
mp 73 ~Ci IR (KBr) 1598 cm-li lH NMR (CD30D) ~ 7.93 (d, ~ =
7.1 Hz, lH), 7.71 (d, ~ = 8.8 Hz, 2H:), 7.56 ~d, J = 7.1 Hz, lH), 7.36 (d, ~ = 8.7 Hz, 4H), 6.88 ( d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.36 (distorted t, 2H), 4.25 15 (distorted t, ~ = 4.8 Hz, 2H), 3.90 (br t, ~ = 4.6 Hz, 4H), 3.61-3.28 (m, 12 H), 2.06 (m, 4H); FDMS 557 (M+l); Anal.
Calcd for C3sH3gN20gS-2C2H204-2H20: C, 57.50i H, 5.74; N, 3.62. Found: C, 57.39; H, 5.56; N, 3.70.
_1~ 18 Preparation of 4-r2-(Diethyl~;no)ethoxy]phenyl 2-~4-[2-(l-Pyrrolidinyl)ethoxylphenyl]benzo~b]thiophen-3-yl ~etone Dioxalate.
~9--~-~--~
~ O~ <
25 Part A. 4-r2-(Diethyl~ ;nQ)ethoxy]phenyl 2-(4-- NethoxyphQnyl)benzo~b]thiophQn-3-yl Ketone.
~~3-o--~
~ OMe <
-100~
By essentially following the procedure ou~lined in Example 3, part D, the title compound was prepared from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzotb]thiophen-3-yl ketone (Example 28, Part A) and 2-diethylaminoethyl chloride in 86%
5 yield. Flash chromatography [sio2; gradient 1-4% of (1:1 -TEA-~eOH) in EtOAc] gave the desired compound as a light oil.
IR (CHCl3) 1598 cm-l; lH NMR (CDC13) ~ 7.86-7.84 (m, lH), 7.83-7.75 (m, 2H), 7.65-7.62 (m, lH), 7.39-7.25 (m, 4H), 6.76 (d, J = 8.5 Hz, 4H), 4.03 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H), 2.66-2.59 (m, 4H), 1.05 (t, J = 7.1 Hz, 6H); FDMS 459 (M+); Anal. Calcd ~or C2gH2gNO3S: C, 73.17; H, 6.36; N, 3.05. Found: C, 73.11; H, 6.49; N, 3.17.
Part B. 4-~2-(Diethylamino)ethoxylphenyl 2-(4-Hydroxyphenyl)benzo[b]thiophQn-3-yl Ketone.
~ \
~ 0~ <
By essentially ~ollowing the procedure outlined in Example 1, part D, the title compound was prepared in 71%
yield from 4-~2-(diethylamino)ethoxy]phenyl 2-(4-methoxy-phenyl)benzo[b]thiophen-3-yl ketone (Part A3 as an orange foam following flash chromatography (sio2; 5% TEA in THF).
lH NMR (CDC13) ~ 7.89-7.86 (m, lH), 7.76 (d, ~ = 8.7 Hz, 2H), 7.72-7.69 (m, lH), 7.39-7.36 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.95 (br s, lH), 6.72 (d, J - 8.7 Hz, 2H), 6.64 (d, J =
8.4 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 2.91 (t, ~ = 5.9 Hz, 2H), 2.70 (q, J = 7.1 Hz, 4H), 1.09 (t. J = 7.1 Hz, 6H).
Part C. 4-~2-(Diethylr ;no)~thoxy]phenyl 2-14-[2-(1-pyrrolidinyl)othoxy~l?henyl]benzo~b]thiophen-3-yl Kotone Dioxalate.
By essentially following the procedure outlined in Example 3, part D, the title compound was prepared from 4-[2-W O 97/25033 PCT~US96/I7995 (diethylamino)ethoxy]phenyl 2-(4-hydroxyphenyl)benzo[b]-thiophen-3-yl ketone (Part B) in 95% yield following flash chromatography (sio2; gradient 60% THF cont~;n;n~ 3% TEA to 80% THF in hexanes) as a tan solid. Conversion to the dioxalate salt was carried out in 94% yield as detailed in Example 1, part C.
mp 176-179 ~Ci lH NMR (CD30D) ~ 7.92 (dd, J = 7.0, 1.5 Hz, lH), 7.74 (d, ~ = 8.9 Hz, 2H), 7.54 (dd, ~ = 7,2, 1.7 Hz, lH), 7.41-7.34 (m, 4H), 6.92 (d, ~ = 8.5 Hz, 2H), 6.90 (d, J
= 8.6 Hz, 2H), 4.36 (distorted t, 2H), 4.27 (distorted t, 2H), 3.59 (m 4H), 3.28 (m, 8H), 2.08 (br s, 4H), 1.31 (t, J =
7.2 Hz, 6H); FDMS 543 (M+l), 634 (M+2+C2H2O4).
Example 19 Preparation of 1-~2-[4-[3-[4-[2-(Diethylamino)ethoxy~-benzyl3benzo[b]thioph~n-2-yliphenoxyleth~l]pyrrolidine Dioxalate.
~~~
By essentially following the procedure outlined in Example 2, part D, the title compound was prepared in 91%
yield from 4-[2-(diethylamino)ethoxy]phenyl 2-[4-[2-(1-pyrro-lidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone ~Part C).
Flash chromatography [sio2i 80% THF in hexanes with 3% TEA
(v/v)] gave a white gummy solid which was converted to the dioxalate salt following the method described in Example 1, part C.
lH NMR (DMSO-d6) ~ 7.99 (m, lH), 7.59 ( br d, J = 6.3 Hz, lH), 7.50 (d, J = 8.3 Hz, 2H), 7.36 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.89 (d, ~ = 8.3 Hz, 2H), W O 97/25033 PCTrUS96/17995 4.38 (br s, 2H), 4.27 (br. s, 2H), 4.22 (br s, 2H), 3.57 (br s, 2H), 3.44 (br s, 2H), 3.35 (br. s, 4H), 3.16 (dt, J = 7.1, 6.7 Hz, 4H), 1.96 (br s, 4H), 1.21 (t, ~ = 6.9 Hz, 6H); FDMS
529 (M+l; Anal. Calcd for C33H40N2o2s-2c2H2o4-H2o: C, 61.14;
H, 6.38; N, 3.85. Found: C, 61.04; H, 6.32; N, 3.61.
Example 20 Pre~aration o~ 6-Hydroxy-2-E4-l2-(~ ~lidinyl)-othoxy]phenyl~bonzo~b]thiophen-3-yl 4-~trans-2-(1-Piperidyl)cyclohexyl]ox~]phenyl Ketone Dioxalate.
o~~ b ' 2C2H204 HO ~ O--N
Part A. (+)-tr~ns-(1-Piperidyl)cyclohexan-2-ol.
Q
HO~O
To a solution of 41.63 g (0.30 mol) of K2CO3 in ca. 200 mL of H2O was added 12.16 g (0.10 mol) of piperidine hydrochloride at 0 ~C, followed by 10.1 mL (0.10 mol) of cyclohexene oxide. After 5 min at 0 ~C, the ice bath was removed and the cloudy solution was stirred at room temperature overnight (18 h). The mixture was then extracted with EtOAc (3 x 500 mL) which was washed with 200 m~ of H20 and 200 mL of brine. The combined extracts were dried over MgSO4, concentrated, and dried under vacuum to afford 3.64 g (20~) of the crude amine which was used without further purification for the following reaction.
IR (KBr) 3435 cm-li FDMS 184 (M+l), 229 (100).
CA 02236007 l998-04-27 W O 97/2~033 PCT~US96/17995 Part B. Methyl (+)-4-~[trans-2-(1-pipQridyl)-cyclohexyl]oxy]benzoate.
MeO ~ ~
To a solution of methyl 4-hydroxy~enzoate (1.476 g, 9.70 mmol) in 175 mL of anhydrous THF was added 3.557 g (19.4 mmol) o~ trans-(l-piperidyl)cyclohexan-2-ol, (Part A), 5.090 g (19.4 mmol) of triphenylphosphine and 3.10 mL (19.4 ~mol) of diethyl azodicarboxylate at room temperature. The reaction mixture was stirred for 3 days and then concentrated under reduced pressure. The residue was purified by PrepLC
(2.5 to 4% o~ (10~ concd NH40H in MeOH) in CH2C12) to afford 2.232 g (7.03 mmol, 73~) of an orange solid.
mp 88-91 ~C; lH NMR (CDC13) ~ 7.97 (d, ~ = 8.8 Hz, 2H), 6.92 (d J = 8.9 Hz, 2H), 4.32 (td, ~ = 9.8, 4.2 Hz, lH), 3.88 (s, 3H), 2.80-2.47 (m, 5H), 2.23-2.15 (m, lH), 2.07-1.92 (m, lH), 1.76 (m, 2H), 1.57-1.20 (m, 10H); FDMS 317 (M+).
Part C. (+)-4-lCtrans-2-(l-Piperidyl) cyclohexyl~oxylbenzo~c Acid.
A solution of methyl 4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy]benzoate (Part B) (2.232 g, 7.03 mmol) and 10.6 mL (10.6 mmol) of 1.0 N NaOH in 60 mL of 1:1 mixture of MeOH/THF was stirred at 80 C for 20 h. The mixture was then cooled to room temperature, stirred for additional 7 h, and concentrated under reduced pressure. The residue was dissolved in 50 mL of 1.0 N HCl. This solution was extracted with 200 mL of EtOAc. The organic layer was washed with 200 mL of water. The combined aqueous layers were cooled to 0 C
W O 97/25033 PCT~US96/17995 and neutralized with 15 mL of 2.0 M NaOM. They were then concentrated under reduced pressure and the residue was taken up in 10% MeOH in CH2Cl2 and then filtered. The filtrate was concentrated and the residue was dried over P2Os in a vacuum oven at 55 ~C.
mp 264-266 C (dec); lH NMR ~DMSO-d6) ~ 7.79 (d, ~ = 7.7 ~z, 2H), 6.87 (d, ~ = 8.1 Hz, 2H), 4.40 (m, lH), 2.65-2.55 (m, 4H), 2.07 (m, lH), 1.77-1.58 (m, 3H~, 1.40-1.15 (m, llH);
FDMS 304 (M~l), 482 (base); Anal. Calcd for ClgH2sNO3-0.73NaCl: C, 62.47, H, 7.28, N, 4.05. Found: C, 62.92, H, 7.47, N, 4.15.
Part D. (+)-6-M~thoxy-2-t4-~2-(1-pyrrolidinyl)-ethoxylphenyl]benzolb]thio~hQn-3-yl 4-~ttrans-2-(1-Piperidyl)cyclohexyl}oxy~phenyl Ketone.
oQ~
MeO ~ ~
1.698 g (5.60 mmol) o~ 4-[[trans-2-(1-piperidyl)cyclo-hexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 ~L (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophene (Example 1, Part B). A~ter cooling the slurry to 0 C, aluminum bromide (6.79 ~, 25.4 mmol) was added, producing W O 97/25033 PCTrUS96117995 a dark red mixture. The ice ~ath was removed an~ the reaction mixture was stirred at room temperature for 6 h.
The mixture was poured into 100 mL of cooled (0 ~C) 2.0 N
NaOH. The aqueous layer was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH40H in MeOH) in CH2C12).
mp 68-72 C; lH NMR (CDCl3) ~ 7.76 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, lH), 7.36 (d, J = 8.8 Hz, 2H), 7.31 (d, J =
2.4 Hz, lH), 6.94 (dd, ~ = 8.9 and 2.4 Hz, lH), 6.78 (d, J =
8.-8 Hz, 4H), 4.26 (td, J = 9.8, 4.1 Hz, lH), 4.09 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H), 2.92 (t, J = 5.8 Hz, 2H), 2.69 (m, 7H), 2.50 (m, 2H), 2.17-1.95 (m, 2H), 1.84 (m, 4H), 1.73 (m, 2H), 1.50-1.15 (m, 10H); FDMS 639 (M+); Anal. Calcd for C3gH46N2O4S: C, 73.32; H, 7.26; M, 4.38. Found: C, 73.03;
H, 7.13; N, 4.29.
20 Part E. (+)-6-Hydroxy-2-~4-~2-(1-~,y ~c,lidinyl)-~thoxy]phQnyl]b~nzo~blthioph~n-3-yl 4-~trans-2-(1-Piperidyl)cyclohexyl]oxy]ph~nyl K~tone Dioxalate.
The title compound was prepared from (+)-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[blthiophen-3-yl 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]phenyl ketone (Part D) as a yellow solid by essentially following the procedures described in Example 21, Parts B and C.
mp 140-145~ C; lH NMR (DMSO-d6) ~ 7.70 (d, J = 8.6 Hz, 2H), 30 7.38 (d, J = 2.2 Hz, lH), 7.34 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.7 Hz, lH), 7.06 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 10.9 Hz, lH), 4.69 (m, lH), 4.25 (m, 2H), 3.50 (m, 2H), 3.28 (m, 5H), 3.09 (m, 2H), 2.93 (m, 2H), 2.07 (m, 2H), 1.91 (m, 4H), 1.80 - 1.20 (m, 12H); FDMS 624 35 (M+); Anal. Calcd for C3gH44N204S-2.87C2H204: C, 59.48; H, 5.68; N, 3.17. Found: C, 59.45; H, 5.85; N, 3.35.
W O 97/25033 PCT~US96/17995 ~ rle 21 Preparation of (+)-6-Hydroxy-3-~4-[[trans-2-(1-piperidyl)cycloh~xylloxy]benzyl]-2-l4-t2-(1-~yrro-lidinyl)ethoxylphenyl]benzot b~ thiophene Dioxalat~.
HO ~ ~ 2 C2H2O4 ~
Part A. (+)-6-Methoxy-3-~4-[~tran~-~-(1-~iperidyl)-cyclohexyl~oxy]b~nzyl~-2-l4-l2-(1-pyrroliainyl)-ethoxy]phenyllbenzo lb] thio~hene.
RN
~~ ~
MeO ~ ~
To a solution of 6-methoxy-[2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl] 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]phenyl ketone (Example 20, Part D) (1.340 g, 2.10 mmol) in 21.0 mL of anhydrous THF was added dropwise 2.10 mL (2.10 mmol) of 1.0 M LiAlH4 in THF at 0 C.
The reaction mixture was stirred for l h and 45 min while allowing the temperature to be raised to 20 C. The reaction was then quenched at 0 C by addition of 80 ~L of H20, followed by 80 ~L of 15% NaOH, and then an additional 240 ~L
of H2O (Fieser workup). This mixture was then filtered over a pad of silica gel and washed with THF. The filtrate was concentrated to dryness under reduced pressure. The crude alcohol was dissolved in 21.0 mL of anhydrous CH2Cl2 and cooled to 0 C. To this was added 2.30 mL (14.7 mmol) of triethylsilane, and the reaction mixture was stirred for 5 CA 02236007 l998-04-27 W O 97/2~033 PCT~US96tl7995 ~' -107-min, followed by a dropwise addition of 1.60 mL (21.0 m~ol) of tri~luoroacetic acid. The ice bath was removed and the reaction mixture was stirred further for 3 h 45 min before being ~uenched with 25.0 mL of saturated NaHCO3 at 0 ~C. The - 5 layers were separated and the a~ueous layer was extracted with EtOAc (3 x 200 mL). The com~ined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 57:40:3 hexanes-THF-TEA) to afford 1.251 g (2.00 mmol, 96%) of a clear gel.
lH NMR: (CDC13) ~ 7.41 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.8 Hz, lH), 7.31 (d, ~ = 2.3 Hz, lH), 7.03 (d, ~ = 8.4 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (m, lH), 6.81 (d, J = 8.6 Hz, 2H), 4.15 (m, 5H), 3.86 (s, 3H), 2.94 (t, J = 5.9 Hz, 2H), 2.85-2.55 (m, 9H), 2.20-2.10 (m, 2H), 1.83 (m, 4H), 1.72 (m, 2H) 1.58-1.48 (m, 4H), 1.42-1.18 (m, 6H); FDMS 625 (M+);
Anal. Calcd for C39H4gN2O3S: C, 74.96; H, 7.74; N, 4.48.
Found: C, 75.00; H, 7.94; N, 4.35.
Part B. (+)-6-Hydroxy-3- 14 - 1 l tran~- 2 - ( 1-piperidyl)-cyclohexyl]oxylbenzyl]-2-14-r2-(1-pyrrolidinyl)-ethoxy]phQnyl3benzolb3thiophene.
~,o",~
HO ~ -To a solution of 1.150 g (1.84 mmol) (+)-6-methoxy-3-[4-[[trans-2-(1-piperidyl)cyclohexylJoxy]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part A) in 20.0 mL o~ anhydrous dichloroethane at 0 C was added 1.10 mL
(14.7 mmol) of ethanethiol, followed by the addition of 30 all]m;n-lm chloride (982 mg, 7.36 mmol). The yellow ~iphasic W O 97/25033 PCT~US96/17995 reaction mixture was allowed to warm to room temperature and stirred ~or 3 h. The reaction wa5 ~uenched at 0 C with 20 mL of saturated aqueous NaHCO3. The aqueous layer was separated and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with 150 mL of brine, dried over MgSO4, and concentrated under reduced pressure.
The crude product was puri~ied by using ~lash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 1.067 g (1.75 mmol, 95~) of a white solid.
mp 179-182 ~C; lH NMR (CDC13) ~ 7.30 (dd, 3 = 8.7, 1.9 Hz, 2H), 7.07 (d, J = 2.2 Hz, lH), 7.01 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 2.2 Hz, lH), 6.77 (m, 5H), 4.14 (t, J = 5.6 Hz, 2H), 4.12 (buried m, lH), 4.10 (s, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.81 (m, 5H), 2.69 (m, 4H), 2.14 (m, 2H), 1.87 (m, 4H), 1.71 (m, 2H), 1.58 (m, 3H), 1.38 (m, 3H), 1.26 (m, 4H); FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S: C, 74.71; H, 7.59; N, 4.59. Found: C, 74.92; H, 7.80; N, 4.53.
Part C. (+)-6-Hydroxy-3-[4-[[tr~n~-2-(1-piperidyl)-cycloh~xyl~oxy]b~nzyl]-2-~4-r2-(1-pyrroliainyl)-othoxy]phQnyl]benzo[b]thiophene Dioxalate.
In approximately 4 mL of CHCl3-EtOAc (1:1) was dissolved 14.7 mg (0.164 mmol) of oxalic acid. To this was added dropwise 50.0 mg (0.082 mmol) of (+)-6-hydroxy-3-[4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzyl]-2-[4-[2-(1-pyrro-lidinyl)ethoxyJphenyl]benzo[b]thiophene (Part C) in 7 m~ of CHCl3. A white precipitate was formed, and the slurry was sonicated for 30 min and filtered with EtOAc rinse. The precipitate was dried over P2Os at 55 C in a vacuum oven.
mp 163-165 ~C; lH NMR (DMSO-d6) ~ 7.44 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, lH), 7.27 (s, lH), 7.09 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.81 35 (dd, J = 8.7, 2.1 Hz, lH), 4.49 (m, lH), 4.33 (br t, 2H), 4.12 (s, 2H), 3.51 (br t, 2H), 3.28 (m, 5H), 3.15 (m, 2H), 3.01 (m, 2H), 2.10 (m, 2H), 1.92 (m, 4H), 1.75-1.60 (m, 6H), W O 97/25033 PCT/US96/179gS
1.55-1.40 (m, 3H), 1.26 (m, 3H); FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S 2.0C2H204 0.24CHC13: C, 61.90; H, 6.18; N, 3.42. Found: C, 61.90; H, 5.99; N, 3.37.
Example 22 Pr~paration of (+)-6-Hy~roxy-2-t4-12-(1-~yrroli~inyl)-ethoxy~ph~nyl]benzo[b]thioph~n-3-yl 6-~[trans-2-(1-Piperidyl)cyclohexyl]oxy]pyri~-3-yl Ketone.
oQ~
HO ~ -l?art A. (t)-6-lltran~-2-(1-Piperidyl)cyclohexyl]oxy]-3-pyriainecarboxylic Acid.
HQ
The title compound was prepared from methyl (+)-6-[[trans-2-(1-piperidyl)cyclohexyl]oxy~-3-pyridinecarboxylate as an o~f-white solid by essentially following the procedure described in Example 20, Part C.
H NMR (DMSO-d6) ~ 10.00 (m, lH) 8.73 (dd, J = 2.4, 0.5 Hz, lH), 8.21 (dd, ~ = 8.7, 2.4 Hz, lH), 7.04 (d, ~ = 8.6 Hz, 20 lH), 5.35 (m, lH), 3.60 (br t, lH), 3.49 (br d, J = 11.6 Hz, lH), 3.40 (br d, J = 11.4 Hz, lH), 3.18 (br q, lH), 2.73 (br ~ q, ~ = 11.2 Hz, lH), 2.48 (m, lH), 2.23 (m, lH), 2.10-1.83 (m, 2H), 1.83-1.58 (m, 6H), 1.45-1.12 (m, 4H).
; 25 Part B. ~+)-6-Hydroxy-a-[4 t2-(1-~yrroli~inyl)-othoxylphenyllbenzotb]thiophen-3-yl 6-[ttraAs-2-(1-Pi~eridyl)cyclohexyl]oxy]~yrid-3-yl Ketone.
W O 97/25033 PCT~US96/17995 The title compound was prepared in 29% yield ~rom 6-methoxy-2-~4-[2~ pyrrolidinyl)ethoxy]phenyl]benzo[b}-thiophene (Example 1, Part B) and (+)-6-[[trans-2-(1-piperidyl)cyclohexyl~oxy]-3-pyridinecarboxylic acid (Part A) by essentially following the procedures detailed in Example 20, Parts D and E.
lH NMR (CDC13) ~ 8.32 (d, J = 2.4 Hz, lH), 7.70 (dd, ~ = 8.6, 2.4 Hz, lH), 7.41 (d, ~ = 8.9 Hz, lH), 7.30 (d, J = 2 1 Hz, lH), 7.06 (d, ~ = 8.6 Hz, 2H), 6.81 (dd, ~ = 8.8, 2.2 Hz, lH), 6.62 (d, ~ = 8.6 Hz, 2H), 6.44 (d, ~ = 8.6 Hz, lH), 5.22 (m, lH), 4.07 (t, J = 5.4 Hz, 2H), 3.00 (t, ~ = 5.4 Hz, 2H), 2.87-2.57 (m, 9H), 2.20-2.00 (m, 2H), 1.95-1.65 (m, 6H), 1.60-1.20 (m, lOH); FDMS 626 (M~); Anal. Calcd for C37H43N3O4S-0.59H2O: C, 69.83; H, 7.00; N, 6.60. Found: C, 69.58; H, 6.73; N, 6.99.
r~ le 23 Pr~paration of (+) -6-Hydroxy-3-t6-l~trans-2-(1-pi~eridyl)cyclohexyl]oxyl~yrid-3-yl]methyl-2- r4- 12-(1-~yrrolidinyl~ethoxy]~henyl]~enzotb]thiophene Dioxalate.
~ C2H204 Part A. ~+)-6-Hydroxy-3-[6-l[trans-2-(1-piperidyl)-cyclohexyl]oxy]pyri~-3-yl~methyl-2-t4- r2- (1-pyrro-lidinyl)ethoxylphenyllbenzolblthiophene.
W~D97/25033 PCTAUS96/1799 .. ~ ~
HO~ N
The title compound was prepared in 39~ yield from 6-hydroxy-2- E 4-[2-(l-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophen-3-yl 6-[[trans-2-(1-piperidyl)cyclohexyl]oxy3pyrid-3-yl ketone (Example 22, Part B) by essentially following the procedures detailed in Example 21, Parts A and B.
mp 170-174 C; lH NMR (CDCl3) ~ 7.89 (d, ~ = 2.2 Hz, lH), 7.31-7.21 (m, 4H), 7.03 (d, J = 2.1 Hz, lH), 6.80 (d, J = 8.6 Hz, 3H), 6.54 (d, ~ = 8.5 Hz, lH), 5.11 (m, lH), 4.14 (t, J =
5.4 Hz, 2H), 4.05 (s, 2H), 2.99 (t, ~ = 5.4 Hz, 2H), 2.80 (m, 5H), 2.59 (m, 4H), 2.16 (m, 2H), 1.87 (m, 4H), 1.69 (m, 3H), 1.43-1.25 (m, 9H); FDMS 611 (M+); Anal. Calcd for C37H4sN3O3S: C, 72.63; H, 7.41, N, 6.87. Found: C, 72.34, H, 7.64, N, 6.61.
Part B. (+)-6-Hydroxy-3-~6-~t~ans-2-~1-~iperidyl)-cyclohexyl]oxy]~yria-3-yl]methyl-2-14-12-~1-pyrro-lidinyl)~thoxy]phenyl~benzo~b]thiophene Dioxalate.
The title compound was prepared from (+)-6-hydroxy-3-[6-[ [ trans- 2-(1-piperidyl)cyclohexyl]oxy]pyrid-3-yl]methyl-2-~4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b~thiophene (Part A) by essentially ~ollowing the procedures detailed in Example 20, Part C.
mp 128-133 C (dec); lH NMR (DMSO-d6) ~ 7.93 (s, lH), 7.47 (dd, J = 8.7 Hz, 2.7 Hz, 2H), 7.38 (m, 2H), 7.27 (d, ~ = 2.0 Hz, lH), 7.10 (d, J = 8.6 Hz, 2H) 6.83 (d, J = 8.6 Hz, lH), 6.77 (d, ~ = 8.4 Hz, lH), 5.13 (m, lH), 4.35 ~br t, 2H), 4.14 (s, 2H), 3.56 (br t, 2H), 3.33-3.00 (m, 9H), 2.12 (m, 2H), 1.99-1.94 (m, 4H), 1.75-1.62 tm, 6H), 1.28-1.17 (m, 6H); FDMS
612 (M+); Anal. Calcd for C37H4sN3O3S 2.36C2H204: C, 60.79;
H, 6.08; N, 5.10. Found: C, 60.76; H, 6.25i N, 5.26.
Exampl~ 24 Pr~paration of 2-~4-12-(1-Pyrro~ yl)ethoxy]phenyl3-3,4-~ihydronaphth-1-yl 4-12-(1-Piperidyl)ethoxy]phenyl Ketone Dioxalate.
~ O - N ~ 2 c2H2~4 Part A. 2-(4-Hydroxyphenyl)-3,4-aihydronaphth-1-yl 4-~2- (1-Piperidyl)ethoxy]~henyl Ketono.
--N~J
~_ OH
The title compound was prepared in 95% yield from 2-(4-methoxyphenyl)-3,4-dihydronaphth-1-yl 4-[2-(1-piperidyl)-ethoxy]phenyl ketone by essentially ~ollowins the procedure detailed in Example 21, Part B.
mp 83-85 C; lH NMR (CDC13) ~ 7.75 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 7.1 Hz, lH), 7.16-7.05 (m, 4H), 6.94 (d, ~ = 7.8 Hz, lH), 6.60 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.5 Hz, 2H), 4.01 (t, ~ = 5.6 Hz, 2H), 3.03 ~distorted t, 2H), 2.81 (t, J
= 8.4 Hz, 2H), 2.74 (t, ~ = 5.6 Hz, 2H), 2.53 (br s, 4H), 1.61 (m, 4H), 1.43 (m, 2H); FDMS 453 (M+); Anal. Calcd ~or C30H31NO3 0~56CH2C12: C, 73.24; H, 6.46; N, 2.79. Found:
C, 73.27; H, 6.50; N, 2.72.
Part B. 2-14-12-(1-Pyrroli~inyl)ethox~]ph~nyl]-3,4-aihy~ronaphth-1-yl 4-r2-(1-Piperidyl)ethoxy]phenyl Ketone Dioxalate.
CA 02236007 l998-04-27 W O 97/25033 PCTrUS96/17995 ~ 0 ~
~ ~ o 2 C2H2~4 To a solution of 731.0 mg (1.61 mmol) 2-(4-hydroxy-phenyl)-3,4-dihydronaphth-1-yl 4-[2~ piperidyl)ethoxy]-phenyl ketone (Part A) in 16.0 mL of anhydrous DMF at room temperature was added Cs2CO3 ~1.575 g, 4.83 mmol), ~ollowed by addition of 1-(2-chloroethyl)pyrrolidine hydrochloride (411 m~, 2.42 mmol). The light yellow slurry was then heated to 85 C and stirred ~or 3.5 h. The reaction mixture was cooled to room temperature and 80 mL of H2O was added. This mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 100 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 821.5 mg (1.49 mmol, 93%) of a yellow gel. The free diamine was then used to prepare the title compound by essentially following the procedure detailed in Example 21, Part C.
mp 93-97 C; lH NMR (DMSO-d6) ~ 7.77 (d, ~ = 8.7 Hz, 2H), 7.26-7.01 (m, 5H), 6.92 (d, ~ = 8.8 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 7.7 Hz, lH), 4.33 (br t, 2H), 4.18 (br t, 2H), 3.45 (m, 2H), 3.36 (m, 2H), 3.25 (m, 4H), 3.13 (m, 4H), 2.99 (br t, 2H), 2.72 (br s, 2H), 1.87 (m, 4H), 1.68 (m, 4H), 1.46 (m, 2H); FDMS 551 (M+), 641 (M + 1.0 C2H204); Anal.
Calcd ~or C36H42N203-2.68C2H2O4: C, 62.72i H, 6.03; N, 3.54.
Found: C, 62.32; H, 5.71; N, 3.64.
~ Example 25 Preparation of 1-t4-t2-(1-P~peridyl)ethoxy]bQnzyl]-2-l4-~2~ ?yrrolidinyl)ethoxy]phenyl~-3,4-dihydronaph-thalone Dioxalate.
w 097/25033 PCT~US96/17995 ~3~ --N~ 2 C2H2~4 ~ N~
The title compound was prepared in 68% yield from 2-[4~
[2~ PYrrO1idinY1)ethOXY]PhenY1]- 3,4 -dihydronaphth-l-yl 4-[2- (l-piperidyl)ethoxy]phenyl ketone by essentially 5 following the procedures detailed in Example 21, Parts A and C.
mp 140-143 ~C; 1H NMR (DMSO-d6) ~ 7.36 (d, .J = 7.9 Hz, lH), 7.19-7.02 (m, 6H), 6.94-6.79 (m, 5H), 4.96 (S, 2H), 4.24 (m, 4H), 3.36-3.30 (m, 7H), 3.15 (m, 4H), 3.05-2.90 (m, 3H), 2.80-2.55 (m, 2H), 1.92 (m, 4H), 1.72 (m, 4H), 1.50 (m, 2H);
FDMS 534 (M-2); Anal. Calcd for C36H44N2O2 2.0C2H204 C, 67.02; H, 6.75; N, 3.91. Found: C, 67.32; H, 6.69; N, 4.10.
r~ le 26 Preparation of 2-14-12- (l-~y lolidinyl)~thoxy]phenyl~-naphth-l-yl 4- ~2 -(l-Piperidyl)ethoxyl~h~nyl Ketono DioxalatQ .
~,~~--Nl~ 2 C2H2o4 ~ N~
Part A. 2-(4-Hy~l~o,.y~henyl)na};)hth-l-yl 4- [2- (1-Piperidyl)Qthoxy]phenyl K~tone.
o - N
/~ OH
~ , ~
The title compound was prepared in 92% yield from 2-(4-methoxyphenyl)naphth-l-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone by essentially following the procedure described in Example 21, Part B.
mp 167-170 C; lH NMR (CDCl3) ~ 7.98 (d, ~ = 8.5 Hz, lH), 7.91 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.0 Hz, lH), 7.61-7.41 (m, 5H), 7.17 (d, .J = 8.5 Hz, 2H), 6.69-6.59 (m, 4H), 4.05 (t, J = 5.6 Hz, 2H), 2.79 (t, J = 5.4 Hz, 2H), 2.58 (br s, 4H), 1.65 (m, 4H), 1.47 (m, 2H); FDMS 451 (M~).
Part B. 2-14-12-(1-ry~ oli~inyl)ethoxy]~hQnyl~naphth l-yl 4-12-~1-Piperidyl)Qthoxy]phenyl Ketone Dioxalate.
The title compound was prepared ~rom 2-(4-hydroxy-phenyl)naphth-l-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone in 94% yield by essentially following the procedure detailed in Example 3, Part D and Example 21, Part C.
mp 95-100 ~Ci lH MMR (DMSO-d6) ~ 8.11 (d, ~ = 8.6 Hz, lH), 8.03 (d, J = 8.0 Hz, lH), 7.58-7.40 (m, 6H), 7.29 (d, ~ = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz, 4H), 4.30 (br t, 2H), 4.21 (br t, 2H), 3.47 (br t, 2H), 3.34 (br t, 2H), 3.27 (br s, 4H), 3.18-3.04 (m, 4H), 1.88 (br s, 4H), 1.67 (m, 4H), 1.46 (m, 2H); FDMS 549 (M~); Anal. Calcd for C36H4oN2o3-2.27c2H2o4:
C, 64.66; H, 5.96; N, 3.72. Found: C, 64.22 H, 5.89; M, 3.56.
_1~ 27 Preparation of l-l4-l2-(l~piperidyl)Qthoxy]bQnzyll-2 ~4-12-(1-pyrrolidinyl)ethoxy]phQnyl~naphthalenQ
Dioxalat~.
~ N~
The title compound was prepared in 71% yield from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]naphth-1-yl 4-~2-(1-piperidyl)ethoxy]phenyl ketone by essentially following the procedures detailed in Example 21, Parts A and C.
mp 184-187 C; lH NMR (DMSO-d6) ~ 7.96 (d, ~ = 7.7 Hz, lH), 7.91 (d, J = 8.5 Hz, lH), 7.85 (d, ~ = 7.7 Hz, lH), 7.50-7.40 (m, 3H), 7.31 (d, ~ = 8.4 Hz, 2H), 7.05 (d, ~ = 8.4 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.82 (d, 3 = 8.7 Hz, 2H), 4.36 (s, 2H), 4.32 (br t, 2H), 4.20 (br t, 2H), 3.53 (m, 2H), 3.31 (m, 6H), 3.09 (m, 4H), 1.93 (m, 4H), 1.69 (m, 4H), 1.50 (m, 2H); FDMS 535 (M+); Anal. Calcd ~or C36H42N2O2-2.0C2H204:
C, 67.21; H, 6.49; N, 3.92. Found: C, 66.93; H, 6.45; N, 4.05.
ExamplQ 28 Pre~aration of 2-14-~2-(l-~yl~olidinyl)ethoxy]phenyl]-benzo~b~thiophen-3-yl 4-~2-(1-Pi~er~dyl)ethoxylphQnyl Ketone Dioxalate.
-- N~
~o 2 c2E~2~4 Part A. 2-(4-Methoxyphenyl)b~nzolb]thiophen-3-yl 4-HydroxyphQnyl Ketone.
~ OH
O~_y ~ OMe A -0.5 M solution of sodium thioethoxide was prepared by adding ethanethiol (1.60 mL, 21.4 mmol) to a suspension of 60% NaH dispersion in mineral oil (769 mg, 19.2 mmol) in 40 mL of anhydrous DMF at 0 C. The ice bath was removed and the solution was stirred at room temperature for 30 min. The 0.5 M solution of sodium thioethoxide was then added dropwise to the solution of 4.00 g (10.7 mmol) of 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl 4-methoxyphenyl ketone in 10.0 mL of anhydrous DMF at room temperature. The reaction mixture was f heated at 85 C for 3 h, then allowed to cool to room temperature, and acidified with 20 mL of 1.0 N HCl. To this W O 97/25033 PCTfiUS96/17995 was added 200 mL o~ H2O and the mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with 200 mL o~ brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by PrepLC (30% EtOAc in hexanes3 to afford 3.017 g of the title compound ~8.37 mmol, 78%) as a yellow ~oam.
mp 76-77 C; lH NMR (CDC13) ~ 7.85 (m, lH), 7.72 (d, J =
8.7 Hz, 2H), 7.64 (m, lH), 7.38-7.29 (m, 4H), 6.76 (d, J =
8.7 Hz, 2H), 6.68 (d, ~ = 8.7 Hz, 2H), 6.03 (br s, lH), 3.75 (s, 3H); FDMS 360 (M+); Anal. Calcd for C22H16O3S: C, 73.31;
H, 6.20. Found: C, 73.57; H, 4.60.
Part B. 2-(4-Methoxyphenyl3benzotb]thiophen-3-yl 4-[2-(1-Piperidyl)ethoxy~phenyl Ketone.
N
~ OMe ~
The title compound was prepared using 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-hydroxyphenyl ketone and l-(2-chloroethyl)piperidine hydrochloride in 81% yield by essentially following the same procedures detailed in Example 24, Part B.
mp 41-44 C; 1H NMR (CDCl3) ~ 7.85 (m, lH), 7.77 (d, J =
8.8 Hz, 2H), 7.64 (m, lH), 7.40-7.33 (m, 4H), 6.77 (d, J =
8.6 Hz, 4H), 4.11 (t, J = 5.8 Hz, 2H), 3.76 (s, 3H), 2.77 (t, J = 5.8 Hz, 2H), 2.51 (br s, 4H), 1.61 (m, 4H), 1.44 (m, 2H);
FDMS 471 (M+); Anal. Calcd ~or C2gH2gNO3S: C, 73.86; H, 6.20, N, 2.97. Found: C, 73.90; H, 6.20; N, 3.14.
Part ~. 2-(4-Hyd~o~y~henyl~benzo~b]thiophen-3-yl 4-~2-(1-Piperidyl)ethoxy]phenyl Ketone.
W O 97/25033 PCTrUS96/17995 ~ OH ~
The title compound was prepared from 2-(4-methoxy-phenyl)benzo[bJthiophen-3-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone in 93% yield as a yellow foam by essentially following the same procedure detailed in Example 21, Part B.
mp 100-103 C; lH NMR (CDC13) ~ 7.84 (m, lH), 7.70 (m, lH), 7.68 (d, ~ = 8.9 Hz, 2H), 7.34 (m, 2H), 7.19 (d, ~ = 8.7 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 6.58 (d, ~ = 8.6 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 2.78 (t, ~ = 5.6 Hz, 2H), 2.57 (br s, 4H), 1.64 (m, 4H), 1.45 (m, 2H); FDMS 457 (M+); Anal.
Calcd for C2gH27NO3S: C, 73.49; H, 5.95i N, 3.06. Found:
C, 73.76; H, 5.97; N, 3.07.
Part D. 2-~4-~2~ y ~lidinyl)Qthoxylphonyl]-benzolb]thiophen-3-yl 4-C2-(1-Pip~ridyl) ethoxy]phenyl Ketone Dioxalate.
The title compound was prepared in ~uantitative yield ~rom 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone (Part C) by essentially following the procedure detailed in Example 4, Part B, except using 1-(2-hydroxyethyl)pyrrolidine, and Example 21, Part C.
mp 86-90 ~C; lH NMR l~MSO-d6) ~ 8.06 (d, ~ = 7.8 Hz, lH), 7.70 (d, J = 8.7 Hz, 2H), 7.43-7.35 (m, 5H), 6.96 (d, ~ = 8.9 Hz, 2H), 6.95 (d, ~ = 8.6 Hz, 2H), 4.34 (br t, 2H), 4.25 (br t, 2H), 3.48 (br t, 2H), 3.37 (br t, 2H), 3.27 (m, 4H), 3.13 (m, 4H), 1.89 (m, 4H), 1.68 (m, 4H), 1.47 (m, 2H); FDMS 555 (M+); Anal. Calcd for C34H3gN203S 2.0C2H204: C, 62.11; H, 5.76; N, 3.81. Found: C, 61.81; H, 5.61; N, 3.53.
~r _ le 29 W O 97/25033 PCT~US96/17995 Preparation o~ 3-c4-l2-(l-piperidyl)ethoxylbenzyl]-2-~4-~2-(1-pyrrolidinyl)ethoxy]phenyllbenzolb]thiophQne Dioxalate.
~o~
M ~
~ 2 c2H2~4 The title compound was prepared in 63% yield ~rom 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl)benzo[b]thiophen-3-yl 4-[2-(l-piperidyl)ethoxy]phenyl ketone by essentially following the procedures detailed in Example 21, Parts A and C.
mp 188-lgl C; lH NMR (DMSO-d6) ~ 7.96 (m, lH), 7.55 (m, lH), 7.50 (d, J = 7.9 Hz, 2H), 7.34 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.88 (d, 8.5 Hz, 2H), 4.34 (br t, 2H), 4.21 (m, 4H~, 3.55 (m, 2H), 3.33 (m, 6H), 3.11 (m, 4H), 1.94 (m, 4H), 1.70 (m, 4H), 1.51 (m, 2H); FDMS 541 (M+); Anal. Calcd for C34H40N2o2s-2.oc2H2o4: C, 63.32; H, 6.15; N, 3.89. Found: C, 63.03; H, 6.05; N, 3.81.
R~lQ 30 Pr~paration o:E 3- r4- l2-(1-PipQridinyl)ethoxy]benzoyl]-2-14-t2-(l-~ oli~inyl)ethoxy]phQnyl]:benzolb]thio-phene-6-carboxamide Dioxalate.
~N
o~' ~ (C2E~204)2 H2N ~ ~~
Part A. 2-[4- r 1 (1, l-Dime~hylethyl)dimethylsilyl]-oxylphenyl]-6-hy~roxybenzolb]thiophen-3-yl 4-r2-(1-25 Pi~?eri~inyl)ethoxy]ph~nyl Ketone.
~N ..
O
0~
~ osi~su-t)Me2 To a solution of 30 g (58.8 mmol) of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)-ethoxy]phenyl ketone hydrochloride in 120 mL of anhydrous THF
and 60 mL of anhydrous DMF was added 20 mL (144 mmol) of anhydrous triethylamine and 9.75 g (64.7 mmol) of tert-butyldimethylsilyl chloride under a nitrogen atmosphere. The reaction mixture was heated at 60 ~C in an oil bath for 4 h and then cooled to room temperature. The solution was diluted with 225 mL of toluene, filtered through a medium glass frit, and concentrated at reduced pressure. The residue was purified by PrepLC (0 to 4% MeOH in CH2Cl2) to give 6.77 g (11.5 mmol, 20%) of a yellow foam.
lH NMR (CDC13) ~ 7.67 (d, ~ = 8.8 Hz, 2H), 7.45 (d, ~ =
8.8 Hz, lH), 7.23 (m, 3H), 6.83 (d, 3 - 8.8 Hz, lH), 6.68 (m, 4H), 4.18 (br s, 2H), 2.96 (br s, 2H), 2.72 (br s, 4H), 1.75 (br s, 4H), 1.51 (br s, 2H), 0.93 (s, 9H), 0.12 (s, 6H); high resolution FDMS 588.2648 (M+).
Part B. 2-14-t[(1 r 1-Dimethylethyl)dimQthylsilyl]-oxy]ph~nyl~-6-[~(trifluoromethyl)sulfonyl~oxy~-bonzo~b~thiophQn-3-yl 4-[2-(1-PipQridinyl)ethoxy]-phenyl Ketone.
N
~~
0~
,s~ ~ osi(su-t)~e2 To a solution of 6.0 g (10.2 mmol) of 2-[4-[[(1,1-dimethylethyl)dimethylsilyl~oxy]phenyl]-6-hydroxybenzo-CA 02236007 l998-04-27 W O 97/2~033 PC~nUS96~17995 -c -121-[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (Part A) in 60 mL of anhydrous dichloroethane was added 4.13 g (40.8 mmol) of anhydrous trietllylamine and 4.01 g (11.2 Ir~nol) of N-phenyltrifluoromethanesulfonimide under a nitrogen 5 atmosphere. The reaction mixture was stirred at room temperature for 4 h and then filtered through a cotton plug and concentrated at reduced pressure. The residue was chromatographed over silica gel (0 to 3% MeOH in CH2C12) to give 7.20 g (10.0 mmol, 98%) of a brown foam.
1H Nl~ (CDC13) â 7.82 (d, J = 9.O Hz, 2H), 7.75 (d, J =
8.8 Hz, 2H), 7.32 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8 6 Hz, 2H), 4.20 (t, J = 5.6 Hz, 2H), 2.91 (t, J =
5.7 Hz, 2H), 2.66 (br s, 4H), 1.70 (m, 4H), 1.53 (m, 2H), 0.98 (s, 9H), 0.17 (s, 6H); FD~S 719.7 (M+).
Part C. 2 -(4-Hyd ~y~"henyl) -3- ~4- 12- (l-l?iperidinyl) -ethoxy~benzoyl]bQnzo~blthio~one-6-carboxylic Acid M~thyl Ester.
N
~~
~~
MeO2C ~ oH
To a solution of 3.7 mL of anhydrous DMF, 1.8 mL of anhydrous triethylamine, and 1.8 mL of anhydrous methanol was added 1.0 g (1.4 mmol) of 2-[4-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]phenyl]-6-[~(trifluoromethyl)sulfonyl]oxy]-25 benzo[b] thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (Part B) at room temperature. To this were added 29.4 mg (0.13 mmol) of Pd(II) acetate and 53.8 mg (0.13 mmol) of 1,3-bis(diphenylphosphino)propane, and the flask was evacuated and then filled with carbon monoxide in a balloon.
30 The reaction mixture was heated at 55 ~C for 12 h under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, the solution was saturated with W 097/25033 PCTnJS96/17995 nitrogen gas and then concentrated at reduced pressure. To this were added 5 mL of THF and 4 mL of lN HCl, and the solution was stirred at room temperature for 3 h. The reaction mixture was treated with 10 mL of 2N ammonium hydroxide solution for an additional hour at room temperature. The solution was poured into a separatory funnel and the a~ueous layer was saturated with sodium chloride and extracted three times with 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was purified on silica gel (0 to 10% MeOH in CH2C12) to give 578 mg (1.1 mmol, 80%) of an orange ~oam.
lH MMR (CDCl3) ~ 8.62 (s, lH), 8.07 (d, J = 8.5 Hz, lH), 7.92 (d, ~ = 8.5 Hz, lH), 7.68 (d, J = 8.6 Hz, 2H), 7.22 (d, ~ = 8.2 Hz, 2H), 6.69 (d, J = 8.6 Hz, 4H), 4.25 (t, J =
5.6 Hz, 2H), 4.01 (s, 3H), 3.07 (t, J = 4.3 Hz, 2H), 2.87 (br s, 4H), 1.82 (br s, 4H), 1.59 (br s, 2H); FDMS 516 (M+)-Part D. 3-l4-~2-(1-Pip~riainyl)~thoxylbenzoyl3-2-l4-~2-( 1-pyrrolidinyl)~thoxy]phenyl~b~nzo~b]thiophene-6-carboxylic ACid Methyl Ester.
~ N
~_~
MeO2CJ~o~N
To a solution of 1.5 g (2.9 mmol) of 2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-benzo[b]thiophene-6-carboxylic acid methyl ester (Part C) and 544 mg (3.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride in 20 mL of anhydrous DMF was added 2.37 g (7.3 mmol) of cesium carbonate at room temperature under a nitrogen atmosphere. The reaction mixture was heated at CA 02236007 l998-04-27 W O 97~033 PCT~US96/17995 60 ~C for 4 h and then cooled to room temperature and diluted with 125 mL of THF and 75 mL of water. The a~ueous layer was saturated with sodium chloride and extracted twice with 50 mL
portions of THF. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was puri~ied on silica gel (1:1 MeOH/TEA (10~) in THF) to give 1.26 g (2.2 mmol, 77%) of an orange-brown foam.
lH NMR (CDCl3) ~ 8.57 (s, lH), 7.98 (dd, 3 = 8.6, 1.5 Hz, lH), 7.77 (d, ~ = 8.8 Hz, 2M), 7.66 (d, J = 8.5 Hz, lH), 7.38 (d, J = 8.8 ~z, 2H), 6.78 (dd, ~ = 8.7, 6.7 Hz, 4H), 4.18 (m, 4H), 4.01 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.74 (t, ~ = 6.0 Hz, 2H), 2.59 (m, 4H), 2.47 (m, 4H), 1.79 (m, 4H), 1.58 (m, 4H), 1.48 (m, 2H); FDMS 614 (M+l).
Part E. 3-[4-[2-(1-Piperiainyl)ethoxylb~nzoyl]-2-[4-l2-( 1-pyrroli~linyl)ethoxylphenyl~ b~nzo ~blthiophene-6-carboxamide.
~N
~,0 H2N~ 3~ ~N
~
To a solution o~ 4.37 g (7.1 mmol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxylic acid methyl ester (Part D) in 100 mL of methanol was added 35 mL of liquid anhydrous ~mm~n; a. The solution was sealed in a shaker and - heated to 60 ~C for 3 days. The solution was then saturated with nitrogen gas, concentrated at reduced pressure, and chromatographed on silica gel (1:1 TEA/MeOH in THF, 0 to 10%) to give 3.22 g (5.4 mmol, 76%) of a yellow-brown ~oam.
lH NMR (CDC13) ~ 8.40 (s, lH), 7.72 (m, 4H), 7.37 (d, J -8.6 Hz, 2H), 6 78 (dd, ~ = 8.1, 2.1 Hz, 4H), 4.07 (m, 4H), 2.86 (t, ~ = 5.6 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 2.61 (br s, 4H), 2.48 (br s, 4H), 1.80 (br s, 4H), 1.59 (m, 4H), 1.43 (m, 2H); FDMS 597 (M+).
Part F. 3-~4-~2-(1-Piperidinyl)ethoxy]benzoyl]-2-~4-~2-(1-pyrroliainyl)~thoxY]phOnyl]benzO~blthio~hen~-6-carh~x~ ;de Dioxalate.
A solution of 3- E 4-[2-(1-piperidinyl)etho ~]benzoyl]-2-~4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophene-6-car~oxamide (Part E) (131 my, 0.219 mmol) in EtOAc (8 mL) was treated with a solution of oxalic acid (49.3 mg, 0.548 mmol) in EtOAc (8 mL) to form a white suspension. After filtration and drying, 135 mg (79%) of the title compound was obtained as a white solid.
mp 87.0-93.0 ~C; IR (KBr) 3420 (br), 3359 (br), 2681 (br), 1722, 1650, 1599 cm-l; lH NMR (DMSO-d6) ~ 9.20 (br s, 4H), 8.56 (s, lH), 8.06 (s, lH), 7.83 (d, ~ = 8.5 Hz, lH), 7.70 (d, J = 8.3 Hz, 2H), 7.35-7.45 (m, 4H), 6.96 (d, J = 8.3 Hz, 4H), 4.26-4.38 (m, 2H), 4.20-4.26 (m, 2H), 3.40-3.50 (m, 2H), 3.30-3.38 (m, 2H), 3.19-3.30 (m, 4H), 3.02-3.18 (m, 4H), 1.82-1.92 (m, 4H), 1.62-1.72 (m, 4H), 1.20-1.48 (m, 2H); FDMS
m/e 598 (M+-C4H3Og); Anal. Calcd for C3gH43N3O12S: C, 60.22;
H, 5.57; N, 5.40; S, 4.12. Found: C, 6Q.07; H, 5.68; N, 5.18; S, 4.02.
~Y~ I?1Q 31 Preparation of 3-t~4-E2-(1-PiP~ridinYl)ethoxy]phenyl]
mothyll-2-[4-~2-(1-pyrrolidinyl)e~hoxylph~n~lbenzo-~b]thio~hene-6-methA~ 9 Dioxalato.
W O 97/25033 PCT~US96/17995 ~N
O (C2~204 ) 2 H2N ~ ~ N
Part A. 3-~4-~2-(l-piperidinyl)ethoxy]b~nzoyll-2-t4-[2- (l-pyrroliainyl)ethoxy]~henyl]benzo~b] thiophene-6-carbonitrile .
~N
~ O
~~ ~
~ O~
To a solution of 3.1 g (5.2 mmol) of 3-~4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxamide (Example 30, Part E) in 75 mL of anhydrous THF was added 3.1 g (13.0 mmol) of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (inner salt) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 days and then filtered through a medium frit, concentrated at reduced pressure, and chromatographed on silica gel (1:1 TEA/MeOH in THF, 0 to 10%) to give 2.70 g (4.7 mmol, 90%) of a brown foam~
~H NMR (CDCl3) ~ 8.18 (s, lH), 7.72 (d, J = 8.9 Hz, 3H), 7.56 (d, J = 8.1 Hz, lH), 7.38 (d, ~ = 8.6 Hz, 2H), 6.80 (t, J = 8.3 Hz, 4H), 4.22 (br s, 4H), 3.10 (br s, 2H), 2.89 (br s, 6H), 2.64 (br s, 4H), 1.95 (br s, 4H), 1.70 (br s, 4H), 1.43 (br s, 2H); FDMS 580 (M+).
Part B. 6-(~ ;n~- ~thyl)-a-14-~2-(1-piperi~inyl)-ethoxy]phenyl~-2-[4-12-(1-pyrrolidinyl)ethoxy]phenyl~-I:~enzotb]thiophene-3-methanol.
N
H2N J~ ~N
To a solution of 1.35 g (2 3 mmol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carbonitrile (Part A) in 30 mL o~
anhydrous THF under a nitrogen atmosphere was added 414 mg (11.6 mmol) of lithium aluminum hydride. The reaction was stirred ~or 2.5 hours at room temperature and then quenched with 5 mL of ethyl acetate and 5 mL of saturated aqueous potassium sodium tartrate for 16 h. The reaction mixture was poured into 50 mL of water, saturated with sodium chloride, and extracted with three 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous magnesium sulfate, and concentrated to give 1.32 g (95% crude yield) of a brown foam.
lH NMR (CDCl3) ~ 7.68 (m, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.4 Hz, lH), 6.88 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.17 (s, lH), 4.0~ (m, 4H), 3.87 (s, 2H), 2.86 (t, ~ = 5.9 Hz, 2H), ~20 2.72 (t, J = 6.1 Hz, 2H), 2.57 (br s, 4H), 2.47 (br s, 4H), 1.75 (br s, 4H), 1.57 (m, 4H), 1.43 (br s, 2H).
Part C. 3-~14-12-(1-Piperiainyl)ethoxY]ph~nyll-methyl]-2-[4-12~ pyrrolidinyl)Qthoxylph~nyl]-b~nzo~blthioph~ne-6-moth~n~ ;ne.
~) .
~N
H2N "~ ~N
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 To a solution of 1.32 g (2 .3 Ir~nol) of 6-(aminomethyl)-oc-[4-[2- (1-piperidinyl)ethoxy]phenyl]-2-[4- [2- (l-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene-3-methanol in 40 mL of anhydrous dichloroethane at 0 ~C was added 1.84 g (15.8 mmol) of triethylsilane and 2.62 g (23.0 mmol) of trifluoroacetic acid, respectively, under a nitrogen atmosphere. After one hour at 0 ~C, the reaction was warmed to room temperature and stirred for 24 h. The reaction was ~uenched with 10 mL of saturated aqueous sodium bicarbonate and poured into 30 mL of water. The aqueous layer was saturated with sodium chloride, separated from the dichloroethane layer, and extracted with three 50 mL portions of THF. The combined organic layers were dried over anhydrous m~gn~,qium sulfate and concentrated at reduced pressure to give 786 mg ~60% crude yield) of a brown foam. This material was carried on to the salt in Part D.
Part D. 3-~[4-~2-(l-Pi~eridinyl)ethoxylphenyl3 methyl]-2-14-12-(1-pyrrolidinyl)ethoxyl~henyll-benzo~blthiophene-6-mQthAr~A ; r~9 Diox ate.
~ o (C2~2O4)2 /~J ~>
H2N J ~ o~N
3-[l4-[2-(l-piperidinyl)ethoxy]phenyl]methyl]-2-[4-[2-~l-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-met~n~mine ~Part C) was dissolved in 50 mL of ethyl acetate and added to a solution of 100 mg of oxalic acid in 30 mL of ethyl acetate. After ~ing 10 mL of ether to the solution, the precipitate was filtered to give 1.05 g ~99%) of a white solid.
mp 140-142 ~Ci lH NMR (DMSO) ~ 8.04 (s, lH), 7.58 (d, J =
8.3 Hz, lH), 7.47 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.3 Hz, lH), 7.09 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), W O 97/2~033 PCT~US96/17995 6.83 (d, ~ = 8.6 Hz, 2H), 4.20 (m, 4H), 4.13 (s, 2H), 4.06 (t, ~ = 5.6 Hz, 2H), 3.17 (t, ~ = 5.3 Hz, 2H), 2.92 (br s, 4~), 2.86 (t, J = 5.6 Hz, 2H), 2.64 (br s, 4H), 1.81 (br s, 4H), 1.55 (m, 4H), 1.41 (d, ~ = 5.1 Hz, 2H); FDMS 570.4 (M+).
Example 32 PreparatiOn o~ 3-[t4-l2-(l-piperidinyl)ethoxy~phe~
methyl]- 2-~4-l2-( l-pyrrolidinyl)ethoxy]phenyll-bQnzolb]thiophenQ-6-methanol Diox 1 e.
O (C2H202 ) 2 ~~
Part A. oc( 3)-~4-t2-( l-Piperidinyl)ethoxy~phenyl~ -2-[4-~2-(1-pyrrolidinyl)ethoxy3phenyl~benzo ~b~ thio};)hene-3, 6-~lim~thanol.
N
~~
~ \ ~ o ~ ~
Diisobutylall]m;nll~ hydride (1.0 M in toluene, 3.59 mL) was added dropwise to a stirred solution of 3-[4-[2-(1-piperidinyl~ethoxy]benzoyl]-2-[4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxylic acid methyl ester (550 mg, 0.898 mmol) in anhydrous THF (6 mL) at 0 ~C under argon.
The mixture was stirred at 0 ~C for 1.5 h. Methanol (2 mL) and saturated aqueous potassium sodium tartrate solution (15 mL) were sequentially added to the mixture, and the resultant two-layered solution was stirred vigorously at ambient temperature for 2 h. The mixture was extracted with a mixed solvent of ethyl acetate/THF (1:1, 30 mL x 2). The combined organic layers were dried over MgSO4, filtered, and WO 97/25033 PCT~US96/17995 -12g-concentrated to give 496 mg (crude yield 94%) of the diol as a gum.
-H NMR (CDCl3) ~ 7.79 (s, lH), 7.68 (d, ~ = 8.4 Hz, lH), 7.36 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, lH), 7.13-7.19 (m, 2H), 6.84 (d, ~ = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 6.17 (s, lH), 4.72 (s, 2H), 3.98-4.08 (m, 4H), 3.25 (br s, lH), 2.90 (t, J = 5.8 Hz, 2H), 2.76 tt, ~ = 5.8 Hz, 2H), 2.60-2.68 (m, 4H), 2.45-2.55 (m, 4H), 1.78-1.85 (m, 4H), 1.55-1.65 (m, 4H), 1.38-1.46 (m, 2H).
Part B. 3-~4-~2-(1-Piperi~inyl)ethoxy~henyl]-methyl]-2-~4-~2-(1-~yrrolidinyl)ethoxy]phenyl]benzo-~b~thioph~no-6-met~ol Dioxalate.
~N
O (C2H202)2 ~ ~N
Triethylsilane (0.946 m~, 5.92 mmol) and trifluoroacetic acid (O.652 mL, 8.46 mmol) were added consecutively to a stirred solution of a(3)-r4-[2-(1-piperidinyl)ethoxy]-phenyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy3phenyl]benzo[b]-thiophene-3,6-dimethanol (Part A) (496 mg, 0.846 mmol) in dry 1,2-dichloroethane (5 mL) at 0 ~C under argon atmosphere, and the resultant solution was stirred at 0 ~C for 6 h. After dilution with THF (25 mL), the mixture was washed with saturated aqueous NaHCO3 (15 m~) and the aqueous layer was extracted with 'l'~ (15 mL). The combined organic layers were washed with brine l15 mL), dried over MgSO4, filtered, and concentrated. The gummy residue was chromatographed on silica [gradient TEA/i-PrOH (1:2) 0-4% in THF] to isolate 110 mg 123%) of the free base as a gum. The free ~ase was then ; 30 dissolved in EtOAc (5 mL) and treated with a solution of oxalic acid (39.9 mg, 0.443 mmol) in EtOAc (5 mL) to form a CA 02236007 l998-04-27 W 097/25033 PcT~us96/l799s white suspension. After filtration and drying, 120 mg (83%) of the title compound was obtained as a white solid.
mp 102.0-106.0 ~C; IR (KBr) 3410 (br), 2700 (br), 1725 cm~l;
lH N~IR (DMSO-d6) ~ 1.40-1.50 (m, 2H), 1.60-1.70 (m, 4H), Y
1.85-1.95 (m, 4H), 3.00-3.18 (m, 4H), 3.22-3.40 (m, 6H), 3.45-3.53 (m, 2H), 4.15 (s, 2H), 4.18-4.25 (m, 2H), 4.25-4.35 (m, 2H), 4.55 (s, 2H), 6.82 (d, ~ = 8.3 Hz, 2H), 6.98 (d, ~ -8.3 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 10 lH), 7.43 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.2 Hz, lH),7.84 (s, lH), 8.60 (br s, 4H); FDMS m/e 571 (M+-C4H3Og); Anal.
Calcd for C3gH46N2OllS: C, 62.38; H, 6.17; N, 3.73; S, 4.27.
Found: C, 62.63; H, 6.36i N, 3.91; S, 4.07.
F _ 1~ 33 Preparation of 6-Hydroxy-3-~6-[2-(1-~ ~olidinyl)-ethoxy]pyrid-3-ylmothyl~-2-Z4-~2-(1-pyrroliainyl)-ethoxy]phenyl]benzo ~b~ thiophene Dioxalate.
~o~N
HO ~ "'~" N ~ 2 C2H2~4 Part A. 6-~ethoxy-2-14-~2-(1-~ ~lidinyl)ethoxy]-phenyllbenzo ~b] thio~hsn-3-yl 6-Chlo ~id-3-yl Ketone.
~ Cl MeO ~ "~_,N ~
The title compound was prepared from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and 6-chloronicotinic acid in 51% yield (based on 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo [b] thiophene) by essentially following the proceedures described in Example 1, Part C.
-Part B. 6-MQthoxy-2-[4-~2-(l~lolidinyl)ethoxy~-phenyl3bonzol~b]thiophon-3-yl 6-~2-(1-Pyrrolidinyl)-~thoxy~pyrid-3-yl Ketone.
0~ ~ Nf~
MeO~ ~ ~,N~
The title compound was prepared in 84% yield :Erom 6-methoxy-2-[4-[2~ pyrrolidinyl)ethoxy]phenyl]benzo [b] -thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) and 1-(2-hydroxyethyl)pyrrolidine by essentially Eollowing the procedures described in Example 9, Part B.
FDMS 572 (M+l; 100); Anal. Calcd for C33H37N304S: C, 69.33;
H, 6.52; M, 7.35. Found: C, 6g.10; H, 6.76; N, 7.08.
Part C. 6-~othoxy-3-16-[2-(1-~yrrolidinyl)ethoxyl-pyrid-3-ylmethyl]-2-[4-~2-(1-~yrrolidiny].)Qthoxy~-phe~yllbenzo~b]thio~h~ Dioxalate Hemih~dr~t~.
~ 0~ N~
MeO /~ N~ 2 C2H204 0~~
The title was prepared in 3796 yield :Erom 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo [b] thiophen-3-yl 6-[2-(l-pyrrolidinyl)ethoxy]pyrid-3-yl ketone (Part B) by essentially f~ollowing the procedure described in Example 3, Part E.
W O 97/25033 PCT~US96/17995 FDMS 558 (M+l; 100); Anal. Calcd ~or C33H39N3O3~. 2C2H2~4- 0-5 H2O: C, 59.51; H, 5.94i N, 5.63. Found: C, 59.39; H, 5.76 N, 5.76.
Part D. 6-Hyaroxy-3-~6-t2-(1-~yrroli~inyl)-ethoxy]pyria-3-ylmethyll-2-~4-12-(1-pyrrolidinyl)-othoxyl~henyl]benzo~blthiophene Dioxalat~.
The title compound was prepared in 59% yield from 6-methoxy-3-~6-[2-(1-pyrrolidinyl)ethoxy~pyrid-3-ylmethyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene ~Part C~ by essentially following the procedure described in Example 1, Part D.
lH NMR (DMSO-d6) ~ 7.88 (d, J = 1.8 Hz, lH), 7.43-7.32 (m, 4H), 7.23 (d, J = 2.1 Hz, lH), 7.07 (d, J = 8.4 Hz, 2H), 6.78 (dd, J = 8.4 and 2.1 Hz, lH), 6.71 (d, J = 8.6 Hz, lH), 4.42 (t, ~ = 4.9 Hz, 2H), 4.30 (t, J = 4.6 Hz, 2H~, 4.09 (s, 2H), 3.53 (t, J = 4.3 Hz, 2H), 3.46 (t, J = 4.6 Hz, 2H), 2.50-2.33 ~m, 8H), 1.96-1.73 (m, 8H); FDMS: 544 (M + l; 100).
- _le 34 Pre~aration o~ 6-Hydroxy-3-14~ olidinyl)-methyl] benzyl]-2-[4-~(1-pYrrOlidinyl)methyl]l?hen bQnzolblthiophene Dioxa}ate.
HO~V
2(c2H2~4) Part A. 1-Bromo-4-[(1-~ loli~inyl)methylJb~nzene.
Br ~ N
Pyrrolidine (20.0 mL, 0.240 mole) was added to a stirred solution of 4-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous CH2C12 (20 mL) at 0 ~C under nitrogen. The resultant solution was allowed to stir at room temperature CA 02236007 l998-04-27 W O 97/2~033 PC~nJS96/~7995 for 1 h. The reaction mix~ure was diluted with EtOAc (150 mL) before it was washed with half-saturated aqueous NaHCO3 (50 mL). After drying over MgSO4, filtration, and concentration, the oily residue was chromatographed on silica [20% EtOAc in hexanes, then 10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 9.02 g of the benzyl pyrrolidine (94%) as an oil.
IR (neat) 2966,1488 cm-l; lH NMR (CDC13) ~ 1.79 (br s, 4H), 2.49 (br s, 4H), 3.57 (s, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H);
~?art B. 2-DimethylA ;~-6-m~thoxybonzo[blthiophen-3-yl 4- ~ y olidinyl)methyl3phenyl Kston~.
MeO ~
4-(Chloromethyl)benzoyl chloride (105 mg, 0.558 mmol) was added to a stirred solution of 2-dimethylamino-6-methoxybenzo[b]thiophene (105 mg, 0.507 mmol) in chlorobenzene (1 mL) under nitrogen. The resultant mixture was heated in an oil bath at 110 ~C for 2.5 h. The mixture was cooled to 0 ~C, treated with pyrrolidine (5 mL), then allowed to stir at room temperature for 2 h. After dilution with THF (20 mL), the mixture was washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 2~-40% EtOAc in hexanes, then 0-10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 148 mg (74%) of the ketone as a foam.
IR (neat~ 2957, 1625, 1603 cm~ ; H MMR (CDC13) ~ 1.83 (br s, 4H), 2.53 (br S, 4H), 2.87 (s, 6H), 3.69 (s, 2H), 3.83 (s, 3H), 6.81 (dd, J = 9.0 and 3.0 Hz, lH), 7.12 (d, J = 3.0 Hz, lH), 7.36 (d, J = g.0 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2H), '7.82 (d, J = 8.1 Hz, 2H); FDMS m/e 394 (M~).
W 097/2~033 PCTAJS96/17995 Part C. 6-Mothoxy-2-[4-~(1-~ Lolidinyl)methyl3-~henyl]benzotblthiophen-3-yl 4-[(1-Pyrrolidinyl)-m~thyl]phonyl Ketono.
MeO ~ ~
The aryl bromide of Part A (146 mg, 0.608 mmol) was added to a stirred suspension o~ magnesium ribbons (13.9 mg, O.570 mmol) in anhydrous THF (2 mL) under argon atmosphere, ~ollowed by the addition of a small iodine crytal. The resultant mixture was heated in an oil bath at 60-65 ~C for 2 h to form a homogeneous Grignard solution. The Grignard solution was cooled to room temperature before it was added to a stirred solution of the benzothiophene of Part B (150 mg, 0.380 mmol) in anhydrous THF (2 mL) at 0 ~C under argon atmosphere. The resultant mixture was stirred at 0 ~C ~or 1.5 h, then guenched with saturated aqueous NH4Cl (3 mL).
After extraction with EtOAc (15 mL x 2), the combined organic layers were dried over MgSO4, ~iltered, concentrated, and chromatographed on silica [gradient 0-4% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 170 mg (88%) of the trisubstituted benzothiophene as a ~oam.
IR (neat) 2964, 1647, 1603 cm-l; lH NMR (CDC13) ~ 1.77 (br s, 8H), 2.40-2.50 (m, 8H), 3.52 (s, 2H), 3.55 (s, 2H), 3.91 (s, 3H), 7.05 (dd, J = 8.9 and 2.3 Hz, lH), 7.17 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.32 (d, ~ = 8.1 Hz, 2H), 7.34 ld, J = 2.3 Hz, lH), 7.65 (d, J = 8.9 Hz, lH), 7.70 (d, J =
8.2 Hz, 2H); FDMS m/e 510 (M+).
Part D. 6-Mothoxy-3-t4~ r lolidinyl)m~thyll ~
benzyll-2-14-~(1-pyrrolidinyl)methyllphenyl]benzo-lb}thio~hene.
W O 97/25033 PCT~US96/17995 MeO ~ ~
DIBAL-H (0.911 mL, 1 M in toluene) was added to a stirred solution of the ketone of Part C (310 mg, 0.607 mmol) in anhydrous CH2C12 (4 mL) at 0 ~C under nitrogen atmosphere, and the resultant solution was stirred at 0 ~C for 40 min.
The reaction mixture was treated sequentially with MeOH (0.5 mL) and saturated aqueous Rochelle's salt solution (10 mL), and then the two-layered solution was stirred vigorously at room temperature for 1 h. A~ter extraction with EtOAc (50 mL), the organic layer was dried over MgSO4, ~iltered, and concentrated to yield 280 mg of the corresponding alcohol.
The above alcohol was dissolved in anhydrous CH2C12 (3 mL) and cooled down to 0 ~C be~ore it was sequentially treated with Et3SiH ~0.611 mL, 3.83 mmol) and TFA (0.421 mL, 15 5.46 mmol). The resultant mixture was stirred at 0 ~C for 1 h. After cautious treatment with saturated aqueous NaHCO3 (8 mL), the mixture was allowed to warm to room temperature and extracted with EtOAc (15 mL x 2). The com~ined organic layers were dried over MgSO4, filtered, concentrated, and 20 chromatographed on silica [gradient 0-4% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 220 mg (81%) o~ the corresponding methylene compound as a foam.
IR (neat) 2963, 1603 cm~l; lH NMR (CDCl3) ~ 1.75-1.87 (m, 25 8H), 2.45-2.60 (m, 8H), 3.57 (s, 2H), 3.64 (s, 2H), 3.87 (s, 3X), 4.24 (s, 2H), 6.90 (dd, J = 8.9 and 2.4 Hz, lH), 7.09 (d, ~ = 8.0 Hz, 2H), 7.21 (d, ~ = 8.0 Hz, 2H), 7.33 (d, ~ =
2.4 Hz, lH), 7.35 (d, J = 8.2 Hz, 2H), 7.39 (d, ~ = 8.9 Hz, lH), 7.45 (d, ~ = 8.2 Hz, 2H); FDMS m/e 496 (M+).
Part E. 6-Hy~roxy-3-14- r (~ o~ nyl)m~thyl~ -- benzyll-2-t4-[(1-~yrrolidinyl)methyllphenyl]bQnzo-lblthiorhe~e Dioxalate.
W O 97/25033 PCT~US96/17995 AlCl3 (354 mg, 2.66 mmol) was added to a stirred solution of the methoxy benzothiophene (220 mg, 0.443 mmol) in anhydrous CH2C12 (5 mL) at room temperature under nitrogen atmosphere. The resultant suspension was stirred for 3-5 min before it was treated with EtSH (0.2g5 mL, 3.99 mmol), and the mixture was stirred for an additional 35 min. After dilution with THF (15 mL), the mixture was cooled to 0 ~C and sequentially treated with saturated aqueous NaHC03 (15 mL) and saturated aqueous Rochelle's salt solution (10 mL). The two~layered solution was stirred vigorously for 70 min. The organic layer was separated and the aqueous layer was extracted with THF (25 mL x 2). The combined organic layers were dried over MgSO4, filtered, concentra~ed, and chromatographed on silica [gradient 0-4% EtOH/Et3M (2/1) in THF/hexanes (1/1)] to give 205 mg (96%) of the hydroxy benzothiophene as a foam.
A solution of oxalic acid (76.5 mg, 0.850 mmol) in EtOAc (4 mL) was added dropwise to a stirred solution of the above hydroxy benzothiophene in EtOAc (4 mL). The resultant w~ite suspension was filtered and the white solid was dried at 8Q
~C under vacuum to provide 240 mg (85%) of the dioxalate.
IR (neat) 3400-2500 (br), 1721, 1600 cm-l; lH NMR (CDC13) ~
1.75-1.95 (m, 8H), 2.95-3.20 (m, 8H), 4.17 (s, 2H), 4.21 (s, 2H), 4.26 (s, 2H), 6.81 (dd, ~ - 8.7 and 2.1 Hz, lH), 7.11 (d, J = 7.9 Hz, 2H), 7.28 (d, 3 = 2.1 Hz, lH), 7.35 (d, J =
7.9 Hz, 2H), 7.37 (d, ~ = 8.7 Hz, lH), 7.50 (d, J = 8.1 Hz, 2H), 7.56 (d, ~ = 8.1 Hz, 2H); FDMS m/e 483 (M+1-2C2H2O4);
Anal. Calcd for C31H34N20S 1.8C2H204: C, 64.46; H, 5.88i N, 4.34. Found: C, 64.17; H, 5.92; N, 4.47.
. ~le 35 Pre~aration of 6-Hydroxy-2-[4-~(4-morpholinyl)methyl]-phenyl]b~nzo[blthiophen-3-yl 4-~(1-Pyrrolidinyl~-methyl]phenyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 N~
2(c2H2o4) Part A. 4-l(4-Bromophenyl)methyl]morpholine~
Br ~ N-Following the procedure o~ Example 34, Part A, the benzyl morpholine was obtained as an oil in 100~ yield.
IR (~3r) 2803, 1487, 1111 cm-l; lH NMR (CDC13) ~ 2.43 (t, J =
4.5 Hz, 4H), 3 45 (s, 2H), 3.71 (t, J = 4.5 Hz, 4H), 7.22 (d, .J = 8.1 Hz, 2H), 7.45 (d, ~ = 8.1 Hz, 2H); FDMS m/e 255 (M+, 79Br) and 257 (M+, 81Br); Anal. Calcd for CllH14BrNO: C, 51.58; H, 5.51; N, 5.47. Found: C, 51.77; H, 5.66; N, 5.68.
Part B. 6-MQthoxy-2-[4-~(4-morpholinyl)methyl]-phenyllbenzo~b~thio~hen-3-yl 4-~(1-Pyrrolidinyl)-methyl]phenyl Ketone.
MeO ~ N~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the above aryl bromide as a foam in 88% yield.
IR (neat) 2954, 1649, 1602 cm-l; lH MMR (CDC13) ~ 1.77 ~r s, 4H), 2.35 (br s, 4H), 2.40 (br s, 4H), 3.39 (s, 2H), 3.56 (s, 2H), 3.68 (t, J = 4.2 Hz, 4H) 3.92 (s, 3H), 7.02 (dd, J = 8.7 and 2.1 Hz, lH), 7.14-7.37 (m, 7H), 7.64 (d, 8.7 Hz, lH), 7.70 (d, 7.8 Hz, 2H); FDMS m/e 527 (M+l).
CA 02236007 l998-04-27 Part C. 6-Hydroxy-2-~4-[(4-mOrpholinyl)methyll-phenyllbenzo[blthiophen-3-yl 4-~(1-Pyrrolidinyl)-methyl]phe~yl Ketone Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy ketone was obtained as a yellowish solid in 55% t yield.
IR (KBr) 3420 (br), 2990 ~br), 2830-2200 (br), 1641, 1608 cm~1; 1H N ~ (DMSO-d6) ~ 1.79 (br s, 4H), 2.37 (br s, 4H), 2.53 (br s, 4H), 3.39 (s, 2H), 3 .60 (s, 2H), 3 .68 (t, ~ - 4.2 Hz, 4H), 6.40 (dd, ~ = 8.7 and 2.1 Hz, lH), 6.69 (d, ~ = 2.1 Hz, lH), 7.12 (d, ~J = 8.1 Hz, 2H) 7.21-7.25 (m, 4H), 7.43 (d, ~J = 8.7 Hz, lH), 7.67 (d, J = 7 .8 Hz, 2H); FDMS m/e 513 (M~1-2C2H204 ) -~ ple 36 Pr~paration of 6-Hydroxy-2-[4-[(4-morpholinyl)methyl~-phenyl]-3-t4-t(1-pyrrolidinyl)mQthyl3benzyl]-benzotb]thio~hone Dioxalate.
HOJ ~ - N~> o 2 0 2 (c2H204 ~
Part A. 6-Methoxy-2-t4-t(4-morpholinyl)methyl]-phenyl]-3-~4-t(1-~yrrolidinyl)~ethyllbenzyll-benzo~b~thiophene.
MeO ~ ~- o Following the procedure of Example 34, Part D, the methoxy benzothiophene was obtained from the above ketone as a ~oam in 57% yie~d.
IR (neat) 2958, 1603 cm-1; lH NMR (CDC13) ~ 1.76-1. 80 (m, 4H), 2.37-2.50 (m, 8H), 3.53 (s, 2H), 3.57 (s, 2H), 3.73 (t, W O 97/2~033 PCTAUS96/17995 ~ = 4.8 Hz, 4H) 3.87 (s, 3H), 4.25 (s, 2H), 6.90 (dd, J = 8.7 and 2.4 Hz, lH), 7.10 (d, ~ = 8.1 Hz, 2H), 7.18-7.41 (m, 6H), 7.45 (d, J = 8.1 Hz, 2H); FDMS m/e 513 (M+l).
Part B. 6-Hydroxy-2-[4-1(4-morpholinyl)methyl]-~henyl]-3-14-[(1-pyrroli~inyl)methyl]bonzyl~-b~nzo Cb] thiophene Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy benzothiophene salt was obtained as a white solid in 57% yield.
IR (KBr) 3445 (br), 2950, 2840-2220 (br), 1720, 1630, 16Q0 Cm-1; 1H NMR (DMSO-d6) ~ 1.88 (br s, 4H), 2.56 (br s, 4H), 3.13 (br s, 4H3, 3.61 (br s, 4H), 3.70 (s, 2H), 4.22 (br s, 4H), 6.79 (dd, J = 8.4 and 2.0 Hz, lH), 7.13 (d, ~ = 7.5 Hz, 2H), 7.27 (d, ~ = 2.0 HZ , lH), 7.34-7.44 (m, 7H); FDMS m/e 499 (M~1-2C2H2O4); Anal. Calcd for C31H34N2O2S-2C2H2O4: C, 61.93; H, 5.64; N, 4.13. Found: C, 62.09; H, 5..77; N, 3.96.
_le 37 Preparation of 3-[3-Bromo-4-c(l-~y ~olidinyl)-methyl]benzyl]-6-hydroxy-2-14-t2-(4-morpholinyl)-Qthoxy~phQnyl]benzo~blthiophe~s Dioxalato.
~ N-~
HO ~ ~ o ~ N
2(caH2~4) Part A.Mothyl 3-Bromo-4-C(~ oli~inyl)methyl~-benzo~to.
Br MeO2C~N
AIBN ~79 mg) was added to a stirred suspension o~ methyl 3-bromo-4-methylbenzoate (11.0 g, 48.0 mmol) and NBS (10.3 g, 57.6 mmol) in CC14 (400 m~), and the resultant mixture was W O 97/25033 PCTnUS96/17995 heated to reflux for 2 h. After cooling to room temperature, the mixture was diluted with hexanes (200 mL) before it was filtered and concentrated to give 14.7 g (crude yield 100%) of methyl 3-bromo-4-(bromomethyl)benzoate.
Part of the crude dibromide (14.7 g) was dissolved in anhydrous CH2C12 (60 mL). The solution was cooled to 0 ~C
and treated with pyrrolidine (9.96 mL, 119 mmol), then it was allowed to stir at room tem.perature for 2 h. The reaction mixture was diluted with EtOAc (500 mL), washed with half-saturated a~ueous NaHCO3 (100 mL), dried over MgSO4, filtered, and concentrated to give an oily residue. The crude product was chromatographed on silica [gradient 0-10 EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 6.45 g of the pyrrolidinyl ester (45%) as an oil.
IR ~neat) 2953, 1728, 1602 cm 1; lH NMR (CDCl3) ~1.82 (br s, 4H), 2.61 (br s, 4H), 3.77 (s, 2H), 3.92 (s, 3H), 7.59 (d, J
- 8.0 Hz, lH), 7.95 (dd, ~ = 8.0 and 1.4 Hz, lH), 8.20 (d, = 1.4 Hz, lH); FDMS m/e 297 (M+, 79Br) and 299(M~, 81Br).
Part B. 3-Bromo-4-[(1-~l~lidinyl)methyl~benzoic Acid Hydrochloride.
Br H02C~N ~Cl LioH (32.4 mL, 1 N) was added to a stirred solution of the above ester (6.45 g, 21.6 mmol) in THF (75 mL) / MeOH (25 mL), and the resultant solution was heated in an oil bath at 50 ~C for 3 h. After cooling to room temperature, the solution was treated in portions with 5 N HCl (22 mL), and then concentrated at 50 ~C under vacuum to give 8.20 g (crude yield 99%) of the benzoic acid as a white solid contAminAted with LiCl.
IR (KBr) 3397 (br), 2924, 2679-2000 (br), 1713, 1634, 1464 cm~l;lH NMR (DMSO-d6) ~1.94 (br s, 4H), 2.95-3.70 (m, 4H), CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 4.54 (s, 2H), 7.92 (d, J = 8.1 Hz, lH), 8.10 (s, lH), 8.12 (d, ~ = 8.1 Hz, lH).
-Part C. 6-Nethoxy-2-[4-[2-(4-morpholinyl)ethoxy]-phenyllbQnzo~b~thiophene.
MeO ~ ~ N J
Cs2CO3 (4.89 g, 15.0 mmol) was added to a stirred solution of 2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene (1.10 g, 4.29 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (3.20 g, 17.2 mmol) in anhydrous DMF (10 mL).
The resultant suspension was heated in an oil bath at 75 ~C
~or 4 h. A~ter cooling to room temperature, the mixture was diluted with EtOAc (60 mL), washed with half-saturated a~ueous NaCl solution (20 mL), dried over MgSO4, filtered, and concentrated to give a solid residue. Chromatography on silica [gradient 0-15% EtOH/Et3N (2/1) in THF/hexanes (1/1)]
provided 1.43 g of the ether (90%) as a solid.
IR (KBr) 2940, 1606 cm~l; lH NMR (CDCl3) ~2.61 (t, ~ = 4.6 Hz, 4H), 2.84 (t, J = 5.7 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.84 (s, 3H), 4.17 (t, ~ = 5.7 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.98 (dd, J = 8.6 and 2.2 Hz, lH), 7.30 (d, J = 2.2 Hz, lH), 7.35 (s, lH), 7.60 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, lH); FDMS m/e 369 (M~).
Part D. 3-Bromo-4-1(1-~y~ olidinyl)methyllphenyl 6-Methoxy-2-~4-[2-(4-mor~holinyl~Qthoxy~phenyl]-bonzolb~thiophen-3-yl Ketone.
Br MeO ~ O ~ N J
Oxalyl chloride (1.11 mL, 12.7 mmol) was added to a stirred suspension of the above benzothiophene (812 mg, 2.53 mmol) in anhydrous ClCH2CH2Cl (6 mL), ~ollowed by the WO 97/25033 PCT~US96tl7995 addition o~ 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 6 h, then it was concentrated to dryness under vacuum at 50 ~C.
To the crude benzoyl chloride suspended in anhydrous CH2C12 (5 mL) was added a solution o~ the benzothiophene of Part C above (624 mg, 1.69 mmol) in anhydrous CH2C12 (10 mL).
The mixture was cooled to 0 ~C, treated with AlCl3 (1.35 g, 10.1 mmol), and stirred for 1 h. THF (10 mL) was added to the mixture at 0 ~C, followed by the slow, sequential additions of saturated aqueous NaHCO3 (30 mL) and saturated aqueous Rochelle's salt solution (10 mL). Then the two-layered solution was stirred vigorously for 70 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (25 mL), dried over MgS04, ~iltered, concentrated, and chromatographed on silica [gradient 0-20% EtOH/Et3N (2/1) in THF/h~n~ (1/1)] to give 695 mg (65%) of the ketone as a foam.
IR (neat) 2961, 1645, 1606 cm~l; lH NMR (CDC13) Sl.80 (br s, 4H), 2.52-2.57 (m, 8H), 2.76 (t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.72-3.89 (m, 4H), 3.91 (s, 3H), 4.04 (t, ~ = 5.7 Hz, 2H), 6.75 (d, ~ = 8.7 Hz, 2H), 7.20 (dd, ~ = 8.9 and 2.3 Hz, lH), 7.25-7.30 (m, 2H), 7.34 (d, ~ = 2.3 Hz, lH), 7.38 (d, ~
= 7.9 Hz, lH), 7.62 (dd, ~ = 7.9 and 1.6 Hz, lH), 7.68 (d, J
= 8.9 Hz, lH), 7.91 (d, ~ = 1.6 Hz, lH); FDMS m/e 634 (M+, 79Br) and 636(M+, 81Br).
Part E. 3-~3-Rromo-4-~ r y olidinyl)methyl~benzyl]-6-methoxy-2-[4-[2-(4-morpholinyl)ethoxy]~henyljbenzo-~b~thiophene. Br MeO ~ ~J~
W O 97/25033 pcTrus96ll7995 Following the procedure of~ Example 34, Part D, the corresponding methylene compound was obtained as a foam in 86% yield.
IR (neat) 2958, 1608 cm~l; FDMS m/e 621 (M+l, 79Br) and 623 (M+l, 81Br) Part F. 3-13-Bromo-4-t(1-~Y ~olidinyl)mQthyllben 6-hyaroxy-2-l4-l2-(4-morpholinyl)ethoxylphen benzo~b~thiorhs~e Dioxalate.
Following the procedure o~ Example 34, Part E, the h~droxy benzothiophene salt was obtained as a white solid in 55% yield.
~DMS m/e 607 (M+l, 79Br) and 609 (M~l, 81Br).
Example 38 Proparation o~ 6-Hydroxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl3-2-[4-[2-(4-morpholinyl)-ethoxyl~hQnyl]benzolblthiophone Dioxalate.
Me ~ N~
HO ~ O ~ N~J~
2tc2H2~4) Part A. 6-Methoxy-3-[3-mQthyl-4-1(1-~y lolidinyl)-methyl]b~nzyll-2-[4-12-(4-mor~holinyl)Qthoxy]phenyl]-benzolblthiophene.
Me ~ N~
MeO ~ O ~ N ~
A sealed tube cont~;n;n~ a stirred mixture of the aryl ~romide o~ Example 37, Part E, (283 mg, 0.456 mmol), -- tetramethlytin (0.316 mL, 2.28 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (16 mg, 0.014 mmolj in o-xylene (5 mL) was heated in an oil bath at 155 ~C for 1 h. A black CA 02236007 l998-04-27 W 097/25033 PCT~US96/17sss precipitate was formed. The mixture was cooled to room temperature and subjected to chromatography on silica [gradient 0-2096 EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 94 mg (37%, low yield attributed to spill) o~ the corresponding aryl methyl compound as a foam.
IR (neat) 2957, 1608 cm~l; lH NMR (CDC13) ~ 1.78 (br s, 4H), 3.3Q (s, 3H), 2.54-2.61 (m, 8H), 2.82 (t, LJ = 5.7 Hz, 2H), 3.57 (s, 2H), 3.75 (t, ~J = 4.5 Hz, 4H), 3.87 (s, 3H), 4.14 (t, .J = 5.7 Hz, 2H), 4.18 (s, 2H), 6.88-6.96 (m, 4H), 7.18 (d, J = 7.9 Hz, lH), 7.32-7.44 (m, 5H); FDMS m/e 556 (M+).
Part B. 6-Hydroxy-3-13-methyl-4-~ olidinyl)-methyl]benzyll-2-~4-12-(4-morpholinyl)ethoxy]~henyl]-benzo ~b] thiophene Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy benzothiophene salt was obtained as a white solid in 55% yield.
20 IR (KBr) 3455 (br), 2970, 2840-2220 (br), 1723, 1630 (br), 1610 cm~ H NMR (DMSO-d6) ~ 1.79-1.89 (m, 4H), 2.27 (s, 3H), 2.63-2.71 (m, 4H), 2.90-3.12 (m, 6H), 3.55-3.63 (m, 4H), 4.13-4.24 (m, 6H), 6.88-7.04 (m, 5H), 7.28-7.39 (m, 5H); FDMS
m/e 543 (M+l).
Exa~le 39 Preparation of 6-Hydroxy-2-~4-~2-(1-~ olidinyl)-othyl]phenyllbenzo[blthiophen-3-yl 3-Methyl-4-~
olidinyl)mQthyl3phenyl Ketone Dioxalate.
Me HO
2(c2H204) Part A. l-Bromo-4-~2-(1-~ olidinyl)ethyl~benzene.
=
W O 97/25033 PCT~US96/1799 _ -145-Br ~ ~
Methanesulfonyl chloride (2.12 mL, 27.4 mmol) was added to a stirred solution of 4-bromophenethyl alcohol (5.00 g, 24.9 mmol) and anhydrous pyridine (2.21 mL, 27.4 mmol) in anhydrous CH2C12 (25 mL) at 0 ~C under nitrogen atmosphere.
Upon the completion of the addition the mixture was allowed to stir at room temperature for 8 h. Then the reaction mixture was cooled to 0 ~C and treated with pyrrolidine ~10 4 mL, 124 mmol). After stirring at room temperature ~or 2 h, the mixture was diluted with EtOAc (120 mL), washed with half-saturated NaHCO3 (30 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-10%
EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 5.37 g (85~) of the substituted pyrrolidine as an oil.
IR (CHC13) 2933, 1489 cm-l; lH NMR (CDC13) ~ 1.80 (br s, 4H), 2.56 (br s, 4H), 2.64-2.80 (m, 4H), 7.10 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H); FDMS m/e 253 (M+, 79Br) and 255 (M+, 81Br) .
Part B. 2-Dimethyl~ i~-6-~methoxy~benzo[b]thiophen-3-yl 3-Methyl-4-1(1-~ L~lidinyl)methyl]phenyl Ketone.
Me MeO ~ N~
Oxalyl chloride (2.57 mL, 29.5 mmol) was added to a stirred suspension of 3-methyl-4-[(1-pyrrolidinyl)methyl]-benzoic acid hydrochloride (1.76 g, 5.90 mmol) in anhydrous ClCH2CH2Cl (12 mL), followed by the addition of 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 6 h, then it was concentrated to dryness under vacuum at 50 ~C.
To the crude benzoyl chloride obt~l n~ and suspended in anhydrous chlorobenzene (10 mL) was added 2-dimethylamino-6-W O 97/25033 PCTrUS96/17995 methoxybenzo[b]thiophene (1.02 g, 4.92 mmol. The resultant mixture was heated in an oil bath at 110 ~C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL), washed with saturated NaHCO3 (25 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-10% EtOH/Et3N (2/1) in THF/hexanes (1/1)3 to give 1.50 g (75%) o~ the ketone as a foam.
IR (CHCl3) 2950, 1647, 1601 cm-l; lH NMR (CDC13) ~ 1.81 (br s, 4H), 2.39 (s, 3H), 2.56 (br s, 4H), 2.89 (s, 6H), 3.65 (s, 2H), 3.83 (s, 3H), 6.80 (dd, J = 9.0 and 2.4 Hz, lH), 7.12 (d, J = 2.4 Hz, lH), 7.32 (d, J = 9.0 Hz, lH), 7.39 (d, J =
8.1 Hz, lH), 7.63 (d, J = 8.1 Hz, lH), 7.69 (s, lH); FDMS m/e 408 (M+); Anal. Calcd for C24H2gN2O2S: C, 70.56; H, 6.91i N, 6.86. Found: C, 70.75; H, 7.15; N, 6.91.
Part C. 6-Methoxy-2-t4-[2-(1-~y~l~lidinyl)ethyl]-phenyl]benzo~b]thiophen-3-yl 3-Methyl-4-[(1-~lidinyl)mQthyl]~henyl Keton~.
Me MeO ~ N~
Following the procedure of Example 34, Part C, thetrisubstituted benzothiophene was obtained ~rom the aryl bromide of Part A above and the amino benzothiophene of Part B above as a foam in 96~ yield.
IR (CHC13) 2964, 1647, 1603 cm~l; lH NMR (CDC13) ~ 1.75-1.82 (m, 8H) 2.25 (s, 3H), 2.44 (br s, 4H), 2.51-2.61 (m, 6H), 2.71-2.76 (m, 2H), 3.53 (s, 2H), 3.90 (s, 3H), 6.99 (dd, J =
8.7 and 2.1 Hz, lH), 7.05 (d, J = 8.1 Hz, 2H), 7.23 (d, J =
7.8 Hz, lH), 7.29-7.34 (m, 3H), 7.52 (d, J - 7.8 Hz, lH), 7.58 (s, lH), 7.60 (d, J - 8.7 Hz, lH); FDMS m/e 538 (M~);
Anal. Calcd for C34H3gN2O2$: C, 75.80; H, 7.11; N, 5.20.
Found: C, 75.67; H, 7.10; N, 5.25.
, CA 02236007 l998-04-27 Part D. 6-Hydroxy-2-[4-12-(1-~yrrolidinyl)ethyl3-phenyl]benzolblthiophen-3-yl 3-Methyl-4-t( pyrroli~inyl~methyll~henyl K~tone Dioxalate.
Following the procedure of Example 34, Part E, the title compound was obtained as a yellowish solid in 77% yield.
IR (KBr) 3420 (br), 2970, 2850-2300 (br), 1721, 1641, 1607 cm~l; lH NMR (DMSO-d6) ~.1.83 (br s, 4H), 1.88 (br s, 4H), 10 2.26 (s, 3H), 2.81-2.91 (m, 6H), 3.21 (br s, 6H), 4.07 (s, 2H), 6.88 (dd, J = 8.7 and 2.1 HZ, lH), 7.17 (d, J = 8.0 Hz, 2H), 7.26 (d, ~J = 8.0 Hz, 2H), 7.33-7.39 (m, 3H), 7.46 (d, ~
8.7 Hz, lH), 7.54 (s, lH); FDMS m/e 525 (M+-2C2H2O4); Anal.
Calcd for C33H36N2O2S-2C2H204: C, 63.05; H, 5.72; N, 3.97.
15 Found: C, 63.24; H, 6.02; N, 4.22.
Exam~le 4~
Preparation of 6-Hydroxy-3-t3-methyl-4-t(1-~ lO-liainyl)methyl]benzyl~-2-t4-12-(1-pyrrolidinyl)Qthyll-phQnyl3benzotb~thiophQne Dioxalat~.
Me HO~--VN~
2(c2H2o4) Part A. 6-Methoxy-3-[3-m~thyl-4-[(1-~ ~.olidinyl)-ethyllbenzyl~-2-14-t2-(1-pyrrolidinyl)QthyllphQnyl]-benzotb]thiophen~.
Me MeO ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 39, Part C, as a foam in 67% yield.
CA 02236007 l998-04-27 W 097/25033 PCTAJS96/l79s~
I~ tKBr) 2953, 1601 cm-l; lH N ~ (CDCl3) ~ 1.77 (br s, 4H3, 1.83 (br s, 4H), 2.29 (s, 3H), 2.51 (br s, 4H), 2.60 rbr s, 4H), 2.70-2.75 (m, 2H), 2.85-2.88 (m, 2H), 3.54 (s, 2H), 3.88 (s, 3H), 4.20 (s, 2H), 6.88-6.95 (m, 3H), 7.17 (d, ~ = 7.8 Hz, lH), 7.24 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 2.1 Hz, lH), 7.38-7.45 (m, 3H); FD~S m/e 524 (M+); Anal. Calcd for C34H40N2OS: C, 77.82; H, 7.68; N, 5.34. Found: C, 78.03; H, 7.58; N, 5.54.
Part B. 6-Hydroxy-3-[3-methyl-4-[(1-~olidinyl)-methyl~benzyll-2-[4-12-(1-~yrrolidinyl)othyl~phenyl~-bonzolb~thio~hene Dioxalate.
Me HO ~ N
2(c2H2O4) Following the procedure of 33xample 34, Part D, the hydroxy benzothiophene salt was obtained as a white solid in 73% yield.
IR (KBr) 3420 (br), 2976, 2830-2230 (br), 1722, 1613 cm-l; lH
N~IR (DMSO-d6) ~ 1.81-1.91 (m, 8H), 2.26 (s, 3H), 2.95-3.11 (m, 6H), 3.19-3.35 (m, 6H), 4.15 (s, 2H), 4.17 (s, 2H), 6.79 (dd, J = 8 .6 and 2.0 Hz, lH), 6.89 (d, J = 8.4 Hz, lH), 6.99 (s, lH), 7.26 (d, J = 2.0 Hz, lH), 7.29-7.43 (m, 6H); FDMS
m/e 511 (M~1-2C2H204); Anal. Calcd for C33H3gN20S 2C2H20~: C, 64.33; H, 6.13; N, 4.06. Fourld: C, 64.42; H, 6.40; N, 4.11.
Exaunplo 41 Preparation of 6-Hydroxy-2-[4-12-(1-~1~olidinyl~-ethyl]phenyl~benzo[b~thiophen-3-yl 3-Methoxy-4-~(1-pyrrolidinyl)methyl~phenyl Ketone Dioxalate.
-W O 97/25033 PCT~US96/17995 -14g -OMe HO ~ N~
2(c2H2~4) Part A. Methyl 3-Methoxy-4-~ oli~lnyl)methyl]~
b~nzoate.
OMe MeO2C~N
Following the procedure of Example 37, Part A, the substituted pyrrolidine was obtained ~rom methyl 3-methoxy-4-methylbenzoate as an oil in 65% yield.
I3~ (CEIC13) 2954, 1716 cm-l; 1H NMR (CDC13) ~ 1.95 (br s, 4H), 2.89 (br s, 4H), 3.91 (s, 3H), 3.92 (s, 3H), 3.98 (br t, J =
6.8 Hz, 2H), 7.56 (s, lH), 7.61-7.67 (m, 2H); FDMS m/e 249 (M+).
Part B. 3-Methoxy-4~ oli~inyl)methyl]benzoic 15 Acia Hy~rochloride.
OMe H02C~N HCl Following the procedure of Example 37, Part B, the acid was obtained from the above ester as a yellowish solid in 65%
crude yield.
H NMR (DMSO-d6) ~1.89-1.94 (br s, 4H), 3.01-3.05 (br s, 2H), 3.26-3.34 (br s, 2H), 3.88 (s, 3H), 4.32 (s, 2H), 7.53 (s, lH), 7.54 (d, .J = 7.7 Hz, lH), 7.70 (d, IJ = 7.7 Hz, lH); FDMS
m/e 235 (M+).
r Part C. 6-Benzyloxy-2-(dimethylamino)benzolb~thio-~hen-3-yl 3-Methoxy-4-[(1-pyrrolidinyl)methyl~phenyl KetonQ.
W O 97/2~033 PCTfUS96/17995 OMe BnO~
Following the procedure of Example 39, Part B, the ketone was obtained from the above acid and 6-benzyloxy-2-dimethylaminobenzo[b]thiophene as a foam in 81% yield.
IR (CHC13) 2970, 1621, 1600 cm-l; lH NMR (CDC13) ~ 1.85 (br 5, 4H), 2.70 (br s, 4H), 2.89 (s, 6~I), 3.80 (s, 2H), 3.88 (s, 3H), 5.08 (s, 2H), ~.89 (dd, ~ = 8.9 and 2.5 Hz, lH), 7.20 (d, ~ = 2.3 Hz, lH), 7.33-7.47 (m, 9H); FDMS m/e 500 (M+).
Part D. 6-Bonzyloxy-2-14-[2-(~-~y olidinyl)ethyll-phenyl~bonzolblthiophen-3-yl 3-Methoxy-4-1(1-~olidinyl)~ethyl]phonyl Ketone.
OMe BnO~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the dimethylamino compound of Part C as a foam in 81% yield.
IR (CHCl3) 2965, 1648, 1601 cm~l; lH NMR (CDCl3) ~ 1.77-1.82 (m, 8H), 2.52 (br s, 4H), 2.60 (br s, 4H), 2.61-2.67 (m, 2H), 2.75-2.80 (m, 2H), 3.63 (s, 2H), 3.80 (s, 3~), 5.16 (s, 2H), 7.06 (d, J = 8.1 Hz, 2 + lH superimposed), 7.25-7.50 (m, llH), 7.61 (d, ~ = 8.9 Hz, lH); FDMS m/e 631 (M+l).
Part E. 6-Hydroxy-2- 14-12-(1-1?YrrolidinYl)ethyl]-phenyl]benzorb]thioph~n-3-yl 3-Methoxy-4-[(1-~y~ ol~dinyl)methyll~h~nyl Kotone Dio~alat~.
To a stirred solution of the above benzyloxy benzothiophene (440 mg, 0.698 mmol) in THF (8 mL) under nitrogen atmosphere were se~uentially added 10~ Pd/C (440 mg) CA 02236007 l998-04-27 W~97/25033 P ~ AUSg6~79g5 and 25% aqueous HC02NH4 (2 mL). The resultant mixture was stirred under a balloon nitrogen atmosphere ~or 7 h. After ~ filtration, the ~iltrate was diluted with EtOAc (50 mL), washed with half-saturated NaCl (15 mL), dried over MgSO4, filtered, concentrated, and chromatoyraphed on silica [gradient 0-20% EtOH/TEA (2/1) in THF/hexanes (1/1)] to give 225 mg (60~) of the hydroxy benzothiophene as a foam.
A solution of oxalic acid (64.2 mg, 0.712 mmol) in EtOAc (6 mL) was added dropwise to a stirred solution of the hydroxy benzothiophene (175 mg, 0.323 mmol) in THF (4 mL).
The resultant white suspension was filtered and the white solid was dried at 60 ~C under vacuum to provide 213 mg (91%) of the corresp~n~'ng dioxalate.
IR (neat) 3450 (br), 2964, 2830-2220, 1719, 1640, 1607 cm-1;
1H NMR (DMSO-d6) ~ 1.83-1.88 (br s, 8H), 2.83-2.93 (m, 6H), 3.18 (br s, 6H), 3.75 (s, 3H), 4.06 (s, 2H), 6.90 (dd, J =
8.8 and 2.2 Hz, lH), 7.15-7.39 (m, 8H), 7.43 (d, ~ = 8.8 Hz, lH); FDMS m/e 541 (M~1-2C2H204); Anal. Calcd for C33H36N2O3S-2C2H2O4: C, 61.66; H, 5.59; N, 3.89. Found: C, 61.91; H, 5.69; N, 4.00.
ExamplQ 42 PrQparation of 6-Hy~roxy-3-~3-methoxy-4- r (1-~yrrolidinyl)methyl]benzyl~-2-[4-[2-(1-~yrrolidinyl)-Qthyl]ph~nyllb~nzo[b]thiophQnQ Dioxalate.
OMe HO
2(c2H2~4) Part A. 6-Benzyloxy-3-t3-m~thoxy-4-~(1-~y~ oli~inyl)-m~thyl]b~nzyl~-2-[4- r 2-(1-~yrrolidinyl)ethyl]phenyll-benzorb]thiophene.
CA 02236007 l998-04-27 W 097/25033 PCT~USs6/l7sss ~152-OMe BnO ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 41, Part D as a foam in 62% yield.
IR (CHC13) 2966, 1601 cm 1; lH NMR (CDC13) ~ 1.82 (br s, 8H), 2.60 (br s, 8H), 2.68-2.75 (m, 2H), 2.72-2.95 (m, 2H), 3.68 (s, 5H, OCH3 and CH2), 4.22 (s, 2H), 5.13 (s, 2H), 6.64 (s, lH), 6.71 (d, J = 7 .5 Hz, lH), 6.98 (dd, J = 8.5 and 2.0 Hz, lH), 7.23 (br s, 2H), 7.30-7.50 (m, 10H); FDMS m/e 616 (M+).
Anal. Calcd for C40H44N2o2s: C, 77.88; H, 7.19; N, 4.54.
Found: C, 77.93; H, 7.22; N, 4.61.
Part B. 6-Hydroxy-3-~3-methoxy-4-[(1-p~ r Lolidinyl) ~
15 m~thyllb~nzyl]-2-~4-12-(1-pyrrolidinyl~ethyl~phenyl]-b~nzolb~thio~hene Dioxalate.
Following the procedure of Example 41, Part E, the title hydroxy benzothiophene salt was obtained from the benzyl ether as a white solid in an overall 65% yield.
IR (KBr) 3420 (br), 2980, 2830-2240 (br), 1720, 1613 cm~l; lH
NMR (DMSO-d6) ~ 1.86-1.93 (m, 8H), 2.96-3.01 (m, 2H), 3.06-3.21 (m, 4H), 3.25-3.50 (m, 6H), 3.70 (s, 3H), 4.14 (s, 2H), 4.20 (s, 2H), 6.60 (d, J = 7.9 Hz, lH), 6.81 (dd, J = 8.7 and 25 2.1 Hz, lH), 7.26 (d, J = 8.2 Hz, 2 + lH superimposed), 7.36 (d, J = 8.2 Hz, 2H) 7.42-7.46 (m, 3H); FDMS m/e 527 (M+l-2C2H204); Anal. Calcd for C33H3gN2O2S-1.7C2H2O4: C, 64.31; H, 6.14; N, 4.12. Found: C, 64.25; H, 6.42; N, 4.02.
Example 43 Pr~paration o~ 6-Hyaroxy-2-t4-t2-~1-t(5)-2-hydroxymethyl]~yrrolidinyl]ethyl]~henyl~benzotb]--CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/l7995 thiophon-3-yl 3-M~thoxy-4- e ( 1-pyrrolidiny:L)methyl3-phenyl Ketone Dioxalate.
OMe 2(c2H2O4) OH
Part A. l-Bromo-4-[2-(triisopro~ylsilyloxy)ethyl]-benzene.
Br ~ O-TIPS
Triisopropylsilyl tri~luoromethanesulfonate (35.1 mL, 130 mmol) was added to a stirred solution o~ 4-bromophenethyl alcohol (20.2 g, 100 mmol) and anhydrous triethylamine (27.8 mL, 200 mmol) in anhydrous CH2C12 (200 mL) at room temperature under nitrogen atmosphere. The resultant mixture was stirred for 3 h. A~ter dilution with EtOAc (200 mL), the mixture was washed with a mixed aqeous solution o~ saturated NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica (gradient 0-10%
EtOAc in hexanes) to give 33.5 g (94%) of the silyl ether as an oil.
IR (CHCl3) 2944, 148g cm~l; lH NMR (CDC13) ~1.03 (br s, 3H), 20 1.39 (br s, 18H), 2.81 (t, J = 6.8 Hz, 2H), 3.86 (t, J = 6.8 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H);
FDMS m/e 356 (M+, 79Br) and 358 (M+, 81Br).
~?art B. 6-Benzyloxy-2-t4-(2-hydloxyethyl)~hQnyl]-25 benzo~blthiophen-3-yl 3-Melthoxy-4-~(l-pyrroli~linyl)-rlethyl]phenyl K~tone.
OMe ; BnO
OE~
CA 02236007 l998-04-27 W O 97/2~033 PCTrUS96/17995 The above silyl ether (571 mg, 1. 60 mmol) was added to a stirred suspension of magnesium ribbons (36. 4 mg, 1.50 mmol) in anhydrous THF (2 mL) under argon atmosphere, followed by the addition o~ a small iodine crystal. The mixture was heated in an oil bath at 60-65 ~C for 2 h to form a homogeneous Grignard solution. The Grignard solution was cooled to room temperature before it was added to a stirred solution o~ the compound o~ Example 41, Part C (500 mg, 1.00 mmol) in anhydrous THF (4 mL) at 0 ~C under argon atmosphere.
The resultant mixture was stirred at 0 ~C for 1.5 h, then quenched with saturated aqueous NH4Cl (5 mL). After extraction with EtOAc (25 mL x 2), the combined organic layers were dried over MgSO4, filtered, and concentrated to give a gummy residue (597 mg).
The residue was dissolved in anhydrous THF (5 mL) and treated with tetrabutylammonium fluoride (1.20 mL, 1 M in THF) at room temperature under nitrogen atmosphere. A~ter stirring ~or 1.5 h, the mixture was concentrated under vacuum and chromatographed on silica [gradient 0-30% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 395 mg (68%) of the alcohol as foam.
IR (CHCl3) 2960, 1646, 1601 Gm-1; 1H NMR (CDC13) ~ 1.80 (br s, 4H), 2.54 (br s, 4H), 2.75 (t, J = 6.2 Hz, 2H), 3.59 (s, 2H), 3.74 (t, ~ = 6.2 Hz, 2H), 3.79 (s, 3H), 5.18 (s, 2H), 7.05 (d, J = 8.1 Hz, lH), 7.09-7.50 (m, 13H), 7.74 (d, ~ =
8.g Hz, lH); FDMS m/e 578 (M+1); Anal. Calcd for C36H3sNO4S:
C, 74.84; H, 6.11; N, 2.42. Found: C, 7S.02; H, 6.34; N, 2.50.
Part C. 6-Benzyloxy-2-~4-~2-11-~(S)-2-hydroxymethyl]-~yrroli~inyllethyl]phenyl~benzo~blthio~hen-3-yl 3-Methoxy-4-~ olidinyl)mQthyl]PhQn~l Ketone.
W 097/25033 PCT~US96/17995 OMe ~3nO ~ ~
OH
Methanesulfonyl chloride (0.420 mL, 5.43 mmol) was added to a stirred solution of the above alcohol (2.09 g, 3.62 mmol) in anhydrous pyridine (5 mL) at 0 ~C under nitrogen atmosphere, and the reaction mixture was allowed to stir at room temperature for 2 h. (S)-Prolinol (1.25 mL, 12.7 mmol) was added and the resultant mixture was heated at 70 ~C ~or 2 h. After dilution with EtOAc (120 mL), the mixture was washed with half-saturated NaHCO3 (30 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-25% EtOH/Et3N (2/1) in THF/hexanes (1/1)~ to give 2.01 g (84%) of the substituted pyrrolidine a foam.
IR (neat) 3355 (br), 2958, 1646, 1600 cm~l; lH MMR (CDCl3) 1.63-2.19 (m, 8H), 2.25-2.80 (m, 8H), 2.87 (t, ~ = 7.7 Hz, 2H), 3.15-3.58 (m, 4H), 3.44 (dd, ~ = 11.5 and 3.6 Hz, lH), 3.60 (dd, J = 11.5 and 3.6 Hz, lH), 3.62 (s, 2H), 3.80 (s, 3H), 7.04-7.08 (m, 3H), 7.23-7.47 (m, llH), 7.62 (d, ~ - 9.0 Hz, lH); FDMS m/e 661 (M+l).
Part D. 6-Hydroxy-2-~4-12-~ (~)-2-hydroxymethyl]-]pyrrolidinyl]Qthyl]phenyl~b~nzo~b]thioph~n-3-yl 3-M~thoxy-4-[(1-pyrrolidinyl)mothyl]phenyl Ketone ~Dioxalate.
Following the procedure of Example 41-E, the title salt was obtained ~rom the above methoxy benzothiophene as a yellowish solid in an overall 6% yield. The free base of the title compound was unstable.
lH NMR (CD30D) ~ 1.75-2.25 (m, 8H), 2.82-3.05 (m, 2H), 3.15-3.23 (m, 4H), 3.38-3.91 (m, 6H), 3.80 (s, 3H), 4.01-4.13 ~m, W O 97/25033 PCTrUS96/17995 lH), 4.28 (s, 2H), 6.92 (br d, J = 6.3 Hz, lH), 7.03-7.37 (m, 8H), 7.56 (m,lH); FDMS m/e 571 (M+l).
~ e 44 Preparation of 6-Hydroxy-3-t3-methyl-4-~1-[(S)-2-mothoxymethyl]pyrrolidinyl~methyl~benzyll-2-~4-12-(1-pyrrolidinyl)ethoxy]phenyl]benzotb]thiophene Dioxalate.
Me HO ~ O ~'N~e 2~c2H2~4~
Part A. Methyl 3-Bromo-4-~ (S)-2-methoxymethyl]-~yrrolidinyl]methyl]benzoate.
Br MeO2C~
OMe Following the procedure of Example 37, Part A, the substituted pyrrolidine was obtained from methyl 3-bromo-4-methylbenzoate and (S)-2-(methoxymethyl)pyrrolidine as an oil in 6396 yield.
IR (neat) 2950, 1727 cm-l; FDMS m/e 341 (M~, 79Br) and 343 (M+, 81Br); Anal. Calcd for ClsH20BrNo3: C, 52.64; H, 5.89;
N, 4.09. Found: C, 52.91; H, 5.93; N, 3.85.
Part B. 3-Bromo-4-[[1-1(5)-2-methoxymethyl]-~yrrolidinyl]msthyl~benzoic acid hydrochloride.
Br H02C~, Cl OMe Following the procedure of Example 37, Part B, the acid was obtained from the above ester as a white solid in.l00%
yield.
CA 02236007 l998-04-27 W 097/25033 pcTrus96~I799s lH NMR (DMSO-d6) ~ 1.60-1.78 (m, lH), 1.80-2.05 (m, 2H), 2.08-2.22 (m, lH), 3 .10-3. 50 (m, 2H), 3.29 (s, 3H), 3 .60-3.65 (m, lH), 3.75-3.95 (m, 2H), 4.46 ~br d, J = 13.4 Hz, lH), 4.76 (d, ~T = 13.4 Hz, lH), 7.93 (d, J = 8.0 Hz, lH), 8.03 (d, LJ = 8.0 Hz, lH), 8.12 (S, lH), 11.15 (br s, lH), 13.55 (br S,lH).
Part C. 3-Bromo-4-t~ (S)-2-methoxymethyl~-~yrrolidinyl]methyl]~henyl 2-Dimethyl~ ; no- 6 -mothoxybenzo[b]thio~hen-3-yl Ketone.
Br MeO ~ N~'OMe Following the procedure oi~ Example 39, Part B, the ketone was obtained :Erom the above acid as a foam in 75%
yield.
IR (neat) 1626, 1544 cm-l; FDMS m/e 516 (M+, 79Br) and 518 (M+, 81Br); Anal. Calcd for C2sH2gBrN2O3S: C, 58.03; H, 5.65;
N, 5. 41. Found: C, 58.15i H, 5.40; N, 5.29.
Part D. 3-Bromo-4-~[1-~($)-2-methoxymethyll-~yrrolidinyllmothyllphenyl 6-Methoxy-2-[4-~2-~1-~yrrolidinyl)ethoxy~phenyl]benzo~b]thioph~n-3-yl Ketone.
Br MeO ~ oN~ 'N~ e Following the procedure o~ Example 3 4, Part C, the trisubstituted benzothiophene was obtained from the above benzothiophene and the corresponding aryl bromide as a foam in 95% yield.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 IR (neat) 2962, 1645, 1606 cm-l; FDMS m/e 662 (M+, 79Br) and 664 (M+, 81Br); Anal. Calcd for C3sH3gBrN204S: C, 63.34; H, 5.92; N, 4.22. Found: C, 63.18; H, 5.84; N, 4.44.
Part E. 3-c3-Bromo-4-lll-[(s)-2-methoxymethyl]-pyrrolidinyl]methyllb~nzyll-6-methoxy-2-14-~2-(1-~yrrolidinyl)ethoxyl~hQnyl]benzo~b~thiophQn~.
MeO ~ N~
Following the procedure oE Example 34, Part D, the methylene compound was obtained from the above ketone as a foam in 7g% yield.
IR (neat) 2963, 1607 cm-l; FDMS m/e 648 (M+, 79Br) and 650 (M+, 31Br); Anal. Calcd for C3sH41BrN203S: C, 64.71; H, 6.36;
15 N, 4.31. Found: C, 64.93; H, 6.42; N, 4.35.
Part F. 6-Methoxy-3-t3-methyl-4-ttl-1(5)-2-methoxymethyllpyrroli~inyl]m~thyl~benzyl]-2-14-~2-(1-~yrrolidinyl)othoxylphQnyllb~nzotblthiophene.
Me ~ ~OMe MeO' ~ ~
Following the procedure of Example 38, Part A, the aryl methyl compound was obtained ~rom the above aryl bromide as a foam in 85% yield.
25 IR (neat) 2962, 1608 cm~l; FDMS m/e 584 (M+) and 585 (Mtl);
Anal. Calcd for C36H44N203S: C, 73.94; H, 7.58; N, 4.79.
Found: C, 73.84; H, 7.42; N, 4.50.
Part G. 6-Hy~roxy-3-13-methyl-4~ (S)-2-mothoxymothyl]pyrroli~inyl]mothyl]benzyl]-2-~4-~2-(1-_ -159-pyrroliainyl)ethoxylphenyl~benzo~b]thiophene Dioxalate .
Following the procedure of Example 34, Part D, a mixture of the free bases of the compounds of this example and the following example were obtained from the above dimethoxy compound. Following conversion to the dioxalate, the title compound was obtained as a white solid in a 2-step yield of 19%.
10 IR (KBr) 3450-2500 (br), 1718, 1609 cm 1; FDMS m/e 571 (M+l-2C2H2O4); Anal. Calcd for C3sH42N2O3S 2C2H2O4: C, 62.39; H, 6.18; N, 3.73. Found: C, 62.61; H, 6.02; N, 3.72.
Examplo 45 15 Preparation of 6-Hy~roxy-3-[3-methy~-4-[tl-[(5~-2-hydroxymethyl]~yrroliainyl~m~thyllbenzyll-2-14-12-(1-~yrrolidinyl)ethoxy~henyll~enzolblthioph~ne Dioxalate.
Me HO f' ~ N~O>
2(CaH2O4) Following separation of the free base in Part ~ of the above example, the dihydroxy compound was converted into the title dioxalate which was obt~; n~ in a white solid in a 2-step yield of 33%.
25 IR (KBr) 3400-2500 (br), 1721, 1609 cm~l; FDMS m/e 557 (M+l-2C2H2O4); Anal. Calcd for C34H4QN2O3S 1.6C2H2O4: C, 62.39; H, 6.18; N, 3.73. Found: C, 62.61; Il, 6.02i N, 3.72.
>
~v~ 1~ 46 30 Preparation of 6-Hy~lroxy-2-1:4-t2-(1-~r~lolidinyl)-othoxy]phenyl]benzolb]thi.ophen-3-yl 3-Methyl-4-~(4-mor~holinyl)methyl~honyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 Me N
~~~
2(c2H2~4) Part A. Methyl 3-Bromo-4-~(4-morpholinyl)meth~l]-b~zoat~- Br MeO2C~N~
~0 Following the procedu~e of Example 37, Part A, the substituted morpholine was obtained from methyl 3-bromo-4-methylbenzoate and morpholine as an oil in 53% yield.
IR (neat) 2953, 1727 cm~l; lH NMR (CDCl3) ~ 2.48-2.60 ~m, 10 4H), 3.63 (s, 2H), 3.70-3.80 (m, 4H), 3.93 ~s, 3H), 7.59 (d, J = 8.0 Hz, lH), 7.95 (d, J = 8.0 Hz, lH), 8.23 (s, lH); FDMS
m/e 313 (M+,79Br) and 315 (M+,81Br); Anal. Calcd for C13H16BrNO3: C, 49.70; H, 5.13; N, 4.46. Found: C, 49.42; H, 4.98; N, 4.55.
Par~ B. 3-Bromo-4-[(4-~orpholinyl)methyl]benzoic Acid Hydrochloride.
~ Br H02C~--N~l ~0 Following the procedure of Example 37, Part B, the acid was obtained ~rom the above ester as a white solid in 100 yield.
lH NMR (DMSO-d6) ~ 3.25 (br s, 4H), 3.88 (br s, 4H), 4.51 ~s, 2H), 7.93 (d, ~ = 8.Q Hz, lH), 8.12 (s, lH), 8.19 (br d, J =
8.0 Hz, lH).
PCT~US96/17995 W O 97nso33 Part C. 3-Bromo-4-~(4-morpholinyl)methyl~phonyl 2-Dimothylamino-6-methoxybenzo~b]thioph~n-3-yl Ketone.
Br ~~
MeO ~ N' Following the procedure o~ Example 39, Part C, the ketone was obtained from 2-dimethyl~m,no-6-methoxybenzo[b]thiophene and the above acid as a foam in 80%
yle~
IR (neat) 1622, 1540 cm~l; lH NMR (CDC13) ~ 2.52-2.60 (m, 4H), 2.89 ~s, 6H), 3.65 (s, 2H), 3.72-3.80 (m, 4H), 3.83 (s, 3H), 6.84 (dd, ~ = 8.9 and 2.4 Hz, lH), 7.13 (d, ~ = 2.4 Hz, lH), 7.39 (d, ~ = 8.9 Hz, lH), 7.58 (d, ~ = 8.0 Hz, lH), 7.77 (dd, ~ = 8.0 and 1.4 Hz, lH), 8.05 (d, ~ = 1.4 Hz, lH); FDMS
m/e 488 (M+,79Br) and 490 (M+,81Br).
I?art D. 3-Bromo-4-~(4-morpholinyl)methyl]ph~nyl 6-Methoxy-2-l4-~2-(1-pyrrolidinyl)ethoxy]phenyll-b~nzo~b]thio~hen-3-yl K~tonQO
Br ~ N
MeO ~ o ~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obt;~;n~ from the corresponding aryl bromide and the above benzothiophene as a foam in 80~ yield.
25 IR (neat) 2959, 1622, 1598 cm-l; FDM~ m/e 635 (M+l, 79Br) and 637 (M+l, 79Br).
Part E. 6-M~thoxy-2-[4-~2-(1-pyrrolidinyl)ethoxy]-~henyl]benzo~blthio~hQn-3-Yl 3-Methyl-4- r ( 4-mor~holinyl)m~thyl]phenyl K~tono.
Me MeO ~
Following the procedure of Example 34, Part E, the aryl methyl compound was obtained from the above aryl bromide as a foam in 76% yield.
IR (neat) 2958, 1643, 1603 cm-1; FDMS m/e 570 (M+).
Part F. 6-Xydroxy-2-14-12-(1-~y olidinyl)~thoxy]-phenyl~ benz o 1 b lthiol?hen-3-yl 3-Mothyl-4-[(4-morpholinyl)methyl]phenyl Ketono Dioxalato.
Following the procedure o~ Example 34, Part E, the salt of the hydroxy benzothiophene was obtained from the above methoxy ben~othiophene as a yellowish solid in a 2-step yield of 69%.
IR (KBr) 3400-2500 (br), 1725, 1639 cm-l; FDMS m/e 557(M+1-2C2H204); Anal. Calcd for C33H36N204S 2C2H204: C, 60.32; H, 5.47; N, 3.80. Found: C, 60.60; H, 5.53; N, 4.01.
Exam~le 47 Preparation of 3-l3-Bromo-4-l(4-mor~holinyl)meth benzyll-6-hydroxy-2-14- r 2-(1-~yrrolidinyl)ethoxy}-~honyl~benzo[bl thio~hene Dioxalate.
Br ~ N
HO ~ o ~ N~
2(C2H2O4) Part A. 3-[3-Bromo-4-t(4-morpholinyl)methyl]benzyl]-6-methoxy-2-14-12-(1-pyrrolidinyl)othoxy]phenyl}-bQnzolb] thiophone-W O 97/25033 PCTnJS96/1799 Br ~ N
MeO ~ ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone of Example 46, Part A as a foam in 84% yield.
IR (neat) 2958, 1608 cm~l; FDMS m/e 621 (M+1,79Br) and 623 (M~1,81Br); Anal. Calcd for C33H37BrN2O3S: C, 63.76; H, 6.00;
N, 4.51. Found: C, 63.50; H, 5.82; N, 4.38.
Part s. 3-13-sromo-4-1(4-morpholinyl)m~thyl]bQnzyl~-G-hydroxy-2-14-12-(1-pyrrolidinyl)ethoxylph~nyl]-benzolb]thiorhs~e Dioxalate.
Following the procedure of Example 34, Part E, the title hydroxy benzothiophene salt was obtained ~rom the above methoxy benzothiophene as a white solid in 66% yield.
IR (KBr) 3400-2500 (br), 1721, 1607 cm-l; FDMS m/e 607 (M+l-2C2H204,79Br) and 609 (M+1-2C2H204,81Br); Anal. Calcd for C32H35BrM2O3S 1.5C2H2O4: C, 56.61i H, 5.16; N, 3.77. Found: C, 56.70; H, 5.13; N, 3.95.
~ Y~ _le 48 Preparation of 6-Hydroxy-3 t3-methyl-4-[(A-morpholinyl)methyllbQnzyll-2-14-12~ pyrroli~inyl)-~thoxy]phenyl]bonzo lb] thiophene Dioxalate~
Me HO~o~ON~
2(c2H2o4) Part A. 6-Methoxy-3-13-methyl-4-1(4-morpholinyl)-methyl]b~nzyl]-2-14-12-(1-~yrrolidinyl)ethoxyl-~henyl]benzo tb] thiophene.
W O 97/25033 PCTnJS96/17995 Me MeO~O~N~>
Following the procedure o~ Example 38, Part A, the aryl methyl compound was obtained ~rom the aryl bromide of Example 47, Part A as a foam in 91% yield.
IR (neat) 2957, 1608 cm~l; FDMS m/e 556 (M+).
Part B. 6-Hy~roxy-3-13-methyl-4-1(4-morpholinyl)-m~thyllbQnzyll-2-14- r2 - ( 1-~yrroli~inyl)ethoxy]-phenyl]benzo~b]thiophQne Dioxalate.
Following the procedure of Example 34, Part E, the titlehydroxy benzothiophene salt was obtained ~rom the above methoxy benzothiophene as a white solid in a 2-step yield o~
79%.
IR (KBr) 3400-2500 (br), 1722, 1610 cm-l; FDM~ m/e 543 (M~-2C2H2O4); Anal. Calcd ~or C33H3gN2O3S 1.5C2H2O4: C, 63.79; H, 6.10; N, 4.13. Found: C, 63.92; H, 6.15; N, 4.31.
~YA _le 49 Preparation of 6-Hy~oxy-2-14-[2-(1-~ olidinyl)-~thoxy]~henyl]bQnzo[b]thiophen-3-yl 3-Methoxy-4-1(4-morpholinyl)methyl]phenyl Ketone Dioxalate.
OMe HO ~ N~
2(c2H2~4) Part A. Methyl 3-Methoxy-4-(4-mor~holinyl)benzoate.
OMe Meo2c~<~?
Following the procedure of Example 37, Part A, the substituted morpholine was obtained from methyl 4-methyl-3-methoxybenzoate and morpholine as an oil in 79% yield.
IR (neat) 2953, 1723, 1582 cm 1; FDMS m/e 265 (M+); Anal.
>
Calcd for C14HlgNO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.11; H, 7.20; N, 5.50.
Part B. 3-Methoxy-4-(4-morpllolinyl)benzoic Acid Hydrochloride.
OMe H02C~N~l ~0 Following the procedure of Example 37, Part B, the acid was obtained from the ester as a white solid in 100~ yield.
1H NMR (DMSO-d6) ~ 3.05 (br s, 2H), 3.15-3.25 (m, 2H), 3.85 (s, 2H), 3.87 (s, 5H, OCH3 and CH2), 4.29 (s, 2H), 7.52 (s, lH), 7.53 (d, J = 8.0 Hz, lH), 7.77 (d, J = 8.0 Hz, lH), 11.65 (br s, lH), 13.15 (br s, lH).
Part C. 6-BQnzyloxy-2-(dimethyl~ Q) benzolb~-thiophen-3-yl 3-Methoxy-4-~(4-mor~holinyl)methyl~-phenyl Ketone.
OMe ~ N
BnO ~ N' ~
Following the procedure of Example 39, Part B, the ketone was obtained from 6-benzyloxy-2-(dimethyl~m; no) -benzo~b]thiophene and the above acid as a foam in 81% yield.
IR (neat) 2954, 1625, 1600 cm 1; FDMS m/e 516 (M+); Anal.
Calcd for C30H32N2O4S: C, 69.74; H, 6.24; N, 5.42. Found: C, '70.03; H, 6.47; N, 5.44.
CA 02236007 l998-04-27 W 097/25033 PCT~USg6/l7995 Part D. 6-Benzyloxy-2-[4-[2-(1-~ ~olidinyl)ethoxy~-phenyl]benzotb~thiophen-3-yl 3-Methoxy-4-[(4-mor~holinyl)methyl~phenyl Ketone.
OMe BnO ~ O ~ M~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the corresponding aryl bromide and the above benzothiophene as a foam in 88% yield.
10 IR (neat) 2961, 1651 cm-li FD~qS m/e 662 (M+) and 663 (M+l);
Anal. Calcd for C40H42N2OsS: C, 72.48; H, 6.39; N, 4.23.
Found: C, 72.47; H, 6.35; N, 4.43.
Part E. 6-Hydroxy-2-14-[2-(l-~y ~olidinyl~ethoxyl-15 phenyl~benzolb~thiophen-3-yl 3-Methoxy-4-[(4-morpholinyl)methyllphenyl Ketone Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 74% yield.
IR (KBr) 3400-2500 (br), 1722, 1633, 1606 cm~l; FDMS m/e 573 (M+1-2C2H2O4); Anal. Calcd for C33H36N2OsS-2.3C2H2O4: C, 57.91; ~I, 5.25; N, 3.59. Fotm d: C, 57.93; H, 5.37; M, 3.78.
~Y~ _ le 50 Pre~aration of 6-Hydroxy-3-[3-methoxy-4-[(4-morpholinyl)methyl]benzyl]-2-[4-[2-(1-~yrrolidinyl?-ethoxy~phenyl~benzo[b]thio~he~e Dioxalate.
OMe ~ N ~
HO ~ M~>
2(C2H2O4) W O 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-3-[3-methoxy-4-[(4-morpholinyl)-m~thyl]bQnzyl~-2-[4-~2-(1-pyrrolidinyl)ethoxy]ph~nyl]-benzolb]thiophene.
OMe N
BnO ~ O ~ ON~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone of Example 49, Part D as a ~oam in 82% yield.
IR (neat) 2961, 1609 cm-l; FDMS m/e 649 (M+1); Anal. Calcd for C40H44N2O4S: C, 74.04; H, 6.84; N, 4.32. Found: C, 74.30;
H, 7.18; N, 4.34.
Part B. 6-Hydroxy-3-C3-methoxy-4-~(4-morpholinyl)-methyllbQnzyll-2-14-~2-(1-~yrrolidinyl)ethoxy~ph~nyl3-bonzotb~thiophon~ Dioxalate.
Following the procedure of Example 41, Part E, the salt o~ the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 90% yield.
IR (KBr) 3400-2500 (br), 1613 cm-l; FDMS m/e 559 (M+1-2C2H2O4); Anal. Calcd ~or C33H3gN2O~S-1.4C2H2O4: C, 62.79; H, 6.01; N, 4.09. Found: C, 62.73; H, 5.93; N, 4.04.
Example 51 Preparation of 6-Hydroxy-2-~4-~2-~ olidinyl~-ethyl]phenyl~benzolb]thiophen-3-yl 3-Methoxy-4-~(4-morpholinyl)mQthyl]phenyl RQtone Dioxalate.
OMe 2(C2H2O4) WO 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-2-t4-12-(1-~ olidinyl)ethyll-phenyllbenzotblthiophQn-3-yl 3-Nethoxy-4-1(4-morpholinyl)methyl]phenyl ~etone.
OMe BnO~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained ~rom the aryl bromide of Example 39, Part A and the ketone o~ Example 49, Part C as a foam in ~1% yield.
IR (neat) 3400 (br), 2959, 1651, 1600 cm-1; FDMS m/e 646 (M+); Anal. Calcd for C40H42N2O4S: C, 74.27; H, 6.54; N, 4.33. Found: C, 74.09; H, 6.74i N, 4.38.
Part B. 6-Hydroxy-2-~4-t2-(1-pyrrolidinyl)ethyl3-phenyllbenzo[blthiophen-3-yl 3-Methoxy-4-~(4-morpholinyl)methyl~henyl Ketone Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 83% yield.
IR (KBr) 3400-2500 (br), 1718, 1645 cm-1; FDMS m/e 557 (M+1-2C2H204); Anal. Calcd for C33H36N204S-2C2H204: C, 60.32; H, 5.47; N, 3.80. Found: C, 60.06; H, 5.43; N, 4.00.
r-- _,le 52 Preparation of 6-Hy~roxy-3-[3-methoxy-4-~(4-mor~holinyl)methyllbenzyl]-2-14-12-(1-pyrroli~inyl)-ethyllphenyl~benzo~b]thiophene Dioxalate.
OMe HO ~ /
2(c2H2~4) W O 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-3-r3-methoxy-4-1(4-m4rpholinyl)-m~thyl]benzyl]-2-[4-~2-(1-pyrrolidinyl)ethyllphenyl]-~onzo[b]thiophQno.
OMe BnO ~ ~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone o~
Example 51, Part A as a :Eoam in 100% yield.
IR (neat) 2957, 1600 cm-l; FDMS m/e 632 (M+); Anal. Calcd 10 for C40H44N2O3S: C, 75.92; H, 7.01; N, 4.43. Found: C, 75.93;
H, 7.00; N, 4.39.
Part B. 6-Hydroxy-3-[3-methoxy-4-~4-morpholinyl)-mQthyl]~Qnzyl~-2-14-12-(1-pyrrolidinyl)~thyl~h~nyll-15 benzo[blthiophene Dioxalate.
Following the procedure o~ Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 83% yield.
20 IR (KBr) 3400-2500 (br), 1719, 1612 cm-l; FDMS m/e 543 (M+l-2C2H2O4); Anal. Calcd for C33H3gM2O3S 1.7C2H2O4: C, 62.83; H, 6.00; N, 4.03. Found: C, 62.72; H, 6.05; N, 4.16.
Fxample 53 25 Pr~paration of 6-Hydroxy-2-t4-[2-[1-[~5)-2-hydroxymethyl]pyrrolidinyllethyl]phenyl]b~nzo[bl-~hiophen-3-yl 3-Methoxy-4-1(~-morpholinyl)methyll-phenyl Ketono DioxalatQ.
CA 02236007 l998-04-27 OMe ~ N
HO
2(C2H2O4) OH
Part A. 6-Benzyloxy-2-[4-(2-hydroxyethyl)phenyl]-benzolblthiophen-3-yl 3-Methoxy-4-l(4-morpholinyl) methyll~henyl Ketone.
OMe ~ N ~
BnO ~ OH
Following the procedure of Example 43, Part A, the trisubstituted benzothiophene was obtained ~rom the ketone of Example 49, Part C as a foam in an overall 95% yield.
10 IR (neat) 3424 (br), 2936, 1647, 1600 cm~l; FDMS m/e 593 (M+); Anal. Calcd for C36H3sNOsS: C, 72.83; H, 5.94; N, 2.36.
Found: C, 72.66; H, 5.g5; N, 2.59.
Part B. 6-Benzyloxy-2-~4-~2-~ (5)-2-hydroxymethyl]-~yrrolidinyl~ethyl]~henyl]benzorb]thiophen-3-yl 3-Methoxy-4-[(4-mor~holinyl)methyl]~henyl ~etone.
OMe ~ N
BnO
OH
Following the procedure of Example 43, Part B, the substituted prolinol was obtained from the above alcohol and (S)-prolinol as a foam in an overall 43% yield.
IR (neat) 3389 (br~, 2954, 1654, 1600 cm-l; FDMS m/e 677 (M~l); Anal. Calcd for C41H44N20sS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.78; H, 6.46; N, 4.14.
CA 02236007 l998-04-27 WO 97/25033 PCT/USg6/17995 Part C. 6-Hydroxy-2-~4-[2-~1-1(5)-2-hydroxymethyl]-pyrrolidinyl~ethyllphenyl]benzolblthiophen-3-yl 3-Mothoxy-4-~14-morpholin~l)methyllph~nyl K~tone Dioxalate.
Following the procedure of Example 41, Part E, the salt o~ the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 65% yield.
IR (KBr) 3377 (br), 3400-2500 (br), 1718, 1638, 1609 cm-l;
FDMS m/e 587 (M+1-2C2H2O4). Anal. Calcd for C34H38N205S 1.4C2H204: C, 62.01; H, 5.77; N, 3.93. Found: C, 61.99; H, 5.80; N, 4.12.
_le 54 Pr~p~ration of 6-Hydroxy-2-~4-[2-~ (g)-2-hydroxymethyllpyrroliainyl]ethyllphenyl}-3-~3-methoxy-4-~(4-morpholinyl)mothyllbenzyl]benzo~blthiophene ~ioxalate.
OMe ~<
~N--HO J~,~
2 (c2H2o4) OE
Part A. 6-Benzyloxy-2-~4-l2~ (5)~2-hYdrOXYmethYll-pyrrolidinyllQthyl~phenyll-3-~3-methoxy-4-~( 4-morpholinyl)methyllbenzyllbQnzo~blthiopheno.
OMe ~<
~ N
BnO
OH
$ 25 Following the procedure o~ Example 34, Part D, the methylene compound was obtained ~rom the above ketone as a ~oam in 88% yield.
W O 97/25033 PCT~US96/17995 IR (neat) 3390 (br), 2955, 1600 cm~l; FDMS m/e 663 (M+l).
Anal. Calcd for C41H46N204S: C, 74.29; H, 6.99; N, 4.23.
Found: C, 74.40; H, 6.97; N, 4.18.
Part B. 6-Hydroxy-2-14-l2-~ (s)-2-hydroxymethyl3 ~yrrol i~inyl 1 ethyllphenyl}-3-[3-methoxy-4-~4-morpholinyl)methyllbenzyl]benzo{blthioPhene Dioxalate.
Following the procedure o~ Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 73% yield.
IR (KBr) 3376 (br), 3400-2500 (br), 1719, 1612 cm-l; FDMS
m/e 573 (M+1-2C2H2O~]. Anal. Calcd for C34H40N2O4S-l-2C2H2O4:
C, 64.22; H, 6.28; N, 4.11. Found: C, 64.01; H, 6.10; N, 3.97.
_le 55 Preparation o~ 6-Hyaroxy-2-[4-~2-tl-l(R)-2-hydroxy-methyl]pyrrolidinyl]ethyllphenyllb~nzotb]thiophen-3-yl 3-MQthoxy-4-[(4-morpholinyl)m~thyllphenyl KetonQ
Dioxalate.
OMe HO
2(C2H2O4) ~OH
Part A. Preparation of 6-Benzyloxy-2-[4-12-tl-~(R)-2 hydroxymethyllpyrrolidinyllethyllphenyllbenzolblthio-phen-3-yl 3-Methoxy-4-[(4-morpholinyl)methyl]phenyl KQ tone.
CA 02236007 l998-04-27 OMe BnO ~ l ~ ¦
OH
Following the procedure of Example 43, Part C, the substituted prolinol was obtained from the alcohol of Example 53, Part A and (R)-prolinol as a foam in an overall 4896 yield.
IR (neat) 3378 (br), 29S6, 1648, 1600 cm-li FDMS m/e 677 (M+l). Anal. Calcd for C4lH44N2OsS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.96; H, 6.32; N, 4.20.
Part B. 6-Hydroxy-2-14-t2-11-t(R)-2-hydroxymethyl}-~yrrolidinyl~ethyl~phenyl]benzotb]thiophen-3-yl 3-Methoxy-4-[(4-morpholinyl3mothyl]phenyl Ketone Diox~latQ .
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a yellowish solid in an overall 63% yield.
IR (KBr) 3384 (br), 3400-2500 (br), 1719, 1638, 1607 cm-l;
FDMS m/e 587 (M+1-2C2H2O4). Anal. Calcd for C34H3gN2OsS-1.4C2H2O4: C, 62.01; H, 5.77; N, 3.93. Found: C, 61.73; H, 5.90; N, 4.14.
_le 56 Pr~paration o:E 6-Hy~lroxy-2-t4-~2-~ (~)-2-hydroxymethyl~pyrroli~inyl~ethyl]phenyl]-3-13-methoxy-4-[(4-morpholinyl)methyl]benzyllbenzolb]thiophene Dioxalate.
CA 02236007 l998-04-27 W 097125033 PCT~US96/17995 OMe ~ N
HO ~
2(C2H2O4) ~OH
Part A. 6-Benzyloxy-2-~4-12-tl-~(R)-2-hyaroxy~ethyl]-~yrrolidinyl]ethyllphenyl]-3-~3-methoxy-4-1(4-mor~holinyl)methyl~benzyl}benzo[b]thiophene.
OMe BnO ~ ~
OH
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone o~ Example 55, Part A as a :Eoam in 83% yield.
IR (neat) 3426 (br), 2955, 1600 cm~l; FDMS m/e 663 (M+l).
Anal. Calcd for C41H46N2O4S: C, 74.29; H, 6.99; N, 4.23.
Found: C, 74.29; H, 6.98; N, 4.33.
Part B. 6-Xydroxy-2-~4-r2-~ (R)-2-hydroxymethyl]-pyrrolidinyl]ethyl]~henyl~-3-~3-methoxy-4-t(4-morpholinyl)msthyl]benzyl]bonzo~b]thio~hene Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a white solid in an overall 77% yield.
IR (KBr) 3401 (br), 3400-2500 (br), 1718, 1612 cm-l; FD~S m/e 573 (M+l-2C2H2O4). Anal. Calcd ~or C34H40N2O4S 1~5C2H2O4: C, 62.79; H, 6.12; N, 3.96. Found: C, 62.68; H, 5.88; N, 4.13.
Exam~le 57 Prep~ration of 3,5-Dimethoxy-4-[(1-~y~ olidinyl)-methyl~phenyl 6-Hydroxy-2-~4-t2-(1-pyrrolidinyl)-Qthoxyl~henyl3benzo~blthiophen-3-yl Ketone.
OMe HO ~ Oe~ N~
2(H2C2O4) ~?art A. Nethyl 3,5-Dimetho~cy-4-l(l-~yllolidinyl) methyl3benzoate.
OMe MeOac ~ N~
OMe Following the procedure o~ Example 37, Part A, the .substituted pyrrolidine was obtained from methyl 3,5-dimethoxy-4-methylbenzoate and pyrrolidine as an oil in 51%
yield.
IR (KBr) 2964, 1721 cm~l; FDMS m/e 279 (M+~. Anal. ~alcd for ClsH21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.56; H, 7.65; N, 5.04.
P~rt B. 3,5-Dimethoxy-4-~(1-~y~ olidinyl)methyl~-~benzoic Acid Hydrochloride.
OMe HO2C ~ N~
OMe Following the procedure o~ Example 37, Part B, the acid was obt~; n~ ~rom the above ester as a white solid in 100%
yield.
lH NMR (DMSO-d6) ~1.80-2.00 (m, 4H), 3.00 (br s, 2H), 3.32 (br s, 2H), 3.86 (s, 6H), 4.20 (s, 2H), 7.20 (s, 2H).
CA 02236007 l998-04-27 Part C. 6-Benzyloxy-2-(dimethylamino)benzoCb]thio-~h~n-3-yl 3,5-Dimethoxy-4-[(1-pyrrolidinyl)methyl]-~henyl Ketono.
OMe ~ , OMe ~
Following the procedure of Example 39, Part C, the ketone was obtained from 6-benzyloxy-2-(dimethyl~m;no)-benzo[b]thiophene and the above acid as a foam in 71% yield.
IR (neat) 2957, 1625, 1601 cm~l; FDMS m/e 530 (M+).
Part D. 6-Benzyloxy-2-14-12-(1-~ lolidinyl)ethoxy~-phenyl]benzoCb~thiophen-3-yl 3,5-Dimothoxy-4-~(1-olidinyl)methyl]~h~nyl ~etone.
OMe BnO ~ OeN~ N~
Following the procedure of Example 34, Part C, the ketone was obtained from the corresponding aryl bromide and the above ketone as a foam in 88% yield.
IR (neat) 2957, 1647, 1606 cm-l; FDMS m/e 677 (M~l). Anal.
Calcd for C41H44N2OsS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.55; H, 6.76; N, 4.19.
Pa~t E. 3,5-Dimethoxy-4-~( 1-~r,olidiny})~ethyl~-phenyl 6-Hydroxy-2-C4-c2~ y~rolidinyl)eth phenyll bonzorb]thiophen-3-yl Keton~.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a yellowish solid in an overall 70% yield.
W O 97/25033 PCT~US96/17995 IR (KBr) 3450-2500 (br), 1720, 1643 cm-l; FDMS m/e 587 ~M+l-2C2H2O4). Anal. Calcd for C34H3gN2OsS-2C2H2O4: C, 59.52; H, ~ 5.52; N, 3.65. Found: C, 59.71; H, 5.78; N, 3.56.
Examl?le 58 Prep~ration of 3-13,5-DimQthoxY-4-~(l-~y ~olidinyl)-methyl]benzy$~-6-hydroxy-2-{4-[2-(1-pyrrolidinyl)-~thoxy]~henyl]benzo~ b] thiophene Dioxalate.
OMe HO~oeN~>
2(C2HaO4) Part A. 6-Benzyloxy-3-13,5-~imethoxy-4-~
~yrrolidtnyl)methyl]benzyl]-2-[4-12-(1-pyrrolidinyl)-~thoxy]phQnyl]benzolb]thiophene.
OMe BnO'C~Oe~>N~>
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 57, Part D as a foam in 79% yield.
IR (neat) 2961, 1606 cm-l; FDMS m/e 663 (M+l). Anal. Calcd for C41H46N2O4S: C, 74.29; H, 6.99; N, 4.23. Found: C, 74.48;
H, 7.15; N, 4.37.
Part B. 3-l3~5-Dimethoxy-4-l(l-~yl oli~inyl)methyl]-benzyl]-6-hydroxy-2-14-~2-(l~yrroli~inyl)Qthoxy]-phenyl]benzo lb] thiophene Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 71% yield.
CA 02236007 l998-04-27 W O 97/25033 PCT~US96tl7995 IR (KBr) 3450-2500 ~br), 1721, 1609 cm-l; FDMS m/e 573 (M~l-2C2H2O4). Anal. Calcd for C34H40N2o4s-2c2H2o4: C, 60.63; H, 5.89; N, 3.72. Found: C, 60.92i H, 6.11; N, 3.94.
E:xample 59 Preparation of (1)-6-Hydroxy-3-t4-[[tran~-2-(l-~yrrolidinyl)cyclohexylloxylbenzyll-2-~4-~2-(1-pyrrolidinyl)etho~y~pheny}]b~nzo~b]thiophene Dioxalat~.
o""~
HO~ 2C~H204 ~
~art A. 6-Methoxy-2-[4-~2-(1-pyrroliainyl)ethoxy~-~henyl]b~nzo~b~thiop~en-3-yl 4-Fluorophanyl Ketone.
F
MeO~ ~
To 671.4 mg of 6-metho~-2-[4-[2-(1-pyrrolidinyl)-15 ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 10 mL
of l,2-dichloroethane was added 1.114 g o~ AlC13 at 0 ~C, followed by dropwise addition of 0.30 mL o~ 4-:Eluorobenzoyl chloride. The deep red solution was stirred at 0 ~C ~or 1 h and then at 0 to 15 ~C ~or 19 h. The reaction was quenched 20 by pouring the reaction mixture into 50 mL of ice-cold 2.0 N
NaOH solution. The mixture was then extracted with 3x100 mL
of EtOAc which was washed with 50 mL oi~ H20 and brine.
Combined organic layers were dried over MgSO4, concentrated, and puri:Eied by ~lash chromatography with 5 v/v % (10% conc W O 97/25033 PCT~US96/17995 NH40H in MeOH) in CH2C12 to give 826.4 mg (92%) of the product ketone as viscous oil.
;
FDMS 475 (M+); Anal Calcd for C2gH26FN03S: C, 70.71i H, 5.51; N, 2.94. Found: C, 70.75; H, 5.58; N, 3.15.
Part B. (I)-6-Methoxy-2-[4-[2-(l-~yrrolidinyl)-ethoxylph~nyl~b~nzo~b~thioph~n-3-yl 4- 11 tranB-2 Pyrrolidinyl)cyclohexyl~oxy~henyl Ketone.
Q
o",~
MeO ~ ~ ~ N
~
To a suspension of ca. 60 mg of NaH (60% oil dispersion) in 2.0 mL of freshly distilled THF was added 330.9 mg of (~)trans-2-(l-pyrrolidinyl)cyclohexanol in 2.0 mL of THF at room temperature. The mixture was heated at reflux for 45 min, cooled down to room temperature, and then to this was added 0.90 mL of 1.086 M of the fluoride (Part A). The mixture was heated at reflux for 24 h, cooled down, and then the reaction was quenched with 20 mL of H2O. The mixture was extracted with 3x50 mL of EtOAc which was washed with 25 mL
of brine. The combined extracts were dried over MgSO4, concentrated, and purified by flash chromatography with 40:5:55 THF-Et3N-hexanes to afford 349.9 mg (57%) of the product along with 49.0 mg (10%) of recovered fluoride.
mp 39-47 ~C; FDMS 624.9 (M+), 500.8 (base); Anal. Calcd for C3gH44N2O4S: C, 73.05; H, 7.10; N, 4.48. Found: C, 73.01;
H, 7.25; N, 4.21.
Part C. (~)-6-Hydroxy-3-~4~tr~n~-2~
pyrroliainyl)cyclohoxyl]oxy~b~nzyl~-2- r4 r2- (l-W O 97/25033 PCT~US96/17995 pyrroli~inyl)ethoxy]phenyl~benzotb]thiophQne Dioxalate.
The title compound was prepared in 36% yield for ~our steps from the ketone (Part B) by essentially following the procedures detailed in Example 21, Parts A-C.
mp >105 ~C (decomp?); FDMS 597.1 (M+l); Anal. Calcd for C37H44N2O3S 2~5c2Hao4: C, 61.38; H, 6.01i N, 3.41. Found:
C, 61.63; H, 5.77; N, 3.01.
~ Yr l~ 60 Pr~paration of ( + ) - 6-Hy~roxy-3-14-lltrans-2-(hexahydro-lH-azepin-1-yl)cyclohexyl]oxY]benzyl]-2-t4-[2-(l-~yrrolidinyl)ethoxy]ph2nyl]benzo lb] thiophene Dioxalate.
C~
,13'~"'~
HO~ ~ 2C2 ~~4 Part A. (+)-6-Methoxy-2-t4-12-(1-pyrroli~inyl)-~thoxy]phenyl]benzo tb] thiophen-3-yl 4-[ltrans- a -(Hexahydro-lH-azepin-1-yl)cyclohexyl]oxy]~henyl KQtonQ.
o~ ""~
MeO ~ ~
CA 02236007 l998-04-27 The title compound was prepared in 54% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl] 4-fluorophenyl ketone and (+)-trans-2-(hexahydro-lH-azepin-l-yl)cyclohexanol by essentially 5 ~ollowing the procedures detailed in Example 59, Part B.
mp 43.5-51.5 ~C; FDMS 653.1 (M+l); Anal. Calcd i~or C40H4gN2O4S: C, 73.59; H, 7.41; N, 4.29. Found: C, 73.61;
H, 7.61; N, 4.07.
Part B. (I)-6-Hydroxy-3-~4-t~tr~n3-2-(hexahydro-lH-azel?in-l-yl)cyclohexyl]oxy]bQnzyl] -2- ~4- t2- (1-pyrrolidinyl)ethoxy~phenyllbenzo[b~thiophQne Dioxalate.
The title compound was prepared in 29% yield ~or four steps from the ketone (Part A) by essentially following the procedures detailed ~n Example 21, Parts A-C.
mp >114 ~C (decomp?); FDMS 625.1 (M~l); Anal. Calcd for C39H48N203S 2.5C2H204: C, 62.18; H, 6.28; N, 3.30. Found:
C, 62.02; H, 6.28; N, 3.12.
r~ le 61 Pr~arntion o~ (I)-6-Hydroxy-3-[4-t~trans-2-(imidazol-25 1-yl)cyclohexyl~oxylbenzyl~-2-14-t2-(1-pyrrolidinyl)-ethoxylphenyl]benzotb~thiophene Dioxalate.
N~
N
,~o b HO~-- 2(~2HZO4 1 Part A. (~)-tran~-2-(Imidazol-1-yl)cycloh~YAnol.
CA 02236007 l998-04-27 W 097/25033 PCTrUS96/17995 ~182-N
H~b A mixture of 20.18 g of imidazole, 81.95 g of K2CO3, and 20.0 mL of cyclohexene oxide in ca. 200 mL of H20 was stirred at room temperature for l9 h, at l00 ~C (bath temp.) for 7 h, and then at room temperature overnight. The mixture was extracted with 3x500 mL of EtOAc and 500 mL of CH2Cl2. The organic layers were washed with 2x300 mL, of H20 and 300 mL of brine. Combined organic layers were dried over MgSO4 and concentrated. The crude product was crystallized from EtOAc to yield 8.57 g (26%) oi~ the crystalline solid.
mp 127-131 ~C; FDMS 167 (M~l); Anal Calcd for CgH14N2O 0.22H20: C, 63.~i2; H, 8.55; N, 16.46. Found: C, 63.63; H, 8.30; N, 16.11.
Pa~t B. (l)-6-Methoxy-2-14-[2-(l-~yrrolidinyl)-ethoxy]~henyl]bQnzotb]thioph~n-3-yl 4- 1 ~ tr~ns- 2 -(Imidazol-l-yl)cyclohexyl~oxy]phenyl Ketone.
N ~
o~~ b Meof ~ ~
The title compound was prepared in 71% yield from 6-methoxy-2-[4-[2-(l-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl~ 4-fluorophenyl ketone and (+)-trans-2-(imidazol-l-yl)cyclohexanol (Part A) by essentially following the procedures detailed in Example 59, Part B.
W O 97/25033 PCTnUS961I7995 mp 68-78 ~C; FDMS 622 4 (M+1); Anal Calcd for C37H3gN304S-0.35NH40H: C, 70 09i H, 6.48; N, 7.40 Found:
C, 69.75i H, 6.14i N, 7.03 P~rt C. (+)-6-Hydroxy-3-14-[[trans-2-(imidazol-1-yl)cyclohexyl~oxy]b~nzyl3-2-14-t2-(1-pyrroliainyl)-~thoxy~phenyllbenzolblthiorhe~e Dioxalate.
The title compound was prepared in 81~ yield for four steps from the ketone ~Part B) by essentially following the procedures detailed in Example 21, Parts A-C.
mp >103 ~C (decomp?); FDMS 594 (M+1); Anal. Calcd for C36H3gN303S-2.1C2H204-l.lC4HgO2: C, 60.89; H, 5.96; N, 4.78.
Found: C, 60 49; H, 5.59; N, 4.95.
-~1Q 62 Preparation of (+)-6-Hydroxy-3-t4-r[trans-2-(4-morpholinyl)cyclohexyl]oxy]b~nzyll -2-l4- 12-(1-pyrrolidinyl)ethoxy]~henyl]benzo l b~ thio~hene Dioxalate.
'~"'~
~_ 2C2 ~4 Part A. (+)-6-Methoxy-2-14-[2-(1-~yrrolidinyl)-Qthoxy~phQnyl~benzot b~ thio}~hen- 3 -yl 4-lttr~ns-2-(4-Morpholinyl)cyclohexyl]oxy]phenyl Keton~.
W O 97/25033 PCT~US96/17995 o N
~ob MeO ~ ~
The title compound was prepared in 80% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl] 4-fluorophenyl ketone and (+) -trans-2- (4-morpholinyl)cyclohexanol by essentially following the procedures detailed in Example 59, Par~ B.
mp 50-57 ~C; FDMS 640.6 IM+); Anal. Calcd for C3gH44N2OsS 0.14CH2Cl2: C, 70.18; H, 6.84; N, 4.29. Found:
C, 70.20; H, 6.82; N, 4.35.
Part B. (1)-6-Hydroxy-3-14-lltrans-2-(4~morpholinyl) cyclohexyl]oxy]b~nzyl]-2-14-lZ-(l-~yrrolidinyl)-~thoxy]phenyl]b~nzo~blthiop~s~ Dioxalate.
The title compound was prepared in 72% yield for ~our steps from the ketone (Part A~ by essentially following the procedures detailed in Example 21, Part A-C.
mp ~110 ~C (decomp?); FDMS 613.4 (M+1); Anal Calcd for C37H44N2O4S 2.3C2H204 l.lC4HgO2: C, 60.26; H, 6.31; N, 3.06.
Found: C, 59.88; H, 5.94; N, 3.00.
le 63 Preparation o~ 6-Hydroxy-2-~4-~2-(1-~yrrolidinyl)-~thoxy~phenyl~benzolb]thiophen- 3-yl~ 3 -D~ethoxy-4-[ltran~-2-(l-pyrrolidinyl)cyclohQxyl~oxy]phenyl Ketone Dioxalate.
CA 02236007 l998-04-27 Wo 97/25033 PCT/US96rl7995 C~
OMe N
~0",~
HOJ~ 2C~ 2~4 Part A. 3-Methoxy-4-~trans-2~ ~yrrolidinyl)-cyclohexyl]oxylbenzoic Acid.
~) OMe N~
H02CJ~
The title compound was prepared in 96% f~or two steps from methyl vanillate similarly as described in Example 20, Parts B and C.
lH NMR (CDCl3) d 7 . 68 (m, 2H), 7 . 17 (d, J = 8 . 8 Hz, lH), 4 . 80 10 (m, lH), 3.88 (s, 3H), 3.63 (m, 2H), 3.35 (m, 2H), 3.11 (m, lH), 2 .35-1.25 (m, 12H).
Part B. (~)-6-Benzyloxy-2-[4-~2-(1-pyrrolidinyl)-~thoxy]phenyl]benzo~b]thio~hen-3-yl 3-Mothoxy-4-15 ~ ~ trans-2-(1-pyrroli~inyl)cyclohexylloxy]phQnyl Ke t onQ .
OMe N
~,o""~
The title compound was prepared in 43 % yield :Eor two steps from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene by 20 essentially following the procedures outlined in Example 41, W O 97/25033 PCT~US96/17995 Part C (but using thionyl chloride to form the acid chloride) and Example 81, Part E.
mp 50-54 ~C; FDMS 731.8 (M+1); Anal. Calcd for C4sHsoN2OsS:
C, 73.94; H, 6.90; N, 3.83. Found: C, 73.73; H, 6.96; N, 4.00.
Part C. (1)-6-Hy~roxy-2-[4-t2-~1-pyrrolidinyl)-othoxy3phenyl3benzotb]thiophen-3-yl 3-Methoxy-4-[ltr~n~-2-(l-pyr olidinyl)cyclohexylloxylphenyl KQtone Dioxalate.
The title compound was prepared in 12% yield for two steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl~ethoxy]-phenyl]benzo[b]thiophen-3-yl [3-methoxy-4-[[trans-2-(1-pyrro-lidinyl)cyclohexyl]oxy]phenyl] ketone (Part B) by essentially following the procedures described for debenzylation and oxalate salt formation in Example 81, Part I.
FDMS 641.3 (M+1); Anal. Calcd for C38H44N205S 2C2H204: C, 61.45; H, 5.89; N, 3.41. Found: C, 61.27; H, 5.77; N, 3.40.
~Yr ~le 64 Preparation of (t)-6-Hydroxy-3-[3-methoxy-4- r ~tran~-2-(1-pyrrolidinyl)cyclohexyl~oxy]benzyl]-2-14-r2-(1-pyrrolidinyl)ethoxylphenyl]benzolblthiophene Dioxalate.
OMe Q
b HO~ 2C ~204 The title compound was prepared in 59~ yield for four steps from (+)~6-benzyloxy-2-[4-[2-(1-pyrrolidinyl~ethoxy]-phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-[[trans-2-(1-W O 97/25033 PCT~US96~17g95 pyrrolidinyl)cyclohexyl]oxy]phenyl ketone (Example 63, Part B) by essentially following the procedures outlined in Example 85, Part B.
FDMS 627.3 (M+l); Anal. Calcd for ~38H46M2o4s-2c2H2o4: C, 62.52; H, 6.25; N, 3.47. Found: C, 62.73; H, 6.18; N, 3.43.
_1~ 65 Preparation o~ 6-Hyaroxy-3-[3-hy~roxy-4-~trans-2-10 (1-pyrrolidinyl)cyclohexyl]oxy]benzyl]-2-~4-~2-(1-~pyrroliainyl)ethoxylphenyllb~nzolblthio~hene.
OH ~
~,0""~
HO ~ ~
The title compound was prepared in 29% yield from (+)-6-hydroxy-3-[3-methoxy-4-[~trans-2-(1-pyrrolidinyl3cyclohexyl]-oxy]benzyl~-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophene (free base of Example 64) by essentially following the procedure outlined in Example 21, Part B.
FDMS 613.3 (M+l).
_1~ 66 Preparation o~ (1)-6-Hydroxy-2-~4-~2-(l-pyrroliainyl)-ethoxy~phenyl]benzo~b~thiophen-3-yl 3-Fluoro-4-[~trans-2-(1-~yrroliainyl)cyclohexyl]oxylphenyl Ketone Dioxalato.
W O 97~033 PCTAUS96/17995 F ~
0~ "~ ~
HO ~ C,H204 Part A. 6-Benzyloxy-2-(dimethyl~i~o)benzotblthi phen-3-yl 3,4-Difluorophenyl Ketone.
~ F
0~
~f 0~ \
The title compound (oil) was prepared in g5% yield from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene and 3,4-difluorobenzoyl chloride by essentially ~ollowing the procedure outlined in Example 81, Part C.
FDMS 423 (M+); Anal. Calcd for C24H1gF2NO2S: C, 68.07; H, 4.52; N, 3.31. Found: C, 68.36; H, 4.75; N, 3.37.
Part B. (~)-6-Benzy}oxy-2-[4-t2-(1-pyrrolidinyl)-ethoxy3~henyl]benzolb~thiophen-3-yl 3-~luoro-4-lttran~-2-(l-pyrrolidinYl)cyclohexyl3oxylphon Ketone.
=
W O 97/25033 PCT~US96/17995 The title compound was prepared in 67~ yield for two steps from 6-benzyloxy-2-(dimethylamino)benzo[b3thiophen-3-yl 3,4-difluorophenyl ketone (Part A) similarly as described in Example 59, Part B and Example 81, Part E.
mp 47-51 ~Ci FDMS 719 (M+l); Anal. Calcd for C44H47FN2O4S:
C, 73.51; H, 6.59; N, 3.90. Found: C, 73.28; H, 6.71; N, 4.01.
Part C. (_)-6-H~droxy-2-14-~2-(1-pyrrolidinyl)ethoxy~-phenyl]bQnzolb~thiophen-3-yll 3-Fluoro-4-Cltrans-2-( ~y lolidinyl)cyclohexyl]oxy]phenyl Ketone Dioxalate.
The title compound was obtained in 81% for two steps ~rom the ketone (Part B) via debenzylation and oxalate salt formation as described in Example 81, Part I.
FDMS 629.3 (M+l); Anal. Calcd for C37H41FN2O4S-2C2H204: C, 60.88; H, 5.61; N, 3.46. Found: C, 60.97; H, 5.70; N, 3.59.
R~A _le 67 Preparation of (_)-6-Hydroxy-3-13-fluoro-4-[[tran~-2-(l-~yrroli~inyl)cyclohexylloxy]benzyl]-2-14-12-(1-pyrrolidinyl)ethoxy]phenyllbanzo~b]thiophena Dioxalate.
F N
~¢~~"'~
HO~ 2c2H2O4 ~
The title compound was prepared in 66% yield for four steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl 3-fluoro-4-[[trans-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl ketone (Example 66, W O 97/25033 PCT~US96/17995 Part B) using similar procedures to those of Example 85, Part B.
mp >111 ~C (decomp.?); FDMS 614.8 (M+); Anal. Calcd for C37H43FN203S 2C2H2O4: C, 61.95; H, 5.96; N, 3.52. Found:
C, 61.81; H, 6.16; N, 3.38.
~r rle 68 Preparation of (~)-6-Hydroxy-2-[4-[2-(1-~yrrolidinyl)-ethoxy]~henyl]b~nzolblthiophen-3-yl 3-Fluoro-4-lltran~-2-(l-~iperidyl)cyclohexylJoxyl~h~nyl Ketona Dioxalate.
F N
o~~ b ~ ~r~ ~4 The title compound was prepared in 13% for four steps from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3,4-difluorophenyl ketone (Example 66, Part A) using similar methods to those of Example 66, Parts B and C.
FDMS 643.4 (M~1); Anal. Calcd for C3gH43FN2O4S-2C2H2O4: C, 61.30; H, 5.76; N, 3.41. Found: C, 61.57; H, 5.74; N, 3.59.
~xample 69 Praparation of (~)-6-Hydroxy-3-[3-fluoro-4-~trans-2-(1-pi~eridyl)cyclohoxylloxyJb~nzyll-2-~4-~2-(1-pyrro-lidinyl)ethoxy3phenyllbenzo~blthiophene Dioxalate.
W O 97~5033 PCTfUS96/1~995 F ~ ~
HO N
The title compound was prepared in 62% ~or three steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 3-fluoro-4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy]phenyl ketone (an intermediate ln thepreparation of Example 68) using procedures similar to those o~ Example 85, Part B.
FDMS 629.4 (M+l); Anal. Calcd for C38H45FN203S-2C2H204 1.1C4H80: C, 62.74; H, 6.56; N, 3.15.
Found: C, 63.14; H, 6.27; N, 2.92.
F.~ pl~ 70 Preparation of (I)-6-Hydroxy-3-~4-[[tran~-2-(l-pyrrolidinyl)cyclohexyl]oxyl-3-(trifluoromethyl)-benzyll-2- r4- ~2-(1-~yrrolidinyl)ethoxy]phenyllbQnzo-~blthiophene Dioxalate.
~,o"~
HO~ 2C H~04 Part A. 6-BQnzyloxy-2-(~imethyl~ ;~o)benxo~blthiophen-3-yl 4-Fluoro-3-(tri~luoromethYl)phenyl Ketone.
W O 97/2~033 PCT~US96/17995 ~ F
¢~ 0~
The title compound was prepared in 93% yield from 6-benzyloxy-2-(dimethylamino~benzo[b]thiophene and 4-fluoro-3-(trifluoromethyl)benzoyl chloride by essentially ~ollowing the procedure outlined in Example 81, Part C, and Example 85, Part B.
mp 164-167 ~C; F~MS 473 (M+); Anal. Calcd for C2sH19F4NO2S:
C, 63.42; H, 4.04; N, 2.96. Found: C, 63.65; H, 4.17; N, 2.81.
Part B. (~)-6-Hydroxy-3-[4-lltran~-2-(l-pyrrolidinyl)-cyclohexyl~oxy~-3-(trifluoromethyl)-benzyl]-2-l4-l2-(1-pyrroliainyl)ethoxy]phonyllb~nzo-[blthio~ s Dioxalate.
The title compound was prepared in 41% for six steps ~rom 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 4-fluoro-3-(trifluoromethyl~phenyl ketone (Part A) using similar procedures to those of Example 66, Parts B and C.
mp >124 ~C (decomp?); FDMS 665.2 (M+1); Anal. Calcd for C38H43F3N203S-2C2H204: C, 59.71; H, 5.61; N, 3.32. Found:
C, 59.48; H, 5.55; N, 3.44.
~ le 71 Preparation o~ 6-Hydroxy-5-methoxy-3-[4-[[tra~s-2-~1-pyrrolidinyl)cyclohexyl]oxy]benzyl]-2-[4-12-(1-~yrroli~inyl)~thoxy~phenyl]benzolb~thiophene ~ioxalate.
W V 97/25033 PCT~US96/17995 o ~ 'O
MeO ~ 2CZ~2O4 Part A. 6-Benzyloxy-2-dimethylr-in~-5-m~thoxy-benzolblthiophene.
MeO~ /
The title compound was prepared in 17% for two steps from 4-benxyloxy-3-methoxybenzaldehyde and N,N-dimethylthioformamide using similar procedures to those of Example 81, Parts A and B.
mp 140-142 ~C; FDMS 313 (M+); Anal. Calcd for C1gH1gNO2S: C, 68.98; H, 6.11; N, 4.47. Found: C, 68.81; H, 6.32i N, 4.17.
Part B. (~)-6-Hydroxy-5-methoxy-3-l4-[[tran~-2-(1-pyrroli~inyl)cyclohexyl]oxy]benzyl3-2-{4-l2-(1-pyrroli~inyl)ethoxy~phenyl~bsnzo[blthiophQne Dioxalate.
The title compound was prepared in 37~ for seven steps from 6-benzyloxy-2-dimethyl~m; no-5-methoxybenzo[b]thiophene ~Part A) using procedures similar to those of Example 70, Parts A and B.
mp >100 ~C (decomp?)i FDMS 627 (M+1~; Anal. Calcd for C38H46N2o4s 2~4C2H204 0~6C4H802: C, 60.49; H, 6.31; N, 3.07.
Found: C, 60.11; H, 6.11; N, 3.43.
CA 02236007 l99X-04-27 ~ le 72 Pre~aratlon of (+)-5-Methox~-2-~4-[2-(1-~rrolidinyl)-ethoxy~phenyl~benzorb~thiophen-3-yl 4-~trans-2-(1-Pipe~idyl)cyclohex~rl]oxyl3;~henyl Ketone Dioxal~te.
~ob MeO~ Z CzH2O4 Part A. 5-Meth~yL~lLzo[b]thiophene.
MeO~[~>
5-Bromobenzo[b]thiophene was prepared in quantitative yield for two steps from 4-bromobenzenethiol and bromoacetaldehyde dimethyl acetal as described in the preparation of 4- and 6-methoxybenzo [b] thiophene (see Example g2, Part A): mp 40-43.5 ~C; FDMS 212.1 (M-1); Anal. Calcd for CgHsBrS-0.10C7HgOS: C, 46.01; H, 2.57i S, 15.53. Found:
C, 46.19; H, 2.49; S, 15.79.
To a solution of 1.8 g of 5-bromobenzo [bJ thiophene in 2 mL of anhydrous DM~ and 1 mL of MeOH was added 686 mg of NaOMe. The mixture was heated to 110 ~C (bath temp), and 121 mg of CuBr was added. The brown suspension was heated at 110 ~C for ~2 h and at -145 ~C for 30 min. The reaction was ~uenched with ca. 50 mL of H20 and the mixture was extracted with 100 mL of Et20 (2x), EtOAc (lx), and CH2C12 (lx). The organic layers were washed with 50 mL of brine, combined, dried over MgSO4, concentrated, and flash chromatographed with 3% Et2O-hexanes to afford 894.5 mg (64%) of the title compound along with 168.8 mg (9.4~) of 5-bromobenzo[b]-thiophene.
W O 97/Z5033 PCTnJS96/17995 mp 39-41.5 ~C; FDMS 164.2 (M+); Anal. Calcd for CgHgOS O.llH2O: C, 65.04; H, 4.98; S, 19.29. Found: C, 65.07; H, 4.95; S, 18.96.
Part B. 5-Methoxybenzolb]thiophene-2-boronic Acid.
MeO ~ B(OH)2 The title compound was prepared in 50% yield by essentially following the procedures in Example 1, Part A
from 5-methoxybenzo[b]thiophene (Part A).
mp 226-228 ~C; FDMS 569; Anal. Calcd for CgHgBO3S: C, 51.96; H, 4.36. Found: C, 51.85; H, 4.15.
Part C. 5-Methoxy-2-[4-[2-(1-~y oli~inyl)~thoxy~-phenyllbenzolb]thiophene.
MeO~_O
The title compound was prepared in 47% yield by essentially following the procedures in Example 1, Part B, from 5-methoxybenzo[b]thiophene-2-boronic acid (Part B) and 1-(2-(4-bromophenoxy)ethyl)pyrrolidine.
mp 123-126 ~C; FDMS 353 (M+); Anal. Calcd for C21H23N02S:
C, 71.36; H, 6.56; N, 3.96. Found: C, 71.07; H, 6.44; N, 4.01.
Part D. 4-Fluorophenyl 5-Methoxy-2-14-12-(1-~y~ r 0-lidinyl)ethoxy]phenyl~benzolb]thiophen-3-yl Ketone.
~ ~ F
0~
MeO~_ O
W O 97/25033 PCT~US96/17995 The title compound was prepared by essentially following the procedure detailed in Example 1, Part C, from 5-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part C) and 4-~1uorobenzoyl chloride. The crude product was purified by flash chromatography (silica gel, 55:42:3 THF-hexanes-Et3N) to afford 2.11 g (4.44 mmol, 71%) of a yellow semi-solid.
FDMS 475 (M+); Anal. Calcd for C2gH26FNo3s: C,70.72; H, 5.51; N, 2.95. Found: C, 70.50; H, 5.49; N, 2.83.
Part E. (+)-5-M~thoxy-2-14-12~ oliainyl)-~thoxyl~henyl]benzo~b]thiophQn-3~yl 4-t[tran~-2-(1-Piperidyl)cyclohexyl]oxy~phenyl K tone.
o~~"'~
MeO~ ~ _O
To a slurry of NaH (530 mg, 13.2 mmol, 60% dispersion in mineral oil) in 28 mL of anhydrous DMF was added dropwise 1.61 g (8,77 mmol) of (i)-trans-2~ piperidyl)cyclohexanol (Example 20, Part A) in 7 mL of DMF at room temperature over a period of 20 min. A heat gun was applied to the reaction mixture to facilitate alkoxide formation. Slow evolution of hydrogen gas was observed. The slurry was stirred at room temperature for 1 h, and to this was added the 4-fluorophenyl ketone (2.09 g, 4.39 mmol) (Part D) in 8 ml of DMF via a c~nnllla over 10 min period at room temperature. The slurry immediately turned reddish orange. The reaction was carried to completion by stirring overnight (18 h). The reaction was then quenched at 0 ~C with slow addition of 75 mL of H20.
The mixture was taken up in EtOAc and partitioned. The a~ueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over MgSO4 after washing with 300 mL of brine and then concentrated under reduced pressure. The residue was purified by PrepLC (40:57:3 THF-hexanes-Et3N) to afford 2.24 g (3.51 mmol, 80%) of a yellowish white foam.
mp 63-66 ~C; FDMS 639 (M+); Anal. Calcd for C3gH46N2O4S: C, 73.32; H, 7.26; N, 4.38. Found: C, 73.03; H, 7.38; N, 4.20.
Part F. (+)-5-Methoxy-2-t4--~2-(1-~y~ olidinyl)-~thoxy]phenyl~benzo~b~thio~h~n-3-yl 4-[ltran~-2-(1-- Piperidyl)cyclohexyl]oxy]ph~nyl Ketone Oxalate.
The title compound was prepared in 97% from the ketone (Part E) by essentially following the procedure outlined in Example 21, Part C.
mp 144-147 ~C; FDMS 639.3 (M+); Anal. Calcd for C39H48N2O3S 2.64C2H2O4: C, 60.67; H, 5.90; N, 3.20. Found:
C, 60.66; H, 5.89; N, 3.24.
Example 73 Preparation of (+)-5-M~thoxy-3-[4- r ~trang-2- (1-~iperiayl)cycloh~xyl]oxy~benzyl~-2-~4-~2-(1-pyrro-lidinyl)ethoxy~phenyl]benzo~b]thiophene Dioxalate.
~ob Me~ 0 2 c2H2~4 I ~
The free base of the compound was prepared in 69~ yield from the ketone (Example 72, Part E) by essentially following the procedures detailed in Example 21, Part A. The title compound was prepared by essentially following the procedure outlined in Example 21, Part C.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 Free base: mp 53-56 ~C; FDMS 625 (M+).
Dioxalate: mp 139-145 ~C; FDMS 625 (M+); Anal. Calcd ~or C39H48N2O3S 2.OC2H2O4: C, 64.16; H, 6.51; N, 3.48. Found:
C, 63.88; H, 6.57; M, 3.41.
le 74 Preparation of (+)-5-Hydroxy-3- t4- C ~trans-2- (1-pip~ridyl)cyclohexyl]oxylbQnzyl]-2-{4-[2-(1-pyrro-lidinyl)ethoxyl~h~nyllbenzolb]thiophene Dioxalate.
[~
~,o",~
HO ~ o 2 c~H2O4 Part A. (+)-5-Hydroxy-3-t4-~tran~-2- (l-piperidyl)-cyclohoxylloxy]b~nzyl] -2 - ~4-~2-~1-pyrrolidinyl)-ethoxy~phenyl~benzorb]thiophene.
~o",~
HQ ~ O
1~
The title compound was prepared in 89% yield ~rom the methoxybenzo[b]thiophene (free base o~ Example 73) by essentially following the procedures detailed in Example 21, Part B.
W O 97~5033 PCTnJS96/17995 mp 103-106 ~C; FDMS 610 (M+); Anal. Calcd for C3gH46N203S-1.48H20: C, 71.59; H, 7.74; N, 4.39. Found: C, 71.59; H, 7.44; N, 4.32.
Part B. ~+)-5-Hydroxy-3-t4-~[~rans-2-(1-piperidyl)-cyc lohexyl 1 oxy 1 benzyll-2-[4-12-(1-pyrrolidinyl)-ethoxy~phenyl] benzo lb] thiop~s~e Dioxalate.
The title compound was prepared from the free base by essentially following the procedures detailed in Example 21, Part C.
mp 172-176 ~C (dec); FDMS 611 (M+); Anal. Calcd for C38H46N203S 2C2H204 1.5H20: C, 61.67; H, 6.53; N, 3.42.
Found: ~, 61.41; H, 6.21; N, 3.40.
~ xampl~ 75 Preparation of (+)-7-Hy~roxy-2-~4-~2-(1-~ ~oliainyl)-ethoxy]phenyl~benzo~blthiophQn-3-yl 4-~tr~ns-2-(1-Piperiayl) cyclohexyll oxylphenyl Retone Dioxalate.
~~"'0 ~ 2 c2H~o4 Part A. 2-Methoxybenzenethioacetaldehyae Diethyl Acetal.
~~~
MeO O~_~-The title compound was prepared in 90% crude yield from 2-methoxybenzenethiol by essentially following the procedures detailed in Graham, S.L., et. al. J. Med. Chem . 1989, 32, 2548-2554.
W O 97/2~033 PCT~US96/17995 -200~
Part B. 7-Methoxybenzo [b] thiophene.
MeO
To a biphasic mixture of polyphosphoric acid (PPA; 64.1 g) and 600 mL of dry chlorobenzene heated to re~lux at 140 ~C
was added dropwise 2-methoxybenzenethioacetaldehyde diethyl acetal (Part A) (30.0 g, 117 mmol) in 75 mL of chlorobenzene over a period of 1.5 h. The dark green biphasic mixture was stirred at re~lux for an additional 1.5 h. The reaction mixture was cooled to room temperature and the organic layer was decanted off the PPA layer. The PP~ layer was cooled to O ~C and diluted with 500 mL of H20. This aqueous layer was extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with 200 mL o~ brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified using a PrepLC with a gradient elution (0 to 7~ Et2O
in hexanes) to afford 10.3 g (63.1 mmol, 54%) of a green oil.
FDMS 164 (M+); Anal~ Calcd for CgHgOS 0.06CH2C12: C, 64.27;
H, 4.83. Found: C, 64.15; H, 4.81.
Part C. 7-Nethoxybenzo~b]thiophene-2-boronic Acid.
~ B(OH)2 MeO
The title compound was prepared in 44% yield (51% SM
recovery) by essentially following the procedures in Example 1, Part A from 7-methoxy[b]benzothiophene (Part B).
mp 272-275 ~C; FDMS 569; Anal. Calcd for CgHgBO3S: C, 51.96;
H, 4.36; N, 0.00. Found: C, 51.71; H, 4.15; N, 0.00.
Part D. 7-Methoxy-2-t4-[2-(1-~ olidinyl)ethoxy]-phenyl]benzotb~thiophene.
W O 97t25033 PCT~US96/17995 N
MeO ~
The title compound was prepared in 31% yield by essentially following the procedures outlined in Example 1, Part B from 7-methoxybenzo[b~thiophene-2-boronic acid (Part C).
mp 88-90 ~C; FDMS 353 (M+); ~nal. Calcd for C21H23MO2S: C, 71.36; H, 6.56; N, 3.96. Found: C, 71.17; H, 6.58; N, 3.83.
Part E. 7-Hydroxy-2-~4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]bQnzolb]thiophone.
~o OH
The title compound was prepared by essentially following the procedures outlined in Example 21, Part B from 7-methoxy-benzo[b]thiophene (Part D) and recrystallized ~rom EtOAc-hexanes to af~ord 944 mg (2.78 mmol, 56%) of light orange needle-like crystals.
mp 180-183 ~C; FDMS 339 (M+); Anal. Calcd ~or C20H21NO2S 0.3H2O: C, 69.66; H, 6.31; N, 4.06. Found: C, 69.62; H, 6.21; N, 4.46.
Part F. 3-(4-Fluoro~henyl)carbonyl-2-~4 [2-(1-pyrrolidinyl)~thoxylphenyl]benzo~b~thiophQn-7-yl 4-Fluoro}~enzoate.
WO 97/25033 PCT~US96/17995 ~F
-- N
0~0 ~ ' F
To a slurry of 7-hydro~-2- r4-~2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene (Part E) (244 mg, O.808 ~nol) in 5.0 mL of anhydrous dichloroethane was added 4-fluorobenzoyl chloride (105 IlL, O.888 ~mnol) at room temperature. The white slurry was stirred at room temperature for 3 h to form the int~l~me-l;ate ester. The reaction was then cooled to O ~C and another 105 ,UL (0.888 mmol) of 4-fluorobenzoyl chloride was added, followed by 10 addition of aluminum chloride (431 mg, 3.23 mmol) which turned the slurry into a dark red homogeneous solution. The reaction was slowly warmed to room temperature over 2 h and then stirred for 2.5 days. The reaction mixture was then poured into 20 mL of ice-cold 2.0 N NaOX solution. The 15 mixture was then taken up in EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgS04 and concentrated under reduced pressure. The residue was purified by ~lash chromatography (silica gel, 496(10% NH40H in MeOH)/CH2Cl2) to afford 408 mg (.700 mmol, 87%) of an off-white foam.
mp 64-68 ~C; FDMS 583 (M+); Anal. Calcd for C34H27F2N04S 0.08CH2Cl2: C, 69.33; H, 4.64i N, 2.37. Found:
C, 69.36; H, 4.61; N, 2.01.
Part G. 4-Fluorophenyl 7-Hyaroxy-2-14-~2-(l-~y o-lid~nyl)ethoxyl~henyl~benzo[blthiophen-3-yl Ketone.
~ N
OH ~
To a slurry of NaH (14.4 mg, 0.171 mmol, 60% dispersion in mineral oil) in 0.5 mL of anhydrous THF (or DMF) was added (+3-trans-2-(1-piperidyl)cyclohexanol in 0.5 mL of THF (or DMF) via a cannula. The reaction mixture was warmed with a heat gun to initialize the alkoxide formation and then stirred at room temperature for 2 h. The slurry was cooled to 0 ~C and to this was added dropwise 4-fluorobenzoate (Part F) (100 mg, 0.171 mmol) in 0.5 mL of THF (or DMF). The reaction was stirred at 0 ~C for 1 h and then allowed to warm to room temperature while stirring for 45 min. The reaction was quenched at 0 ~C with 15 mL of H20. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 70:27:3 THF-hexanes-Et3N) to afford 67.9 mg (.147 mmol, 86%) of a brown solid.
mp 138-142 ~C, FDMS 462 (M+); Anal. Calcd for C27H24FN03S-0.57H20: C, 68.73; H, 5.37i N, 2.97. Found: C, 68.95; H, 5.66; N, 3.30.
Part H. (+)-7-Hydroxy-2-~4-12-(1-~ olidinyl)-ethoxylphenyllbenzolblthiophen-3-yl 4 - [ 1 trans- 2-(1-Pil?e-idyl)cyclohexyl30xy]phenyl Ketone Dioxalate.
The free base of the title compound was prepared in 18%
yield by essentially following the procedures in Example 72, Part E, from 4-fluorophenyl ketone (Part G) and (+)-tra~s-2-(1-piperidyl)cyclohexanol (Example 20 Part A). The dioxalate was then prepared by essentially following procedures in Example 21, Part C from the ~ree base.
W O 97/2~033 PCT~US96/17995 FDMS 625 (M+)i Anal. Calcd for C38H44N2O~S 2 5C2H204 3 2H2~
C, 56.91; H,6.15; N, 3.09. Found: C, 56.61; H, 5.80; N, 3.47.
~Y~ _le 76 Pruparation of (+) -6-Hy~roxy-3-[4- r ltrang-2- (1-piperidyl)cyclopentyl3Oxy]benzyl]-2-14-r2-(1-pyrro-li~inyl)Qthoxylph~nyllbenzolblthiophene Dioxalate.
~~"'~ ' H0~ 2 C2H2~4 Part A. (+)-trans-2-(1-Pi~eridyl)cyclopentanol.
~I0,~2 The title compound was prepared in 81% yield from cyclopentene oxide and piperidine ~y essentially following the procedures outlined in Example 20, Part A.
FDMS 169.1 (M+); Anal. Calcd for CloHlgNO 0.24H20: C, 69.19;
H, 11.31; N, 8.07. Found: C, 69.19; H, 11.40; N, 8.21.
Part B. (+)-6-Methoxy-2-[4-t2-(1-~yrrolidinyl)-ethoxyJ~henylJbenzo[b]thio~hQn-3-yl 4-1~(+)-tr~n~-2-(1-Piperidyl)cyclo~entyl~oxy]~henyl X~ton~.
0~' "'C~>
MeO ~ ~
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 72, Part E, ~rom 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+)-trans-2-(1-piperidyl)-cyclopentanol (Part A).
mp 68-72 ~C; FDMS 625 (M+); Anal. Calcd for C3gH44N2O4S: C, 73.05; H, 7.10; N, 4.48. Found: C, 73.27; H, 6.96; N, 4.30.
Part C. (+)-6-Methoxy-3-14-[[trans-2-(1-pip~ridyl~-cyclopentylloxy~benzyl]-2-[4-12-(1-pyrrolidinyl)-~thoxy~ phenyllbenzo[b~thiophQne.
~o",~
MeOJ~ ~
The title compound was prepared in 57% yield from theketone (Part B) by essentially following the procedures detailed in Example 21, Part A.
mp 61-64 ~C; FDMS 611 (M+); Anal Calcd for C3gH46N2O3S O.39H20: C, 73.87; H, 7.63; N, 4.53. Found: C, 73.85; H, 7.53; N, 4.83.
-20~-Part D. (~)-6-Hydroxy-3-t4-[[tran~-2~ piperidyl)-cyclopentyl30xy]bQnzyll-2-~4-~2-(l-pyrrolidinyl)-~thoxy~phenyllbenzo~b]thiophene Dioxalat~.
The free base of title compound was prepared in 79%
yield ~rom the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
The title compound was prepared by essentially following 10 the procedures detailed in Example 21, Part C.
mp 1~5-150 ~C; FDMS 597 (M+); Anal. Calcd for C37H44N2O3S 2.1C2H2O4 1.6H2O: C, 60.74; H, 6.36; N, 3.44.
Found: C, 60.41; H, 6.46; N, 3.37.
~r ~le 77 Proparation o~ (+)-3-[4-~rtran~-2-(Di~thylamino)-Cyclohexyl]oxylbQnzyl]-6-hydroxy-2-14-~2-(1-pyrro-lidinyl)ethoxylphQnyl3benzo~b3thio~hQnQ Dioxalate.
NJ
,~o b 2 C2H2~4 HO ~ ~
Part A. (~)-tran~-2-(Diethylamino)cycloh~Y~nol.
~J
HO", ~
The title compound was prepared from N,N-diethylamine and cyclohexene oxide by essentially following the procedures 25 outlined in Example 20, Part A. s CA 02236007 l998-04-27 FDMS 171 (M+, base); Anal. Calcd ~or CloH21NO 0~26CH2Cl2: C, 63.73; H, 11.22; N, 7.24. Found: C, 63.80; H, 11.35; N, 7.52.
Part B. (+) -4-rrtran~-2-(Die~thylamino)cyclohexyl]-oxylph~nyl 6-Methoxy-2-[4-~2-(1-pyrroli~inyl)Qthoxy]-~henyl3benzo~blthio~hen-3-yl Ketone.
NJ
o~~ b MeO~ ~ ~
The title compound was prepared in 67~ yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophen-3-yl ketone (Fxample 59, Part A) and (+)-trans-2-(diethyl ~mi no)-cyclohexanol (Part A).
FDMS 627 (M+); Anal. Calcd for C3gH46N2O4S: C, 72.81; H, 7.40; N, 4.47. Found: C, 73.06; H, 7.44; N, 4.6S.
Part C. (+)-3-[4-rttranJ-2-~Diethylamino)cyclohexyl]-oxy]benzyl~-6-methoxy-2-~4-~2-(1-pyrrolidinyl)ethoxy]-~henyl]benzotb3thio~hene.
NJ
~~"'~
MeO~ ~
CA 02236007 l998-04-27 W 097/25033 PCT~US96tl7995 The title compound was prepared in 79% yield from the ketone (Part B) by essentially ~ollowing the procedures detailed in Example 21, Part A.
5 FDMS 613 (M+); Anal. Calcd for C3gH4gN2O3S: C, 74.47; H, 7.89; N, 4.57. Fourld: C, 74.49; H, 8.18; N, 4.66.
Part D. (i) -3- [4- t [trans-2- (Diethylamino)cyclohexyl]-oxylbenzyl~-6-hyaroxy-2-~4-~2-(l-~yrroliainyl)eth phenyl]benzo[b~thiophene.
NJ
~~"'~
HO ~
The title compound was prepared in 73% yield ~rom the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
mp 95-100 ~C; FDMS 599 (M+); Anal. Calcd for C37H46N2O3S 0.2CH2C12: C, 72.55; H, 7.59; N, 4.55. Found C, 72.21; H, 7.59; N, 4.87.
Part E. (~)-3-[4-t[tr~n~-2-(DiethYl~ ;~o)cyclohQxyl]-oxy~benzrll-6-hyaroxy-2-14-t2~ ~yrrolidinyl)ethoxy~-phenyl]benzo~blthiophene Dioxalate.
The title compound was prepared from the ~ree base (Part D) by essentially following the procedures detailed in 25 Example 21, Part C.
mp 143-146 ~C; FDMS 599 (M+); Anal. Calcd for C37H46N2O3S 2.0C2H204 1.8H20: C, 60.64; H, 6.66i N, 3.45. t Found: C, 60.63; H, 6.31; N, 3.26.
W O 97/25033 PCT~US96/17995 Pro~aration of (+)-3-{4-ltci~-2-(Dimethylamino)-cyclohexyl30xy]benzyl]-6-hyaroxy-2-14-12-(l-pyrro-li~inyl)ethoxy]~henyl]benzolb]thiophene Dioxalate.
O
/ 2 c2H204 ~
Part A. (+)-4-~cis-2-(Dimethylamino)cyclohoxyloxy]-~h~nyl 6-Methoxy-2-~4-12-(1-~rrrol~dinyl)Qthoxy]-phenyllbonzolblthiophen-3-yl Ketone.
N
~~~~
MeO~~ ~
The title compound was prepared in 71% yield by essentially following the procedures outlined in Example 72, Part E, ~rom 4-~luorophenyl 6-methoxy-2-[4-[2~
pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+) -cis-2- (dimethylamino)-cyclohexanol.
mp 61-64 ~C; FDMS 5g9 (M+); Anal. Calcd ~or C36H42N2O4S: C, 72.21; H, 7.07; N, 4.68. Found: C, 72.15; H, 7.30; N, 4.64.
Part B. (+)-3-[4-l[ci~-2-(DimQthylamino)ayclohexyl~-oxylbenzyll-6-methoxy-2-14-12-(1-pyrrolidinyl)ethoxy]-phenyl]benzolb]thiophone.
CA 02236007 l998-04-27 N
~~b MeO ~ ~
The title compound was prepared in 57% yield from the ketone (Part A) by essentially following the procedures detailed in Example 21, Part A.
FDMS 585 (M+); Anal. Calcd for C36H44N203S 0.27CH40: C, 73.41; H, 7.66; N, 4.72. Found: C, 73.62i H, 7.74; N, 4.32.
Part C. (+) -3- t4- C lcis-2- (Dimethylamino)cyclohexyl]-10 oxy3benzyl3 -6-hydroxy-2-l4-[2-( 1-pyrrolidinyl)ethoxy3-phenyl]benzolblthiophene.
N
,~ob HO ~ N
The title compound was prepared in 75% yield from the methoxybenzo[b]thiophene (Part B) by essentially following the procedures detailed in Example 21, Part B.
mp 95-98 ~C; FDMS 571 (M+); Anal. Calcd for C35H42N2O3S: C, 73.65; H, 7.42; N, 4.91. Found C, 73.39; H, 7.63; N, 4.78.
Part D. (+)-3-14-~lcis-2-(Dimethylamino)cyclohexyl]-oxy3benzyl3-6-hy~roxy-2-14-12-(1-pyrrolidinyl)ethoxy]-phenyllbenzo~b3thiophene Dioxalate.
The title compound was prepared from the free base (Part C) by essentially following the procedures detailed in Example 21, Part C.
CA 02236007 l998-04-27 mp 103-106 ~C (dec.); FDMS 571 (M+); Anal. Calcd for 35H42N203S 2 0C2H204 1.7H20: C, 59.94; H, 6.37; N, 3.58.
Found: C, 59.81; H, 6.09; N, 3.44.
~ Y~ _le 79 Preparation of (+)-3-14-lltrans-2-(Dimethylamino)-cyclohexylloxylbenzyll-6-hydroxy-2-14-12-(1-pyrro-lidinyl)ethoxy]phenyl]~enzolb]thiophene Dioxalate.
N
~0".~
HO~ ~ C2H2~4 Part A. (~)-trans-2-(DimQthylamino)cyclohe~ol.
HO" ~
To a solution of cyclohexene oxide (3.64 mL, 36.0 mmol) in 30 mL of dry methanol was added dropwise 2.0 M
dimethylamine in THF ~15.0 mL, 30.0 mmol). The reaction mixture was stirred at 0 ~C for 4 h. The solution was then warmed to room temperature and stirred for 18 h. The reaction mixture was then concentrated under reduced pressure to afford 1.11 g (26% crude yield) of the crude product which was used in the following reaction without purification.
Part B. (+)-4-l[trans-2-(Dimethylamino)cyclohexyl]-oxy]phenyl 6-Methoxy-2-14-12-(1-pyrrolidinyl)ethoxy3-phenyl~benzo~b]thiophen-3-yl Ketone.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 N
o~~ b ~eo ~ ~
The title compound was prepared in 77% yield by essentially i~ollowing the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl3benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+)-trans-2-(dimethylamino)cyclohexanol (Part A).
mp 65-70 ~C; FDMS 599 (M+); Anal. Calcd for C36H42N204S: C, 72.21; H, 7.07; N, 4.68. Found: C, 71.98; H, 6.96; N, 4.44.
Part C. (+)-3-[4-[[tr~n~-2-(Dimothylamino)-cyclohQxylJoxy]benzyl]-6-methoxy-2-~4-12-(1-pyrroliainyl)othoxy~henyllbenzolb]thiophene.
N
~o",~
MeO ~ ~ ~ N
~
The title compound was prepared in 66% yield ~rom the ketone (Part B) by essentially following the procedures detailed in Example 21, Part A.
mp 58-61 ~C, FDMS 585 (M+); Anal. Calcd ~or C36H44N203S: C, 73.94; H, 7.58; N, 4.79. Found: C, 74.19; H, 7.55; N, 5.07.
Part D. (+)-3-[4-l~tr~ns-2-(Dimethylamino)-cycloh~xyl30xy]b~nzyl3-6-hy~roxy-2-[4-12-(1-pyrrolidinyl)ethoxy]phenylJbonzo[b]thiophene.
-wa, 97/2S033 PCT/US96/1799~;
~o"~
HO ~ ~
The title compound was prepared in 77% yield from the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
mp 97-102 ~C; FDMS 571 (M+); Anal. Calcd ~or C3sH42N2O3S O.l9CH2C12: C, 72.01; H, 7.28; N, 4.77. Found C, 72.04; H, 7.32; N, 4.43.
Part E. (+)-3-~4-~[tr~ns-2-(Dimethylamino)cyclo-hexylloxy]benzyl]-6-hy~roxy-2-14-~2-(1-pyrro-lidinyl)ethoxyl-phenyllbenzo~b]thiophe~e Dioxalate.
The title compound was prepared from the free base (Part D) by essentially following the procedures detailed in Example 21, Part C.
mp 104-106 ~C (dec.); FDMS 571 (M+); Anal. Calcd ~or C35H42N203S 2.0C2H204 1.2H20: C, 60.44; H, 6.41; N, 3.51.
Found: C, 60.07; H, 6.26; N, 3.21.
~ .~A _ le 80 Preparation of (+)-7-Hydroxy-3-[4-~trans-2-(1-piperi~yl)cyclohoxylloxy]benzyll-2-14-~2-(1-pyrro-li~inyl)ethoxylphenyllbenzo~blthiophene Dioxalate.
W o 97/25033 PCT~US96/17995 ~,o",~
~_ :2 C2H204 OH
Pa~t A. 4-Fluorophenyl 7-~ethoxy-2-14-~2-(1~
lidinyl)ethoxylphenyl]bQnzo ~blthiop~en-3-yl KetonQ.
I~F
~~
~ N
MeO ~
To a suspension of powdered KOH (177 mg, 3.15 mmol) in 1.6 mL of dry DMSO was added 4-fluorophenyl 7-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (350370) (Example 75, Part G) (364 mg, .788 mmol) at room temperature. The reaction mixture turned orange in color.
To the alkoxide was added slowly methyl iodide (49 ~L, .79 mmol) over a period of 15 min. The reaction mixture was then stirred for 1.5 h. Another portion of MeI (20 ~L, .32 mmol) was added, stirred for 1.5 h., followed by another addition of 20 ~L (0.32 mmol) of MeI and stirring for an additional 30 min at room temperature. The rection mixture was then poured into 20 mL of H20. This mixture was extracted with CH2C12 (3 x 20 mL). The combined organic layers were washed with H20 (5 x 10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 4%[10~ NH40H in MeOH]/CH2C12) to afford 108 mg (.226 mmol, 29%) of a white foam.
FDMS 475 (M+); Anal. Calcd for C2gH26FNO3S: C, 70.71; H, 5.51; N, 2.94. Found: C, 70.48; H, 5.77; N, 2.72.
W O 97/2~033 PCT~US96/17995 Part B. (+)-7-Methoxy-2-[4-12-(1-~yl r olidinyl)-ethoxy]phenyl]benzolb]thiophen-3-yl 4-lttrans-2-(1-Pip~ridyl)cyclohoxyl~oxy~ph3nyl Ketone.
o b ~ N
MeO ~
The title compound was prepared in 7496 yield by essentially following the procedures outlined in Example 72, Part E, from the 4-fluorophenyl ketone (BZ4-GCY-222) (Part A) and (+)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
mp 66-69 ~Ci :~DMS 639 (M+); Anal. ~alcd for C36H46N2O4S:
C, 73.32i H, 7.26i N, 4.38. Found: C, 73.60; H, 7.53i N, 4.65.
Part C. (+)-7-Methoxy-3-[4-lltr~ns-2-(1-piperidyl)-~yclohexyl]oxy]benzyl]-2-14-12-(1-pyrroli~inyl)-ethoxy]phenyl]benzo[b~thioph~ne Dioxalate.
~o b ~ 2 C2H2O4 MeO ~
The free base of the title compound was prepared in 6396 20 yield from the ketone (Part B) by essentially following the procedures detailed in Example 21, Part A. The title compound was prepared by essentially following the procedures outlined in Example 21, Part C from the i~ree base obtained.
W O 97n5033 PCT~US96/17995 --216-- r FDMS 625 (M+), Anal. Calcd for C3gH4gN203S-2.1C2H204 1.4H20.
C, 61.83; H, 6.61; N, 3.34. Found: C, 61.49i H, 6.58; N, 3.44.
Part D. (+)-7-~yaroxy-3-t4-[ttrans-2-(1-~iperidyl)-cyclohexyl]oxy~benzyl~-2-l4-r2-(1-pyrrolidinyl)-ethoxy~phenyllbenzotb~thio~hene Dioxalate.
~ e ~ree base of the title compound was prepared in 7 6%
yield from the methoxybenzothiophene (free base of Part C) by essentially following the procedures detailed in Example 21, Part B. The title compound was prepared b~ essentially following the procedures outlined in Example 21~ Part C from the free base obtained.
FDMS 611 (M+); Anal. Calcd for C38H46N2o3s~2 ~OC2H204 3.3H20:
C~ 59~35i H, 6~71; N, 3~30~ Found: C, 59~33; H~ 6~66; N, 3 ~45 ~
R~-q 1~ 81 Preparation of (+)-3-14-[[tran~-2-(Dimethylamino)-¢yclohexylloxy]-3-methoxyb~nzrl~-6-hydroxy-2-t4-t2-(1-pyrrolidinyl)ethoxylphenyl~benzo[b~thio~hene Dioxalate.
~ N
,~o b HO~ ~ 2 C2H2O4 Part A. 4-Benzyloxy-~-hyaroxy-N,N-(dimethyl)phenyl-thioacetamida.
W O 97/25033 PCT~US96117995 OH
~ N~
o~ S
To a solution of distilled diisopropylamine (22.9 mL, 175 mmol) in 400 mL of anhydrous THF at -78 ~C was added 1.6 M n-butyllithium in hexanes (100 mL, 160 mmol) over a period o~ 45 min. The mixture was stirred at -78 ~C ~or 1.5 h. To the solution was c~nn~ ted over a period of 1 h a solution of 4-benzyloxybenzaldehyde ~30.9 g, 146 mmol) and N,N-dimethylthioformamide (13.7 mL, 160 mmol) in 100 mL of distilled THF. The reaction mixture was stirred at -78 ~C
for 16 h. The reaction was then ~enched with 500 mL o~
saturated NH4Cl solution. The mixture was extracted with EtOAc (3 x 1 L), and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was then recrystallyzed from EtOAc/hexanes to afford 20.0 g (66.5 mmol, 46%) of an off-white solid.
mp 104-107 ~C; FDMS 301 (M+); Anal. Calcd for C17HlgNO2S: C, 67.75; H, 6.35i N, 4.65. Found: C, 67.61i H, 6.37; N, 4.57.
]?art B. 6-Benzyloxy-2-(dimethylAmino)benzo[b~-thiophene.
~ ~ N
To a solution of thioacetamide (Part A) (500 mg, 1.66 mmol) in 65 mL of dry dichloroethane at room temperature was added dropwise methanesulfonic acid (0.54 ml, 8.3 mmol). The red reaction mixture was stirred ~or 1.5 h and then poured into 10 mL of saturated aqueous NaHCO3 solution, followed by addition of 3 mL of H2O, and stirred vigorously. The layers W O 97~5033 PCTrUS96/17995 were separated and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 10%
Et2O/hexanes) to afford 327 mg (1.15 mmol, 70%) of a white solid.
mp 78-81 ~C; FDMS 283 (M+)i Anal. Calcd for C17H17NOS: C, 72.05i H, 6.05; N, 4.94. Found: C, 72.22; H, 6.15; N, 4.89.
Part C. 6-Benzyloxy-2-(dimethylamino)benzo~b~thio-phQn-3-yl 3,4-Dimethoxyph~nyl Xetone.
o~o\
0~ \
To a solution of 3,4-dimethoxybenzoyl chloride (1.250 g, 6.231 mmol) in 18 mL of chlorobenzene was added 6-benzylo~y-2-(dimethylamino)benzo[~]thiophene (Part B) (1.059 g, 3.738 mmol). The dark blue reaction mixture was then heated to 110 ~C and stirred for 17 h by which time the solution turned to brown. The brown solution was then quenched at 0 ~C with 30 mL of saturated aqueous NaHCO3 solution and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with 200 mL with brine, dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 50:50 EtOAc-hexanes) to afford 1.265 g (2.826 mmol, 76%) of a yellow foam.
mp 69-72 ~C; FDMS 447 (M+); Anal. Calcd for C26H2sNO4S: C, 69.78; H, 5.63; N, 3.13. Found: C, 69.93; H, 5.77; N, 3.25.
Part D. 4-~2-(1-~yl~olidinyl)ethoxy]~hQnyl Ma~nosium Bromid~.
W O 97/25033 PCT~US96/17995 BrMg ~
To a solution of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine in 24.1 mL o~ freshly distilled THF was added 293 mg of magnesium turnings. The mixture was heated at reflux for 3 h or until all the magnesium was consumed to afford ~24.1 mL of 0.48 M Grignard reagent solution.
l?art E. 6-Renzyloxy-2-~4-[2-~ olidinyl)ethoxy]-l?henyl]bQnzo~b~thiophen-3-yl 3,4-DimethoxyphQnyl l~eto~e.
~<
~~o\
o~o ~ ~\
To the dimethylaminobenzo[b]thiophenyl ketone (Part C) (1.237 g, 2.763 mmol) in 30 ml of freshly distilled THF was added dropwise 0.48 M 4-[2-(1-pyrrolidinyl)ethoxy]phenyl magnesium bromide in THF (Part D) (8.63 mL, 4.14 mmol) at 0 ~C. The resultant bright red solution was stirred at 0 ~C
for 2 h 15 min. The reaction was quenched at 0 ~C with 30 mL
of saturated aqueous NH4Cl solution. The mixture was diluted with 15 mL of H20 and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and then purified by flash chromatography (silica gel, 60:37:3 THF-hexanes-Ft3N) to afford 1.507 g (2.538 mmol, 92%) of a yellow foam.
mp 74-77 ~C; FDMS 593 (M+); Anal. Calcd for C36H3sNOsS: C, 72.83; H, 5.94; N, 2.36. Found: C, 72.91; H, 5.94; N, 2.62.
., CA 02236007 l998-04-27 W 097/2~033 PCT~US96/17sss P~rt F. 6-Benzyloxy-2-~4-[2-(1-~y olidinyl)ethoxyl-phenyl~b~nzo~b]thiophen-3-yl 4-Hydroxy-3-~ethoxyphenyl KQtone .
O~ OH
0~ ~0 ~ ~\
To the 3,4-dimethoxyphenyl ketone (Part E) (1.496 g, 2. 519 mmol) in 15 ml of dry DMF was added sodium thioethoxide (848 mg, 10.1 Imnol), and the reaction mixture was stirred at 80 ~C for 3h. The mixture was then cooled to 0 ~C and quenched with 15 mL of saturated aqueous NH4Cl solution.
This mixture was extracted with CHC13 (3 x 150 mL). The combined organic layers were washed with 450 mL of H20 and 150 mL o~ brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromato~raphy (silica gel, 696[1096 NH40H in MeOH]/CH2C12) to 15 afford 1.251 g (2.159 r~nol, 86%) o~ a yellow foam.
FDMS 579 (M+); Anal. Calcd for C3sH33NOsS: C, 72.52; H, 5. 74; N, 2.42. Found: C, 72.63; H, 5.73; N, 2.64.
P~rt G. (+)-6-Benzyloxy-2-~4-~2-(1~ olidinyl)-ethoxy]~henyl~benzo~b~thiophen-3-y} 4-[tr~n~-2-(Dimethyl~ ;~o)cyclohoxyl]oxy-3-methoxyPhenyl Ketone.
O N
o~-~ b J~O
~ ~ ..
W O 97/25033 PCTnJS96~7995 The title compound was prepared in 93~ yield by essentially following the procedures outlined in Example 20, Part B from the phenol (Part F) and (+)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A).
mp 66-69 ~C; FDMS 705 (M+); Anal. Calcd for C43H48N205S-0.62NH50: C, 71.08; H, 7.09; N, 5.05. Found: C
'70.88; H, 6.76; N, 4.65.
:Part H. (+)-6-Benzyloxy-a~[4-~ltrans-2-(~imethyl-;~o)cycloh~xyl30xy~-3-m~thoxyphenyll-2-C4-12-(l-~yrroli~inyl)ethoxy~phcnyl~benzo[b]thio~hene-3-methanol.
O N
HO ~
0~\ ~
The title compound was prepared in by essentially following the procedures outlined in Example 31, Part B from the ketone ~Part G). The crude product was purified by flash chromatography (silica gel, 10%[10% NH40H in MeOH]/ CH2Cl2) to afford 418 mg (.591 mmol, 69%) of a white foam.
FDMS 708 (M+l); Anal. Calcd for C43H50N205S 0.22CH2C12: C, 71.54; H, 7.12; N, 3.86. Found: C, 71.52; H, 7.31; N, 4.06.
Part I. (+)-3-l4-[ltrans-2-(DimethylA ;~o)cyclohexyl~-oxy] -3-methoxybenzyl3-6-hydroxy-2-C4-C2-(l-pyrroli-dinyl)~thoxylphenyl~benzo1b~thiophene Dioxalate.
The 6-benzyloxy protected title compound was prepared from the disubstituted methanol (Part H) by essentially following procedures outlined in Example 31, Part C. A
slurry o~ the crude (+3-6-benzyloxy-3-[4-l[trans-2-(dimethylamino3cyclohexyl]oxy]-3-methoxybenzyl] -2-~4-l2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b~thiophene (374 mg, .542 mmol) and Pd/C (10%, 375 mg) in 5.4 mL of a 1:1 mixture of THF-EtOH was stirred under positive hydrogen pressure (from balloon) for 19 h. The reaction mixture was filtered through a pad of diatomaceous earth and washed with THF. The filtrate was then concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%[10% NH40H
in MeOH]/CH2C12) to afford 200 mg (.333 mmol, 61~ from alcohol) of an off-white foam. The title compound was then prepared by essentially following the procedures outlined in Example 21, Part C from the free base.
mp 167 ~C (dec.); FDMS 601 (M+); Anal. Calcd for 15 C36H44N2O4S 1.83C2H204: C, 62.22; H, 6.27; N, 3.66. Found:
C, 62.26; H, 6.40; N, 3.28.
r~ le 82 Preparation of (+)-4-~t~ans-2-(Dimothyla~i~o)-cyclohexyl~ox~l -3-methoxyphenyl 6-Hydroxy-2-14- r2- (l-pyrroli~inyl)ethoxy]phenyl]benzorb]thiophen-3-yl Ketone Dioxalate.
o N
o~~ b HO ~ 2 C2H2O4 The title compound was prepared from the free base (Example 81, Part G) by essentially following the procedures outlined in Example 81, Part I and Example 21, Part C.
mp 170 ~C (dec.); FDMS ~15 (M+); Anal. Calcd for C36H42N20sS 1.82C2H204: C, 61.15; H, 5.91; N, 3.60. Found:
C, 61.12; H, 6.05; N, 3.66.
W O 97/25033 PCTnUS96~1799S
~r le 83 Pr~paration Of 3-~3-Chloro~4~ r oliainyl) ~
methyllbenzyll-2-~4-~2-(1-pyrrolidinyl)ethoxy~phenyl3-b~nzo~blthio~hene Dioxalate.
Cl N
~_ :Z C2H2~4 ~
Part A. M~thyl 4-~ - -thyl-3-chlore~e~70ate.
Cl O Br The title compound was prepared in 56% yield by essentially following the procedure outlined in the first part of Example 37, Part A, from methyl 3-chloro-4-methylbenzoate.
FDMS 264 (M+); Anal. Calcd for CgHgBrClO2: C, 41.02; H, 3.06. Found: C, 41.10; H, 3.10.
Part B. Methyl 3-Chloro-4-[(1-~r~olidinyl)methyl~-benzoate.
Cl MeO ~
The title compound was prepared in 44~ yield by essentially following the procedures outlined in the second part of Example 37, Part A, from methyl 4-bromomethyl-3-chlorobenzoate (Part A).
F FDMS 253 (M+); Anal. Calcd ~or C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.24; H, 6.11; N, 5.53.
W O 97/25033 PCTrUS96/17995 Part C. 3-Chloro-4-1(1-~ ~olidinyl)methyl~benzoic Acid cl HO~--~
The title compound was prepared in 72% crude yield by essentially following the procedures outlined in Example 20, Part C, from methyl 3-chloro-4-[~1-pyrrolidinyl)methyl]-benzoate (Part B). This compound was used without purification.
Part D. 3-Chloro-4-t(l-~ olidinyl)methyl]phenyl a- t4-t2-(1-~yrroli~inyl)Qthoxy]~hQnyllbenzolblthio-phen-3-yl Ketono Dioxal~te.
N ~
2 c2H2~4 ~~ ~
The free base of the title compound was prepared in 55%
yield by essentially following the procedures outlined in Example 1, Part C from 2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene (Example 4, Part A) and 3-chloro-4-[(l-pyrrolidiny)lmethyl]benzoic acid (Part C). The title compound was then prepared by essentially following the procedures outlined in Example 21, Part, C from the free base.
mp 97-102 ~Ci FDMS 544 (M-l); Anal. Calcd for C32H33ClN2O2S 2.0C2H2O4: C, 59.62; H, 5.14; N, 3.86. Found:
C, 59.41; H, 5.28; N, 3.90.
Part E. 3-~3-Chloro-4-t(l-~ lolidinyl)methyl]-benzyl]-2-t4-[2-(1-~yrrolidinyl)ethoxy]phonyl3-benzotb3thiophene Dioxalate.
W O 97/25033 PCT~US96/17995 The ~ree base o~ the title compound was prepared in 57%
yield by essentially following the procedures in Example 21, Part A from the ketone (~ree base o~ Part D). The title compound was prepared by essentially following the procedures outlined in Example 21, Part C from 3-r3-chloro-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene.
mp 126-130 ~C dec.; FDMS 531 (M+); Anal. Calcd ~or C32H3sClN2OS 2.0C2H2O4: C, 60.80; H, 5.53i N, 3.94. Found:
C, 60.63; H, 5.81; N, 3.87.
Exam~le 84 Preparation of 3-[3-~hloro-4-~ olidinyl3methyll-bonzyl~-6-hydroxy-2-14-12-(1-~yrroliainyl)ethoxyl-~henyllbenzo ~b~ thio~hene Dioxalate.
2 c2H2~4 HO ~ ~ N
Part A. 6-Benzyloxy-2-(dimethylr ;~o)benzo ~b~ thio-phen-3-yl 3-~hloro-4-t(1-pyrrolidinyl)methyl]phenyl Retone. Cl ~Nl~>
\
The title compound was prepared in 93% yield by essentially ~ollowing the procedures outlined in Example 41, Part C (but using thionyl chloride to ~orm the acid chloride) W O 97/25033 PCTrUS96/17995 ~rom 6-benzyloxy-2-(dimethylamino~benzo[b]thiophene (Example 81, Part B) and 3-chloro-4-[(1-pyrrolidinyl)methyl]benzoic acid (Example 83, Part C).
FDMS 504 (M-l); Anal Calcd. ~or C2gH29ClN2O2S: C, 68.96; H, 5.79; N, 5.55. Found: C, 69.00; H, 5.62; M, 5.55.
Part B. 6-Benzyloxy-2-[4-[2-(1-~ lolidinyl)ethoxyl-phQnyllbsnzolblthio~hen-3-yl 3-Chloro-4-1(l-~y ~olidinyl)methyl]phenyl Ketone.
N~
0~
The title compound was prepared in 94% yield by essentially following the procedures in Example 81, Part E, ~rom 4-[2-(l-pyrrolidinyl)ethoxy]phenyl magnesium bromide (Example 81, Part D) and 6-benzyloxy-2-(dimethyl ~m; nQ) -benzo[b]thiophen-3-yl 3-chloro-4-[(1-pyrrolidinyl)methyl]-phenyl ketone (Part A).
FDMS 651 (Mt).
Part C. 3-Chloro-4-[(1-pyrrollainyl)methyl3~henyl 6-Hydroxy-2-[4-[2-(1-~yrrolidinyl)ethoxy~phenylJ-benzo~b~thiophen-3-yl Ketone Dioxalate.
Cl N
HO~ ~ C2H2~4 CA 02236007 l998-04-27 The :Eree base of the title compound was prepared in 71%
yield by essentially following the procedures outlined in Example 81, Part I from the ketone. The title compound was prepared by essentially ~ollowing the procedure outlined in Example 21, Part C.
mp 174-178 ~C; FDMS 561 (M+); Anal. Calcd for C32H33ClN2O3S 1.75~2H2O4: C, 59.33; H, 5.12; N, 3.78.
Found: 59.33; H, 5.27; N, 3.90.
Part D. 3-13-Chloro-4-t(l-~Ylloli~inYl)m~thYll-benzyl]-6-hydroxy-2-14-12-(1-pyrroli~inyl)ethoxy]-phenyl]benzolblthiophene DioxalatQ.
The free base o:E the title compound was prepared in 38%
yield by essentially following the procedures outlined in Example 21, Part A, from the above ketone (Part C). The title compound was then prepared ~y essentially following the procedures outlined in Example 21, Part C.
FDMS 547 ~M+); Anal. Calcd for C32H3sClN2O2S 1.66C2H204: C, 60.90; H, 5.54; N, 4.02. Found: C, 60.90; H, 5.72; N 3.99.
_ 1Q 85 Preparation of (+)-6-Hyaroxy~3-[3-methoxy-4-l[trans-2-(1-pi~eri~yl)cyclohQxyl]oxy]benzyl]-2-[4-1i2-(1-pyrro-li~inyl)ethoxy3phenyl~bQnzotb3thio~hQne Dioxalate.
o Q
~o"~
HO~o 2 c2H204 Part A. (+)-6-Benzyloxy-2-14-12-(1-~y lolidinyl)-~thoxy]ph~nyl]bonzolb]thiophQn-3-yl 3-Methoxy-4-l[tran~-2-(l-piperidyl)cyclohexyl]oxy]phenyl Ketone.
W O 97~5033 PCTrUS96/17995 o~ ~
o~~"'~
o~~
,~
The title compound was prepared in 72% yield by essentially following the procedures outlined in Example 20, Part B, from 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-~l 4-hydroxy-3-methoxyphenyl ketone (Example 81, Part F) and (+)-trans-2-(1-piperidyl)-cyclohexanol (Example 20, Part A).
FDMS 746 (M+); Anal. Calcd for C46Hs2N20sS-0.19CH2C12: C, 72.89; H, 6.94; N, 3.68. Found: C, 72.84; H, 6.98; N, 4.03.
Part B. (+)-6-~ydroxy-3-13-methoxy-4-~tr~ns-2-(1-pi~eridyl)cyclohexyl]oxylbenzyll-2-t4-12-(1-pyrro-lidinyl)ethoxyl~honyllbonzo[b]thiophQne Dioxalate.
The free base of the title compound was prepared in 46%
yield by essentially following the procedures outlined in Example 21, Part A and Example 81, Part I from the ketone (Part A). The tîtle compound was then prepared by essentially following the procedure outlined in Example 21, Part C.
mp 167-171 ~C (dec.); FDMS 641 (M+~; Anal. Calcd for C3gH4gN204S-1.88C2H204: C, 63.39; H, 6.44; N, 3.46. Found:
C, 63.39; H, 6.61; N, 3.27.
~ Y~ _le 86 Preparation of (i)-6-xydroxy-2-14-[2-(1-~ olidinyl)-ethoxy]phenyl]benzo~b]thiophen-3-yl 3-Methoxy-4-~ttrans-2-(1-~iperidyl)cyclohexy]loxylphenyl Ketone Dioxalat~.
o~
" ~~ '~
HO~o C2H204 The free base of the ~itle compound was prepared in 41%
yield by essentially following the debenzylation procedure in Example 81, Part I, ~rom the ketone (Example 85, Part A).
The title compound was then prepared by essentially following the procedures in Example 21, Part C.
mp 151-155 ~Ci FDMS 655 (M~); Anal. Calcd for C3gH46N20sS-1.76C2H204: C, 62.79; H, 6.14; N, 3.44. Found:
C, 62.56; H, 6.54; N, 3.31.
_le 87 Preparation of (+)-3-[~tran~-2-(Dimethylamino)-cyclohexylloxy~isoxazol-5-yl 6-Hydroxy-2-14-[2-( ~yrrolidinyl)ethoxylphenyllbenzorb]thioph~n-3-yl Ketone Dioxalate.
--N
3¢~N 2 c2H2~4 P~rt A. (+)-Methyl 3-Eltran~-2-(Dimethylamino) cyclohexyl]oxyli~oxazolo-5-carboxylate.
., WO 97/2~033 PCTAJS96/17995 - N
~,o~
MeO
The title compound was prepared in 73% yield ~y essentially following the procedures outlined in Example 20, Part B ~rom methyl 3-hydroxyisoxazole-5-carboxylate and (+)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A) ~DMS 268 (M~); Anal. Calcd ~or Cl3H20N2o4: C, 58.19; H, 7.51; N, 10.44. Found: C, 58.31; H, 7.51; N, 10.54.
Part B. (~)-3-~[trans-2-(Dimethylamino)cyclohexyl~-oxylisoxazolQ-5-carboxylic Acid.
o~
~ ~ ,N
HO
The title compound was prepared by essentially following the procedures outlined in ~xample 20, Part C, from the ester (Part A).
Part C. (~)-6-Benzylox~-2-(dimQthyl~;~o)benzo[b]-thiophen-3-yl 3- r [trans-2-(Dimethylamino)cyclohexyl~-oxyli~oxazol-5-yl KetonQ.
- N
01~
O ~ ,N
0~ \
~
W O 97/25033 PCTnJS96/17995 The title compound was prepared in 92% yield by essentially following the procedures outlined in Example 84, - Part A from the isoxazole-5-carboxylic acid (Part B) and 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (Example 81, Part B).
FDMS 519 (M+); Anal. Calcd for C29H33N304S-0.52H20: C, 65.84i H, 6.49; N, 7.94. Found: C, 65.87; H, 6.12; N, 7.56.
Part D. (~)-6-Benzyloxy-2-~4-~2-(1-~y ~oliainyl)-othoxylphenyl~benzolblthio~hen-3-yl 3-1ltran~-2-(Dimethylamino)cyclohexyllo~yl isoxazol-~-yl Ketone.
- N
~ ~ ~ N ~
The title compound was prepared in 77% yield by essentially following the procedures outlined in Example 81, Part E from the ketone (Part C) and 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl magnesium bromide (Example 81, Part D).
FDMS 666 (M+).
2~
Part E. (+)-3-1ltrans-2-(Dimethylamino) cyclohexyll-oxy]isoxazol-5-yl 6-Hydroxy-2- 14-[2- ~1-pyrrolidinyl)-~thoxy]~hQnyl]benzolblthio~hQn-3-yl Ketone Dioxalato.
The ~ree base of the title compound was prepared in 51%
yield by essentially following the debenzylation procedure outlined in Example 81, Part I from the ketone (Part D). ~he title compound was prepared by essentially following the procedures in Example 21, Part C.
W O 97/2~033 PCT~US96/17995 FDMS 576 (M+).
Example 88 Prsparation of 3-~4-~(DimQthyl~;no)methyl]-3-methoxybQnzyl]-6-hydroxy-2-t4-12-(1-pyrrolidinyl)-~thoxy]phenyl~benzo~b]thiophsne Dioxalate.
o N -~ I
HO ~ ~ N
Part A. 4-Allyloxy-~-hydroxy-N,N-dimethylphenyl-thioacetamide.
qH
~ N~
o~ S
The title compound was prepared in 70% yield by essentially ~ollowing the procedure in Example 81, Part A
from 4-allyloxybenzaldehyde.
FDMS 251 (M+).
Part B. 6-Allyloxy-2-(dimethylamino)benzo[b~thiophene.
The title compound was prepared in 49% yield by essentially following the procedures outlined in Example 81, Part B from the thioacetamide (Part A).
FDMS 233 (M+); Anal. Calcd for C13HlsNOS: C, 66.92; H, 6.48;
N, 6.00. Found: C, 66.76i H, 6.54; N, 5.82.
Part C. Methyl 4-(Dimethyl~-;no)methyl-3-methoxy-- henzoate.
MeO~ N
The title compound was prepared in 77% yield by essentially following the procedure outlined in Example 37, Part A from methyl 4-bromomethyl-3-methoxybenzoate (see Example 37, Part A) and dimethylamine.
FDMS 223 (M+); Anal. Calcd. for C12H17N03: ~, 64.55; H, 7.67; N, 6.27. Found: C, 64.52; H, 7.68; N, 6.43.
Part D. 4-(DimethylA ;no)methyl-3-methoxybenzoic Acid.
H~ ' N
o The crude title compound (+30% NaCl by weight) was prepared by essentially following the procedures outlined in Example 20, Part C from the methyl benzoate (Part C).
Part E. 6-Allyloxy-2-(dimQthyl~ ino)benzo~b~thiophen-3-yl 4-(Dimethylamino)methyl 3-methoxyphenyl Ketone.
o~
N--~N
J
The title compound was prepared in 73% yield (23% SM
recovered) by essentially following the procedures outlined in ~xample 84, Part A from 6-allyloxy-2-(dimethylamino)benzo-[~]thiophene (Part B) and 4-(dimethylamino)methyl-3-methoxybenzoic acid (Part D).
FDMS 424 (M+); Anal. Calcd for C24H28N2O3S: C, 67.90; H, 6.65; N, 6.60. Found: C, 68.18; H, 6.77; N, 6.81.
Part F. 6-Allyloxy-2-[4-r2-(1-pyrrolidinyl)ethoxy]-~hen~l]benzo~b]thiophen-3-yl 4-(Dimethyl~ ;~o)mothyl-3-mothoxyphonyl Ketone.
0~/
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 81, Part E from the ketone (Part E) and 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl magnesium bromide (Example 81, Part D).
FDMS 570 (M~); Anal. ~alcd for C34H3gN2O4S: C, 71.55; H, 6.71; N, 4.91. Found: C, 71.30; H, 6.85; N, 4.89.
Part G. 3-E4-(Dimothylamino)mQthyl-3-methoxybenzyl}
6-hydroxy-2-l4-~2-(1-pyrrolidinyl)ethoxy~phenyl]-bonzoEb~thio~hene Dioxalate.
Deoxygenation of the ketone (Part F) was accomplished in 57% crude yield by essentially following the procedures outlined in Example 21, Part A.
The ~ree base of the title compound was prepared by stirring a slurry of the above crude product (139 mg, .250 mmol), 10% Pd/C (150 mg), and p-toluenesulfonic acid monohydrate (105 mg, .551 mmol) in 3 mL o~ a 5:1 mixture of MeOH-THF solution at re~lux ~or 22 h. The reaction was ~uenched with 3.5 mL of saturated a~ueous NaHCO3 solution, CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 stirred vigorously for 15 min, and then concentrated to dryness under reduced pressure. The residue was taken up in - 200 mL of THF and stirred vigorously for 30 min. The slurry was ~iltered through a pad of diatomaceous earth and washed with THF. The filtrate was concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%~10% NH40H in Me0H~/CH2Cl2) to afford 66.7 mg (.129 mmol, 52%) of a light brown foam. The title compound was prepared by essentially following the procedures outlined in Example 21, Part C.
FDMS 517 (M+); Anal. Calcd for C31H36N203S 2 OC2H2o4 0~7H2o-l-2c4Hgo2 (Hygroscopic): C, 58.65; H, 6.31; N, 3.44. Found: C, 58.27; H, 6.31; N, 3.41.
_ 1~ 89 Pr~paration of 2-14- r2- (Dimethylamino)ethoxy]phenyl]-3-~4-(dimethylamino)methyl-3-methoxybenzyl]-6-hyaroxy-benzolb]thiophene Dioxalate.
o ,~f7-HO~ N--Part A. 12-(4-Chlorophe~o~y)ethyl]dimethyl~ ;ne.
o Cl ~
N--The title compound was prepared in 61% yield (26% SM
recovered) by essentially following the procedure outlined in Example 34, Part A from 2-bromoethyl 4-chlorophenyl ether and dimethylamine.
FDMS 199 (M+); Anal. Calcd for C1oH14ClN0: C, 60.15; H, 7.07; M, 7.01. Found: C, 59.88; H, 7. 03; N, 7. 22.
CA 02236007 l998-04-27 W O 97/2~033 PCT~US96/17995 Part B. Pro~aration of 4-~2-(DimothylA-ino)ethoxy]-~honyl Magnesium Chloride.
g ~
N--To the chlorobenzene (Part A) in 23.6 I~ oi~ ~reshly distilled THF was added 216 mg of magnesium turnings and a catalytic amoun~ o~ iodine crystals. The mixture was heated at reflux for 3 6 h or until all the magnesium was consumed to af~ord ~23.6 mL, o:E 0.3 8 M Grignard reagent solution as a milky white suspension.
Part C. 6-Allyloxy-2-[4-~2-(dimethylamino)Qthoxy]-~henyll ben z o [ b] thi ophen-3-yl 4-(Dim~thylamino)methyl-3-methoxyphenyl Ketono.
o~3~ N--~J
The title compound was prepared in 80% yield by essentially ~ollowing the procedures outlined in Example 81, Part E ~rom the ketone (Example 88, Part E) and the Grignard reagent (Part B).
FDMS 544 (M+); Anal. Calcd ~or C32H36N2O4S: C, 70.56; H, 6.66i N, 5.14. Found: C, 70.33; H, 6.73; N, 5.10.
Part D. 2-[4-[2-(DimethYl~ ;no)ethoxy]phenyll-3-C4-~dimethylamino)methyl-3-methoxybenzyl3-6-hydroxy-b~nzoCblthiopheno Dioxalat~.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/1799 Deoxygenation of the ketone (Part C) was accomplished in 46% by essentially following the procedures outlined in ~ Example 21, Part A.
The ~ree base of the title compound was prepared in 45%
yield by essentially following the procedures outlined in Example 88, Part G. The title compound was then prepared by essentially following the procedure outlined in Example 21, Part C.
FDMS 491 (M+); Anal. Calcd for C2gH34N203S 2.0C2H204 1.06C4HgO2 (Hygroscopic): C, 58.54i H, 6.13; N, 3.67. Found: C, 58.62; H, 6.39; N, 3.79 Example 90 Preparation of 2-[4-[2-(Dim~thy}~ ;no)ethoxy]phenyl]-6-hydroxybonzo[blthiophen-3-yl 4-(Dimethylamino)-methyl-3-methoxyphenyl Ketone Dioxalate.
o~
N -0~ 1 HO~ ~3~ 2 C2H204 The free base of the title compound was prepared in 37%
yield by essentially following the procedures outlined in Example 88, Part G from 6-allyloxy-2-[4-[2-(dimethylamino)-ethoxy]phenyl]benzo[b]thiophen-3-yl 4-(dimethylamino)methyl-3-methoxyphenyl ketone (Example 89, Part C). The dioxalate was then prepared by using the procedures from Example 2~, Part C from the free base.
FDMS 505 (M+); Anal. Calcd for C29H32N2O4S 2 ~C2H2~4 C, 57.89; H, 5.30; N, 4.09. Found: C, 57.75; H, 5.47; N, 4.13.
..
W O 97/25033 PCT~US96/17995 ~Y;' _ 1~3 91 PrQparation of 4-(Dim~thylamino)methyl-3-methoxy-phenyl 6-Hydroxy-2-C4-l2-(l-~yrrolidinyl)ethoxy3 phenyl]bQnzo[blthiophen-3-yl Ketone Dioxalate.
o ~f HO~o 2 c2H2o4 <
The free base of the title compound was prepared in 81 yield by essentially following the procedures outlined in Example 88, Part G ~rom 6-allyloxy-2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl 4-(dimethylamino)methyl-3-methoxyphenyl ketone (Example 88, Part F). The dioxalate was then prepared by using the procedures ~rom Example 21, Part C from the free base.
FDMS 531 (M+); Anal. Calcd for C31H34N204S-2.0C2H204: C, 59.15; H, 5.39; N, 3.94. Found: C, 58.96; H, 5.73; N, 4.00.
Example 92 Preparation of (+)-4-Hydroxy-3-14-C[trans-2-~l-piperi~yl)cyclohexylloxylbenzyll-2-[4-C2-(l~pyrro-lidinyl)ethoxy]~henyl]benzo [b3 thiophene Dioxalate.
OH ~ o", b ~ o 2 C2H2~4 Part A. 4-Methoxybenzo ~b3 thiophene an~ 6-Methoxy-b~nzo lb3 thiophene.
W O 97/25033 PCT~US96/17995 ,. -239-OMe MeOJ~
To a mixture of 25.10 g of 3-methoxybenzenethiol and 19.2 ml, of bromoacetaldehyde dimethyl acetal in 200 mL of acetone was added 27 g of K2CO3 in one portion at room temperature. The white suspension was stirred vigorously at room temperature for 2 h. The mixture was filtered with thorough ethereal rinse. The filtrate was concentrated, taken up in 500 mL of Et20, and washed with 300 mL of H20, 0.5 N KOH, H2O, and brine. The washings were back extracted with Et2O (3 x 500 mL). Combined organic layers were dried over MgSO4 and concentrated to afford 37. 46 g (quantitative) of the crude 3-methoxybenzenethioacetaldehyde dimethyl acetal.
To a heated biphasic solution of 53.9 g of PPA in ca.
500 mL of chlorobenzene at 14S ~C (bath temp.) was added dropwise 18.44 g of the crude acetal in ca. 100 mL of chlorobenzene over 4.5 h period. The dark green biphasic solution was heated at reflux with vigorous stirring for another 2 h. After cooling to room temperature, the organic layer was separated, concentrated, taken up in 500 mL of EtOAc, and washed with 300 mL of H2O and brine. The PPA
layer was dissolved in ca. 1.0 L of H2O and extracted with EtOAc (4 x 500 mL). The extracts were washed with 300 mL of H2O and 1:1 mixture of saturated aqueous NaHCO3 and brine.
Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with hexanes to yield 2.40 g of 4-methoxybenzo[b] thiophene and 7.96 g of 6-methoxybenzo [b] -thiophene (78% total) which were cleanly separated.
4-methoxybenzothiophene: FDMS 164.0 (M+); Anal. Calcd for CgH8OS: C, 65.82i H, 4.91; S, 19.52. Found: C, 66.01; H, 4.90i S, 19.60.
6-methoxybenzothiophene: FDMS 164.0 (M+).
W O 97/25033 PCT~US96/17995 Part B. 4-Methoxybenzolb]thiophene-2-boronic Acid.
OMe ~ B (OH)2 The title compound was prepared in 62~ yield by essentially ~ollowing the procedures in Example 1, Part A
from 4-methoxybenzothiophene (Part A).
mp 267-270 ~C; FDMS 570.
Part C. 4-Methoxy-2-~4-~2-~ t oli~inyl)ethoxy]-phenyl~benzolb]thioph~ne.
OMe The title compound was prepared in 53% yield by essentially following the procedures outlined in Example 1, Part B from 4-methoxybenzo[b]thiophene-2-boronic acid (Part B).
FDMS 353 (M+).
Part D. 4-Hydroxy-2-[4-C2~ ~y~lolidinyl)ethoxy~-phonyl]benzolb]thiophono.
OH
~~
The title compound was prepared by essentially following the procedures outlined in Example 21, Part B from the methoxybenzo[b]thiophene (Part C). Recrystallization from 25 EtOAc-hexanes afforded 712 mg (2.09 mmol, 38%) of off-white needle-like crystals.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 mp 191-193 ~C; FDMS 339 (M+); Anal. Calcd for C20H2lNo2s-o~l7H2o: C, 70.13; H, 6.28; N, 4.09. Found: C, ~ 69.81; H, 6.10; N, 3.85.
Part E. 2-14-[2-(1-~y ~olidinyl)Qthoxy]phenyl~-benzolb]thiophen-4-yl 4-Fluorobenzoate.
A mixture of 4-hydroxybenzo[b]thiophene (Part D) (607 mg, 1.79 mmol) and 4-fluorobenzoyl chloride (233 ~L, 1.97 mmol) in 10 mL of anhydrous dichloroethane was stirred at room temperature for 18 h. Another portion of 4-~luorobenzoyl chloride (166 ~L, 1.48 mmol) was added and the reaction mixture was stirred for 3 days. A third portion of acid chloride (233 ~l, 1.97 mmol) was added and the mixture was stirred for an additional 4 h. The reaction was then quenched with 25 mL of satd. NaHC03 soln, and the mixture was extracted (3 x 100 mL) with EtOAc. The combined organic layers were washed with 100 mL of brine, dried over MgS04, concentrated under reduced pressure, and ~lash chromatographed (silica gel, 5%[10% NH40H in MeOH]/CH2Cl2) to afford 699 mg (1.51 mmol, 85~) of a white solid.
FDMS 461 (M+); Anal. Calcd for C27H24FN03S 0.16NHsO: C, 69.42; H, 5.35; N, 3.48. Found: C, 69.40; H, 5.30; N, 3.65.
Part F. 3-(4-Fluorophenyl)carbonyl-2-~4-12-(1-Pyrrolidinyl)ethoxy]phenyl~benzo~b]thiophen-4-yl 4-Fluorobonzo~te.
x W O 97/25033 PCT~US96/17995 F
0 0~
To a solution of 4-fluorobenzoate ~Par~ E) (683 mg, 1.48 mmol) in 10.0 mL of anhydrous dichloroethane was added 4-fluorobenzoyl chloride (192 ~L, 1.63 mmol) at room temperature. The reaction mixture was cooled to 0 ~C, and aluminum chloride (789 mg, 5.92 mmol) was added which turned the slurry into a dark red homogeneous solution. The reaction mixture was slowly warmed to room temperature and then stirred ~or 24 h. Another portion of aluminum chloride (395 mg, 2.94 mmol) and 4-fluorobenzoyl chloride (95 ~L, .80 mmol) were added, and the reaction mixture was stirred at room temperature for another 24 h. The reaction mixture was then poured into 25 mL of ice-cold saturated aqueous NaHCO3 solution. The mixture was taken up in EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (4 x 150 mL). The combined organic layers were washed with 100 mL of brine, dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (MPLC, silica gel, 40:57:3 THF-hexanes-Et3N) to afford 193 mg (.331 mmol, 22%) of white foam.
mp 58-63 ~C; FDMS 583 (M+); Anal. Calcd ~or C34H27F2NO4S: C, 69.97; H, 4.66; N, 2.40. Found: C, 70.37; H, 5.00; N, 2.30.
Part G. (+)-4-~ydroxy-2-t4-12-(1-1?yrrolidinyl)-~thoxyl~henyl]bQnzo[~thiophen-3-yl 4-l[trans-2-(1-PipQridyl)cyclohexyl]oxy]phenyl Ketone.
W O 97/25033 PCT~US96/17995 OH ~
.. ~~
The title compound was prepared in 32% yield by essentially following the procedures in Example 75, Part G, from the 4-~1uorobenzoate (Part F) and (+)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
FDMS 625 (M+); Anal. Calcd for C38H44N2O4S 2-5C2H2~4 3- 2 C, 56.91; H,6.15; N, 3.09. Found: C, 56.61; H, 5.80; N, 3.47.
~art H. (+)-4-Hydroxy-3- 14- ~ ~trans-2- ( l-piperidyl)-cyclohexyl]oxy]benzyl]-2 - ~4 - 12 - ( l-pyrrolidinyl)-~sthoxy~phcnyl~bonzorb~thiophon~.
OH ~
~ N
The title compound was prepared in 24% yield by essentially following the procedures outlined in Example 21, Part A from the ketone (Part G).
FDMS 610 (M+).
Part I. (+)-4-Hydroxy-3- ~4- ~ l trans-2- ( l-piperidyl)-cyclohexyl~oxy]benzyl] -2- ~4- ~2- ( l-pyrrolidinyl)-ethoxy]phenyl]benzolb]thiophone Dioxalate.
W O 97/25033 PCT~US96/17995 The title compound was prepared by essentially ~ollowing the procedure outlined in Example 21, Part C from the ~ree base (Part H).
FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S 2.1C2H204 3.3H20:
C, 58.98; H, 6.66; N, 3.26. Found: C, 58.70i H, 6.32; N, 3.28.
~,~r _ le 93 Preparation of 5-Methoxy-3-E3-methoxy-4~
pyrrolidinyl)methyllbenzyl~-2-14- r2- (l-pyrrolidinyl)-ethoxy]phQnyllbenzolblthiophene Dioxalate.
~ N ~
Part A. 5-Mothoxy-2-~4-~2-(1-pyrrolidi~yl)ethoxy]-phenyl]benzolb]thiophen-3-yl 3-Methoxy-4~
~yrroli~inyl)methyl]phenyl Ketone Dioxalat~.
~_ z c2H2~4 <~
The free base of the title compound was prepared in 37%
yield by essentially ~ollowing the procedures outlined in Example 41; Part C ~rom 5-methoxy-2-[4-[2-(l-pyrrolidinyl~-ethoxy]phenyl]benzo[b]thiophene (Example 71, Part C) and 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoic acid (Example 41, Part B). The title compound was prepared by essentially CA 02236007 l998-04-27 W 097/25033 PCT~US96117995 following the procedures outlined in Example 21, Part C from the free base.
-FDMS 571 (M+); Anal. Calcd for 5 C34H38N2O4S-2.0C2H204-0.48C4H802: C, 60.46; H, 5.83; N, 3.53. Found: C, 60.57; H, 6.08; N, 3.58 Part B. 5-Methoxy-3-[3-methoxy-4-(1-~1lolidinyl-methyl)benzyl]-2-14-12-(1-pyrrolidi~yl)ethoxy]phenyl]-benzo~b]thiophene Dioxalate.
I~he free base of the title compound was prepared in 68%yield by essentially following the procedures in Example 21, Part A from the free base of ketone (Part A). The title compound was prepared by essentially following the procedures in Example 21, Part C from the free base.
Free base: FDMS 557 (M+); Anal. Calcd ~or C34H40N2O3S: C, 73.35; H, 7.24; N, 5.03. Found: C, 73.49; H, 7.12; N, 5.03.
Dioxalate: FDMS 557 (M+); Anal. Calcd for C34H40N2O3S 1-7c2H2o4 0-5C4H8o2 C, 62-77i Found: C, 62.63; H, 6.73; N, 3.97.
~ le 94 Preparation of 1-12- 12-Fluoro-4- 112-14-12- (1-pyrro-li~inyl)ethoxy]phenyl~benzolb]thiophen-3-yl]methyl~-l?h9~oxy]ethyl]~yrrolidine Dioxalate.
A O'' ~ -'N
W O 97~5033 PCT~US96/17995 Part A. 3~4-Difluoro~henyl 2-L4-12-(1-Pyrrolidinyl)-ethoxy]phenyl~benzolb]thiophen-3-yl Ketone.
~'o ~ ~N ~
A slurry oE 3.23 g (10 mmol) o:E 2- [4-[2-(1-pyrro-lidinyl)ethoxy)phenyl]benzo[b]thiophene in 50 mL of 1,2'dichloroethane was treated with 1.76 g (10 mmol) of 3,4-di~luorobenzoyl chloride at 0 ~C. The mixture was protected ~rom light and 4.4 mL (40 mmol) TiC14 was added dropwise. The reaction was stirred at 0 ~C for 5 h at which time it was quenched by carefully pouring it into 400 mL o~
saturated aqueous NaHCO3. To this was added EtOAc (200 mL), and the two layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give a crude oil which was puri~ied by chromatography (sio2; 2%
MeOH in CHCl3) to afford 1.7 g (3.7 mmol; 37%) of the ketone as a VlSCOUS oil.
lH NMR (CDCl3) ~ 7.87-7.75 (m, 2H), 7.63-7.56 (m, lH), 7.48-7.31 (m, 3H), 7.30-7.25 (m, 2H), 7.03-6.94 (m, lH), 6.79-6.75 (m, 2H), 4.1 (t, 2H), 2.8 (t, 2H), 2.7-2.5 (m, 4H), 1.84-1.80 (m, 4H); FDMS 463 (M+); Anal. Calcd for C27H23F2N02S-1-08C~C13: C, 56.93; H, 4.1i N, 2.36. Found: C, 56.90; H, 4.05; N, 2.45.
Part B. 3-Fluoro-4-C2-t~ r Loli~inyl) ethoxy~phenyl 2-14-12-(1-Pyrroli~inyl)othoxyphenyllb~nzolb~thio~hen-3-yl ~etono.
W O 97/25033 PCTnUS96/17995 ~, A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was rinsed with hexanes and dried under reduced pressure. To this was added 30 mL o~ dry THF, followed by 1.1 g (9.8 mmol) of 1-(2-hydroxyethyl)pyrrolidine. After gas evolution had ceased, a solution of 2.27 g (4.90 mmol) of the 3,4-difluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]-benzo[~]thiophen-3-yl ketone in 30 mL of THF was added. The reaction was stirred under a nitrogen atmosphere for 3 h at ambient temperature after which it was poured into a mixture of 100 mL of brine and 60 mL of EtOAc. The layers were separated and the aqueous layer was extracted with 30 mL of EtOAc. The combined organic layer was washed with brine (2 X
100 mL), dried over Na2S04, and concentrated under reduced pressure to give 3.2 g of an oil. This was purified twice by chromatrography (SiO2i 50/45/5% THF/Hex/Et3N; tllen 5% CHCl3 in MeOH) to afford 1.6 g (2.9 mmol; 58~) of the desired compound as a viscous oil.
20 1H NMR (CDC13) ~ 7.87-7.84 (m, lH), 7.69-7.66 (m, lH), 7.58-7.54 (m, lH), 7.50-7.47 (m, lH), 7.38-7.26 (m, 3H), 6.81-6.75 (m, 4H), 4.15 (t, 2H), 4.06 (t, 2H), 2.91-2.86 (m, 4H), 2.62-2.61 (m, 8H), 1.82-1.77 (m, 8H); FDMS 461 (M-97), 559 (M+l);
Anal. Calcd for C33H3sFN2O3S 1.45CHCl3: C, 56.54; H, 5.02; N, 25 3.83. Found: C, 56.45; H, 5.0; N, 3.87.
100 mg was converted to the dioxalate salt.
~ Anal. Calcd for C33H3sFN2O3S 2 C2H2O4-1 H2O: C, 58.72; H, 5.46; N, 3.70. Found: C, 58.46; H, 5.06; N, 3.32.
W O 97/25033 PCTnUS96/17995 Part C. 1-12-~2-Fluoro-4~1~2-~4-~2-(1-pyrrolidinyl)-Qthoxy]phenyl]benzo~b]thio~hen-3-yl]~ethyl]phenoxy~-othylJ~y r lolidine Dioxalate.
A solution of 1.1 g (2 mmol) of 3-fluoro-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-~1-pyrrolidinyl)ethoxy-phenyl]benzo[b]thiophen-3-yl ketone in 25 mL of THF at 0 ~C
was treated with 10 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 30 min and was ~uenched by the addition of 5 mL of EtOAc and concentrated in vacuo. The resulting residue was immersed in an ice bath, then cautiously treated with 10 mL of TFA, followed by 186 mg (5 mmol) of NaBH4. The reaction was stirred ~or 2 h, then evaporated in vacuo. The residue was taken up in 50 mL of 5 N NaOH and extracted with CH2C12 (2 X 30 mL). The combined extracts were dried over Na2SO4 and evaporated in vacuo to give 900 mg of an oil. Purification by chromatography (MPLC
Sio2; 60/35/5 THF/Hex/TEA) afforded 135 mg (0.25 mmol, 12%) o~ the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
lH NMR (CDC13) ~ 7.95-7.85 (m, lH), 7.75-7.7 (m, lH), 7.6-7.65 (m, lH), 7.55-7.5 (m, lH), 7.45-7.38 (m, 4H), 7.05 (s, lH), 6.85-6.8 (m, 2H), 5.05 (s, 2H), 4.20 (t, 2H), 4.1 (t, 2H), 3.0-2.9 (m, 4H), 2.7-2.6 (m, 8H), 1.8-1.9 (m, 8H); Anal.
Calcd for C33H37FN202S-1.65 C2H2O4: C, 62.89; H, 5.86; N, 4.04. Found: C, 62.93; H, 6.05; N, 4.00.
Example 95 Preparation of 1-~2-~4-~2-~4-12-(1-~y r olidinyl)-ethoxy]p~enyl~benzo~blthiophen-3-yllmethyll-2-tri~luoromethylphenoxy]ethyl]pyrrolidine Dioxalate.
WO 97/25033 PCTn~S96/17995 N ~ 2C2HaO4 ~ ~N ~
Part A. 4-Fluoro-3-trifluoromethylphenyl 2-~4-~2-(1-Pyrroli~inyl)~thoxy~ph~nyl~b~nzo[b]thiophen-3-yl ~tone.
J
"~--'N
~
A slurry o~ 8 g (38.4 mmol) of 4-fluoro-3-trifluoromethyl benzoic acid in 30 mL of dichloromethane and 2 drops of DMF
was treated with 6.70 mL (76.9 mmol) of (COCl)2 and the mixture was stirred at ambient temperature for 4 h. The resulting solution was evaporated in vacuo, and the residual oil was distilled under reduced pressure to yield 7.2 g (31.8 mmol, 83%) of the acid chloride as a colorless oil.
A solution of 3.38 g (10.45 mmol) of 2-[4-[2-(1-pyrro-lidinyl)ethoxy)phenyl]benzo[b]thiophene was dissolved in 200 mL of 1,2-dichloroethane and treated with 2.4 g (10.45 mmol) of the above acid chloride at 0 ~C The reaction was protected ~rom light and 4.4 mL (39.8 mmol) TiC14 was added dropwise. The reaction was stirred at ambient temperature for 4 h at which time it was quenched by carefully pouring it into 500 mL of saturated aqueous NaHCO3. EtOAc (400 mL) was added and the two layers were separated. The a~ueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give an oil which was purified by chromatography (sio2i 78/20/2% Hex/THF/Et3N) to afford 3.64 g (7.1 mmol; 68%) of the ketone as a solid.
lH NMR (CDC13) ~ 7.95-7.85 (m, 3H), 7.45-7.35 (m, 3H), 7.30-7.2 (m, 2H), 7.1-7.00 (m, lH), 6.79-6.72 (m, 2H), 4.05 (t, 2H), 2.85 (t, 2H), 2.7-2.5 (m, 4H), 1.85-1.75 (m, 4H); FDMS
514 (M+1); Anal. Calcd for C2gH23F4NO2S: C, 65.89; H, 4.51;
N, 2.73. Found: C, 65.75; H, 4.68; N, 2.78.
Part B. 2-[4-[2-(1-Pyrroliainyl)ethoxyphenyl]-:benzo~b]thiophen-3-yl 4-~2-(1-Pyrrolidinyl)ethoxy]-3-tri:~luorophenyl Ketone.
''"--'N ~
A 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol) was rinsed with hexanes and dried under reduced pressure. To this was added 25 mL of dry DMF followed by 1.35 g (11.7 mmol) 1-(2-hydroxyethyl)pyrrolidine. After gas evolution had ceased, a solution of 3 g (5.8 mmol) of 4-fluoro-3-trifluoromethylphenyl 2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl ketone in 30 mL of DMF
was added. The reaction was stirred under a nitrogen atmosphere overnight at ambient temperature, after which it was poured into a mixture of 100 mL of brine and 60 mL of EtOAc. The layers were separated and the a~ueous layer was extracted with 30 mL of EtOAc. The combined organic layer was washed with brine (2 X 100 mL), dried over Na2SO4, and concentrated under reduced pressure to 3.8 g of an oil. This was purified by chromatrography (SiO2; 5% MeOH/1~ NH40H in WO 97/25033 PCT/US96~1799~;
CHC13) to afford 3.07 g (5 mmoli 87%) of the named compound as a viscous oil.
-FDMS 609 (M+1) 5412 mg was converted to the dioxalate salt.
lH NMR (DMSO-d6) ~ 8.1 (d, lH), 8.0-7.9 (m, 2H), 7.65 (d, lH), 7.5-7.4 (m, 2H), 7.4-7.3 (m, 2H), 7.15 (d, lH), 6.9-7.0 (d, 2H), 4.55 (bs, 4H), 4.55-4.4 (m, 2H), 4.2-4.3 (m, 2H), 3.4-3.6 (m, 4H); 3.1-3.3 (m, 8H), 1.8-1.95 (m, 8H); Anal.
Calcd for C34H3sF3N2O3S 1.5C2H2O4: C, 59.75; H, 5.15; N, 3.77. Found: C, 59.61; H, 5.16; N, 3.80.
Part C. 1-12-[4-[[2-[4-[2-(1-Pyrrolidinyl)ethoxy~-phenyllbenzolb]thio~hen-3-yllmethyl~-2-trifluoro-methyl~henoxy3ethyl~ olidine Dioxalate.
A solution of 1 g (1.64 mmol) of the 2-[4-[2-(1-pyrro-lidinyl3ethoxyphenyl]benzo[~]thiophen-3-yl 4-[2-(1-pyrro-lidinyl)ethoxy]-3-trifluorophenyl ketone in 30 mL of THF at 0 ~C was treated with 9 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 1 h and was quenched by the addition of 5 mL of EtOAc and concentrated in vacuo. The resulting residue was immersed in an ice bath then cauiously treated with 10 mL of TFA followed by 124 mg (3.30 mmol) of NaBH4. The reaction was stirred for 2 h then evaporated in vacuo. The residue was partitioned between saturated a~ueous NaHCO3 (25 mL) and CHCl3 (50 mL). The layers were separated and the aqueous layer was extracted with CHCl3 (3 X 30 mL).
The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 1.1 g of an oil. Purification by chromatography (SiO2; 2% MeOH in CHCl3) afforded 353 mg (0.59 mmol 36%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
1H NMR (Free Base-CDCl3) ~ 7.84-7.81 (m, lH), 7.48-7.45 (m, lH), 7.4-7.31 (m, 3H), 7.31-7.15 (m, 2H), 7.15-7.11 (m, lH), 6.93-6.98 (m, 2H), 6.82 (d, lH), 4.2 (s, 2H), 4.15-4.1 (m, 4H), 2.95 (t, 4H); 2.65-2.55 ~m, 8H), 1.85-1.75 (m, 8H);
Anal. Calcd for C3gH41F3N2O1oS: C, 58.91; H, 5.33; N, 3.62.
Found: C, 58.80; H, 5.27; N, 3.57.
~.YA _ le 96 Preparation of 3-Nitro-4-~2-(1-~lidinyl)ethoxy]-phenyl 2-14-~2-(1-~y lolidinyl)ethoxyphenyl]benzo~b]-thiophen-3-yl Ketone Dioxalate.
q N ~ 2C~H204 ~ 'N
~/
Part A. Methyl 3-Nitro-4-~2-(1-y~lLolidinyl)ethoxyl-bonzoate ~yarochlori~e.
N~ "~o, ~HCl A mixture of 32 g (162.4 mmol) of methyl 4-hydroxy-3-nitrobenzoate, 51.13 g (194.9 mmol) of triphenylphosphine, 22.45 g (194.9 mmol) of 1-(2-hydroxyethylpyrrolidine), and 600 mL of CH2C12 was cooled to 0 ~C and treated with 33.95 g of (194.9 mmol) diethyl azodicarboxylate. The cooling bath was removed and the reaction was stirred at ambient temperature for 16 h. It was concentrated to dryness under reduced pressure, mixed with 200 mL of CHC13 and filtered.
The filtrate was chromatographed (sio2; 3% MeOH in CHCl3) to give 14.63 g of product still contA~;nAted with methyl 4-hydroxy-3-nitrobenzoate. It was dissolved in 200 mL of EtOAc and treated with HCl gas for 2 min. The resulting W097/25033 PCT~Sg6/17995 solid was filtered to yield 11.81 g (36 mmol, 22%) of the HCl salt of the named product.
-1H NMR (DMSO-d6 ) ~ 10 . 85-11 (bs, 1H), 8.45 (d, 1H), 8.25 (dd, lH), 7.58 (d, lH), 4.65 (t, 2H), 3.9 (s, 3H), 3.7-3.55 (m, 4H), 3.05-3.4 (m, 2H); 2.1-1.8 (m, 4H); FDMS 294 (M+); Anal.
Calcd for C14HlgN2Os-HCl: C, 50.84; H, 5.79; N, 8.47. Found:
C, 50.84; H, 5.70; N, 8.62.
Part B. 3-Nitro-4-[2-(1-pyrrolidinyl)ethoxy]benzoic A~id Hydrochloride.
''"~'o ~ OH
~HCl NO2 Methyl 3-nitro-4-E2-(1-pyrrolidinyl)ethoxy]benzoate (5.9 g, 20 mmol) was mixed with 60 mL o~ 5 N aqueous HCl and refluxed 16 h. It was mixed with toluene/EtOH and concentrated under reduced pressure to dryness. The resulting solid was tritrated with hot EtOAc to afford 5.7 g (18 mmol, 90%) of the benzoic acid hydrochloride.
20 1H NMR (DMSO-d6) ~ 8.36 (d, lH), 8.22(dd, lH), 7.45 (d, lH), 4.21 (t, 2H), 3.65-3.4 (m, 5H), 3.0-3.2 ~m, 3H), 2.1-1.7 (m, 4H); FDMS 280 (M+); Anal. Calcd ~or C13H16N2Os HCl 0.11toluene: C, 50.60; H, 5.50; N, 8.47.
Found: C, 50.60; H, 5.51; N, 8.57.
Part ~. 3-Nitro-4-12-(1-~ Lolidinyl)ethoxylphenyl a - t4-12-(1-Pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl Ketone Dioxalate.
A mixture of 2 g (6.3 mmol) of 3-nitro-4-[2-(1-pyrro-30 lidinyl)ethoxy]benzoic acid hydrochloride, 20 mL of SOCl2, 50 A- mL of 1,2-dichloroethane and 2 drops of DMF was heated at reflux for 16 h then evaporated in vacuo to dryness. The resulting solid was dissolved in 50 mL o~ 1,2-dichloroethane W097/25033 pcT/us96ll7sss -254~
and concentrated under reduced pressure. It was redissolved in 50 mL of 1,2-dichloroethane and treated sequentially with a solution of 2 g (6.2 mmol) of 2-[4-[2-(1-pyrrolidinyl)- ~
ethoxy]phenyl]benzo[b]thiophene in 150 mL of 1,2-dichloroethane and 3.3 g (24.7 mmol) of AlC13 at 0 ~C. The reaction was protected from light and stirred at 0 ~C ~or 5 h at which time it was quenched by carefully pouring it into 200 mL of vigorously stirred saturated aqueous NaHCO3. A
solution of 200 mL of EtOAc and 400 mL o~ THF was addea and the mlxture was filtered through diatomaceous earth and the two layers were separated. The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to gi~e an oil which was purified by chromatography (sio2; 10~ MeOH
in CHC13) to afford 1.26 g (2.2 mmol; 36%) of the desired compound as an oil. A sample of 200 mg was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free Base-CDCl3) ~ 8.17 (d, lH), 7.93 (dd, lH), 7.87 (dd, lH), 7.81-7.78 (m, lH), 7.41-7.38 (m, 2H), 7.31-7.27 (m, 2H), 6.93 (d, lH), 6.78-6.75 (m, 2H), 4.22 (t, 2H), 4.04 (t, 2H), 2.92 (t, 2H), 2.86 (t, 2H), 2.61-2.58 (m, 8H~, 1.81-1.76 (m, 8H); FDMS 586 (M+l); Anal. Calcd for C33H35N305S-2C2H204:
C, 58.03; H, 5.13; N, 5.49. Found: C, 58.30; H, 5.13; N, 5.74.
_le 97 Proparation o~ 3-Amino-4- r2- (l-pyrrolidinyl)ethoxy}-phenyl 2-[4-~2-(1-Pyrrolidinyl)e'choxyphenyl]-30 bonzo[}~ thiophen-3-yl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 ~>
~ ~N ~ 2C2H204 A solution o~ 3-nitro-4-[2-(l-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone (O.57 g 1 mmol) in 10 mL of EtOH and 10 mL of HOAc was hydrogenated in a shaken hydrogenation apparatus ~or 60 h with 0.5 g of 5% Pd/C and an initial hydrogen pressure of 4.1 bar. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to an oil. This was partitioned between 10 mL of saturated aqueous NaHC03 and a 70/30 mixture of EtOAc and MeOH. The organic layer was dried over Na2S04 and concentrated in vacuo to an oil which was purified by chromatrography (siO2; 5% MeOH/1% NH40H in CHC13) to afford 0.26 g (0.47 mmol; 47%) o~ the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
lH NMR (Free Base-CDCl3) ~ 7.82-7.79 (m, lH), 7.57-7.55 (m, lH), 7.37-7.30 (m, 2H), 7.29-7.26 (m, 3H), 7.12-7.08 (m, lH), 6.78-6.75 (m, 2H), 6.58 (d, lH), 4.07 (t, 2H), 4.04 (t, 2H), 4.00 (bs, 2H), 2.88-2.81 (m, 4H), 2.59-2.55 (m, 8H), 1.79-1.74 (m, 8H); FDMS 556 (M+l); Anal. Calcd ~or C33H37N303S-0.6C2H204-1.8 MeOH: C, 56.69; H, 5.87; N, 4.95.
Found: C, 55.98i H, 5.88; N, 5.24 F.YA 1~ 98 Pre~ration of 1-12-[2-Nitro-4-112-14-12-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl3-methyl]p~oxy]ethyl]pyrroli~ine Dioxalate.
W O 97/25033 PCT~US96/17995 ~ 2 c ~H2o4 A solution of 5.7 g (9.7 mmol~ of 3-nitro-4-~2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy-phenyl]benzo[b~thiophen-3-yl ketone in 200 mL of CH2C12 at 0 ~C was treated with 49 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 1 h then concentrated in vacuo to an oil. The resulting residue was immersed in an ice bath then cautiously treated with 25 mL of TFA dropwise, followed by 736 mg (19.5 mmol) of NaBH4. The reaction was stirred for 30 min then evaporated in vacuo . The residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (300 mL). Aqueous 5 N NaOH (50 mL) was added, and the layers were separated. The a~ueous layer was extracted with EtOAc (3 X 100 mL). The combined organic layers were dried over Na2SO4 and evaporated in ~acuo to give 8 g o~ an oil Purification by chromatography (sio2i 2~ MeOH in CHCl3) af~orded 3.1 g (5.4 mmol 56%) of the title compound as an oil which was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free Base-CDC13) ~ 7.85-7.82 (m, lH), 7.62 (d, lH), 7.46-7.43 (m, lH), 7.38-7.29 (m, 4H), 7.20 (dd, lH), 6.97-6.91 (m, 3H), 4.22 (s, 2H), 4.19-4.12 (m, 4H), 2.92 (t, 4H), 2.65-2.60 (m, 8H), 1.84-1.76 (m, 8H); FDMS 572 (M+l); Anal.
Calcd ~or C33H37N3O4S-2C2H2O4: C, 59.11; H, 5.50; N, 5.59.
Found: C, 59.40; H, 5.46; N, 5.87 W O 97/25033 PCr~US96/17995 ~rle g g Preparation of l-t2-[2-A ;no-4-[t2-t4-[2~(1-- ~yrroli~inyl)ethoxy]phonyl~benzotb~thiophen-3-yl]-methyl]phenoxy]ethyl~pyrroli~ine Dioxalate.
N ~
O~ 'N 2C2H204 ~
The title compound was prepared in 36% yield from 1-[2-[2-nitro-4-[[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b3thiophen-3-yl]methyllphenoxy]ethyl]pyrrolidine by essentially following the procedure detailed ~or the preparation of Example 97.
Anal. Cal~d for C33H3gN302S 2C2H204 0.95 MeOH: C, 60.59; H, 6.27; N, 5.59. Found: C, 60.62; H, 6.12; N, 5.30 ~Y~ _le 100 Preparation of 3-Bromo-4-t2-(1-pyrroli~inyl)ethoxy]-phenyl 2-{4-t2-(1-Pyrrolidi~yl)ethoxyphenyl]benzotb]-thiophen-3-yl Ketone Dioxalate.
N
" "-'N ~ 2C2H20~
Part A. 3-Bromo-4-methoxyph~nyl 2-(4-Methoxyphenyl)-benzo~b]thiophen-3-yl Keton~.
W O 97/25033 PCT~US96/17995 ~ 3 A slurry of 13.35 g (58 mmol) o~ 3-bromo-4-methoxybenzoic acid in 120 mL of 1,2-dichloroethane and 1 mL of DMF was treated with 8.4 mL (116 mmol) of SOC12 and the mixture was heated at re~lux Eor 16 h. The resulting solution was evaporated in vacuo to an oil which was mixed with 50 mL o~
1,2-dichloroethane and reconcentrated under reduced pessure.
A solution of the above oil in 120 mL o~ 1, 2 -dichloro-ethane was treated with 13.86 g (58 mmol) of 2-[4-methoxy)-phenyl]benzo[b]thiophene. The mixture was cooled to 0 ~C,protected ~rom light and treated with 25 mL (228 mmol) of TiC14 dropwise. The reaction was stirred at 0 ~C for 3 h at which time it was quenched by the care~ul addition o~ 100 mL
of saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with saturated a~ueous NaHCO3.
It was dried over Na2SO4 and evaporated in vacuo to give 28 g of a solid which was purified by chromatography (SiO2; 50%
CHC13 in Hex) to afford 17.13 g (37.81 mmol; 65%) of the ketone as a solid.
H MMR (CDCl3) ~ 8.03 (d, lH), 7.88-7.85 (m, lH), 7.72-7.67 (m, 2H), 7.38-7.33 (m, 4H), 6.81-6.71 (m, 3H), 3.88 (s, 3H), 3.76 (s, 3H).
P~rt B. 3-Bromo-4-hydroxyphenyl 2-(4-Hyd oxy~henyl)-benzo ~b~ thio~hen-3-yl Ketone .
W O 97~5033 PCTAUS96/17995 ~ OH
A 0 ~C solution of 6.5 g (14.3 mmol) of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone in 300 mL of dichloromethane was treated with 15.3 g (115 mmol) o~ AlCl3, followed by 17 mL (230 mmol) of ethanethiol.
The cold bath was removed and the reaction was stirred at ambient temperature for 3.5 h. The reaction mixture was cooled to 0 ~C and poured into cold water. The layers were separated and the a~ueous layer was extracted with EtOAc (2 X
150 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 5.9 g (13.9 mmol, 97%) of an oil which crystallized out when mixed with CH2C12.
lH NMR (DMSO-d6) ~ 11.4 (bs, 2~), 8.1-8.05 (m, lH), 7.8 (d, lH), 7.62-7.5 (m, 2H), 7.45-7.35 (m, 2H), 7.25 (d, 2H), 6.85 (d, lH), 6.75 (d, 2H); FDMS 425.8 (M+l).
Part C. 3-Bromo-4-~2-(1-~yrrolidinyl)ethoxy]phenyl 2-~4-12-(1-Pyrrolidinyl)ethoxyphenyl~benzo[b]thiophen-3-yl Ketone Dioxalate.
A solution of 1 g (2.4 mmol) of the above bis-hydroxy-benzothiophene in 25 mL of DMF was treated with 1.6 g (9.6 mmol) of l-(2-chloroethyl)pyrrolidine hydrochloride followed by 4.7 g (14.4 mmol) of Cs2C03. The mixture was heated to 85 ~C for 16 h at which time it was cooled and poured into 100 ~L of brine and extracted with EtOAc (3 X 50 mL). The combined organic layers were dried over MgSO4 and evaporated to give 1.1 g of an oil which was purified by radial chromatography (sio2; 60:35:5 hexanes-THF-TEA) to afford 0.68 g (1.1 mmol; 46~) of an oil. The oil was converted to the dioxalate salt according to the method of Example 1, Part C.
1H NMR (Free Base-CDCl3) ~ 8.31 (d, lH), 7 84 (dd, lH), 7.71-7.68 (m, lH), 7.65 (dd, lH), 7.38-7.32 (m, 3H), 6.98 (s, lH), 6.8-6.77 (m, 2H), 6.69 (d, lH),4.13 (t, 2H), 4.05 (t, 2H), 2.93 (t, 2H), 2.86 (t, 2H), 2.67-2.57 (m, 8H), 1.81-1.76 (m, 8H); FDMS 619 (M+).
~le 101 Preparation of 1-~2-~2-Bromo-4-[~2-~4-~2-~1-pyrrolidinyl)~thoxy~phQnyl~bQnzo~b~thiophQn-3-yl]-methyl~phe~ry]~thyl~ olidine Dioxalate.
N ~
o 2C2H2O4 ~ ~N ~
To a solution of 83 mg (2.20 mmol) of LAH in 20 mL of dry THF was added dropwise a solution o~ 0.68 g (1.1 mmol) of 3-bromo-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone in 15 mL o~ dry THF at 0 ~C. The reaction was stirred at ambient temperature for 2 h then quenched with 5 mL of EtOAc and poured into 100 mL of brine. The mixture was extracted with 150 mL o~ 20% MeoH in EtOAc. The extracts were dried over MgSO4 and concentrated to 537 mg of an oil.
The resulting oil was mixed with 10 mL of TFA, cooled to 0 ~C and treated with 65 mg (1.73 mmol) o~ NaBH4. The cooling bath was removed and the reaction was stirred for 16 h. It was evaporated in vacuo and partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (30 mL). The layers were separated and the a~ueous layer was extracted with EtOAc (3 X 20 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to give 450 mg o~ an oil. Purification by chromatography (SiO2; 1% MeOH/0.5~
CA 02236007 l998-04-27 WO 97/25033 PCTfJSg6/17995 NH40H in CHCl3) afforded 122 mg (0.2 mmol 23%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Par~ C.
FDMS 605 (M+).
~ Y~rle 102 Preparation of 1-[2-12-MQthoxy-4-~2-[4-12-(1-pyrrolidin~l)ethoxy~ph~nyl]b~nzo~b~thioph~n-3-yl]-methyllphenoxylethyl~yrroli~ ne Dioxalate.
'' " ~'N
Part A. Methyl 3-~ethoxy-4 12-(1-~. olidinyl)-Qthoxy] benzoatQ .
The substituted pyrrolidine was prepared in 94% yield from methyl 4-hydroxy-3-methoxybenzoate and K2C03 by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR (CDC13) ~ 7.63 (d, lH), 7.53 (s, lH), 6.9 (d, lH), 4.2 (t, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.96 (t, 2H), 2.64-2.61 (m, 4H), 1.85-1.75 (m, 4H); FDMS 279 (M+).
Part B. 3-~ethoxy-4-12-(1-~yrrolidinyl)ethoxy]benzoic Acid Hydrochloride.
W O 97/25033 PCT~US96/1799 N~ " ~o ~ OH
~HCl OCH3 The benzoic acid hydrochloride was prepared in 63% yield from methyl 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]benzoate by essentially following the procedure detailed for the preparation of Example 96, Part B.
H N ~ (DMSO-d6) ~ 11.27 (bs, 2H), 7.57 (d, lH), 7.55 (5, lH), 7.12 (d, lH), 4.44 (t, 2H), 3.82 (s, 3H), 3.5 (bs, 4H), 3.1 (bs, 2H); 1.98 (bs, 2H), 1.89 (bs, 2H); Anal. Calcd for C14HlgNO4 HCl: C, 55.72; H, 6.68; N, 4.64. Found: C, 56.01;
H, 6.88i N, 4.70.
Part C. 3-Methoxy-4-[2-~1-pyrrolidinyl)ethoxy~phenyl 2-~4-~-(1-Pyrrolidinyl)etho~yphenylbenzol~thiophen-3-yl Ketono.
~ ~N ~
The ketone was prepared in 33% yield from 3-methoxy-4-[2-(l-pyrrolidinyl)ethoxy]benzoic acid hydrochloride by essentially following the procedure detailed for the preparation of Example 96, Part C.
1H MMR (Free Base-CDCl3) ~ 7.86-7.83 (m, lH), 7.67-7.64 (m, lH), 7.49 (d, lH), 7.38-7.26 (m, 5H), 6.8-6.76 (m, 2H), 6.67 (d, lH), 4.12 (t, 2H), 4.06 (t, 2H), 3.83 (t, 3H), 2.94 (t, W O 97~5033 PCTnJS96/t7995 2H), 2.88 (t, 2H), 2.62-2.58 (m, 8H), 1.81-1.76 (m, 8H); FDMS
570 (M+).
., Part D. 1-[2-~2-M~thoxy-4-l~2-[4-~2-(1-pyrrolidinyl)-ethoxy]phenyl]benzotb]thiophen-3-yllmethyl]phenoxyJ-ethyl~pyrrolidinQ Dioxalat~.
The title compound was prepared in 10~ yield from 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzorb]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
H NMR (Free Base-CDC13) ~ 7.98-795 (m, lH), 7.64-761 (m, lH), 7.50 (d, 2H), 7.36-7.33 (m, 2H), 7.12 (d, 2H), 6.87-6.84 (m, 2H), 6.51 (d, lH), 6.2 (bs, 4H), 4.34 (t, 2H), 4.20 (s, 2H), 4.16 (t, 2H), 3.68 (s, 3H), 3.5 (t, 2H), 2.86 (t, 2H), 2.67-2.57 (m, 8H), 2.0-1.9 (m, 8H); FDMS 557 (M+l); Anal.
Calcd for C34H40N2O3S 2C2H2O4: C, 61.94; H, 6.02; N, 3.80.
Found: C, 62.23; H, 6.09; N, 3.89.
~ Y~ _le 103 Preparation of 3-Hydroxy-4-C2-(~ olidinyl)-Qthoxy~phenyl 2-[4-~2-(1-Pyrrolidinyl)ethoxyphenyl]-benzotb]thiophQn-3-yl Ketone Dioxalate.
OH
M ~ 2C2H2O4 ''"--'N
The title compound was prepared in 83% yield from 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-~4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part B.
Anal. Calcd for C33H36N204S 2C2H204 1.25H20: C, 58.53; H, 5.64; N, 3.69. Found: C, 58.42; H, 5.27; N, 3.86.
Example 104 Preparation of 1-[2-c2-Hy~roxy-4-[[2-~4-l2-(l-pyrrolidinyl)ethoxylphQnyllb~nzolblthiophan-3-yll-methyl]ph~noxy]ethyll~y olidine Dioxalat~.
OH
¦ ~ ~ N ~ 2C2H2O4 ''~'~'N ~
The title compound was prepared in 29% yield from 3-hydroxy-4- [2- (1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[~]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 95, Part C.
FDMS 541.9; Anal. Calcd for C33H3gN203S-1.75C2H204: C, 62.6;
H, 5.97; N, 4.00. Found: C, 62.44; H, 6.09; N, 4.11.
~Yr~ 1Q 105 Pr~l?aration of 3-Propyl-4-[2-(1~ olidinyl)ethoxy]-phenyl 2-t4-12-(1-Pyrrolidinyl)ethoxyphenyl]-benzolblthio~hen-3-yl Ketono Dioxalate.
N ~ 2C2H204 ''~'--'N ~
W O 97/25033 PCT~US96/1799 Part A. 2-(4-Methoxyphenyl)benzolb~thiophen-3-yl 4-M~3thoxy-3-propylphenyl Ketone.
O
' 3 A mixture of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl ketone (1 g, 2.2 mmol), tetrapropyltin ~1.6 g, 5.5 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) and toluene (20 mL) was heated in a sealed tube at 130 ~C for 18 h. The mixture was concentrated under reduced pressure, mixed with 30 mL of diethyl ether and stirred vigorously with 30 mL saturated aqueous KF for 2 h.
The layers were separated and the organic layer was dried over MgSO4 then concentrated to dryness. Purification by chromatography (sio2; 45~ ClCH2CH2Cl in Hex) afforded 0.88 g (2.1 mmol 96%) of the propyl compound as a solid.
FDMS 416 (M+); Anal. Calcd for C26H24O3S H2O: C, 71.86; H, 6.03. Found: C, 71.46; H, 5.82.
Part B. 2-(4-Hydroxyphenyl)benzo[b]thiophen-3-yl 4-Hydroxy-3-propylphenyl Ketone.
o~
OH
The named compound was prepared in quanitative yield from 2- ~4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxy-3-propyl-W O 97/25033 PCT~US96/17995 phenyl ketone by essentially following the procedure detailed ~or the preparation o~ Example 100, Part B.
FDMS 388 (M+); Anal. Calcd for C24H2003S-0.72CHCl3: C, 62.69;
H, 4.44. Found: C, 62.58; H, 4.4.
Part C. 3-~ o~yl-4-12-(1-~y olidinyl)ethoxylphenyl 2-14-[2-(1-Pyrrolidinyl)Qthoxyphenyl]b~nzo[blthioph~n-3-yl Ketone Dioxalate.
The title compound was prepared in 69% yield from 3-propyl-4-hydroxyphenyl 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR ~Free base-CDCl3) ~ 7.86-7.83 (m, lH), 7.67-7.58 (m, 3H), 7.38-7.32 (m, 4H), 6.79-6.76 (m, 2H), 6.66 (d, lH), 4.09 (t, 2H), 4.03 (t, 2H), 2.89 (t, 2H), 2.85 (t, 2H), 2.62-2.59 (m, 8H), 2.51-2.46 (m, 2H), 1.79-1.65 (m, 8H), 1.52-1.44 (m, 2H~, 0.84 (t, 3H); FDMS 583 (M~l); Anal. Calcd ~or C36H42N203S-2C2H204-0.15CCl4: C, 71.66; H, 6.99; N, 4.62.
Found: C, 71.85; N, 7.23; N, 4.23.
~.Y~m~le 106 Pr~aration of 3-Ethyl-4-t2-(1-~ olidinyl)ethoxyl-phenyl 2-t4-t2-(1-Pyrrolidirlyl)ethoxyphenyl]-bcnzolb]thiophQn-3-yl Ketone Dioxalate.
2C~H~04 "~'--'N ~
Part A. 3-Ethyl-4-methoxyphenyl 2-(4-Methoxy~henyl)-~nzolb]thiophQn-3-yl K~tone.
O ~
The ethyl compound was prepared in 45% yield ~rom 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone and tetraethyltin by essentially following the procedure detailed for the preparation of Example 105, Part A.
Anal. Calcd for C25H22O3S: C, 74.6; H, 5.51. Found: C, 74.9;
N, 5.65.
~?art B. 3-Ethyl-4-hyd~y~henyl 2-(4-Hydroxyphenyl)-benzolb]thiophQn-3-yl Ketone.
~ OH
~\>~
OH
The named compound was prepared in 96% yield from 3-ethyl-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b~thiophen-3-yl ketone by essentially following the procedure detailed ~or the preparation of Example 100, Part B.
FDMS 374 (M+); Anal. Calcd ~or C23HlgO3S 0.lCHC13: C, 71.81;
H, 4.72. Found: C, 71.92; M, 4.81.
P2lrt C. 3-Ethyl-4-t 2-(1~ lidinyl) ethoxylphenyl a -14-l2-(l-Pyrrolid~inyl)etho:cyphenyllbenzo[blthiophen 3-yl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 The title compound was prepared in 42% yield from 3-ethyl-4-hydroxyphenyl 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR (Free base-CDC13) ~ 7.91-7.88 (m, lH), 7.73-7.62 (m, 3H), 7.43-7.35 (m, 4H), 6.82 (d, 2H), ~.71 (d, lH), 4.15 (t, 2H), 4.09 (t, 2H), 2.95 (t, 2H), 2.90 (t, 2H), 2.67-2.55 (m, 10H), 1.9-1.84 (m, 8H), 1.13 (t, 3H); FDMS 569 (M+l); Anal.
Calcd for C3sH40N2O3S 2C2H2O4: C, 62.55; H, 5.92; N, 3.74.
Found: C, 62.33; H, 5.85; N, 3.74.
~ ~le 107 Preparation of 3-Butyl-4-t2-(1-pyrrolidinyl)ethoxy]-phenyl 2-~4-~2-(1-Pyrrolidinyl)ethoxyphenyl]-benzo ~b~ thiol?hen-3-yl Ketone.
~ ~N ~
Part A. 3-Butyl-4-methoxy~henyl 2-(4-Methoxyphenyl)-benzo ~b] thiophen-3-yl Ketone.
The butyl compound was prepared in 49% yield from 3-bromo-4-methox~phenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone and tetrabutyltin by essentially following the CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 procedure detailed for the preparation of Example 105, Part A.
FDMS 430 (M+); Anal. Calcd for C27H2603S 0.25H20: C, 74.54;
H, 6.14. Found: C, 74.79; N, 6.32.
~.
Part B. 3-Butyl-4-hyd o~y~h9nyl 2-(4-Hydroxyph~nyl)-benzolblthio~hQn-3-yl KetonQ.
l ~ s\ ~7 ~
The named compound was prepared in 98g6 yield from of 3-butyl-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part B.
Anal. Calcd for C25H22O3S-0.5CHC13: C, 66.27; H, 4.91.
Found: C, 66.29; N, 4.84.
l?art C. 3-Butyl-4-~2-(1-~ lolidinyl)Qthoxylph~nyl a- ~4-12-(1-Pyrrolidinyl)ethoxyphenyl]benzo~blthiophen-3-yl Ketone.
The title compound was prepared in 49% yield from 3-butyl-4-hydroxyphenyl 2-( 4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed ~or the preparation of Example 100, Part C.
lH N ~ (Free base-CDC13) ~ 7.86-7.83 (m, lH), 7.67-7.58 (m, 3H), 7.38-7.32 (m, 4H), 6.79-6.76 (m, 2H), 6.66 (d, lH), 4.09 (t, 2H), 4.03 (t, 2H), 2.89 (t, 2H), 2.85 (t, 2H), 2.62-2.56 ~m, 8H), 2.50 (t, 2H), 1.94-1.78 (m, 8H~, 1.46-1.38 (m, 2H), 30 1.28-1.2 (m, 2H), 0.88 (t, 3H); FDMS 597 (M+l); Anal. Calcd for C37H44N203S-0.7Hex: C, 75.3; H, 8.25; N, 4.26. Found: C, 75.24; H, 7.90; N, 3. 87.
W O 97/25033 PCT~US96/17995 ~ . ~r-~.le 108 Preparation of 1-[2-12-Propyl-4-~[2-14- r2- (l-pyrrolidinyl)ethoxylphQnyllbenzolblthiophen-3-yll-mothyl] phenoxylethyllpyrroli~ine Dioxalate.
~< /J
''~'--'N ~
1 ~
The title compound was prepared in 56% yield from 3-propyl-4-[2-(1-pyrrolidinyl~ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo~b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
1H NMR (Free base-CDCl3) ~ 7.84-7.81 (m, lH), 7.54-7.51 (m, lH), 7.44-7.42 (m, 2H), 7.32-7.24 (m, 3H), 6.96-6.93 (m, 2H), 6.87-6.84 (m, lH), 6.71-6.68 (m, lH), 4.18 (s, 2H), 4.14 (t, 2H), 4.05 (t, 2H), 2.94-2.87 (m, 4H), 2.63-2.58 (m, 8H), 2.53 (t, 2H), 1.84-1.77 (m, 8H), 1.59-1.51 (m, 2H), 0.89-0.86 (m, 3H); FDMS 569 (M+1); Anal. Calcd for C36H44N2o2s-l.75c2H2o4:
C, 65.7; H, 6.74; N, 3.78. Found: C, 65.g9; N, 6.54; N 3.71.
Example 109 Preparation of 1-[2-[2-Ethyl-4-[12-[4-[2-(1-pyrrolidinyl)ethoxyl~hQnyllbenzo[b]thiophen-3-yll-mcthylll?honoxy]ethyl]pyrroli~ine Dioxalate. t W O 97/25033 PCT~US96/17995 O/--O" "--'N ~
The title compound was prepared in 56% yield from 3-ethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2~(1-pyrrolidinyl~ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
lH NMR (Free base-CDC13) ~ 7.84-7.81 (m, lH), 7.55-7.51 (m, lH), 7.45-7.41 (m, 2H), 7.30-7.28 (m, 3H), 6.97-6.93 (m, 2H), 6.87-6.83 (m, lH), 6.73-6.68 (m, lH), 4.19 (s, 2H), 4.14 (t, 2H), 4.06 (t, 2H), 2.94-2.87 (m, 4H), 2.65-2.55 (m, lOH), 1.84-1.79 (m, 8H), 1.14 (s, 3H); Exact Mass Calcd for C35H42N202S: 555.3045. Found: 555 3057 1;!YA 16~ 110 Pre~aration of 1-[2-t2-Butyl 4-112-[4-~2-(1-~yrrolidinyl)ethoxy]phenyl~enzo[b]thiophen-3-yl]-m~thyl]~h~o~y~Qthyl~y olidine Dioxalate.
~ M ~ 2C2H204 ~
The title compound was prepared in 64% yield from 3-butyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially ~ollowing the procedure detailed for the preparation o~ Example 101.
1H NMR (DMSO-d6) ~ 7.98-7.94 (m, lH), 7.58-7.5 (m, lH), 7.47 (d, 2H), 7.34-7.32 (m, 2H), 7.1 (d, 2H), 6.9 (s, lH), 6.8 (s, 2H) 4.5 (bs, 4H), 4.35 (t, 2H), 4.21 (t, 2H), 4.17 (s, 2H), 3.54-3.50 (m, 4H), 3.4-3.2 (m, 8H), 2.5-2.4S (m, 2H), 1.93-1.85 (m, 8H), 1.44-1.39 (m, 2H), 1.26-1.21 (m, 2H), 1.17 (t, 3H); FDMS S82 (M+1); Anal. Calcd for C37H46N202S-1-75C2H204:
C, 6S.7; H, 6.74; N, 3.78. Found: C, 65.99; N, 6.54; N 3.71.
lS ~ ~l~ 111 Preparation of 1- ~2-[2-Acetamido-4-~12-[4-[2-(1-p~rrolidinyl)~thoxylphenyl]benzoC b ] thi ophen-3- yl~-methyl~honoxy]othyl]pyrrolidine Dioxalate.
NHAc 1-[2-[2-Amino-4-[[2-[4-[2-~1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl]methyl]phenoxy]ethyl]pyrrolidine (178 mg,0.33 mmol3 was treated with 2 mL of acetic anhydride and 2 mL o~ pyridine. This was stirred at ambient temperature for 16 h and concentrated under reduced pressure.
The resulting oil was mixed with toluene and reconcentrated to dryness. Purification by chromatography (sio2i 95/5 THF/Et3N) afforded 70 mg (0.12 mmol 36%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
W O 97/25033 PC~US96/I7995 1H NMR (Free base-CDCl3) ~ 8.93 (s, lH), 8.33 (d, 1H), 7.82-7.79 (m, lH), 7.54-7.50 (m, lH), 7.46-7.43 (m, 2H), 7.28-7.24 (m, 2H), 6.96-6.93 (m, 2H), 6.73 (d, lH), 6.62 ~d, lH), 4.22 (s, 2H), 4.13 (t, 2H), 4.08 (t, 2H), 2.91 (t, 2H), 2.77 (t, 2H), 2.63-2.61 (m, 8H), 2.17 (s, 3H), 1.84-1.79 (m, 8H); FDMS
584 (M+l); Anal. Calcd for C3sH41N3O3S-2C2H2O4: C, 61.32; H, 5.94; N, 5.50. Found: C, 61.59; H, 5.98; N, 5.59.
- _le 112 Preparation o~ 2-~2-EthylA ;~-4-[~2-t4-~2-(1-pyrrolidinyl)ethoxy]phenyl]benzo~b]thiophen-3-yl~-m~thyllph~noxylethyll~yrrolidine Dioxalat~.
NHEt N
1-[2-[2-Acetamido-4-[[2-[4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl3methyl~phenoxy]ethyl]pyrrolidine ~600 mg, 1.1 mmol) was dissolved in 20 mL of dry THF and added to a mixture of 20 mL of THF and 84 mg (2.2 mmol) of LAH. The reaction was heated at reflux for 3 h then quenched with 5 mL of EtOAc. To this was added 25 mL of saturated aqueous potassium sodium tartrate. The mixture was stirred ~or 30 min and extracted with EtOAc (3 X 30 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to 450 mg of an oil which was puri~ied by chromatrography (sio2; 5~ MeOH/1% NH40H in CHCl3) to a~ford 55 mg (0.1 mmol; 9%) of the title compound as an oil which was converted to- the dioxalate salt according to the method of Example 1, Part C.
W O 97/25033 PCT~US9G/1799 H NMR (Free base-CDCl3~ ~ 7.82-7.80 (m, lH), 7.59-7.55 ~m, lH), 7.47-7.44 (m, 2H), 7.29-7.27 (m, 2H), 6.96-6.93 (m, 2H), 6.62 (d, lH), 6.44 (d, lH), 6.34 (dd,lH), 4.22 (bs, lH), 4.17 (s, 2H), 4.13 (t, 2H), 4.07 (t, 2H), 3.05 (q, 2H), 2.94-2.86 (m, 4H), 2.65-2.59 (m, 8H), 1.84-1.77 (m, 8H), 1.21 (t, 3H);
FDMS 572 (M+3); Anal. Calcd ~or C3sH43N3O2S-2C2H204: C, 62.47; H, 6.32; N, 5.60. Found: C, 62.46; H, 6.19; N, 5.43.
~Y~ _le 113 Preparation of l-~-t2-Meth~sulfonamido-4-~t2-l4-l2 ~l-pyrrolidinyl)ethoxy]phenyl3benzolbJthio~hen-3-yll-methyl]phenoxylethyllpyrrolidin~ Dioxalate.
2C2H2O~
A solution of 1-[2-[2-amino-4-~[2-[4-[2-~1-pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl]methyl]-phenoxy]ethyl]pyrrolidine (750 mg, 1.4 mmol) in 25 mL of CH2C12 at 0 ~C was treated with 159 mg (107 mL, 1.4 mmol) o~
methanesulfonyl chloride. The reaction was stirred at 0 ~C
for 8 h then concentrated under vaccuum. The residue was purified by chromatrography (sio2i 5% MeOH/1% NH40H in CHCl3) to afford 447 mg (0.72 mmol; 52%) of the title compound as an oil which was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free base-CDC13) ~ 7.84-7.81 (m, lH), 7.55-7.53 (m, lH), 7.52-7.41 (m, 3H), 7.30-7.27 (m, 3H), 6.98-6.94 (m, 2H), 6.85 (d, lH), 6.76 (dd,lH), 4.21 (s, 2H), 4.15 (s, 2H), 4.09 (t, 2H), 2.93 (t, 2H), 2.82 (s, 3H), 2.65-2.60 (m, 10H), 1.89-1.84 (m, 4H), 1.83-1.80 (m, 4H); FDMS 619 (M+); Anal.
W O g7/25033 PCT~US96/17995 _ -275-Calcd for C34H41N3O4S2 2C2H2O4 1H2O-0.lEtOAc: C, 55.79; H, 5.83; N, 5.08. Found: C, 56.01; H, 5.98; N, 4.71.
.
RYA _ le 114 Preparation of 1-[2-12-Phenylsulfonamido-4-~[2-[4-12-(1-pyrrolidinyl)ethoxylphenyl]benzolb]thiophen-3-yl]-methyl~henoxy3Qthyllpyrrolia.ine Dioxalate.
NHS02Ph This compound was prepared in 35% yield from phenylsulfonyl chloride and 1-[2-[2-amino-4-[[2-~4-[2-(1-pyrrolidinyl)ethoxy]phenyl]~enzo[b]thiophen-3-yl]methyl]-phenoxy]ethyl]pyrrolidine by essentially following the procedure detailed for the preparation of Example 113.
lH NMR (Free base-CDCl3) ~ 8.1 (bs, lH), 7.84-7.81 (m, lH), 7.58-7.54 (m, 2H), 7.49-7.35 (m, 5H), 7.31-7.21 (m, 4H), 6.98-6.95 (m, 2H), 6.72-6.78 (m, 2H), 4.17-4.12 (m, 4H), 3.92 ~t, 2H), 2.92 (t, 2H), 265-2.54 (m, 10H), 1.94-193 (m, 4H), 1.83-1.79 (m, 4H); FDMS 682 (M+1); Anal. Calcd for C39H43N3O4S2 1.5C2H204-0.2H20: C, 61.48; H, 5.70; N, 5.12.
Found: C, 61.25; H, 6.05; N, 4.97.
~r le 115 Pr~paration of 2-14-(2-~ ;n~Qthoxy)phenyl]-6-hy~Lroxy-3-~3-methyl-4-[(1-pyrroli~in~l)mQthyl]benzyl]-benzo~b]thiophQnQ Dioxalate.
W O 97/25033 PCT~US96/17995 ~0 1 ~ ' 0 ~ NH2 Part A. 4-(6-Methoxybenzo~b~thiophen-2-yl)phQnyl Trii~o~ropyl~ilyl Ether.
H3C0 ~ ,S ~
A solution of 6-methoxy-2-(4-hydroxyphenyl)benzo[b~-thiophene (16 g, 62.4 mmol) in 160 mL of dry DMF was treated with Et3N (12.6 g, 124.8 mmol) at 0 ~C. To this was added in a dropwise manner 28.7 g (93.6 mmol) of triisopropyl trifluoromethanesulfonate. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h before being poured into 200 mL of saturated aqueous NaHCO3 and 300 mL of brine. This was extracted with 10% EtOAc in hexanes (3 X 200 mL). The combined extracts were washed with brine (2 X 300 mL), dried over MgSO4 and concentrated under reduced pressure to give 32 g of an oil which was purified by chromatrography (sio2; 5~ EtOAc in Hexanes) to yield 12.3 g (29.8 mmol, 48%) of the silyl ether as a white solid.
FDMS 412 (M+); Anal. Calcd for C24H32O2SSi 0.65EtOAc: C, 68.50; H, 8.18. Found: C, 68.55; H, 8.16.
Part B. 6-Methoxy-2-[4-~(triisopropylsilyl)oxy]-25 phonyl]bQnzo~b~ thiophen-3-yl 3-Methyl-4-~ pyrro-lidinyl)methyl~ph~nyl Ketone wo 97/25033 PCT/US96/17995 H3CO ~
The ketone was prepared in 83% yield from the above benzothiophene, TiC14, and 3 -methyl-4-[(1-pyrro-lidinyl)methyl]benzoic acid hydrochloride by essentiallyfollowing the procedure detailed for the preparation of Example 96, Part C.
FDMS 613 (M~); Anal. Calcd for C37H47No3SSi- 0 .23CHC13: C, 10 69.5; H, 7.40; N, 2.18. Found: C, 69.43; H, 7.48; N, 2.34.
Part C. 2-(4-Hydoxyphenyl)-6-methoxybenzo~b]thiophen-3-yl 3-Methyl-4-~ olidinyl)methyl~phenyl Ketone.
H3 co 1 ' A solution of the above silyl ether (5.23 g, 8.5 mmol) in THF ~50 mL) was treated with a 1 M THF solution o~
tetrabutylammonium fluoride ( 8 .5 mL) at ambient temperature.
The reaction was stirred for 16 h, concentrated in vacuo, 20 mixed with CHC13 and purified by chromatography (sio2i 2.5%
MeOH in CHC13) to afford 3.8 g (8.3 mmol, 98%) of the phenoxy product as an oil.
W O 97~5033 PCTAJS96/17995 H NMR (Free base-CDC13) ~ 7.65 (d, lH), 7.53 (s, lH), 7.48 (d, lH), 7.32 (d, lH), 7.21-7.16 (m, 3H), 6.99-6.97 (m, lH), 6.57 (d, 2H), 5.75 (bs, lH), 3.89 (s, 3H), 3.59 (s, 2H), 2.6-2.5 (m, 4H), 2.25 (s, 3H), 1.85-1.78 (m, 4H).
Part D. 2-(4-Hydroxyphonyl)-6-methoxy-3-~3-methyl-4-C(l-pyrrolidinyl)mothyl]benzyl]benzo[b]thioph~ne.
H3CO ~
A solution of the above ketone (4 g, 8.7 mmol) in THF
(100 mL) was cooled to 0 ~C under N2 and treated with a 1 M
solution of LAH in THF (17.4 mL). The bath was removed and the reaction was stirred at ambient temperature ~or 2 h. It was quenched by the dropwise addition of 500 mL o~ H20 at 0 ~C, followed by 200 mL o~ EtOAc and 50 g diatomaceous ear~h.
The mixture was ~iltered, the layers were separated, and the organic layer was dried over MgSO4 and concentrated to give 4 g of the benzyl alcohol.
The foam was dissolved in 100 mL of ClCH2CH2Cl and cooled to 0 ~C under N2. The colorless solution was treated with 5.1 g (43.5 mmol) of Et3SiH and 10 g (87.4 mmol) o~ TFA. The reaction was stirred at 0 ~C for 1 h then ~uenched with 50 mL
of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with 100 mL o~ CH2C12. The combined organic layer was dried over MgSO4 and concentrated to an oil. Purification by chromatography (sio2; 65/30/5%
Hex/THF/Et3N) a~forded 3.5 g (7.9 mmol 91%) o~ the methylene compound as a ~oam.
lH NMR (Free base-DMSO-d6) ~ 7.55 (d, lH), 7.4 (d, lH), 7.36 (d, 2H), 7.1 (d, lH), 6.95-6.80 (m, 5H), 4.15 (s, 2H), 3.80 W O 97/25Q33 PCT~US96/17995 (s, 3H), 3.4 (s, 2H), 3.3 (bs, lH), 2.43-2.30 (m, 4H), 2.20 (s, 3H), 1.65-1.60 (m, 4H); FDMS 443 (M+).
,.
P~rt E. 6-Methoxy-3-13-methyl-4-1(1-yy r olidinyl)-methyl~benzyl]-2-~4-12-(phthalimido)Qthoxy]phenyl]-b~nzotb~thioph~ne.
H3COm~ G
The named compound was prepared in 29% yield from 2-(4-10 hydrox~phenyl)-6-methoxy-3-[3-methyl-4-[(1-pyrrolidinyl)-methyl]benzyl3benzotb]thiophene and hydroxyethylphthalimide by essentially following the procedure detailed for the preparation of Example 20, Part B.
15 FDMS 616 (M+); Anal. Calcd for C3gH36N204S-1.2H20: C, 71.49;
H, 6.06; N, 4.39. Found: C, 71.58; H, 6.10; N, 4.36.
Part F. 6-Hydroxy-3-[3-methyl-4-~ olidinyl)-methyl]benzyl]-2-14-12-(phthalimidyl)etho~y]phenyl]-20 blenzo lb] thiophene Dioxalate.
/~/~
J~o ~~
2C2H204 ~
W O 97/25033 PCT~US96/17995 This compound was prepared in 52% yield ~rom the above 6-methoxybenzo[b]thiophene by essentially ~ollowing the procedure detailed for the preparation of Example 1, Part D.
lH NMR (~ree base-CDC13) ~ 7.88-7.84 (m, 2H), 7.74-7.71 (m, 2H), 7.34-7.29 (m, 2H), 7.19-7.15 (m, 2H), 7.1 (d, lH), 6.92 (s, lH), 6.88-6.84 (m, 3H), 6.41-6.37 (m, lH), 4.24 (t, 2H), 4.14-4.10 (m, 3H), 3.61 (s, 2H), 2.69-2.61 (m, 6H), 2.27 (s, 3H), 1.80-1.79 (m, 4H); FDMS 603 (M+l).
Part G. 2-14-(2-~ ;noethoxy)phenyl]-6-hydroxy-3-~3-methyl-4-~ yrrolidinyl)methyl]benzyll-benzolb]thiophene Dioxalate.
A mixture of the above phthalimide (0.4 g, 0.66 mmol) and 1 mL hydrazine hydrate in 50 mL o~ EtOH was heated at re~lux ~or 1 h then concentrated to dryness under reduced pressure.
The residue was mixed with 50 mL o~ 1 N aqueous NaOH and 50 mL of 10% MeOH in EtOAc. The layers were separated and the a~ueous layer was extracted with 25 mL of 10% MeOH in EtOAc.
The combined organic layer was dried over MgSO4, concentrated to dryness and purified by chromatrography (sio2; 5% MeOH, 1%
NH40H in CHC13) to af~ord 230 mg (0.49 mmol, 74%) of the title product as a solid which was converted to its dioxalate salt according to the method o~ Example 1, Part C.
1H NMR (Free base-CDC13) ~ 8.3 (s, lH), 7.39 (d, lH), 7.37-7.2 (m, 3H), 7.05 (d, lH), 7.0 (d, 2H), 6.85 (s, lH), 6.82-6.7 (m, 2H), 4.08 (s, 2H), 3.94 (t, 2H), 3.41 (s, 2H), 3.34 (bs, 2H), 2.88 (t, 2H), 2.39-2.35 (m, 4H), 2.18 (s, 3H), 1.65-1.6 (m, 4H); FDMS 472 (M~).
- _le 116 Preparation of (R) -6-HYarOXY-2- r4- ~2-hydroxy-3-(1-~yrroli~inyl)pro~oxylphenyll-3-[3-methyl-4-~(1-~yrro-l idinyl)methyllbenzyl]benzolblthio~hene Dioxalate.
CA 02236007 l998-04-27 CH
HO ~ S
O ~ N
Part A. (2R)-2-E4-(Glycidyloxy)phenyl~-6-methoxy-3- r 3-methyl-4-l(l-~yrrolidinyl)methyl]benzyl~-benzo~b~thiophQne.
H3CO ~
O
A 60% dispersion o~ sodium hydride (141 mg,3.5 mmol) was rinsed with hexanes under a nitrogen atmosphere and dried under reduced pressure. To this was added a solution of the hydroxyphenylbenzo[b]thiophene of Example 115, Part C (1.3 g, 2.9 mmol) in 30 mL of dry DMF and stirred for 1 h at ambient temperature. The mixture was treated with (2R)-(-)-glycidyl-3-nitrobenzenesulfonate, then stirred for 16 h at ambient temperature. The reaction was poured into a mixture of 50 mL
o~ saturated aqueous NaHCO3, 100 mL of saturated aqueous NaCl and 100 mL of H20. It was extracted with EtOAc (3 X 100 mL).
The extracts were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified by chromatrography to give 1.2 g (2.4 mmol, 81%) o~ the product as an oil.
lH NMR (Free base-CDC13) ~ 7.45-7.38 (m, 5H), 7.33 (d, lH), 7.18 (d, lH), 6.97-6.88 (m, 3H), 4.23-4.18 (m, lH), 4.18 (s, 2H), 4.02-3.96 (m, lH), 3.88 (m, 3H), 3.55 (s, 2H), 3.39-3.37 W O 97n~033 PCT~US96/17995 (m, lH), 2.95-2.92 (m, lH), 2.79-2.71 (m, lH), 2.55-2.49 (m, 4H), 2.3 (s, 3H), 1.8-1.76 (m, 4H).
Part B. (R)-2-t4-[2-Hydroxy-3-(1-~ olidinyl)-}?ropo~ey]phenyll-6-m~thoxy-3-~3-methyl-4-~(1-~yrrolidinyl)methyl~benZyl]bQnZO~b]thiOphenQ.
~ C~
O ~ N
OH
The above (2R)-[(glycidyloxy)phenyl]benzo~b]thiophene (1.18 g, 2.4 mmol) was mixed with pyrrolidine (338 mg, 4.8 mmol) and MeOH (50 mL). The mixture was heated at reflux ~or 6 h, concentrated to an oil and purified by chromatrography (sio2; 30% THF/5% Et3N in hexanes) to afford 1 g of the named product as an oil.
Part C. (R)-6-Hydroxy-2-~4-~2-hydroxy-3-(1-pyrro-lidinyl)propoxylphenyl3-3-~3-methyl-4-[(1-pyrro-lidinyl)methyl]benzyl3benzo~blthiorhe~e Dioxalate.
The title compound was prepared in 61% yield from the above methoxybenzo[b]thiophene by essentially following the procedure detailed for the preparation of Example 115, Parts F and G.
1H NMR (DMSO-d6) ~ 7.4-6.7 (m, llH), 4.3-3.9 (m, 9H), 3.4-3.2 (m, 7H), 3.2-2.29 (m, 4H), 2.25 (s, 3H), 2.00-1.7 ~m, 10H);
FDMS 557 (Mtl).
W O 97/25033 PCTrUS96/17995 RYr~le 117 Preparation of 1-~2-t4-~E5-Fluoro-6-hydroxy-2-~4-l2-r ( l-pyrrolidinyl)e~hoxy]ph~nyl~benzo~b]thiophen-3-yl~-mothyl~phQnoxy~Qthyl~ Loli~lne Dioxalat~.
F~ = ,3~ 2 C H O
Part A. N,N-Dim~thyl-3-fluoro-4-mothoxy-a-hydroxy-phenylthioacetamide.
OH
F~ ,NMe2 MeO
A -78 ~C solution of 18.7 mL ~142.7 mmol) of diisopropylamine in 100 mL of THF was treated with 89.0 mL
(1.6 M in hexanes; 142.2 mmol) of n-BuLi. The reaction mixture was stirred at -78 ~C for 15 min and at 0 ~C for 0.5 h. After cooling back to -78 ~C, a solution of 20.0 g (129.7 15 mmol) of 3-fluoro-4-anisaldehyde and 12.2 mL (143.6 mmol) of N,N-dimethylthioformamide in 100 mL of THF was added slowly.
After complete addition, the reaction was stirred at -78 ~C
for 15 min and was quenched with a solution of 15 mL of HOAc in 100 mL of MeOH. The mixture was concentrated in vacuo and the residue was partitioned between 250 mL of saturated aqueous NaHCO3 and 250 mL of EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give 22.4 g of an oily 25 solid. Trituration with Et2O afforded 16.21 g ~66.6 mmol 51%) of the title compound as a light yellow solid.
Anal. Calcd for CllH14FNO2S: C, 54.30; H, 5.80; N, 5.76.
Found: C, 54.00; H, 5.86; N, 5.77.
W 097125033 PCT~US96/17995 Part B. 2-DimethylA ;~o-5-fluoro-6-methoxy-benzo ~bl thiophene .
MeO~ NMe2 A solution of 16.6 g (68.2 mmol) of N,N-dimethyl-3-fluoro-4-methoxy-2-hydroxyphenylthioacetamide (Part A) in 400 mL of CH2C12 was treated with 22.0 mL (339.0 mmol) of MeS03H
in a dropwise manner. The reaction was stirred at room temperature for 4 h, was cooled to 0 ~C, and was quenched by the careful addition of 500 mL of saturated aqueous NaHCO3.
The two layers were separated and the aqueous layer was extracted with EtOAc (5x200 mL). The combined organic layers were washed with 500 mL of saturated aqueous NaHCO3 and 500 mL of H2O, dried over Na2SO4, and filitered. Evaporation of the solvent in vacuo afforded 21.4 g of an oil which was purified by flash chormatography (sio2; gradient of 10% then 20% EtOAc in hexanes) to give 2.87 g (12.7 mmol; 19~) of the title compound as a light pink solid.
FDMS 225 (M+); Anal. Calcd for CllH12FNOS: C, 58.65; H, 5.37;
N, 6.22. Found: C, 58.37i H, 5.42; N, 6.17.
Part C. 2-Dimethyl~ ;~o-5-fluoro-6-methoxy-benzo ~b3 thiophene-3-yl 4-Nitrophenyl K~tono.
2 5 ~ ~ _ N02 A solution o~ 1.08 g (4.82 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene (Part B) in 15 mL of chlorobenzene was treated with 0.99 g (5.31 mmol) of 4-nitrobenzoyl chloride. The reaction was stirred at room temperature for 17 h and was diluted with 100 mL of EtOAc.
The solution was washed sequentially with 2 N aqueous NaOH (2 x 50 mL), H2O (50 mL) and brine (50 mL), then dried over W O 97/25033 PCTnUS96/1799S
Na2SO4, and filtered. Evaporation of the solvent in vacuo afforded 2.1 g of a dark solid which was purified by flash chromatography (sio2i gradient of 10% then 20~ then 40% EtOAc in hexanes) to give 0.27 g of starting material and 1.25 g ~3.34 mmoli 93% based on consumed starting màterial) of the title compound.
FDMS 374 (M+); Anal. Calcd for ClgHlsFN2O4S: C, 57.75i H, 4.04; N, 7.48. Found: C, 58.04i H, 3.98; N, 7.50.
Part D. 2-Dimethyl~ ;~o-5-fluoro-6-methoxy-h~nzo~b~thiophon-3-yl 4-~2-(1-Pyrrolidinyl)othoxy~-p~enyl Ketone.
~ o A mixture of 2.0 g (5.34 mmol) of 2-dimethylamino-5-~luoro-6-methoxybenzo~b]thiophene-3-yl 4-nitrophenyl ketone (Part C) and 1.4 g (60% dispersion in mineral oil; 35.0 mmol;
washed with hexanes) of NaH in 60 mL of DMF was treated with a solution of 3.75 mL (32.1 mmol) of 1-(2-hydroxyethyl)-pyrrolidine in 10 mL of DMF in such rate to control theeffervescence. After complete addition, the reaction was stirred at room temperature ~or 1 h and was quenched by the careful addition of 5 mL of MeOH. The mixture was diluted with 200 mL of EtOAc and was poured into 200 mL of H20. The two layers were separated and the organic phase was washed with H2O (2 x 100 mL) and brine (100 mL). The organic phase was dried over K2CO3, filtered, and concentrated in vacuo to give 5.21 g of an amber oil. Purification by flash - chromatography (sio2i gradient of 2% then 5% MeOH in CH2C12) afforded 2.10 g (4.74 mmoli 89%) of the title compound as a bright yellow oil.
W O 97/25033 PCT~US9~/17995 FDMS 442 (M+); Anal. Calcd for C24H27FN2O3S: C, 65.14; H, 6.15; N, 6.33. Found: C, 65.08; H, 6.43; N, 6.29.
Part E. 5-Fluoro-6-methoxy-2-~4-~2-(1-pyrrolidinyl)-ethoxy~phenyl]b~nzotblthio~?hQn-3-yl 4-~2-(1-ry ~-lidiny1)ethoxyl~h~nyl Ketone Dioxalat~.
MeO ~ ¦ J ~ ~ 2 C2H2O4 Magnesium turnings (69 gm; 2.84 mmol) were placed in a 3-neck round bottom e~uipped with a stir bar, nitrogen inlet, dropping funnel and reflux co~n~or and flame-dried under a stream of nitrogen. THF (5 mL) was added to the reaction vessel followed by a solution of 732 mg (2.71 mg) of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine and a small I2 crystal. The vessel contents were heated to mild reflux for 7 h at which time all the Mg had been consumed. The reaction was cooled to 0 ~C and was added via a cannula to a 0 ~C solution of 1.00 g (2.26 mmol) of 2-dimethylamino-5-fluoro-6-methoxy-benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) in 10 mL of THF. The mixture was stirred at 0 ~C for 16 h, was ~uenched with 10 mL of H20, and was acidified to pH 7-8 with 1 N a~ueous HCl. The mixture was extracted with CH2C12 (4 x 100 mL). The combined organic extracts were washed with H2O, dried over K2CO3, filtered, and concentrated in vacuo to give 1.53 g of an oil.
Purification ~y flash chromatography (sio2; 4:11:84 TEA/THF/hexanes) afforded 1.18 g (2.12 mmol; 78~) of the title compound as an oil. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 589 (M+1); Anal. Calcd for C34H37FN2O4S-2 C2H2O4: C, 57.22; H, 5.18i N, 3.51. Found: C, 57.48; H, 5.42; N, 3.54.
W O 97~5033 PCT~US96/17995 Part F. 5-Fluoro-6-hydroxy-2-[4-t2-(1-pyrrolidinyl)-r ethoxylphonyllbenzolb~thiophe~-3-yl 4-t2-~1-Pyrro-lidinyl)ethoxy]phenyl Ketone Dioxalat~.
HO ~ 2 C2H~O4 By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared in 61 yield starting from 5-fluoro-6-methoxy-2-[4-t2-~1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[2-(1-10 pyrrolidinyl)ethoxy]phenyl ketone (Part E). A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 575 (M+l); Anal. Calcd for C33H35FN2o4s-2 C2H2~4: C, 15 61.49; H, 5.44; N, 3.88. Found: C, 61.30; H, 5.67; N, 4.09.
~art G. 1-~2-~4-t15-Fluoro-6-Hydroxy-2-14-~2-(1-~yrrolidinyl)ethoxy~phenyl]benzo~blthiophQn-3-yll-methyl~phQnoxy~othyllpyrrolidine DioxalatQ.
The title compound was prepared in 64% yield from 5-fluoro-6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b~thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part F) by essentially following the procedure detailed in Example 3, Part E. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
- FDMS 561 (M+l); Anal. Calcd for C33H37FN2O3S 2 C2H2O4: C, 59.99; H, 5.58; N, 3.78. Found: C, 59.76; H, 5.67; N, 3.68.
W O 97/25033 PCT~US96/17995 ~Y~ _ le 118 Preparation of (+)-5-Fluoro-6-hydroxy-3-l4-lltrans-2-(l-pip~ridyl)cyclohexyl3Oxy]benzyl~-2-t4-r2-(1-pyrro-lidinyl)ethoxylphQnyllbenzolblthiophQne Dioxalate.
~ N ~
Part A. 2-Dimethyl~;~o-5-fluoro-6-methoxy-benzol~lthiophene-3-yl 4-lltrans-2-(l-Piperidyl) cyclohexyl~oxy~phonyl Ketone.
N""
Meo~
The title compound was prepared in 51% ~rom 2-dimethylamino-5-~luoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Example 117, Part C) and (i)-trans-2-(l-piperidyl)cyclohexanol b~ essentially following the procedure detailed in Example 117, Part D.
FDMS 510 (M+); Anal. Calcd ~or C2gH3sFN2O3S: C, 68.21; H, 6.91; N, 5.49. Found: C, 68.32; H, 7.18; N, 5.39.
Part B. (~)-5-Fluoro-6-methoxy-2-14-12-(l-y~ o-20 li~inyl)ethoxy]phQnyllbenzo[blthiophen-3-yl 4-lltrans-2-(1-Piperidyl)cyclohexyl]oxy~phenyl Ketone Dioxalate. t W O 97/25033 PCT~US96/17995 ~/~
N~", ~
~eO~O 2 C~Hz04 The title compound was prepared in 72% yield (based on consumed starting material) from 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy~phenyl ketone (Part A) by essentiallyfollowing the procedure detailed in Example 117, Part E. A
sample was converted to the dioxalate salt according to the method descri~ed in Example 1, Part C.
FDMS 657 (M+1); Anal. Calcd ~or C39H45FN204S 2 C2H2~4: C, 61.71; H, 5.90; N, 3.35. Found: C, 61.45; H, 6 07; N, 3.63.
Part C. (+)-5-Fluoro-6-hyaroxy-2-l4-~2-(1~ o-lidinyl)~thoxylphenyl]benzo~thioph~n-3-yl 4-~tra~-2-(1-Piperidyl)cyclohexyl]oxy]phenyl Ketone Dioxalate.
1~~
~ N"" ~
HO ~--O 2 C2H204 The title compound was prepared in 70% yield from (+)-~ 5-fluoro-6-methoxy-2-[4-[2~ pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 4-[[trans-2-(1-piperidyl)cyclohexyl]-oxy]phenyl ketone (Part B) by essentially following the procedure detailed in Example 1, Part D. A sample was W O 97/25033 PCT~US96/17995 -29~-converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 643 (M+l); Anal. Calcd for C3gH43FN2O4S 2 C2H2O4: C, 61.30; H, 5.76; N, 3.40. Found: C, 61.04; H, 5.84; N, 3.45.
Part D. (+)-5-Fluoro-6-hydroxy-3-14-[ltrans-2-(1-~iperidyl)cyclohexyl~Oxy]bQnzYll-2-l4-l2-(l-~yrr li~inyl)ethoxy~phenyl~benzoCblthioPhene Dioxalate.
The title compound was prepared in 70~ yield from (+)-5-fluoro-6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl 4-[[trans-2-(l-piperidyl)-cyclohe~rl]oxy]phenyl ketone (Part C) by essentially following the procedure detailed in Example 3, Part E. A
15 sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 629 (M+l); Anal. Calcd for C38H45FN2O3S 2 C2H2~4~
62.36; H, 6.11; N, 3.46. Found: C, 62.60; H, 6.11; N, 3.50.
FY~ le 119 Preparation of 1-~2-[4-CC2-[4-12-(1-~ olidinyl)-othoxy~henyl]bQnzofuran-3-yl]mQthyl]phenoxy~ethyl~-pyrroli~ine DioxalatQ.
~~ N~ 2 C2H2O4 ~ N~
Part A. 2-(4-MQthoxyphenyl)benzofuran.
OMe CA 02236007 l998-04-27 A solution of 46.0 g (0.39 mole) of benzofuran in 100 mL
of Et20 was treated with 0.40 mol (1.6 M in hexanes) of n-BuLi at such a rate as to keep the reaction temperature below 25 ~C. The mixture was stirred for 15 min and was added to a 10 ~C solution of 57.2 g (0.40 mole) of CuBr in 100 mL of Et20 at a rate so as to keep the reaction temperature below 10 ~C. The mixture was allowed to reach room temperature over 0.5 h an~ was treated with a solution of 93.6 g of iodoanisole in 300 mL of pyridine. The mixture was heated to 110 ~C for 3 h, allowing the Et20 to boil off.
The reaction mixture was concentrated in vacuo and the residue was dissolved in 3 L of EtOAc. The organic layer was washed several times with 2 N aqueous HC1 and once with H20, dried over MgSO4, and filtered. Concentration in vac~o afforded a residue which was recrystallized from MeOH to afford 44.5 g of the title compound as a solid.
mp 145-147 ~C.
Part B. 2-(4-Methoxyphenyl)benzofuran-3-yl 4-t2-(1-Py oli~inyl)ethoxy]phenyl K~tone.
~ O~ - N ~
The title compound was prepared in 79% yield from 2-(4-methoxyphenyl)benzofuran (Part A) and 4- [2- (1-pyrrolidinyl)-ethoxy]benzoic acid hydrochloride by essentially followingthe procedure detailed in Example 1, Part C.
- mp 92-95 ~C; FDMS 441 (M+);
L'art C. 2-(4-Hydroxyphenyl)benzofuran-3-yl 4-~2-(1-Pyrroliainyl)Qthoxy]phQnyl K~tone.
W O 97/2~033 PCT~US96/17995 By essentially following the procedures described in Example 1, Part D, the title compound was prepared in 81%
yield from 2-(4-methoxyphenyl)benzofuran-2-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part B).
FDMS 427 (M+); Anal. Calcd for C27H2sNO4: C, 75.86; H, 5.89;
N, 3.38. Found: C, 75.59i H, 5.96; N, 3.47.
Part D. 2-C4-~2-(1-~y~ olidinyl)Qthoxy3phenyl~-benzo~uran-3-yl 4-~2-(1-Pyrrolidinyl)ethoxy]phenyl K~tone Dioxalate.
~ O~'-'N ~ 2 C2HaO4 ~~>
By essentially following the procedure described in Example 3, Part D, the title compound was prepared in 76%
yield from 2-(4-hydroxyphenyl)benzo~uran-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) and 1-(2-chloroethyl)pyrrolidine hydrochloride. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 525 (M+l). Anal. Calcd ~or C33H36N204-2 C2H2O4 C, 63.06; H, 5.72 N, 3.98. Found: C, 62.66 H, 5.75; N, 4.06.
WO 97/25033 PCT~US96/17995 Part E. 1-[2-[4-~t2-t4-~2-(1-pyrrolidinyl)ethoxy]-phcnyl~benzofuran-3-yl~methyl~phenoxy3ethyl]-olidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part E, the title compound was prepared in 82%
yield from 2-[4-~2- (l-pyrrolidinyl)ethoxy]phenyl]benzofuran-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D). A
s~mple was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 511 (M+l); Anal. Calcd for C33H3gN2O3-2 C2H2O4-H2O C, 62.70; H, 6.26 N, 3.95. Found: C, 62.83 H, 6.13; N, 3.98.
Ex~mpla 120 Preparation of N-[4-l6-Hyaroxy-3-l~3-methyl-4-[(1-~yrroliainyl)methyl~phenyllmethyl]~enzolb~thiphQn-2-yl]ph~nyl]-a-(l-pyrrolidinyl)acetamide Dioxalate.
Me __~
~ 1.7 C~H2O4 Part A. N-(4-Bromophenyl)-a-chloroacetamide.
Br A mixture of 8. 60 g (0. 05 mol) of 4-bromoaniline, 10.60 g (0.10 mol) of Na2CO3, and 6.78 g (0.06 mol) of chloroacetyl chloride in 100 mL of acetone was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo, 25 and the residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to give 11.4 g of analytically pure title compound as light crystals.
FDMS 248 (M~); Anal. Calcd for CgH7BrClNO: C, 38.67; H, 2.84;
N, 5.64. Found: C, 38.45i H, 2.83; M, 5.56.
Part B. N-(4-Bromophenyl)-a-(l-Pyrrolidinyl)ac~tamido.
Br ~ ~ ~
A solution of 5.0 g (0. 02 mol) of N-(4-bromophenyl)-oc-chloroacetamide (Part A) and 5.05 mL (0.06 mol) of pyrrolidine in 100 mL of THF was stirred overnight at ambient temperature. The mixture was concentrated in vacuo and the residue was partitioned between H20 and EtOAc. The organic layer was separated, washed with H2O, dried over Na2SO4, ~iltered, and evaporated in vacuo to af~ord 5.74 g of analytically pure title compound as crystals.
mp 60-63 ~C; Anal. Calcd ~or C12H15BrN20: C, 50.90; H, 5.34;
N, 9.89. Found: C, 50.62; H, 5.39; N, 9.74.
\
Part C. N-~4-(6-Methoxybenzo[b~thiophen-2-yl)phenyl]-~-(l-pyrroliainyl)acetamide.
MeO ~ ~ N ~
By essentially ~ollowing the procedures described in Example 1, Part B, the title compound was prepared in 97%
yield from N-(4-bromophenyl)-a~ pyrrolidinyl)acetamide (Part B) and 6-methoxybenzo[b]thiophene-2-boronic acid ~Example 1, Part A).
IR (CHC13) 1684; FDMS 366 (M+).
W097/25033 PCT/US96/1799s Part D. N-t4-~6-Methoxy-3-~[3-methyl-4-~(1-pyrroli~linyl)methyl~phenyl~carbonyl]benzo[b]thiophQn-2-yllphenyl~ (1-pyrrolidinyl)acetamide :Dioxalzlte.
Me ~~~
N ~ 2 C2H204 MeOJ~ S>~
By essentially following the procedures described in Example 1, Part C, the title compound was prepared in 68%
yield ~rom the product o~ Part C and 3-methyl-4-~(1-pyrrolidinyl)methyl]benzoic acid. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
IR (CHC13) 1701, 1640; FDMS 567 (M+~. Anal Calcd for C34~37N303S-2 C2H204 C, 61.03; H, 5.53 N, 5.62. Found: C, 60.99 H, 5.72; N, 5.38.
Part E. N-14-[6-Eydroxy-3-~[3-methyl-4-[(1-pyrrolidinyl)methyl~phenyl]carbonyl]bQnzoLb]thiophen-a -yl lphenyl]-oc-(1-pyrroli~linyl)acetamide.
By essentially following the procedures described in Example 1, Part D, the title compound was prepared ~rom the product o~ Part D. A sample was converted to the oxalate salt according to the method described in Example 1, Part C.
FDMS 554 (M+l). Anal. Calcd ~or C33H3sN303S.1.7 C2H204 C, 61.86; H, 5.48 N, 5.95. Found: C, 62.15 H, 5.47; N, 5.78.
Part F. N-14-~6-Hydroxy-3-[[3-methyl-4-~(1-pyrrolidinyl)methyl]phenyl]methyl]benzo[b]thiophen-2-yl~phenyl]-oc-(1-pyrrolidinyl~acetamide Dioxalate.
By essentially ~ollowing the procedures described in Example 3, Part E, the title compound was prepared ~rom the W O 97~5033 PCTAUS96/17995 product of Part E above. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
IR (KBr) 1696, 1607; FDMS 540 (M+1). Anal. Calcd for C33H37N3O2S 1.7 C2H2O4 C, 61.86i H, 5.48 N, 5.95. Found: C, 62.15 H, 5.47; N, 5.78.
Example 121 10 Preparation of 1- ~2-C4-l3-~4- ~1-Ethy:L-2-(1-pyrro-lidinyl)ethoxyl~henyl~methyl3benzotb]thiophen-2-yl]-~henoxy~ethyll~y~olidine Dioxalate.
~ ~ ~ N ~
" "~'N ~
Pa~t A. 1-(1-~y olidinyl)butan-2-ol.
~ N ~
\J ~
A mixture of 2.6 mL (31.1 mmol) of pyrrolidine and 21.6 g ~156.3 mmol) of K2C03 in 100 mL of DMF was treated with 4.7 g (3.20 mL; 90~ tech. grade; 28.2 mmol) of 1-bromo-2-butanone and the reaction was stirred at ambient temperature for 2 h.
The mixture was filtered and concentrated in vacuo. The residue was taken up in 100 mL of 1 N aqueous HCl and the solution was washed with 100 mL of EtOAc. The aqueous layer was basi~ied to pH 13 with solid KOH and was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over K2CO3, filtered, and concentrated in va~uo to give 1.6 g of an oil. The oil was taken up in 100 mL of THF and the solution was treated with 860 mg (22~7 mmol) of LiAlH4 at room temperature for 3 h, and then quenched by the sequential addition of 60 mL of H20, 60 mL of 2 N a~ueous NaOH, and 60 W O 97/25033 PCTnJS96/17995 mL of H20 at O ~C. The mixture was filtered through diatomaceous earth, and the organic solvent was evaporated in vacuo . The aqueous layer was extracted with EtOAc (4xlOO
mL). The combined organic layers were dried over K2C03, filtered, and concentrated in vacuo to give 1.40 g of an oil.
Puriflcation by ~lash chromatography (SiO2; 3% MeOH in CHC13 saturated with NH40H~ afforded 0.95 g of the title compound as an oil.
FDMS 144 (M+l); Anal. Calcd for CgH17NO: C, 67.09; H, 11.96;
N, 9.78. Found: C, 67.34; H, 12.07; N, 10.08.
Part B. 4-~1-Ethyl-2-(1-~yllolidinyl)~thoxy]phenyl 2-[4-[2-~1-Pyrrolidinyl)ethoxy~phenyllbenzolb~thio-~hen-3-yl Ketone Dioxalat~.
I ~
~/
A O ~C mixture of 75.0 mg (1.88 mmol)of NaH and 550 mg (1.23 mmol) of 4-i~ luorophenyl 2-[4- [2-(l-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thien-3-yl ketone in 10 mL of DMF was treated with a solution of 190 mg (1.3 3 mmol) of the alcohol from Part A above in 5 mL of DMF at 60 ~C for 13 h. After cooling to room temperature, the mixture was poured into 100 mL o:~ brine and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H20 (2 x 100 mL) and brine (100 mL), dried over K2CO3, filtered, and concentrated in vacuo to give 780 mg of an oil. Purification by radial chromatography (sio2; 5% MeOH in CHC13 saturated with NH40H) afforded 210 mg (0.37 mmol; 30%) of the title compound as an oil. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
W O 97t2~033 PCT~US96/17995 FDMS 659 (M+l+C2H204); Anal. Calcd for C3sH40N203S.2 C2H204:
C, 62.55; H, 5.92; N, 3.74. Found: C, 62.32; H, 6.15; N, 3.51.
Part C. 1-~2-t4-[3-[~4-[1-Ethyl-2-~1-~yl olidinyl)-~thoxylphenyllmethyl]benzo~blthiophen-2-yl~phenoxyl-Qthyl]pyrrolidine Dioxalate.
A O ~C solution of the ketone from Part B (135 mg, 0.237 mmol) in 2 .5 mL of anhydrous THF was treated with DIBAL-H
(593 ~L, 0.593 mmol, 1.0 M solution in toluene) dropwise via a syringe. After 1 h at O ~C, the excess DIBAL-H was quenched with excess MeOH (approximately 1 mL). A solution o~ 5 mL of saturated NatK+ tartrate and 5 mL o~ EtOAc were added, and the biphasic mixture was vigorously stirred for 1.5 h at ambient temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was dissolved in 2.5 mL of 1,2-dichloroethane a~d Et3SiH (183 ~L, 2.37 mmol).
Upon cooling to O ~C, TFA (265 ~L, 1.66 mmol) was added in a dropwise fashion. A~ter 1.5 h, the reaction mixture was poured into 50 mL o~ saturated a~ueous NaHC03 solution. The a~ueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Ma2S04, filtered and concentrated in vacuo. Purification by radial chromatography (sio2; gradient 2.5% to 5% MeOH in CHC13, saturated with NH40H) af~orded 62 mg (0.112 mmol; 47%) o~ a yellow oil. The ~ree base was converted to the title dioxalate salt according to the conditions described in Example 1, Part C.
FDMS 555 (M+l); Anal. calcd ~or C3sH42N202S-2C2H20~: C, 63.74; H, 6.31; N, 3.81. Found: C, 63.52; H, 6.26; N, 3.73.
- _le 122 Preparation o~ 2-[4-[3-~4-~2-(1-~y oli~inyl)-butoxy]~phenyl~methyl]benzolb~thiophen-2-yl]-~henoxy]ethyllpyrrolidine Dioxalate.
CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 I ~ 2 C2H2O4 Part A. 2-(1-~y~olidinyl)butanol.
G N J~-The title compound was prepared in 64~ yield for 2 steps from pyrrolidine and ethyl 2-bromobutyrate by essentially following the procedure detailed in Example 121, Part A.
FDMS 144 (M+l); Anal. Calcd for C8H17NO: C 67.09; H 11.96;
N 9.78. Found: C, 66.23; H, 11.36; N, 9.~8.
Part B. 4-~2-(1-Pyrrolidinyl)butoxy]phenyl 2-14-~2-(l-Pyrrolidinyl)Qthoxy]phQnyl]bQnzo~b]thiophen-3-yl Ketone Dioxalate.
~ 2 C2H2O4 The title compound was prepared in 59~ yield from the product of Part A and 4-fluorophenyl 2-[4-[2~
pyrrolidinyl)ethoxy]phenyl]benzo[b]thien-3-yl ketone by essentially following the procedure detailed in Example 121, Part B. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
W O 97/25033 PCT~US96/17995 FDMS 569 (M~l); Anal. Calcd for C3sH40N2O3S 2 C2H2O4: C, 62.55; H, 5.92i N, 3.74. Found: C, 62.39; H, 5.80; N, 3.59.
Part C. 1-12-14-[3- r t4-12-(l-Pyrrolidinyl)but phenyllmethyl~ benzolb~thiophen-2-yl]phenoxy]ethyl]-pyrrolidine Dioxalate.
The title compound was prepared from the free base of the ketone ~rom Part C in 76% yield by essentially following the procedure described in Example 121, Part C.
FDMS 555 (M+l); Anal. calcd for C3sH42N2O2S-2C2H204: C, 63.74; H, 6.31; N, 3.81. Found: C, 63.64; H, 6.07i N, 3.70.
~xample 123 Pre~aration of 1-~2-~15-[6-Hydroxy-3-tl3-methoxy-4-l(l-pyrrolidinyl)methyl]phenyl]methyl]benzo ~b] thio-phen-2-yl~pyrid-2-yl]oxylethyl~yrrolidine Dioxalate.
~ ~
2 C2H2~~
Part A. 6-Benzyloxy-2-16-[2-(1-~y lolidinyl)ethoxy]-pyrid-3-yl~benzo~ b] thiophen-3-yl 3-Methoxy-4-~(1-~y olidinyl)methyl]phenyl Ketone.
CMe ~
~~,D ~ -~Q-~~ L
A -78 ~C solution o~ 5-bromopyrid-2-yl 2 pyrrolidinyl)ethyl ether (3.25 g, 12.0 mmol) in 40 mL o~
. . . . CA 02236007 1998-04-27 '.
DEIVIANDES OU BREVETS VOL~I~VIINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU C~ BREVFr COMPREND PLUS C)'UN TOME.
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THIS S~CTION OF THE APPLICATIONJPATENT CONTAINS MORE
THAN ONE VOLUMI~
T~IS IS VOLUNIE ~ OF _ ' - NOTE' For additional volumes-pl~ase contact the Canadian Patent Offic~ .
.. ,.. . - . ~
., .. ., ,. - . ;. . . ~; :;
FDMS 527 (M+l, 100).
Exam~le 4 Preparation of 2-~4-12-(1-Pyrrolidinyl)ethoxy]phenyl3-benzo[b]thiophen-3-yl 4-13-(l-PYrrolidinyl)pr phenyl Ketone Dioxalat~.
WO 97/25033 PCT~US96/17995 O ~ N ~ ~ C2H2~4 O'-- "--'N~
:eart A. 1-12-[4-(Benzolb]thio~hen-2-yl)phenoxy]-~ethyl~pyrrolidine.
~5 ~
~ ~ ~--~N
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-[2-(4-bromophenoxy)-ethyl]pyrrolidine in 76% yield as a white solid following flash chromatography (sio2; 36:4:60 THF-TEA-hexanes).
FDMS 324 (M+1; 100).
Part B. Methyl 4-~3-(1-Pyrrolidinyl)plG~o~y]benzoate.
MeO2C
O~ "'~_,N ~
A solution of 6.25 g (23.8 mmol) of triphenylphosphine, 3.30 g (21.7 mmol) of methyl 4-hydroxybenzoate, and 2.80 g ~21.7 mmol) of 1-(3-hydroxypropyl)pyrrolidine in 100 mL of CH2Cl2 was treated with 3.80 mL (24.1 mmol) of diethyl azodicarboxylate in a dropwise m~nn~r . The reaction was stirred at ambient temperature for 16 h and was quenched by the addition of 20 mL of brine. The two layers were separated, and the organic layer was dried over K2CO3 and W O 97/25033 PCT~US96/17995 concentrated to give 6.10 g of an oily solid which was purified by flash chromatography (sio2i 0-5% MeOH in CH2Cl2) to afford 2.46 g (9.34 mmol; 43%) of the desired product.
FDMS 263 (M+; 100)i HRMS Calcd for C1sH21NO3: 264.1600.
Found: 264.1609.
Part C. 4-l3~ ~Y~olidinYl)Propoxy]bQnzoic Acid ~ydrochlorid~.
HO2C~
~ O~ "~_,N ~ HC1 A solution of 2.0 g (7. 6 ~mnol) oE the methyl 4-[3-(1-pyrrolidinyl)propoxy]benzoate (Part B) in 90 mL of THF was treated with 90 mL of 0.1 N aq LioH ~or 48 h. The THF was evaporated in vacuo. The aqueous phase was adjusted to pH 11 with 1.0 N aq HC1 and was applied to column of Biorad AG1-X8 Resin (100-200 mesh; acetate ~orm) which had been prewashed with 2 L of 2.0 N aq NaOH. The column was sequentially eluted with 1 L of H2O, 1 L of 50% THF in E2O, 1 L of H2O and 2 L of 3.0 N aq AcOH. The acidic fraction was evaporated in vacuo, the residue was reconstituted in 20 mL o~ 1.0 N ag HCl and the mixture was frozen Lyophilization afforded 1.50 g (3.g mmol; 51%) of the desired product as a white powder.
FDMS 249 (M+; 100); Anal. Calcd ~or C14H1gNO3 HC1: C, 58.84;
H, 7.05; N, 4.90. Found: C, 58.58; H, 6.85; N, 5.13.
Part D. 2-~4-12-(1-Pyrrolidinyl)~thoxy]phenyl]-benzo~blthiophen-3-yl 4-~3-(l-Pyrrolidinyl)pro~oxyl phenyl Ketone Dioxalate.
The title compound was prepared from 4-[3-~1-pyrro-lidinyl)propoxy]benzoic acid hydrochloride (Part C) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Part A) in 55% yield by essentially following the procedure outlined in Example 2, Part C.
CA 02236007 l998-04-27 w 097nso33 PCT~USs6/l7sss lH N~R (DMSO-d6) ~ 8.11 (d, ~ = 7.5 Hz, lH), 7.74 (d, ~ = 8.7 - Hz, 2H), 7.48-7.33 (m, 5H), 7.01 (d, ~ = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.30 (t, J = 3.8 Hz, 2H), 4.11 (t, ~ =
5.2 Hz, 2H), 3.S4 (t, ~ = 4.2 Hz, 2H), 3.43-3.15 (m, 8H), 2.18-2.05 (m, 2H), 2.02-1.85 (m, lOH); FDMS 555 (M+l; 100);
Anal. Calcd ~or C34H3gN2O3S 2C2H2O4: C, 62.11; H, 5.76; M, 3.81. Found: C, 62.08; H, 5.76; N, 3.84.
~.Yr _ 1Q 5 Preparation o~ 2-t4-~2-(l-pyrrolidinyl)ethoxy~phQn benzo~b~-thiophen-3-yl 4-~3 (l-Pyrrolidi~yl)propyll phenyl Ketone Dioxalate.
N~
" "'" N ~
Part A. 2-(4-Methoxyl?henyl)benzo~b~thiophen-3-yl 4-~3-(1-~y lolidinyl)propyl~henyl Ketono.
O~_~N/~
~ OMe By essentially ~ollowing the procedure outlined in Example 2, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3i Part A) and 4-[3-(l-pyrrolidinyl)propyl]benzoic acid hydrochloride in 33%
yield as a viscous oil.
FDMS 456 (M+l; 100~; Anal. Calcd :Eor C2gH2gNO2S: C, 76.45; H, 6.42; N, 3.07. Found: C, 76.21; H, 6.39i N, 3.14.
W O 97/25033 PCT~US96/17995 Part B. 2-(4-Hydroxynphenyl)benzo~bJthiophen-3-yl 4-~3-(1-Pyrrolidinyl)prO~yl~phenyl Ketone.
N
~1~
A 100 mL round bottom flask cont~;n'ng 300 mg (0.66 mmol) of 2-( 4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part A) was filled with 20 g of pyridine hydrochloride. The flask was heated to 160 ~C
to melt the solid. After 16 h, the reaction was cooled to warm temperature, diluted with 50 mL of H20, and transferred to separatory funnel cont~n'ng 50 mL H20 and 50 mL of EtOAc.
The two layers were separated and the a~ueous layer was extracted with EtOAc (2 x 50 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo to give 325 mg o~ a yellow oil. Purification by radial chromatography (sio2i gradient of 2-10% MeOH in CH2Cl2) afforded 200 mg (0.45 mmol; 69~) of the title compound as a viscous yellow oil.
FDMS 441 (M+; 100); Anal. Calcd for C2gH27NO2S: C, 76.16; H, 6.16; N, 3.17. Found: C, 76.59; H, 6.27; N, 3.07.
P~rt C. 2-~4-~2-(1-Pyl oliainyl)ethoxylphenyll-benzolblthiophen-3-yl 4- t3- (l-Pyrrolidinyl)propyl~-phenyl Ketone Dioxalat~a.
By essentially following the procedure outlined in Example 3, Part D, the free base of the title compound was prepared from 2-(4-hydroxyphenyl)benzo~b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 36% yield as a viscous oil following radial chromatography (sio2; gradient of 5-15% MeOH in CH2Cl2). The free base was converted to the W ~ 97/25033 PCTAUS96117995 dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.12 (d, ~ = 7.8 Hz, lH), 7.69 (d, ~ = 7.9 Hz, 2H), 7.45-7.34 (m, 7H), 7.30 (d, J = 8.0 Hz, 2H), 6.99 (d, ~ = 8.4 Hz, 2H), 4.32-4.21 (m, 2H), 3.57-3.43 (m, 2H), 3.35-3.12 (m, 8H), 3.07 (t, ~ = 6.2 Hz, 2H), 2.66 (t, ~ =
6.5 Hz, 2H), 2.04-1.80 (m, 10H); FDMS 539 (M+l; 66); Anal.
Calcd for C3gH3gN2O2S 2C2H2O4: C, 63.50; H, 5.89i N, 3.90.
Found: C, 63.75; H, 6.12; N, 3.85.
~ ple 6 2-[4-~2-(1-Pyrrolidinyl)Qthoxy~phQnyl]benzo[b~thio-phen-3-yl 4-[(1-~y~liainyl)methyl]phenyl Ketone Dioxalate.
''~--'N ~
Part A. Methyl 4-l(l-~y 7 ,~ Linyl)methyl~benzoate.
~ ~ OMe A solution of 6.20 mL (44.5 mmol) of TEA and 4.70 g (21.8 mmol) of 4-carboxybenzyl bromide in 50 mL of DMF was treated with 2.10 mL (25.2 mmol) of pyrrolidine at 50 ~C for 3 h. The reaction mixture was cooled, evaporated in vacuo, and the residue was taken up in 50 mL of MeOH. The solution was treated with a rapid stream of HCl (g) for 15 min, the reaction vessel was sealed and the reaction stirred at ambient temperature for 16 h. Evaporation of the solvent afforded 2.56 g of an oil which was purified by radial W O 97/25033 PCTnUS96/17995 chromatography (sio2; 80:18:2 hexanes-THF-TEA) to afford 2.30 g (10.5 mmoli 48%) o~ the title compound as an oil.
FDMS 219 (M~; 100) Part B. 4~ y~Lolidinyl)m~th~llbenzoic Acid Hydrochloride.
o ~ ~ OH
By essentially following the procedure outlined in Example 4, Part C, the title compound was prepared from methyl 4-[(1-pyrrolidinyl)methyl]benzoate in 22% yield as a white solid ~ollowing ion exchange chromatography.
FDMS 206 (M+1; 100)i Anal. Calcd ~or C12H1sNO2 HCl. 0-2 H2O:
C, 58.75; H, 6.74; N, 5.71. Found: C, 58.95; H, 6.56; N, 5.54.
Part C. 2-t4-~2-(1-Pyrroli~inyl) ethoxyl~henyl~-benzo~b~thioph~n-3-yl 4-~(1-Pyrroliainyl)methyl3phenyl Kotonc Dioxalate.
By essentially ~ollowing the procedure outlined in Example 2, Part C, the ~ree base o~ the title compound was prepared ~rom 4-[(1-pyrrolidinyl)methyl]benzoic acid hydrochloride (Part B) and 1-[2- L4- (~enzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 44%
yield. The ~ree base was conver~ed to the dioxalate salt according to the conditions described in Example 1, Part C.
lH MMR (DMSO-d6) ~ 8.10 (dd, J = 6.5, 1.8 Hz, lH), 7.68 (d, = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, lH), 7.52-7.36 (m, 4H), 7.32 (d, ~ = 8.7 Hz, 2H), 6.90 (d, ~ = 8.7 Hz, 2H), 4.27-4.15 (m, 4H), 3.53-3.43 (m, 2H), 3.34-3.20 (m, 4H), 3.20-2.94 (m, 4H), 1.96-1.80 (m, 8H); FDMS 510 (M+; 100); Anal. Calcd ~or C32H34N2O2S 2C2H2O4: C, 62.60; H, 5.54; N, 4.06. Found: C, 62. 79; H, 5.56; N, 4.00.
~rle 7 - 5 Preparation of 2-t4-[2-(1-Pyrrolidinyl)ethoxy]phenyl~-benzo~b]thiophen-3-yl 4-12-(l-Pyrroli~inyl)Qthyl3 ~henyl Ketone Dioxalate.
_ N ~ 2 ~2H2O4 ~ ~N ~
Part A. Methyl 4-t2-(1-~Y lolidinyl)ethyllbenzoate.
~ OMe lo G
By essentially following the procedure detailed in Example 6, Part A, the title compound was prepared from 4- [2-bromoethyl)benzoic acid and pyrrolidine in 39% yield as an oil following radial chromatography (SiO2; 89:9:2 hexanes-THF-TEA).
FDMS 234 (M+1; 100) Par~ B. 4-t2-(l-Pyrrolidinyl)ethyl]benzoic Acid Hydrochloride.
~ N HCl W O 97/25033 PCT~US96/17995 By essentially ~ollowing the procedure outlined in Example 4, Part C, the title compound was prepared from methyl 4-~2-(1-pyrrolidinyl)ethyl]benzoate (Part A) in 24%
yield as a white solid ~ollowing ion exchange chromatography.
FDMS 220 (M+l; 100); Anal. Calcd for Cl3Hl7NO2-HCl-O.lH2O: C, 60.63i H, 7.12; N, 5.44. Found: C, 60.48; H, 7.08; N, 5.32.
Part C. 2-14-12-(1-1y~ olidinyl)Qthoxylphenyll-benzo~blthiophen-3-yl 4-[2-(1-Pyrrolidinyl)ethyl]-ph~nyl Ketone Dioxalate.
By essentially following the procedure outlined in Example 2, Part C, the free base of the title compound was prepared from 4-[2-(1-pyrrolidinyl)ethyl]benzoic acid hydrochloride (Part B) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 45~
yield. The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.10 (dd, J = 6.4, 2.0 Hz, lH), 7.72-7.61 (m, 3H), 7.45-7.39 (m, 4H), 7.31 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.27-4.04 (m, 4H), 3.53-3.40 (m, 2H), 3.31-3.17 (m, 4H), 3.10-2.92 (m, 2H), 2.87-2.64 (m, 2H), 1.99-1.72 (m, 8H), 1.55-1.40 (m, 2H); FDMS 524 (M+; 100);
Anal. Calcd for C33H36N2O2S-2C2H2O4: C, 63.06; H, 5.72; N, 3.97. Found: C, 63.33; H, 5.67; N, 3.90.
~r rle 8 Preparation of 1-[2-12-Methyl-4-[2-[4-[2-(1-pyrro-lidinyl)~thoxy~phenyllbQnzolb]thiophQn-3-ylmethyl~l-phenoxy]ethyl]~yrrolidine Dioxalate.
Me ~ ~o~ N~3 2 C2H2~4 ~ N~
Part A. 2-(4-Methoxyphenyl)bQnzol~]thioph~n-3 3-Bromo-4-methoxyphQnyl Ketone.
Br ~Oe 5 The title compound was prepared in 76% yield :Erom 2-(4-metho~Z7phenyl)]benzo[b]thi0phene (Example 3, Part A) and 3-bromo-4-methoxybenzoic acid by essentially following the procedures detailed in Example 2, Part C.
10 lH NMR (DMSO-d6) ~ 8.12 (d, J = 7.3 Hz, lH), 7.91 (s, lH), 7.69 (dd, .:T = 8.7, 1.8 Hz, lH), 7.56 (d, J = 8.2 Hz, lH), 7.52-7.41 (m, 2H~, 7.37 (d, ~ = 8.6 Hz, 2H), 7.05 (d, ~ = 8.7 Hz, lH), 6.94 (d, ~J = 8.6 Hz, 2H), 3.89 (s, 3H), 3.75 (s, 3H); FDMS 452 (M-l), 454 (M~l).
Part B. 2-(4-Methoxyphenyl)bQnzo r~] thioFhen-3-yl 3-Methyl-4-methoxyph~nyl Ketone.
Me ~ OMe A slurry of 750 mg (1.65 mmol) of 2-(4-methoxyphenyl)-20 benzo[b]thiophen-3-yl 3-bromo-4-methoxyphenyl }cetone (Part A) in 15 mL of toluene was treated with 75 mg (O.07 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0. 54 mL (3.9 mmol) of tetrabutyltin. The tube was sealed and the contents were heated at 130 ~C for 15 h. The reaction was cooled, evaporated in vacuo, and the residue was taken up in 75 mL of Et20. Saturated a~ KF (75 mL) was added and the mixture was stirred vigorously for 6 h. The two layers were separated and the organic layer was washed with H2O (3 x 75 mL). The organic phase was dried over Na2SO~ and evaporated in vacuo to give 934 mg of an oil which was purified by radial chromatography (sio2; 25% EtOAc in hexanes) to af~ord 602 mg (1.55 mmol; 94%) of the title compound as a white solid.
FDMS 388 (M+), 389 (M~1); HRMS calcd for C24H21O3S, 389.1211.
Found 389.1180.
Part C. 2-(4-Hydroxyphenyl)benzo[b]thiophen-3-yl 3-Methyl-4-hydroxyphenyl Ketone.
Me ~ H
A 0 ~C solution of 700 mg (1.80 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-methoxyphenyl ketone (Part B) in 25 mL of CH2Cl2 was treated with 7.2 mL of BBr3 (1.0 M in CH2C12). The reaction was stirred at 0 ~C for 6 h, then cooled to -78 ~C, and was treated carefully with 50 mL of MeOH. The mixture was allowed to warm to room tem-perature over 1.5 h, and the volatiles were evaporated in vacuo. The dark red residue (monomethyl ether) was taken up in 75 mL dichloroethane and was treated with AlC13 and ethanethiol according to the conditions of Example 1, Part D
to afford 675 mg of an oil. Purification by radial chromatography (sio2i gradient of 20-30~ EtOAc in hexanes) WO 97/25033 PCT~US96/17995 afforded 410 mg (1.14 mmol; 63%) of the title compound as an orange solid.
.
FDMS 360 (M+); Anal. Calcd ~or C22H1603S: C, 73.31i H, 4.47.
Found: C, 73.57; H, 4.66.
Part D. 2-~4-12-(1-~y~ olidinyl)ethoxy]phenyl]-benzolb~thiophen-3-yl 3-Methyl-4-l2-(l-pyrroli~inyl) ethoxylphenyl Ketone Dioxalate.
e ~
~'"--'N
By essentially ~ollowing the procedure detailed in Example 3, Part D, the ~ree base o~ the title compound was prepared from 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-hydroxyphenyl ketone (Part C) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 83% yield as an oilfollowing radial chromatography (sio2; 10~ MeOH and 0.5% TEA
in CH2Cl2). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.10 (d, ~ = 7.8 Hz, lH), 7.64 (s, lH), 7.56-7.34 (m, 6H), 7.00-6.92 (m, 3H). 4.13 (t, ~ = 5.4 Hz, 2H), 4.08 (t, J = 5.7 Hz 2H), 2.95-2.78 (m, 4H) 2.68-2.56 (m, 8H), 2.12 (s, 3H), 1.78-1.64 (m, 8H); FDMS 555 (M+; 100) HRMS C34H3gN2O3S: 555.2681. Found: 555.2706.
Part E. 1-[2-12-Methyl-4-[2-14-12-(1-pyl-rolidinyl)-ethoxy~phenyll~enzo~blthiophen-3-ylmethyl]phenoxy}-~thyl~pyrrolidine Dioxalata.
By essentially following the conditions detailed in Example 2; Part D, the ~ree base o~ the title compound was CA 02236007 l998-04-27 W097/25033 PCT~US96/17995 prepared from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophen-3-yl 3-methyl-4-[ 2-( l-pyrrolidinyl)ethoxy:lphenyl ketone (Par~ D) in 88% yield as an oil :Eollowing radial chromatography (sio2; 10~ MeOH and 0.5% TEA in CH2Cl~). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
H NMR (DMSO-d6) ~ 8.04-7 .95 (m, lH), 7.64-7.56 (m, lH), 7.51 (d, ~ = 8.1 Hz, 2H), 7.42-7.32 (m, 2H). 7.14 (d, ~ = 8.2 Hz, 10 2H), 6.97 (s, lH), 6.92-6.80 (m, 2H), 4.36 (t, .J = 4.8 Hz, 2H), 4.22 (t, .J = 5.0 Hz 2H), 4.18 (s, 2H), 2.95-2.78 (m, 4H) 2.68-2.56 (m, 8H), 2.12 (s, 3H), 1.78-1.64 (m, 8H); FDMS 541 (M+; 100), 631 (M+ + ~2H2O4); Anal. Calcd for C34H~oN2O2S 2C2H2O4 1.9H2O: C, 63.78; H, 6.20; N, 3.93.
15 Found: C, 63.81; H, 6.47; N, 3.82.
RY~ _ le 9 Preparation o~ 2-14-r2-(1-Pyrrolidinyl)ethoxy~phQnyl]-benzo~b~thio~hen-3-yl 6-t2-(l-pyrrolidinyl)eth ~yrid-3-yl Ketone Dioxalate.
" " ~' N ~
Part A. 2-(4-Methoxyphenyl)benzo[b~thiophen-3-yl 6-Chloro-pyrid-3-yl Ketone.
?, ~1 By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared ~rom 6-CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/17995 chloronicotinic acid and 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 31% yield as a yellow solid following ~lash chromatographY (SiO2; CH2C12).
FDMS 379 (M+, 100), 381; Anal. Calcd ~or C21H14ClNO2S: C, 66.40; H, 3.71; N, 3.69 Found: C, 66.20; H, 3.71i N, 3.79.
Part B. 2-(4-Methoxy~henyl)benzolb]thiophen-3-yl 6-12-(1-Pyrroli~inyl)ethoxy]pyria-3-yl Ketone.
0 ~ "~ ,N
OMe A solution o~ 0.50 mL (4.30 mmol) of 1-(2-hydroxyethyl)-pyrrolidine in 10 mL o~ xylenes was treated with 50 mg (2.20 mmol) of Na. The mixture was heated to 50 ~C until all the Na had disappeared, cooled to room temperature, and then treated with a solution of 420 mg (1.10 mmol) of 2-~4-methoxyphenyl)benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) in 5 mL o~ xylenes. The reaction was heated to 50 ~C for 2 h and was evaporated in vacuo. The residue was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 810 mg of a yellow solid. Purification by radial chromatography (sio2; gradient of 1-5% MeOH in CH2Cl2) gave 525 mg (1.09 mmol; 99%) of the title compound as an amber oll .
FDMS 459 (M+; 100); Anal. Calcd ~or C27H26N2O3S: C, 70.72; H, 5.71; N, 6.11. Found: C, 70.43i H, 5.60; M, 6.02.
Part C. 2-(4-Hyd vxy~henyl)benzo[b]thiophen-3-yl 6-[2-(1-Pyrrolidinyl)ethoxy)pyrid-3-yl Ketone.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 ~~~ ~
OH ~
By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-[ 2-(1-pyrrolidinyl)-ethoxy]pyrid-3-yl ketone (Part B) in 89% yield as a yellow solid ~ollowing radial chromatography (sio2~ 5% MeOH in CH2Cl2 ) -FDMS 445 (M+l; lOO)i HRMS calcd for C26H2sN203S: 445.1586.
Found: 445.1569.
Part D. 2-t4-~2-(1-Pyrrolidinyl)ethoxy]phenyl~-benzolbl thiophen-3 -yl 6- ~2- ( 1-~y~ lolidinyl)ethoxy~-pyri~- 3 -yl Ketone Dioxalate.
By essentially following the procedure detailed in Example 3, Part D, the free base of the title compound was prepared from 2-(4 -hydroxyphenyl)benzo[b]thiophen-3-yl 6-[2-(1-pyrrolidinyl)ethoxy)pyrid-3-yl ketone (Part C) and 1-( 2-chloroethyl)pyrrolidine hydrochloride in 84% yield as an oil following radial chromatography (sio2; gradient of 5-20% MeOH
in THF). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
FDMS 542 (M+1); Anal. Calcd for C32H3sN303S-2C2H204 1.5H20: C, 57.74i H, 5.65; N, 5.61. Found: C, 57.68; H, 5.42; N, 5.49.
Example 10 Preparation of 1-~2-14-~[2-~4-[2-(1-Pyrroli~inyl)-ethoxy]~henyl]benzo[b~thiophen-3-yl]thio]phenoxy~-othyl~pyr~olidine Dioxalate.
W O 97/25033 PCT~US96/17995 o~ Nl3 ~~
Part A. 3-Bromo-2-(4-methoxyphenyl)benzo~b]thiophene.
A slurry of 5.0 g (20.8 mmol) of 2-(4-methoxyphenyl)-benzo[b]thiophene (Example 3, Part A) in 400 mL o:E CHCl3 at 0 ~C was treated slowly with 1.6 mL of Br2, resulting in a yellow solution. The reaction was stirred at 0 ~C ~or 1 h and then washed sec~uentially with 200 mL o:E 1.0 N aq Na2S2O3, 200 mL of 1.O N aq NaHC03, and 200 mL of H2O- A~ter drying over Na2SO4, evaporation of the solvent in vacuo gave 6. 24 g (19.5 ~nol; 94%) o~ an off-white solid which was clean by thin layer chromatography.
mp 84.5-86.5 ~C; lH NMR (CDCl3) ~i 7.86 (d, J = 7.9 Hz, lH), 15 7.80 (d, J = 7.9 Hz, lH), 7.72 (d, J = 8.7 Hz, 2H), 7.50-7.37 (m, 2H), 7.02 ( d, J = 8.7 Hz, 2H), 3.88 (s, 3H); FDMS 318 (100), 320 (M+l); Anal. Calcd For ClsHllBrOS: C, 56.44; H, 3.47. Found: C, 56.25; H, 3.38.
Part B. Methyl 4-[~2-(4-Methoxyphenyl)benzo[b]thio-~h~n-3-yl~thio3phQnyl Ether.
To a solution of 1.O g (3.1 mmol) of 3-bromo-2-(4-methoxyphenyl)benzo[b]thiophene (Part A~ in 20 mL of THF was added dropwise 2.9 mL of 1.6 M n-BuLi in hexanes (4.7 mmol) at -70 ~C. The mixture was stirred at -70 ~C for 10 min and then treated with 0.87 g (3.13 mmol) of solid bis(4-methoxyphenyl)disulfide. Stirring was continued at -70 ~C
for 0.5 h and then the reaction was allowed to warm slowly to room temperature. The reaction was ~uenched with 1 mL of saturated aq NH4Cl and 1 mL of MeOH and was concentrated in vacuo. The residue was partitioned between 100 mL of EtOAc and 100 mL of H20. The organic layer was separated, dried over MgSO4, and concentrated in vacuo to afford an oily solid which was subjected to flash chromatography (SiO2; gradient of 1-5% EtOAc in hexanes) to afford 0.82 g of the title compound as an oil.
FDMS 378 (M+l; 100).
Part C. 4-[~2-(4-Hy~roxyph~nyl)benzo~b3thiophen-3-yl]thiol~henol.
S~O~
OH
A solution of 0.82 g (2.2 mmol) of methyl 4-[[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]thio~phenyl ether (Part B) in 50 mL of dichloroethane was treated with 1.2 mL (3.3 g;
13 mmol) of BBr3 at 0 ~C for 5 h. The reaction was ~uenched by the careful addition of 15 mL of MeOH. Evaporation o~ the solvent in vacuo gave a residue which was subjected to flash chromatography (sio2i 1~ MeOH in CHCl3) to afford 0.47 g of the desired product as a solid.
FDMS 350 (M+; 100); Anal. Calcd For C20Hl4o2s2 0~5MeOH: C, 67.19; ~, 4.40. Found: C, 67.04; H, 4.25.
Part D. l-12-[4-1l2-14-t2-(l-~yllolidinyl)ethoxy]-ph~nyl]benzolblthioph~n-3-yl~thio~phonoxy~ethyl]-pyrrolidine Dioxalate.
By essentially following the procedure detailed in Example 4, Part B, except using 1-(2-hydroxyethyl)-pyrrolidine, the ~ree base of the title compound was prepared ~rom 4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]thio]phenol (Part C) and 1-(2-hydroxyethyl)pyrrolidlne in 43% yield as an oil following radial chromatography (sio2; 3% TEA and 37% THF
in hexanes). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 8.12-8.00 (m, lH), 7.76-7.65 (m, 3H), 7.47-7.38 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 4.36 (t, ~ = 5.0 Hz, 2H), 4.19 (d, J = 5.1 Hz, 2H), 3.56 tt, J = 4.8 Hz, 2H), 3.47 (t, ~ =
4.9 Hz, 2H), 3.42-3.18 (m, 8H), 2.03-1.82 (m, 8H); FDMS 545 (M+l), 636 (M+91, 100); Anal. Calcd For C32H36N2O2S2-2C2H2O4-0.4H2O: C, 59.07; H, 5.62; M, 3.83.
Found: C, 59.02; H, 5.49; N, 4.22.
RY~mple 11 ~reparation o~ 2-[4-[3-[4-[2-(l-Pyrrolidinyl)-ethoxyJphenoxy~benzo[b~thiopllen-2-yl]phenoxyl~thyl~-oli~ine Dioxalate.
~ o~ ~N ~ 2 C2H204 ~~ ~>
Part A. Benzolb~thiophen-3-yl 4-Methoxyph~nyl Ether.
W O 97/25033 PCTnUS96/1799S
O ~ OMe A mixture of 4.00 g (19.7 mmol~ of 3-bromobenzo[b]-thiophene, 4. 96 g (40 mmol) of 4-methoxyphenol, 5.52 g (40 mmol) of K2CO3, and 0.20 g (1.0 mmol) of CuI was heated to 140 ~C and sonicated at this temperature for 2 h. The reaction was allowed to cool, taken up in CH2Cl2, and the mixture was washed several times with 0.5 N NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo to an oil that was sub]ected to chromatography (sio2; gradient of 0-5~ EtOAc in hexanes). The fractions cont~ln;ng the desired product were combined, evaporated in vacuo, and the residue was recrystallized from hexanes to afford 500 mg (1.95 mmol; 10%) of the title compound as a white solid.
Anal. Calcd For ClsH21O2S: C, 70.29; H, 4.72. Found: C, 70.56; H, 4.88.
Part B. 2-Iodobenzotb]thioph~n-3-yl 4-Methoxyphenyl Ether.
O ~ OMe A solution of 133 mg (0.52 mmol) of 3-(4-methoxy-phenoxy)benzo[b]thiophene (Part A) in 3 mL of THF was treated with 0.33 mL of 1.6 M n-BuLi in hexanes (0.54 mmol) at -78 ~C
for 15 min and then treated with 138 mg (0.54 mmol) of I2 in 3 m~ of THF. The reaction was allowed to gradually warm to room temperature and then partitioned between brine and EtOAc/hexanes. The two phases were separated, the organic phase was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from hexanes to CA 02236007 l998-04-27 afford 143 mg (O.37 mmol; 7296) of the title compound as a solid.
Anal. Calcd For ClsH20Io2s: C, 47.14; H, 2.90. Found: C, 47.21; H, 2. 98.
Part C. (4-MethoxyphQnyl)~oronic Aci~.
MeO ~ B(OH)2 By essentially following the procedure detailed in Example 1, Part A, the title compound was prepared from 4-iodoanisole.
Part D. 2-(4-Methoxyphenyl)bQnzo~b]thiophen-3-yl 4-Methoxyphenyl Ethor.
~ ; OMe OMe By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from 2-iodo-3-(4-methoxyphenoxy)benzo[b]thiophene (Part B) and (4-methoxyphenyl)boronic acid (Part C) in 70% yield ~ollowing chromatography (sio2i 5% EtOAc in hexanes).
Anal. Calcd For C22HlgO3S: C, 72.90; H, 5.01. Eound: C, 72.82; H, 5.12.
Part E. 4-1[2-(4-Hyd.roxyph~nyl)bonzolb]thiophen-3-yl]oxy~phenol.
W O 97/25033 PCT~US96/17995 By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from 2-(4-methoxyphenyl)-3-(4-methoxyphenoxy)benzo[b]thiophene (Part D) in 87% yield following radial chromatography (sio2i 25% EtOAc in hexanes).
FDMS 334 (M+, 100); Anal. Calcd For C20H14O3S: C, 71.84; H, 4.22. Found: C, 71.94; H, 4.35.
Part F. 1-~2-[4-t3-t4-~2-(l-~y olidinyl)ethoxy]-phenoxy~b~nzo[b]thio~hen-2-yl~phQnoxy~ethyl~-pyrrolidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part D the ~ree base of the title compound was prepared from 4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl~oxy]phenol (Part E) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 52% yield following radial chromatography (SiO2; gradient o~ 2-10~ MeOH in CH2Cl2). The ~ree base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.96 (d, J = 8.0 Hz, lH), 7.68 (d, J = 8.5 Hz, 2H), 7.40-7.23 (m, 3H), 7.04 (d, ~ = 8.5 Hz, 2H), 6.91-6.80 (m, 4H), 4.38-4.13 (m, 4H), 3.55-3.41 (m, 4H), 3.36-3.14 (m, 8H), 1.97-1.78 (m, 8H); FDMS 529 (M+1; 100); Anal. Calcd For C32H36N2O3S-2C2H2O4: C, 61.00; H, 5.69; N, 3.95. Found:
C, 61.06; H, 5.86i N, 4.17.
Example 12 Preparation of 1-~2-~4-~1-12-~4-[2-(1-Pyrrolidinyl)-ethoxy~henyl]benzo~b~thiophen-3-yl~ethenyl]phenoxy~-~thyl~pyrrolidine Dioxalate.
~~V
Part A. Methyl 4- r 1 - [2-(4-Methoxyphenyl)benzo[b]-thiophen-3-ylJQthenyllphenyl Ether.
~ O
A solution of 1.20 g (3.36 mmol) of methyltriphenyl-phosphonium bromide in 50 mL of THF was treated with 0.45 g (4.01 mmol) of potassium tert-butoxide and the mixture stirred at room temperature for 0.5 h. To this was added dropwise 0.80 g (2.14 mmol) o~ 2-(4-methoxyphenyl)benzo[b]-thiophen-3-yl 4-methoxyphenyl ketone (Example 3, Part B) in 10 mL of THF and the reaction was stirred at room temperature for 18 h and then heated at gentle reflux ~or 48 h. The reaction was quenched by 100 mL of brine. The two layers were separated and the organic layer was dried over Na2SO4.
Concentration in vacuo gave 1.36 g of an oil which was pu-rified by radial chromatography (SiO2; 10% EtOAc in hexanes) to afford 0.610 g (1.64 mmol; 77~) of the desired product as an oil.
FDMS 372 ~M+; 100).
Part B. 4-~1-[2-(4-~ydroxylahenyl)benzo[bJthiophen-3-yl]ethenyl~phenol.
., By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from methyl 4-[1-[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]-ethenyl]phenyl ether (Part A) in 67% yield as a yellow solidfollowing radial chromatography (sio2; gradient of 20-40 EtOAc in hexanes).
FDMS 344 (M+; 100).
Part C. 1-~2-[4-~ 2-14-r2-(1-~ L~lidin~l)ethoxy~-phenyl]b~nzotb]thiophen-3-yl]ethenyl]ph~noxy]ethyl]-~rrolidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part D, the free base of the title compound was prepared from 4-[1-[2-(4-hydroxyphenyl)benzoLb]thiophen-3-yl]ethenyl]phenol (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 67% yield as an oil following radial chromatography (Sio2i gradient of 2-10% MeOH in CH2Cl2). The free base was converted to the dioxalate salt according to the conditions described in Example 1, Part C.
lH NMR (DMSO-d6) ~ 7.95 (d, J = 7.5 Hz, lH), 7.49 (d, J = 8.0 Hz, 2H), 7.38-7.16 (m, 5H), 6.95 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 5.99 (s, lH), 5.14 (s, lH), 4.32-4.10 (m, 4H), 3.54-3.36 (m, 4H), 3.29-3.12 (m, 8H), 1.98-1.72 (m, 8H); FDMS 539 (M+l; 100)i Anal- Calcd For C34H38N2O2S-2C2H2O4:
C, 63.49; H, 5.89: N, 3.90. Found: C, 63.78i H, 6.14i N, 4.10.
W O 97/25033 PCT~US96~17995 ~m~l~ 13 Preparation of 4-[2-(Hexahydro-lH-azopin-l-yl)ethoxy]-; ~henyl 2-t4-t2-(1-Pyrrolidinyl)ethoxy]phenyl]-benzo[blthiophen-3-yl Ketone DioxalatQ.
0 ~ ,~~ ,N ~
~N ~
Part A. 4- r2- (H~xahy~ro-lH-azepin-l-yl)ethoxy~ph 2-(4-Nethoxyphenyl)b~nzoIb]thiophen-3-yl Ketone.
O ~
By essentially ~ollowing the procedure detailed in Example 1, Part C, the title compound was prepared ~rom 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[2-(hexahydro-lH-azepin-l-yl)ethoxy]benzoic acid hydrochloride in 35~ yield as an oil following radial chromatography (sio2i gradient of 1-10% isopropanol in CH2Cl2)-FDMS 485 (M+; 100).
Part B. 4-~2-(Hexahydro-lH-azepin-l-yl)ethoxy]phenyl 2-[4-t2-(1-Pyrrolidinyl)ethoxy~phenyllbenzoIb]thio-phen-3-yl Ketone Dioxalate.
Deprotection of the 4-[2-(hexahydro-lH-azepin-l-yl)-ethoxy]phenyl] 2-(4-methoxyphenyl)benzoIb]thiophen-3-yl ketone (Part A) was effected according to the conditions described in Example 1, Part D. The resulting phenol was W O 97/25033 PCT~US96/17995 alkylated with 1-(2-chloroethyljpyrrolidine hydrochloride according to the procedure detailed in Example 3, Part D to afford the free base of title compound which was converted to the dioxalate salt according to the methods described in 5 Example 1, Part C.
FDMS 569 (M+; 100); Anal. Calcd For C3sH3gN2O3S 2C2H2O4 H2O: C, 60.37i H, 6.10; N, 3.61. Found: C, 60.05; H, 5.71; N, 3.84 HRMS Calcd for C3sH40N2o3s: 568.2838. Found: 568.2869.
~ le 14 Preparation of 4-~2-(1-~y~ olidinyl)ethoxy]phenyl 2-~4-~3-(1-Pyrrolidinyl)propyl]~hQnyl]benzolb]thio-phen-3-yl Ketone Dioxalate.
0 ~ ,~_,N ~
M~ 2 C2H204 Part ~. :L- (tran~-4 -Bromoci~namoyl) pyrrolidine .
Br ~N~
A mixture of 5.0 g (22.0 mmol) oi~ 4-bromocinn~m;c acid, 6 rnL of oxalyl chloride and 3 drops of DMF in 40 mL of CH2C12 was heated to gentle reElux until gas evolution ceased. The volatiles were removed in vacuo and the residue was taken up in 50 mL oi~ CH2C12. Pyrrolidine (10 rnL; 120 Im[Lol) was added and the mixture was stirred overnight at room temperature.
The reaction mixture was evaporated in vacuo and chromatographed to a:E~ord 5.36 g rl9.1 mmol; 8796) o~ the title compound.
FDMS 279 (M-1), 281 (M+1); Anal. Calcd For C13H14BrNO: C, 55.73; H, 5.04i M, 5.00. Found: C, 56.00; H, 5.06; N, 5.04.
CA 02236007 l998-04-27 Part B. 1-[trans-4-(Benzolb]thiophen-2-yl)cinn~moyl]-pyrroli~ine.
¢~1 N~>
b-By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-(trans-4-bromo-c;nn~moyl)pyrrolidine (Part A) in 43% yield following chromatography.
FDMS 333 (Mt), 334 (M+13.
Part C. 1-13-[4-(Benzo[b]thlophen-Z-yl)phenyl]-propyl]pyrrolidine.
~ N ~
A solution of 1.2 g (3.6 mmol) of 1-[trans-4-(benzo[b]thiophen-2-yl)cinn~moyl]pyrrolidine (Part B) in 15 mL of THF was treated with 75 mg (2.0 mmol) of LiAlH4 at -15 ~C. After complete consumption of starting material, the reaction was cautiously ~uenched with H2O. The mixture was extracted with EtOAc and the combined organic layers were evaporated in vacuo . Chromatography afforded 600 mg (1.9 mmol; 52% yield) of the desired product.
FDM~ 320 (M-1).
Part D. 4-12-(1-Pyrrolidinyl)ethoxy~phenyl 2-14-13-(1-Pyrroli~inyl)propyl~phe~yl]benzo~b]thiophen-3-yl ~etone Dioxalate.
By essentially following the procedure outlined in Example 1, Part C, the free base of the title compound was W O 97/2~033 PCTAJS96/17995 prepared from l-[3-[4-(benzo[b]thiophen-2-yl)phenyl]propyl]-pyrrolidine (Part C) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 11% yield. Conversion to the dioxalate salt followed from the procedure described in Example 1, Part C.
mp 105 - 112 ~C; FDMS 536 (M+l; 100); Anal. Calcd For C32H3gN2O2S 3C2H2O4: C, 58.16; H, 5.65; N, 3.57. Found: C, 58.06; H, 5.15; N, 3.93.
... ple 15 Prcparation of 4-[2-(1-Pyrroli~inyl)ethoxy]phenyl 2-~4-[3-(1-Pyrrol idinyl ) propoxy~ph~nyl~benzo[b]thio~
phen-3-yl Kotone Dioxalate.
0~ ,N ~ 2 C2H
O'--" "~'N
Part A. 2-(4-Methoxyphenyl)benzoCblthiophen-3 4-C2-(l-Pyrrolidinyl)ethoxy]phenyl Ketone.
, ~ ,N
OMe By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b3thiophene (Example 3, Part A) and 4-C2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59%
yield as an oil following radial chromatography (sio2;
gradient of 2-5% MeOH in CH2Cl2).
Part B. 2-(4-Hyd~y~henyl)bonzo[b]thiophen-3-yl W O 97~033 PCTAUS96/17995 4-[2-(1-Pyrrolidinyl)ethoxylphenyl Ketone.
0 ~ ,~ ,N
~ OH
By essentially following the procedure detailed in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo~b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl ketone (Part A) in 33% yield as an oil ~ol-lowing radial chromatography (sio2; gradient of 2-10~ MeOH in CH2Cl2 ) FDMS 443 (M+; 100); Anal. Calcd For C27H2sNO3S: C, 73.11; H, 5.68; N, 3.16. Found: C, 73.11; H, 5.89; N, 3.20.
Part C. 4-~2-(1-1y ~ in~l)ethoxy~phenyl 2-[4-t3-(1-Pyrroli~inyl)propoxylphanyl~benzo~blthiophen-3-yl Ketone Dioxalat~.
By essentially following the procedure detailed in Example 3, Part D, the ~ree base o~ the title compound was prepared ~rom 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(l-pyrrolidinyl)ethoxylphenyl ketone (Part B) and 1-(2-chloroethyl)pyrrolidine hydrochloride in 69% yield followingradial chromatography (sio2i gradient o~ 5-10% MeOH in CH2C12). The product was converted to the dioxalate salt according to the conditions o~ Example 1, Part C.
lH NMR ~DMSO-d6) ~ 8.04 (d, J = 8.8 Hz, lH), 7.68 (d, J = 8.7 Hz, 2H), 7.42-7.29 (m, 5H), 6.95 (d, J = 8.7 Hz, 2H), 6.89 ~ (d, J = 8.6 Hz, 2H), 4.35-4.23 (m, 2H), 3.98 (t, J = 5.5 Hz, 2H), 3.58-3.42 (m, 2H), 3.34-3.09 (m, 10H), 2.13-1.99 (m, 2H), 1.95-1.76 (m, 8H); FDMS 555 (M+l; 100); Anal. Calcd For C34H3gN2O3S 2C2H2O4 1.5H2O: C, 59.91; H, 5.95i N, 3.68. Found:
C, 59.72; H, 5.70i N, 3.48.
~ v~ le 16 Pre~aration of 4-~2-(1-Pyrrolidinyl)ethoxy]phenyl 2-[6-[2-(1-Pyrrolidinyl)ethoxy] pyrid-3 -yl 3benzo[b3-thiophen- 3 -yl Ketone Dioxalate.
O ~ N ~
S ~ 2 C2H2O4 N O~-~-'N ~
Part A. 5-8romo~yrid-2-yl 2-(1-~y olidinyl)ethyl Ether.
Br ~ N,~~_,O N
A solution of 8.00 g (69.6 mmol) of N-(2-hydroxyethyl)-pyrrolidine in 150 mL of xylenes was treated with 534 mg (23.2 mmol) of Na and the mixture was heated to 80 ~C until all the Na had disappeared. The reaction was cooled to 23 ~C
and 5.50 g (23.2 mmol) of 2,5-dibromopyridine was added. The mixture was stirred at room temperature for 2.25 h and was concentrated in vacuo. Purification by flash chromatography (sio2i gradient of 50-70% EtOAc in hexanes) af~orded 3.53 g (13.0 mmol; 56%) of the title compound.
Part B. 5-(Benzo~b]thiophen-2-yl)pyrid-2-yl 2-(1-Pyrroli~inyl)ethyl Ether.
~ N
~ ;
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from CA 02236007 l998-04-27 Wo 97/25033 PCT/US96/17995 benzo[b~thiophene-2-boronic acid and 5-bromopyrid-2-yl 2 pyrrolidinyl)ethyl ether (Part A) in 68% yield as an oil :Eollowing :Elash chromatography (sio2; gradient of 0-4~6 MeOH
in CHCl3).
FDMS 324 (M+; 100).
Part C. 4-~2-(1-Pyrrolidinyl)ethoxy]ph~nyl 2-[6-12-(l-Pyrrolidinyl)~thoxy]pyrid-3-yl]benzo~b]thiophen-3-yl Ketone Dioxalate.
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 5-(benzo[~]thiophen-2-yl)pyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part B) and 4-[2-(1-pyrrolidinyl)-ethoxy]benzoic acid hydrochloride in 30% yield as a solid following flash chromatography (sio2; 5% MeOH in CHC13) The free base was converted to the dioxalate salt according to the conditions outlined in Example 1, Part C.
FDMS 543 (M+2; 100); Anal. Calcd For C32H3sN3o3s 2c2H2o4: C, 59.91; H, 5.45; N, 5.82. Found: C, 59.80; H, 5.67; N, 5.61.
~Y~ _le 17 Preparation of 4-~2-(4-Morpholinyl)ethoxy]phenyl 2-[4-[2-(1-Pyrroliainyl)ethoxy]phQnyl]benzo~b~thio~hen-3-yl Ketone Dioxalate.
~ ~0~O
Part A. 2-(4-Methoxyphenyl)benzo~b]thiophen-3-yl 4-~2-(4-Morpholinyl)ethoxy]phenyl Ketone.
~1 W O 97/25033 PCT~US96/17995 ~ OMe ~ o By essentially following the procedure outlined in Example 3, part D, the title compound was prepared in 96 yield from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzo[b]-thiophen-3-yl ketone (Example 28, Part A) to yield an off-white foam following column chromatography (sio2i gradient 0-5% MeOH in EtOAc).
1H NMR (CDC13) ~ 7.86-7.83 (m, lH), 7.77 (d, ~ = 8.8 Hz, 2H), 7.65-7.62 (m, lH), 7.39-7.32 (m, 4H), 6.76 (d, J = 8.8 Hz, 4H), 4.08 (t, 3 = 5.6 Hz, 2H), 3.75 (s, 3H), 3.71 (t, J = 4.7 Hz, 4H), 2.77 (t, J = 5.6 Hz, 2H), 2.54 (t, J = 4.5 Hz, 4H).
Part B. 2-(4-Hydroxyphenyl)benzo~b]thio~hen-3-yl 4-~2-(4-D~orpholinyl)ethoxy~phenyl Ketone.
~ OH ~ O
Following the procedure outlined in Example 1, part D, the title compound was prepared in 91% yield from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[2-(4-morpholinyl)-ethoxy]phenyl ketone ~Part A). The desired compound wasisolated as a white solid after flash chromatography (sio2;
gradient 0-10% MeOH in EtOAc) and recrystallization from THF-hexanes.
mp 188-189 ~C; IR (KBr) 1598 cm 1; FDMS 459 (M~); Anal. Calcd for C27H2sNO4S: C, 70.57; H, 5.48; N, 3.05. Found C, 70.58;
H, 5.57; N, 3.35.
_99_ Part C. 4-12-~4-~orpholinyl)ethoxylph~nyl 2-~4-~2-(l-Pyrrolidinyl)ethoxy]phenyllbenzo~b~thiophen-3-yl ICetone Dioxalate.
Followin~ Example 3, part D, the title compound was prepared from 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(4-morpholinyl)ethoxy]phenyl ketone (Part B) i~ 78% yield as a light oil a~ter ~lash chromatography [sio2i gradient 0-12%
(1:2 TEA-i-PrOH) in THF]. Conversion to the dioxalate salt was carried out as detailed in Example 1, part C.
mp 73 ~Ci IR (KBr) 1598 cm-li lH NMR (CD30D) ~ 7.93 (d, ~ =
7.1 Hz, lH), 7.71 (d, ~ = 8.8 Hz, 2H:), 7.56 ~d, J = 7.1 Hz, lH), 7.36 (d, ~ = 8.7 Hz, 4H), 6.88 ( d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.36 (distorted t, 2H), 4.25 15 (distorted t, ~ = 4.8 Hz, 2H), 3.90 (br t, ~ = 4.6 Hz, 4H), 3.61-3.28 (m, 12 H), 2.06 (m, 4H); FDMS 557 (M+l); Anal.
Calcd for C3sH3gN20gS-2C2H204-2H20: C, 57.50i H, 5.74; N, 3.62. Found: C, 57.39; H, 5.56; N, 3.70.
_1~ 18 Preparation of 4-r2-(Diethyl~;no)ethoxy]phenyl 2-~4-[2-(l-Pyrrolidinyl)ethoxylphenyl]benzo~b]thiophen-3-yl ~etone Dioxalate.
~9--~-~--~
~ O~ <
25 Part A. 4-r2-(Diethyl~ ;nQ)ethoxy]phenyl 2-(4-- NethoxyphQnyl)benzo~b]thiophQn-3-yl Ketone.
~~3-o--~
~ OMe <
-100~
By essentially following the procedure ou~lined in Example 3, part D, the title compound was prepared from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzotb]thiophen-3-yl ketone (Example 28, Part A) and 2-diethylaminoethyl chloride in 86%
5 yield. Flash chromatography [sio2; gradient 1-4% of (1:1 -TEA-~eOH) in EtOAc] gave the desired compound as a light oil.
IR (CHCl3) 1598 cm-l; lH NMR (CDC13) ~ 7.86-7.84 (m, lH), 7.83-7.75 (m, 2H), 7.65-7.62 (m, lH), 7.39-7.25 (m, 4H), 6.76 (d, J = 8.5 Hz, 4H), 4.03 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H), 2.66-2.59 (m, 4H), 1.05 (t, J = 7.1 Hz, 6H); FDMS 459 (M+); Anal. Calcd ~or C2gH2gNO3S: C, 73.17; H, 6.36; N, 3.05. Found: C, 73.11; H, 6.49; N, 3.17.
Part B. 4-~2-(Diethylamino)ethoxylphenyl 2-(4-Hydroxyphenyl)benzo[b]thiophQn-3-yl Ketone.
~ \
~ 0~ <
By essentially ~ollowing the procedure outlined in Example 1, part D, the title compound was prepared in 71%
yield from 4-~2-(diethylamino)ethoxy]phenyl 2-(4-methoxy-phenyl)benzo[b]thiophen-3-yl ketone (Part A3 as an orange foam following flash chromatography (sio2; 5% TEA in THF).
lH NMR (CDC13) ~ 7.89-7.86 (m, lH), 7.76 (d, ~ = 8.7 Hz, 2H), 7.72-7.69 (m, lH), 7.39-7.36 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.95 (br s, lH), 6.72 (d, J - 8.7 Hz, 2H), 6.64 (d, J =
8.4 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 2.91 (t, ~ = 5.9 Hz, 2H), 2.70 (q, J = 7.1 Hz, 4H), 1.09 (t. J = 7.1 Hz, 6H).
Part C. 4-~2-(Diethylr ;no)~thoxy]phenyl 2-14-[2-(1-pyrrolidinyl)othoxy~l?henyl]benzo~b]thiophen-3-yl Kotone Dioxalate.
By essentially following the procedure outlined in Example 3, part D, the title compound was prepared from 4-[2-W O 97/25033 PCT~US96/I7995 (diethylamino)ethoxy]phenyl 2-(4-hydroxyphenyl)benzo[b]-thiophen-3-yl ketone (Part B) in 95% yield following flash chromatography (sio2; gradient 60% THF cont~;n;n~ 3% TEA to 80% THF in hexanes) as a tan solid. Conversion to the dioxalate salt was carried out in 94% yield as detailed in Example 1, part C.
mp 176-179 ~Ci lH NMR (CD30D) ~ 7.92 (dd, J = 7.0, 1.5 Hz, lH), 7.74 (d, ~ = 8.9 Hz, 2H), 7.54 (dd, ~ = 7,2, 1.7 Hz, lH), 7.41-7.34 (m, 4H), 6.92 (d, ~ = 8.5 Hz, 2H), 6.90 (d, J
= 8.6 Hz, 2H), 4.36 (distorted t, 2H), 4.27 (distorted t, 2H), 3.59 (m 4H), 3.28 (m, 8H), 2.08 (br s, 4H), 1.31 (t, J =
7.2 Hz, 6H); FDMS 543 (M+l), 634 (M+2+C2H2O4).
Example 19 Preparation of 1-~2-[4-[3-[4-[2-(Diethylamino)ethoxy~-benzyl3benzo[b]thioph~n-2-yliphenoxyleth~l]pyrrolidine Dioxalate.
~~~
By essentially following the procedure outlined in Example 2, part D, the title compound was prepared in 91%
yield from 4-[2-(diethylamino)ethoxy]phenyl 2-[4-[2-(1-pyrro-lidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone ~Part C).
Flash chromatography [sio2i 80% THF in hexanes with 3% TEA
(v/v)] gave a white gummy solid which was converted to the dioxalate salt following the method described in Example 1, part C.
lH NMR (DMSO-d6) ~ 7.99 (m, lH), 7.59 ( br d, J = 6.3 Hz, lH), 7.50 (d, J = 8.3 Hz, 2H), 7.36 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.89 (d, ~ = 8.3 Hz, 2H), W O 97/25033 PCTrUS96/17995 4.38 (br s, 2H), 4.27 (br. s, 2H), 4.22 (br s, 2H), 3.57 (br s, 2H), 3.44 (br s, 2H), 3.35 (br. s, 4H), 3.16 (dt, J = 7.1, 6.7 Hz, 4H), 1.96 (br s, 4H), 1.21 (t, ~ = 6.9 Hz, 6H); FDMS
529 (M+l; Anal. Calcd for C33H40N2o2s-2c2H2o4-H2o: C, 61.14;
H, 6.38; N, 3.85. Found: C, 61.04; H, 6.32; N, 3.61.
Example 20 Pre~aration o~ 6-Hydroxy-2-E4-l2-(~ ~lidinyl)-othoxy]phenyl~bonzo~b]thiophen-3-yl 4-~trans-2-(1-Piperidyl)cyclohexyl]ox~]phenyl Ketone Dioxalate.
o~~ b ' 2C2H204 HO ~ O--N
Part A. (+)-tr~ns-(1-Piperidyl)cyclohexan-2-ol.
Q
HO~O
To a solution of 41.63 g (0.30 mol) of K2CO3 in ca. 200 mL of H2O was added 12.16 g (0.10 mol) of piperidine hydrochloride at 0 ~C, followed by 10.1 mL (0.10 mol) of cyclohexene oxide. After 5 min at 0 ~C, the ice bath was removed and the cloudy solution was stirred at room temperature overnight (18 h). The mixture was then extracted with EtOAc (3 x 500 mL) which was washed with 200 m~ of H20 and 200 mL of brine. The combined extracts were dried over MgSO4, concentrated, and dried under vacuum to afford 3.64 g (20~) of the crude amine which was used without further purification for the following reaction.
IR (KBr) 3435 cm-li FDMS 184 (M+l), 229 (100).
CA 02236007 l998-04-27 W O 97/2~033 PCT~US96/17995 Part B. Methyl (+)-4-~[trans-2-(1-pipQridyl)-cyclohexyl]oxy]benzoate.
MeO ~ ~
To a solution of methyl 4-hydroxy~enzoate (1.476 g, 9.70 mmol) in 175 mL of anhydrous THF was added 3.557 g (19.4 mmol) o~ trans-(l-piperidyl)cyclohexan-2-ol, (Part A), 5.090 g (19.4 mmol) of triphenylphosphine and 3.10 mL (19.4 ~mol) of diethyl azodicarboxylate at room temperature. The reaction mixture was stirred for 3 days and then concentrated under reduced pressure. The residue was purified by PrepLC
(2.5 to 4% o~ (10~ concd NH40H in MeOH) in CH2C12) to afford 2.232 g (7.03 mmol, 73~) of an orange solid.
mp 88-91 ~C; lH NMR (CDC13) ~ 7.97 (d, ~ = 8.8 Hz, 2H), 6.92 (d J = 8.9 Hz, 2H), 4.32 (td, ~ = 9.8, 4.2 Hz, lH), 3.88 (s, 3H), 2.80-2.47 (m, 5H), 2.23-2.15 (m, lH), 2.07-1.92 (m, lH), 1.76 (m, 2H), 1.57-1.20 (m, 10H); FDMS 317 (M+).
Part C. (+)-4-lCtrans-2-(l-Piperidyl) cyclohexyl~oxylbenzo~c Acid.
A solution of methyl 4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy]benzoate (Part B) (2.232 g, 7.03 mmol) and 10.6 mL (10.6 mmol) of 1.0 N NaOH in 60 mL of 1:1 mixture of MeOH/THF was stirred at 80 C for 20 h. The mixture was then cooled to room temperature, stirred for additional 7 h, and concentrated under reduced pressure. The residue was dissolved in 50 mL of 1.0 N HCl. This solution was extracted with 200 mL of EtOAc. The organic layer was washed with 200 mL of water. The combined aqueous layers were cooled to 0 C
W O 97/25033 PCT~US96/17995 and neutralized with 15 mL of 2.0 M NaOM. They were then concentrated under reduced pressure and the residue was taken up in 10% MeOH in CH2Cl2 and then filtered. The filtrate was concentrated and the residue was dried over P2Os in a vacuum oven at 55 ~C.
mp 264-266 C (dec); lH NMR ~DMSO-d6) ~ 7.79 (d, ~ = 7.7 ~z, 2H), 6.87 (d, ~ = 8.1 Hz, 2H), 4.40 (m, lH), 2.65-2.55 (m, 4H), 2.07 (m, lH), 1.77-1.58 (m, 3H~, 1.40-1.15 (m, llH);
FDMS 304 (M~l), 482 (base); Anal. Calcd for ClgH2sNO3-0.73NaCl: C, 62.47, H, 7.28, N, 4.05. Found: C, 62.92, H, 7.47, N, 4.15.
Part D. (+)-6-M~thoxy-2-t4-~2-(1-pyrrolidinyl)-ethoxylphenyl]benzolb]thio~hQn-3-yl 4-~ttrans-2-(1-Piperidyl)cyclohexyl}oxy~phenyl Ketone.
oQ~
MeO ~ ~
1.698 g (5.60 mmol) o~ 4-[[trans-2-(1-piperidyl)cyclo-hexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 ~L (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophene (Example 1, Part B). A~ter cooling the slurry to 0 C, aluminum bromide (6.79 ~, 25.4 mmol) was added, producing W O 97/25033 PCTrUS96117995 a dark red mixture. The ice ~ath was removed an~ the reaction mixture was stirred at room temperature for 6 h.
The mixture was poured into 100 mL of cooled (0 ~C) 2.0 N
NaOH. The aqueous layer was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH40H in MeOH) in CH2C12).
mp 68-72 C; lH NMR (CDCl3) ~ 7.76 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, lH), 7.36 (d, J = 8.8 Hz, 2H), 7.31 (d, J =
2.4 Hz, lH), 6.94 (dd, ~ = 8.9 and 2.4 Hz, lH), 6.78 (d, J =
8.-8 Hz, 4H), 4.26 (td, J = 9.8, 4.1 Hz, lH), 4.09 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H), 2.92 (t, J = 5.8 Hz, 2H), 2.69 (m, 7H), 2.50 (m, 2H), 2.17-1.95 (m, 2H), 1.84 (m, 4H), 1.73 (m, 2H), 1.50-1.15 (m, 10H); FDMS 639 (M+); Anal. Calcd for C3gH46N2O4S: C, 73.32; H, 7.26; M, 4.38. Found: C, 73.03;
H, 7.13; N, 4.29.
20 Part E. (+)-6-Hydroxy-2-~4-~2-(1-~,y ~c,lidinyl)-~thoxy]phQnyl]b~nzo~blthioph~n-3-yl 4-~trans-2-(1-Piperidyl)cyclohexyl]oxy]ph~nyl K~tone Dioxalate.
The title compound was prepared from (+)-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[blthiophen-3-yl 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]phenyl ketone (Part D) as a yellow solid by essentially following the procedures described in Example 21, Parts B and C.
mp 140-145~ C; lH NMR (DMSO-d6) ~ 7.70 (d, J = 8.6 Hz, 2H), 30 7.38 (d, J = 2.2 Hz, lH), 7.34 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.7 Hz, lH), 7.06 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 10.9 Hz, lH), 4.69 (m, lH), 4.25 (m, 2H), 3.50 (m, 2H), 3.28 (m, 5H), 3.09 (m, 2H), 2.93 (m, 2H), 2.07 (m, 2H), 1.91 (m, 4H), 1.80 - 1.20 (m, 12H); FDMS 624 35 (M+); Anal. Calcd for C3gH44N204S-2.87C2H204: C, 59.48; H, 5.68; N, 3.17. Found: C, 59.45; H, 5.85; N, 3.35.
W O 97/25033 PCT~US96/17995 ~ rle 21 Preparation of (+)-6-Hydroxy-3-~4-[[trans-2-(1-piperidyl)cycloh~xylloxy]benzyl]-2-l4-t2-(1-~yrro-lidinyl)ethoxylphenyl]benzot b~ thiophene Dioxalat~.
HO ~ ~ 2 C2H2O4 ~
Part A. (+)-6-Methoxy-3-~4-[~tran~-~-(1-~iperidyl)-cyclohexyl~oxy]b~nzyl~-2-l4-l2-(1-pyrroliainyl)-ethoxy]phenyllbenzo lb] thio~hene.
RN
~~ ~
MeO ~ ~
To a solution of 6-methoxy-[2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl] 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]phenyl ketone (Example 20, Part D) (1.340 g, 2.10 mmol) in 21.0 mL of anhydrous THF was added dropwise 2.10 mL (2.10 mmol) of 1.0 M LiAlH4 in THF at 0 C.
The reaction mixture was stirred for l h and 45 min while allowing the temperature to be raised to 20 C. The reaction was then quenched at 0 C by addition of 80 ~L of H20, followed by 80 ~L of 15% NaOH, and then an additional 240 ~L
of H2O (Fieser workup). This mixture was then filtered over a pad of silica gel and washed with THF. The filtrate was concentrated to dryness under reduced pressure. The crude alcohol was dissolved in 21.0 mL of anhydrous CH2Cl2 and cooled to 0 C. To this was added 2.30 mL (14.7 mmol) of triethylsilane, and the reaction mixture was stirred for 5 CA 02236007 l998-04-27 W O 97/2~033 PCT~US96tl7995 ~' -107-min, followed by a dropwise addition of 1.60 mL (21.0 m~ol) of tri~luoroacetic acid. The ice bath was removed and the reaction mixture was stirred further for 3 h 45 min before being ~uenched with 25.0 mL of saturated NaHCO3 at 0 ~C. The - 5 layers were separated and the a~ueous layer was extracted with EtOAc (3 x 200 mL). The com~ined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 57:40:3 hexanes-THF-TEA) to afford 1.251 g (2.00 mmol, 96%) of a clear gel.
lH NMR: (CDC13) ~ 7.41 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.8 Hz, lH), 7.31 (d, ~ = 2.3 Hz, lH), 7.03 (d, ~ = 8.4 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (m, lH), 6.81 (d, J = 8.6 Hz, 2H), 4.15 (m, 5H), 3.86 (s, 3H), 2.94 (t, J = 5.9 Hz, 2H), 2.85-2.55 (m, 9H), 2.20-2.10 (m, 2H), 1.83 (m, 4H), 1.72 (m, 2H) 1.58-1.48 (m, 4H), 1.42-1.18 (m, 6H); FDMS 625 (M+);
Anal. Calcd for C39H4gN2O3S: C, 74.96; H, 7.74; N, 4.48.
Found: C, 75.00; H, 7.94; N, 4.35.
Part B. (+)-6-Hydroxy-3- 14 - 1 l tran~- 2 - ( 1-piperidyl)-cyclohexyl]oxylbenzyl]-2-14-r2-(1-pyrrolidinyl)-ethoxy]phQnyl3benzolb3thiophene.
~,o",~
HO ~ -To a solution of 1.150 g (1.84 mmol) (+)-6-methoxy-3-[4-[[trans-2-(1-piperidyl)cyclohexylJoxy]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part A) in 20.0 mL o~ anhydrous dichloroethane at 0 C was added 1.10 mL
(14.7 mmol) of ethanethiol, followed by the addition of 30 all]m;n-lm chloride (982 mg, 7.36 mmol). The yellow ~iphasic W O 97/25033 PCT~US96/17995 reaction mixture was allowed to warm to room temperature and stirred ~or 3 h. The reaction wa5 ~uenched at 0 C with 20 mL of saturated aqueous NaHCO3. The aqueous layer was separated and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with 150 mL of brine, dried over MgSO4, and concentrated under reduced pressure.
The crude product was puri~ied by using ~lash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 1.067 g (1.75 mmol, 95~) of a white solid.
mp 179-182 ~C; lH NMR (CDC13) ~ 7.30 (dd, 3 = 8.7, 1.9 Hz, 2H), 7.07 (d, J = 2.2 Hz, lH), 7.01 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 2.2 Hz, lH), 6.77 (m, 5H), 4.14 (t, J = 5.6 Hz, 2H), 4.12 (buried m, lH), 4.10 (s, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.81 (m, 5H), 2.69 (m, 4H), 2.14 (m, 2H), 1.87 (m, 4H), 1.71 (m, 2H), 1.58 (m, 3H), 1.38 (m, 3H), 1.26 (m, 4H); FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S: C, 74.71; H, 7.59; N, 4.59. Found: C, 74.92; H, 7.80; N, 4.53.
Part C. (+)-6-Hydroxy-3-[4-[[tr~n~-2-(1-piperidyl)-cycloh~xyl~oxy]b~nzyl]-2-~4-r2-(1-pyrroliainyl)-othoxy]phQnyl]benzo[b]thiophene Dioxalate.
In approximately 4 mL of CHCl3-EtOAc (1:1) was dissolved 14.7 mg (0.164 mmol) of oxalic acid. To this was added dropwise 50.0 mg (0.082 mmol) of (+)-6-hydroxy-3-[4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzyl]-2-[4-[2-(1-pyrro-lidinyl)ethoxyJphenyl]benzo[b]thiophene (Part C) in 7 m~ of CHCl3. A white precipitate was formed, and the slurry was sonicated for 30 min and filtered with EtOAc rinse. The precipitate was dried over P2Os at 55 C in a vacuum oven.
mp 163-165 ~C; lH NMR (DMSO-d6) ~ 7.44 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, lH), 7.27 (s, lH), 7.09 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.81 35 (dd, J = 8.7, 2.1 Hz, lH), 4.49 (m, lH), 4.33 (br t, 2H), 4.12 (s, 2H), 3.51 (br t, 2H), 3.28 (m, 5H), 3.15 (m, 2H), 3.01 (m, 2H), 2.10 (m, 2H), 1.92 (m, 4H), 1.75-1.60 (m, 6H), W O 97/25033 PCT/US96/179gS
1.55-1.40 (m, 3H), 1.26 (m, 3H); FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S 2.0C2H204 0.24CHC13: C, 61.90; H, 6.18; N, 3.42. Found: C, 61.90; H, 5.99; N, 3.37.
Example 22 Pr~paration of (+)-6-Hy~roxy-2-t4-12-(1-~yrroli~inyl)-ethoxy~ph~nyl]benzo[b]thioph~n-3-yl 6-~[trans-2-(1-Piperidyl)cyclohexyl]oxy]pyri~-3-yl Ketone.
oQ~
HO ~ -l?art A. (t)-6-lltran~-2-(1-Piperidyl)cyclohexyl]oxy]-3-pyriainecarboxylic Acid.
HQ
The title compound was prepared from methyl (+)-6-[[trans-2-(1-piperidyl)cyclohexyl]oxy~-3-pyridinecarboxylate as an o~f-white solid by essentially following the procedure described in Example 20, Part C.
H NMR (DMSO-d6) ~ 10.00 (m, lH) 8.73 (dd, J = 2.4, 0.5 Hz, lH), 8.21 (dd, ~ = 8.7, 2.4 Hz, lH), 7.04 (d, ~ = 8.6 Hz, 20 lH), 5.35 (m, lH), 3.60 (br t, lH), 3.49 (br d, J = 11.6 Hz, lH), 3.40 (br d, J = 11.4 Hz, lH), 3.18 (br q, lH), 2.73 (br ~ q, ~ = 11.2 Hz, lH), 2.48 (m, lH), 2.23 (m, lH), 2.10-1.83 (m, 2H), 1.83-1.58 (m, 6H), 1.45-1.12 (m, 4H).
; 25 Part B. ~+)-6-Hydroxy-a-[4 t2-(1-~yrroli~inyl)-othoxylphenyllbenzotb]thiophen-3-yl 6-[ttraAs-2-(1-Pi~eridyl)cyclohexyl]oxy]~yrid-3-yl Ketone.
W O 97/25033 PCT~US96/17995 The title compound was prepared in 29% yield ~rom 6-methoxy-2-~4-[2~ pyrrolidinyl)ethoxy]phenyl]benzo[b}-thiophene (Example 1, Part B) and (+)-6-[[trans-2-(1-piperidyl)cyclohexyl~oxy]-3-pyridinecarboxylic acid (Part A) by essentially following the procedures detailed in Example 20, Parts D and E.
lH NMR (CDC13) ~ 8.32 (d, J = 2.4 Hz, lH), 7.70 (dd, ~ = 8.6, 2.4 Hz, lH), 7.41 (d, ~ = 8.9 Hz, lH), 7.30 (d, J = 2 1 Hz, lH), 7.06 (d, ~ = 8.6 Hz, 2H), 6.81 (dd, ~ = 8.8, 2.2 Hz, lH), 6.62 (d, ~ = 8.6 Hz, 2H), 6.44 (d, ~ = 8.6 Hz, lH), 5.22 (m, lH), 4.07 (t, J = 5.4 Hz, 2H), 3.00 (t, ~ = 5.4 Hz, 2H), 2.87-2.57 (m, 9H), 2.20-2.00 (m, 2H), 1.95-1.65 (m, 6H), 1.60-1.20 (m, lOH); FDMS 626 (M~); Anal. Calcd for C37H43N3O4S-0.59H2O: C, 69.83; H, 7.00; N, 6.60. Found: C, 69.58; H, 6.73; N, 6.99.
r~ le 23 Pr~paration of (+) -6-Hydroxy-3-t6-l~trans-2-(1-pi~eridyl)cyclohexyl]oxyl~yrid-3-yl]methyl-2- r4- 12-(1-~yrrolidinyl~ethoxy]~henyl]~enzotb]thiophene Dioxalate.
~ C2H204 Part A. ~+)-6-Hydroxy-3-[6-l[trans-2-(1-piperidyl)-cyclohexyl]oxy]pyri~-3-yl~methyl-2-t4- r2- (1-pyrro-lidinyl)ethoxylphenyllbenzolblthiophene.
W~D97/25033 PCTAUS96/1799 .. ~ ~
HO~ N
The title compound was prepared in 39~ yield from 6-hydroxy-2- E 4-[2-(l-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophen-3-yl 6-[[trans-2-(1-piperidyl)cyclohexyl]oxy3pyrid-3-yl ketone (Example 22, Part B) by essentially following the procedures detailed in Example 21, Parts A and B.
mp 170-174 C; lH NMR (CDCl3) ~ 7.89 (d, ~ = 2.2 Hz, lH), 7.31-7.21 (m, 4H), 7.03 (d, J = 2.1 Hz, lH), 6.80 (d, J = 8.6 Hz, 3H), 6.54 (d, ~ = 8.5 Hz, lH), 5.11 (m, lH), 4.14 (t, J =
5.4 Hz, 2H), 4.05 (s, 2H), 2.99 (t, ~ = 5.4 Hz, 2H), 2.80 (m, 5H), 2.59 (m, 4H), 2.16 (m, 2H), 1.87 (m, 4H), 1.69 (m, 3H), 1.43-1.25 (m, 9H); FDMS 611 (M+); Anal. Calcd for C37H4sN3O3S: C, 72.63; H, 7.41, N, 6.87. Found: C, 72.34, H, 7.64, N, 6.61.
Part B. (+)-6-Hydroxy-3-~6-~t~ans-2-~1-~iperidyl)-cyclohexyl]oxy]~yria-3-yl]methyl-2-14-12-~1-pyrro-lidinyl)~thoxy]phenyl~benzo~b]thiophene Dioxalate.
The title compound was prepared from (+)-6-hydroxy-3-[6-[ [ trans- 2-(1-piperidyl)cyclohexyl]oxy]pyrid-3-yl]methyl-2-~4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b~thiophene (Part A) by essentially ~ollowing the procedures detailed in Example 20, Part C.
mp 128-133 C (dec); lH NMR (DMSO-d6) ~ 7.93 (s, lH), 7.47 (dd, J = 8.7 Hz, 2.7 Hz, 2H), 7.38 (m, 2H), 7.27 (d, ~ = 2.0 Hz, lH), 7.10 (d, J = 8.6 Hz, 2H) 6.83 (d, J = 8.6 Hz, lH), 6.77 (d, ~ = 8.4 Hz, lH), 5.13 (m, lH), 4.35 ~br t, 2H), 4.14 (s, 2H), 3.56 (br t, 2H), 3.33-3.00 (m, 9H), 2.12 (m, 2H), 1.99-1.94 (m, 4H), 1.75-1.62 tm, 6H), 1.28-1.17 (m, 6H); FDMS
612 (M+); Anal. Calcd for C37H4sN3O3S 2.36C2H204: C, 60.79;
H, 6.08; N, 5.10. Found: C, 60.76; H, 6.25i N, 5.26.
Exampl~ 24 Pr~paration of 2-~4-12-(1-Pyrro~ yl)ethoxy]phenyl3-3,4-~ihydronaphth-1-yl 4-12-(1-Piperidyl)ethoxy]phenyl Ketone Dioxalate.
~ O - N ~ 2 c2H2~4 Part A. 2-(4-Hydroxyphenyl)-3,4-aihydronaphth-1-yl 4-~2- (1-Piperidyl)ethoxy]~henyl Ketono.
--N~J
~_ OH
The title compound was prepared in 95% yield from 2-(4-methoxyphenyl)-3,4-dihydronaphth-1-yl 4-[2-(1-piperidyl)-ethoxy]phenyl ketone by essentially ~ollowins the procedure detailed in Example 21, Part B.
mp 83-85 C; lH NMR (CDC13) ~ 7.75 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 7.1 Hz, lH), 7.16-7.05 (m, 4H), 6.94 (d, ~ = 7.8 Hz, lH), 6.60 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.5 Hz, 2H), 4.01 (t, ~ = 5.6 Hz, 2H), 3.03 ~distorted t, 2H), 2.81 (t, J
= 8.4 Hz, 2H), 2.74 (t, ~ = 5.6 Hz, 2H), 2.53 (br s, 4H), 1.61 (m, 4H), 1.43 (m, 2H); FDMS 453 (M+); Anal. Calcd ~or C30H31NO3 0~56CH2C12: C, 73.24; H, 6.46; N, 2.79. Found:
C, 73.27; H, 6.50; N, 2.72.
Part B. 2-14-12-(1-Pyrroli~inyl)ethox~]ph~nyl]-3,4-aihy~ronaphth-1-yl 4-r2-(1-Piperidyl)ethoxy]phenyl Ketone Dioxalate.
CA 02236007 l998-04-27 W O 97/25033 PCTrUS96/17995 ~ 0 ~
~ ~ o 2 C2H2~4 To a solution of 731.0 mg (1.61 mmol) 2-(4-hydroxy-phenyl)-3,4-dihydronaphth-1-yl 4-[2~ piperidyl)ethoxy]-phenyl ketone (Part A) in 16.0 mL of anhydrous DMF at room temperature was added Cs2CO3 ~1.575 g, 4.83 mmol), ~ollowed by addition of 1-(2-chloroethyl)pyrrolidine hydrochloride (411 m~, 2.42 mmol). The light yellow slurry was then heated to 85 C and stirred ~or 3.5 h. The reaction mixture was cooled to room temperature and 80 mL of H2O was added. This mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 100 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 821.5 mg (1.49 mmol, 93%) of a yellow gel. The free diamine was then used to prepare the title compound by essentially following the procedure detailed in Example 21, Part C.
mp 93-97 C; lH NMR (DMSO-d6) ~ 7.77 (d, ~ = 8.7 Hz, 2H), 7.26-7.01 (m, 5H), 6.92 (d, ~ = 8.8 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 7.7 Hz, lH), 4.33 (br t, 2H), 4.18 (br t, 2H), 3.45 (m, 2H), 3.36 (m, 2H), 3.25 (m, 4H), 3.13 (m, 4H), 2.99 (br t, 2H), 2.72 (br s, 2H), 1.87 (m, 4H), 1.68 (m, 4H), 1.46 (m, 2H); FDMS 551 (M+), 641 (M + 1.0 C2H204); Anal.
Calcd ~or C36H42N203-2.68C2H2O4: C, 62.72i H, 6.03; N, 3.54.
Found: C, 62.32; H, 5.71; N, 3.64.
~ Example 25 Preparation of 1-t4-t2-(1-P~peridyl)ethoxy]bQnzyl]-2-l4-~2~ ?yrrolidinyl)ethoxy]phenyl~-3,4-dihydronaph-thalone Dioxalate.
w 097/25033 PCT~US96/17995 ~3~ --N~ 2 C2H2~4 ~ N~
The title compound was prepared in 68% yield from 2-[4~
[2~ PYrrO1idinY1)ethOXY]PhenY1]- 3,4 -dihydronaphth-l-yl 4-[2- (l-piperidyl)ethoxy]phenyl ketone by essentially 5 following the procedures detailed in Example 21, Parts A and C.
mp 140-143 ~C; 1H NMR (DMSO-d6) ~ 7.36 (d, .J = 7.9 Hz, lH), 7.19-7.02 (m, 6H), 6.94-6.79 (m, 5H), 4.96 (S, 2H), 4.24 (m, 4H), 3.36-3.30 (m, 7H), 3.15 (m, 4H), 3.05-2.90 (m, 3H), 2.80-2.55 (m, 2H), 1.92 (m, 4H), 1.72 (m, 4H), 1.50 (m, 2H);
FDMS 534 (M-2); Anal. Calcd for C36H44N2O2 2.0C2H204 C, 67.02; H, 6.75; N, 3.91. Found: C, 67.32; H, 6.69; N, 4.10.
r~ le 26 Preparation of 2-14-12- (l-~y lolidinyl)~thoxy]phenyl~-naphth-l-yl 4- ~2 -(l-Piperidyl)ethoxyl~h~nyl Ketono DioxalatQ .
~,~~--Nl~ 2 C2H2o4 ~ N~
Part A. 2-(4-Hy~l~o,.y~henyl)na};)hth-l-yl 4- [2- (1-Piperidyl)Qthoxy]phenyl K~tone.
o - N
/~ OH
~ , ~
The title compound was prepared in 92% yield from 2-(4-methoxyphenyl)naphth-l-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone by essentially following the procedure described in Example 21, Part B.
mp 167-170 C; lH NMR (CDCl3) ~ 7.98 (d, ~ = 8.5 Hz, lH), 7.91 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.0 Hz, lH), 7.61-7.41 (m, 5H), 7.17 (d, .J = 8.5 Hz, 2H), 6.69-6.59 (m, 4H), 4.05 (t, J = 5.6 Hz, 2H), 2.79 (t, J = 5.4 Hz, 2H), 2.58 (br s, 4H), 1.65 (m, 4H), 1.47 (m, 2H); FDMS 451 (M~).
Part B. 2-14-12-(1-ry~ oli~inyl)ethoxy]~hQnyl~naphth l-yl 4-12-~1-Piperidyl)Qthoxy]phenyl Ketone Dioxalate.
The title compound was prepared ~rom 2-(4-hydroxy-phenyl)naphth-l-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone in 94% yield by essentially following the procedure detailed in Example 3, Part D and Example 21, Part C.
mp 95-100 ~Ci lH MMR (DMSO-d6) ~ 8.11 (d, ~ = 8.6 Hz, lH), 8.03 (d, J = 8.0 Hz, lH), 7.58-7.40 (m, 6H), 7.29 (d, ~ = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz, 4H), 4.30 (br t, 2H), 4.21 (br t, 2H), 3.47 (br t, 2H), 3.34 (br t, 2H), 3.27 (br s, 4H), 3.18-3.04 (m, 4H), 1.88 (br s, 4H), 1.67 (m, 4H), 1.46 (m, 2H); FDMS 549 (M~); Anal. Calcd for C36H4oN2o3-2.27c2H2o4:
C, 64.66; H, 5.96; N, 3.72. Found: C, 64.22 H, 5.89; M, 3.56.
_1~ 27 Preparation of l-l4-l2-(l~piperidyl)Qthoxy]bQnzyll-2 ~4-12-(1-pyrrolidinyl)ethoxy]phQnyl~naphthalenQ
Dioxalat~.
~ N~
The title compound was prepared in 71% yield from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]naphth-1-yl 4-~2-(1-piperidyl)ethoxy]phenyl ketone by essentially following the procedures detailed in Example 21, Parts A and C.
mp 184-187 C; lH NMR (DMSO-d6) ~ 7.96 (d, ~ = 7.7 Hz, lH), 7.91 (d, J = 8.5 Hz, lH), 7.85 (d, ~ = 7.7 Hz, lH), 7.50-7.40 (m, 3H), 7.31 (d, ~ = 8.4 Hz, 2H), 7.05 (d, ~ = 8.4 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.82 (d, 3 = 8.7 Hz, 2H), 4.36 (s, 2H), 4.32 (br t, 2H), 4.20 (br t, 2H), 3.53 (m, 2H), 3.31 (m, 6H), 3.09 (m, 4H), 1.93 (m, 4H), 1.69 (m, 4H), 1.50 (m, 2H); FDMS 535 (M+); Anal. Calcd ~or C36H42N2O2-2.0C2H204:
C, 67.21; H, 6.49; N, 3.92. Found: C, 66.93; H, 6.45; N, 4.05.
ExamplQ 28 Pre~aration of 2-14-~2-(l-~yl~olidinyl)ethoxy]phenyl]-benzo~b~thiophen-3-yl 4-~2-(1-Pi~er~dyl)ethoxylphQnyl Ketone Dioxalate.
-- N~
~o 2 c2E~2~4 Part A. 2-(4-Methoxyphenyl)b~nzolb]thiophen-3-yl 4-HydroxyphQnyl Ketone.
~ OH
O~_y ~ OMe A -0.5 M solution of sodium thioethoxide was prepared by adding ethanethiol (1.60 mL, 21.4 mmol) to a suspension of 60% NaH dispersion in mineral oil (769 mg, 19.2 mmol) in 40 mL of anhydrous DMF at 0 C. The ice bath was removed and the solution was stirred at room temperature for 30 min. The 0.5 M solution of sodium thioethoxide was then added dropwise to the solution of 4.00 g (10.7 mmol) of 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl 4-methoxyphenyl ketone in 10.0 mL of anhydrous DMF at room temperature. The reaction mixture was f heated at 85 C for 3 h, then allowed to cool to room temperature, and acidified with 20 mL of 1.0 N HCl. To this W O 97/25033 PCTfiUS96/17995 was added 200 mL o~ H2O and the mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with 200 mL o~ brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by PrepLC (30% EtOAc in hexanes3 to afford 3.017 g of the title compound ~8.37 mmol, 78%) as a yellow ~oam.
mp 76-77 C; lH NMR (CDC13) ~ 7.85 (m, lH), 7.72 (d, J =
8.7 Hz, 2H), 7.64 (m, lH), 7.38-7.29 (m, 4H), 6.76 (d, J =
8.7 Hz, 2H), 6.68 (d, ~ = 8.7 Hz, 2H), 6.03 (br s, lH), 3.75 (s, 3H); FDMS 360 (M+); Anal. Calcd for C22H16O3S: C, 73.31;
H, 6.20. Found: C, 73.57; H, 4.60.
Part B. 2-(4-Methoxyphenyl3benzotb]thiophen-3-yl 4-[2-(1-Piperidyl)ethoxy~phenyl Ketone.
N
~ OMe ~
The title compound was prepared using 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-hydroxyphenyl ketone and l-(2-chloroethyl)piperidine hydrochloride in 81% yield by essentially following the same procedures detailed in Example 24, Part B.
mp 41-44 C; 1H NMR (CDCl3) ~ 7.85 (m, lH), 7.77 (d, J =
8.8 Hz, 2H), 7.64 (m, lH), 7.40-7.33 (m, 4H), 6.77 (d, J =
8.6 Hz, 4H), 4.11 (t, J = 5.8 Hz, 2H), 3.76 (s, 3H), 2.77 (t, J = 5.8 Hz, 2H), 2.51 (br s, 4H), 1.61 (m, 4H), 1.44 (m, 2H);
FDMS 471 (M+); Anal. Calcd ~or C2gH2gNO3S: C, 73.86; H, 6.20, N, 2.97. Found: C, 73.90; H, 6.20; N, 3.14.
Part ~. 2-(4-Hyd~o~y~henyl~benzo~b]thiophen-3-yl 4-~2-(1-Piperidyl)ethoxy]phenyl Ketone.
W O 97/25033 PCTrUS96/17995 ~ OH ~
The title compound was prepared from 2-(4-methoxy-phenyl)benzo[bJthiophen-3-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone in 93% yield as a yellow foam by essentially following the same procedure detailed in Example 21, Part B.
mp 100-103 C; lH NMR (CDC13) ~ 7.84 (m, lH), 7.70 (m, lH), 7.68 (d, ~ = 8.9 Hz, 2H), 7.34 (m, 2H), 7.19 (d, ~ = 8.7 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 6.58 (d, ~ = 8.6 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 2.78 (t, ~ = 5.6 Hz, 2H), 2.57 (br s, 4H), 1.64 (m, 4H), 1.45 (m, 2H); FDMS 457 (M+); Anal.
Calcd for C2gH27NO3S: C, 73.49; H, 5.95i N, 3.06. Found:
C, 73.76; H, 5.97; N, 3.07.
Part D. 2-~4-~2~ y ~lidinyl)Qthoxylphonyl]-benzolb]thiophen-3-yl 4-C2-(1-Pip~ridyl) ethoxy]phenyl Ketone Dioxalate.
The title compound was prepared in ~uantitative yield ~rom 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-piperidyl)ethoxy]phenyl ketone (Part C) by essentially following the procedure detailed in Example 4, Part B, except using 1-(2-hydroxyethyl)pyrrolidine, and Example 21, Part C.
mp 86-90 ~C; lH NMR l~MSO-d6) ~ 8.06 (d, ~ = 7.8 Hz, lH), 7.70 (d, J = 8.7 Hz, 2H), 7.43-7.35 (m, 5H), 6.96 (d, ~ = 8.9 Hz, 2H), 6.95 (d, ~ = 8.6 Hz, 2H), 4.34 (br t, 2H), 4.25 (br t, 2H), 3.48 (br t, 2H), 3.37 (br t, 2H), 3.27 (m, 4H), 3.13 (m, 4H), 1.89 (m, 4H), 1.68 (m, 4H), 1.47 (m, 2H); FDMS 555 (M+); Anal. Calcd for C34H3gN203S 2.0C2H204: C, 62.11; H, 5.76; N, 3.81. Found: C, 61.81; H, 5.61; N, 3.53.
~r _ le 29 W O 97/25033 PCT~US96/17995 Preparation o~ 3-c4-l2-(l-piperidyl)ethoxylbenzyl]-2-~4-~2-(1-pyrrolidinyl)ethoxy]phenyllbenzolb]thiophQne Dioxalate.
~o~
M ~
~ 2 c2H2~4 The title compound was prepared in 63% yield ~rom 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl)benzo[b]thiophen-3-yl 4-[2-(l-piperidyl)ethoxy]phenyl ketone by essentially following the procedures detailed in Example 21, Parts A and C.
mp 188-lgl C; lH NMR (DMSO-d6) ~ 7.96 (m, lH), 7.55 (m, lH), 7.50 (d, J = 7.9 Hz, 2H), 7.34 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.88 (d, 8.5 Hz, 2H), 4.34 (br t, 2H), 4.21 (m, 4H~, 3.55 (m, 2H), 3.33 (m, 6H), 3.11 (m, 4H), 1.94 (m, 4H), 1.70 (m, 4H), 1.51 (m, 2H); FDMS 541 (M+); Anal. Calcd for C34H40N2o2s-2.oc2H2o4: C, 63.32; H, 6.15; N, 3.89. Found: C, 63.03; H, 6.05; N, 3.81.
R~lQ 30 Pr~paration o:E 3- r4- l2-(1-PipQridinyl)ethoxy]benzoyl]-2-14-t2-(l-~ oli~inyl)ethoxy]phQnyl]:benzolb]thio-phene-6-carboxamide Dioxalate.
~N
o~' ~ (C2E~204)2 H2N ~ ~~
Part A. 2-[4- r 1 (1, l-Dime~hylethyl)dimethylsilyl]-oxylphenyl]-6-hy~roxybenzolb]thiophen-3-yl 4-r2-(1-25 Pi~?eri~inyl)ethoxy]ph~nyl Ketone.
~N ..
O
0~
~ osi~su-t)Me2 To a solution of 30 g (58.8 mmol) of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)-ethoxy]phenyl ketone hydrochloride in 120 mL of anhydrous THF
and 60 mL of anhydrous DMF was added 20 mL (144 mmol) of anhydrous triethylamine and 9.75 g (64.7 mmol) of tert-butyldimethylsilyl chloride under a nitrogen atmosphere. The reaction mixture was heated at 60 ~C in an oil bath for 4 h and then cooled to room temperature. The solution was diluted with 225 mL of toluene, filtered through a medium glass frit, and concentrated at reduced pressure. The residue was purified by PrepLC (0 to 4% MeOH in CH2Cl2) to give 6.77 g (11.5 mmol, 20%) of a yellow foam.
lH NMR (CDC13) ~ 7.67 (d, ~ = 8.8 Hz, 2H), 7.45 (d, ~ =
8.8 Hz, lH), 7.23 (m, 3H), 6.83 (d, 3 - 8.8 Hz, lH), 6.68 (m, 4H), 4.18 (br s, 2H), 2.96 (br s, 2H), 2.72 (br s, 4H), 1.75 (br s, 4H), 1.51 (br s, 2H), 0.93 (s, 9H), 0.12 (s, 6H); high resolution FDMS 588.2648 (M+).
Part B. 2-14-t[(1 r 1-Dimethylethyl)dimQthylsilyl]-oxy]ph~nyl~-6-[~(trifluoromethyl)sulfonyl~oxy~-bonzo~b~thiophQn-3-yl 4-[2-(1-PipQridinyl)ethoxy]-phenyl Ketone.
N
~~
0~
,s~ ~ osi(su-t)~e2 To a solution of 6.0 g (10.2 mmol) of 2-[4-[[(1,1-dimethylethyl)dimethylsilyl~oxy]phenyl]-6-hydroxybenzo-CA 02236007 l998-04-27 W O 97/2~033 PC~nUS96~17995 -c -121-[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (Part A) in 60 mL of anhydrous dichloroethane was added 4.13 g (40.8 mmol) of anhydrous trietllylamine and 4.01 g (11.2 Ir~nol) of N-phenyltrifluoromethanesulfonimide under a nitrogen 5 atmosphere. The reaction mixture was stirred at room temperature for 4 h and then filtered through a cotton plug and concentrated at reduced pressure. The residue was chromatographed over silica gel (0 to 3% MeOH in CH2C12) to give 7.20 g (10.0 mmol, 98%) of a brown foam.
1H Nl~ (CDC13) â 7.82 (d, J = 9.O Hz, 2H), 7.75 (d, J =
8.8 Hz, 2H), 7.32 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8 6 Hz, 2H), 4.20 (t, J = 5.6 Hz, 2H), 2.91 (t, J =
5.7 Hz, 2H), 2.66 (br s, 4H), 1.70 (m, 4H), 1.53 (m, 2H), 0.98 (s, 9H), 0.17 (s, 6H); FD~S 719.7 (M+).
Part C. 2 -(4-Hyd ~y~"henyl) -3- ~4- 12- (l-l?iperidinyl) -ethoxy~benzoyl]bQnzo~blthio~one-6-carboxylic Acid M~thyl Ester.
N
~~
~~
MeO2C ~ oH
To a solution of 3.7 mL of anhydrous DMF, 1.8 mL of anhydrous triethylamine, and 1.8 mL of anhydrous methanol was added 1.0 g (1.4 mmol) of 2-[4-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]phenyl]-6-[~(trifluoromethyl)sulfonyl]oxy]-25 benzo[b] thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (Part B) at room temperature. To this were added 29.4 mg (0.13 mmol) of Pd(II) acetate and 53.8 mg (0.13 mmol) of 1,3-bis(diphenylphosphino)propane, and the flask was evacuated and then filled with carbon monoxide in a balloon.
30 The reaction mixture was heated at 55 ~C for 12 h under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, the solution was saturated with W 097/25033 PCTnJS96/17995 nitrogen gas and then concentrated at reduced pressure. To this were added 5 mL of THF and 4 mL of lN HCl, and the solution was stirred at room temperature for 3 h. The reaction mixture was treated with 10 mL of 2N ammonium hydroxide solution for an additional hour at room temperature. The solution was poured into a separatory funnel and the a~ueous layer was saturated with sodium chloride and extracted three times with 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was purified on silica gel (0 to 10% MeOH in CH2C12) to give 578 mg (1.1 mmol, 80%) of an orange ~oam.
lH MMR (CDCl3) ~ 8.62 (s, lH), 8.07 (d, J = 8.5 Hz, lH), 7.92 (d, ~ = 8.5 Hz, lH), 7.68 (d, J = 8.6 Hz, 2H), 7.22 (d, ~ = 8.2 Hz, 2H), 6.69 (d, J = 8.6 Hz, 4H), 4.25 (t, J =
5.6 Hz, 2H), 4.01 (s, 3H), 3.07 (t, J = 4.3 Hz, 2H), 2.87 (br s, 4H), 1.82 (br s, 4H), 1.59 (br s, 2H); FDMS 516 (M+)-Part D. 3-l4-~2-(1-Pip~riainyl)~thoxylbenzoyl3-2-l4-~2-( 1-pyrrolidinyl)~thoxy]phenyl~b~nzo~b]thiophene-6-carboxylic ACid Methyl Ester.
~ N
~_~
MeO2CJ~o~N
To a solution of 1.5 g (2.9 mmol) of 2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-benzo[b]thiophene-6-carboxylic acid methyl ester (Part C) and 544 mg (3.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride in 20 mL of anhydrous DMF was added 2.37 g (7.3 mmol) of cesium carbonate at room temperature under a nitrogen atmosphere. The reaction mixture was heated at CA 02236007 l998-04-27 W O 97~033 PCT~US96/17995 60 ~C for 4 h and then cooled to room temperature and diluted with 125 mL of THF and 75 mL of water. The a~ueous layer was saturated with sodium chloride and extracted twice with 50 mL
portions of THF. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was puri~ied on silica gel (1:1 MeOH/TEA (10~) in THF) to give 1.26 g (2.2 mmol, 77%) of an orange-brown foam.
lH NMR (CDCl3) ~ 8.57 (s, lH), 7.98 (dd, 3 = 8.6, 1.5 Hz, lH), 7.77 (d, ~ = 8.8 Hz, 2M), 7.66 (d, J = 8.5 Hz, lH), 7.38 (d, J = 8.8 ~z, 2H), 6.78 (dd, ~ = 8.7, 6.7 Hz, 4H), 4.18 (m, 4H), 4.01 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.74 (t, ~ = 6.0 Hz, 2H), 2.59 (m, 4H), 2.47 (m, 4H), 1.79 (m, 4H), 1.58 (m, 4H), 1.48 (m, 2H); FDMS 614 (M+l).
Part E. 3-[4-[2-(1-Piperiainyl)ethoxylb~nzoyl]-2-[4-l2-( 1-pyrroli~linyl)ethoxylphenyl~ b~nzo ~blthiophene-6-carboxamide.
~N
~,0 H2N~ 3~ ~N
~
To a solution o~ 4.37 g (7.1 mmol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxylic acid methyl ester (Part D) in 100 mL of methanol was added 35 mL of liquid anhydrous ~mm~n; a. The solution was sealed in a shaker and - heated to 60 ~C for 3 days. The solution was then saturated with nitrogen gas, concentrated at reduced pressure, and chromatographed on silica gel (1:1 TEA/MeOH in THF, 0 to 10%) to give 3.22 g (5.4 mmol, 76%) of a yellow-brown ~oam.
lH NMR (CDC13) ~ 8.40 (s, lH), 7.72 (m, 4H), 7.37 (d, J -8.6 Hz, 2H), 6 78 (dd, ~ = 8.1, 2.1 Hz, 4H), 4.07 (m, 4H), 2.86 (t, ~ = 5.6 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 2.61 (br s, 4H), 2.48 (br s, 4H), 1.80 (br s, 4H), 1.59 (m, 4H), 1.43 (m, 2H); FDMS 597 (M+).
Part F. 3-~4-~2-(1-Piperidinyl)ethoxy]benzoyl]-2-~4-~2-(1-pyrroliainyl)~thoxY]phOnyl]benzO~blthio~hen~-6-carh~x~ ;de Dioxalate.
A solution of 3- E 4-[2-(1-piperidinyl)etho ~]benzoyl]-2-~4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophene-6-car~oxamide (Part E) (131 my, 0.219 mmol) in EtOAc (8 mL) was treated with a solution of oxalic acid (49.3 mg, 0.548 mmol) in EtOAc (8 mL) to form a white suspension. After filtration and drying, 135 mg (79%) of the title compound was obtained as a white solid.
mp 87.0-93.0 ~C; IR (KBr) 3420 (br), 3359 (br), 2681 (br), 1722, 1650, 1599 cm-l; lH NMR (DMSO-d6) ~ 9.20 (br s, 4H), 8.56 (s, lH), 8.06 (s, lH), 7.83 (d, ~ = 8.5 Hz, lH), 7.70 (d, J = 8.3 Hz, 2H), 7.35-7.45 (m, 4H), 6.96 (d, J = 8.3 Hz, 4H), 4.26-4.38 (m, 2H), 4.20-4.26 (m, 2H), 3.40-3.50 (m, 2H), 3.30-3.38 (m, 2H), 3.19-3.30 (m, 4H), 3.02-3.18 (m, 4H), 1.82-1.92 (m, 4H), 1.62-1.72 (m, 4H), 1.20-1.48 (m, 2H); FDMS
m/e 598 (M+-C4H3Og); Anal. Calcd for C3gH43N3O12S: C, 60.22;
H, 5.57; N, 5.40; S, 4.12. Found: C, 6Q.07; H, 5.68; N, 5.18; S, 4.02.
~Y~ I?1Q 31 Preparation of 3-t~4-E2-(1-PiP~ridinYl)ethoxy]phenyl]
mothyll-2-[4-~2-(1-pyrrolidinyl)e~hoxylph~n~lbenzo-~b]thio~hene-6-methA~ 9 Dioxalato.
W O 97/25033 PCT~US96/17995 ~N
O (C2~204 ) 2 H2N ~ ~ N
Part A. 3-~4-~2-(l-piperidinyl)ethoxy]b~nzoyll-2-t4-[2- (l-pyrroliainyl)ethoxy]~henyl]benzo~b] thiophene-6-carbonitrile .
~N
~ O
~~ ~
~ O~
To a solution of 3.1 g (5.2 mmol) of 3-~4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxamide (Example 30, Part E) in 75 mL of anhydrous THF was added 3.1 g (13.0 mmol) of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (inner salt) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 days and then filtered through a medium frit, concentrated at reduced pressure, and chromatographed on silica gel (1:1 TEA/MeOH in THF, 0 to 10%) to give 2.70 g (4.7 mmol, 90%) of a brown foam~
~H NMR (CDCl3) ~ 8.18 (s, lH), 7.72 (d, J = 8.9 Hz, 3H), 7.56 (d, J = 8.1 Hz, lH), 7.38 (d, ~ = 8.6 Hz, 2H), 6.80 (t, J = 8.3 Hz, 4H), 4.22 (br s, 4H), 3.10 (br s, 2H), 2.89 (br s, 6H), 2.64 (br s, 4H), 1.95 (br s, 4H), 1.70 (br s, 4H), 1.43 (br s, 2H); FDMS 580 (M+).
Part B. 6-(~ ;n~- ~thyl)-a-14-~2-(1-piperi~inyl)-ethoxy]phenyl~-2-[4-12-(1-pyrrolidinyl)ethoxy]phenyl~-I:~enzotb]thiophene-3-methanol.
N
H2N J~ ~N
To a solution of 1.35 g (2 3 mmol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carbonitrile (Part A) in 30 mL o~
anhydrous THF under a nitrogen atmosphere was added 414 mg (11.6 mmol) of lithium aluminum hydride. The reaction was stirred ~or 2.5 hours at room temperature and then quenched with 5 mL of ethyl acetate and 5 mL of saturated aqueous potassium sodium tartrate for 16 h. The reaction mixture was poured into 50 mL of water, saturated with sodium chloride, and extracted with three 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous magnesium sulfate, and concentrated to give 1.32 g (95% crude yield) of a brown foam.
lH NMR (CDCl3) ~ 7.68 (m, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.4 Hz, lH), 6.88 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.17 (s, lH), 4.0~ (m, 4H), 3.87 (s, 2H), 2.86 (t, ~ = 5.9 Hz, 2H), ~20 2.72 (t, J = 6.1 Hz, 2H), 2.57 (br s, 4H), 2.47 (br s, 4H), 1.75 (br s, 4H), 1.57 (m, 4H), 1.43 (br s, 2H).
Part C. 3-~14-12-(1-Piperiainyl)ethoxY]ph~nyll-methyl]-2-[4-12~ pyrrolidinyl)Qthoxylph~nyl]-b~nzo~blthioph~ne-6-moth~n~ ;ne.
~) .
~N
H2N "~ ~N
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 To a solution of 1.32 g (2 .3 Ir~nol) of 6-(aminomethyl)-oc-[4-[2- (1-piperidinyl)ethoxy]phenyl]-2-[4- [2- (l-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene-3-methanol in 40 mL of anhydrous dichloroethane at 0 ~C was added 1.84 g (15.8 mmol) of triethylsilane and 2.62 g (23.0 mmol) of trifluoroacetic acid, respectively, under a nitrogen atmosphere. After one hour at 0 ~C, the reaction was warmed to room temperature and stirred for 24 h. The reaction was ~uenched with 10 mL of saturated aqueous sodium bicarbonate and poured into 30 mL of water. The aqueous layer was saturated with sodium chloride, separated from the dichloroethane layer, and extracted with three 50 mL portions of THF. The combined organic layers were dried over anhydrous m~gn~,qium sulfate and concentrated at reduced pressure to give 786 mg ~60% crude yield) of a brown foam. This material was carried on to the salt in Part D.
Part D. 3-~[4-~2-(l-Pi~eridinyl)ethoxylphenyl3 methyl]-2-14-12-(1-pyrrolidinyl)ethoxyl~henyll-benzo~blthiophene-6-mQthAr~A ; r~9 Diox ate.
~ o (C2~2O4)2 /~J ~>
H2N J ~ o~N
3-[l4-[2-(l-piperidinyl)ethoxy]phenyl]methyl]-2-[4-[2-~l-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-met~n~mine ~Part C) was dissolved in 50 mL of ethyl acetate and added to a solution of 100 mg of oxalic acid in 30 mL of ethyl acetate. After ~ing 10 mL of ether to the solution, the precipitate was filtered to give 1.05 g ~99%) of a white solid.
mp 140-142 ~Ci lH NMR (DMSO) ~ 8.04 (s, lH), 7.58 (d, J =
8.3 Hz, lH), 7.47 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.3 Hz, lH), 7.09 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), W O 97/2~033 PCT~US96/17995 6.83 (d, ~ = 8.6 Hz, 2H), 4.20 (m, 4H), 4.13 (s, 2H), 4.06 (t, ~ = 5.6 Hz, 2H), 3.17 (t, ~ = 5.3 Hz, 2H), 2.92 (br s, 4~), 2.86 (t, J = 5.6 Hz, 2H), 2.64 (br s, 4H), 1.81 (br s, 4H), 1.55 (m, 4H), 1.41 (d, ~ = 5.1 Hz, 2H); FDMS 570.4 (M+).
Example 32 PreparatiOn o~ 3-[t4-l2-(l-piperidinyl)ethoxy~phe~
methyl]- 2-~4-l2-( l-pyrrolidinyl)ethoxy]phenyll-bQnzolb]thiophenQ-6-methanol Diox 1 e.
O (C2H202 ) 2 ~~
Part A. oc( 3)-~4-t2-( l-Piperidinyl)ethoxy~phenyl~ -2-[4-~2-(1-pyrrolidinyl)ethoxy3phenyl~benzo ~b~ thio};)hene-3, 6-~lim~thanol.
N
~~
~ \ ~ o ~ ~
Diisobutylall]m;nll~ hydride (1.0 M in toluene, 3.59 mL) was added dropwise to a stirred solution of 3-[4-[2-(1-piperidinyl~ethoxy]benzoyl]-2-[4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene-6-carboxylic acid methyl ester (550 mg, 0.898 mmol) in anhydrous THF (6 mL) at 0 ~C under argon.
The mixture was stirred at 0 ~C for 1.5 h. Methanol (2 mL) and saturated aqueous potassium sodium tartrate solution (15 mL) were sequentially added to the mixture, and the resultant two-layered solution was stirred vigorously at ambient temperature for 2 h. The mixture was extracted with a mixed solvent of ethyl acetate/THF (1:1, 30 mL x 2). The combined organic layers were dried over MgSO4, filtered, and WO 97/25033 PCT~US96/17995 -12g-concentrated to give 496 mg (crude yield 94%) of the diol as a gum.
-H NMR (CDCl3) ~ 7.79 (s, lH), 7.68 (d, ~ = 8.4 Hz, lH), 7.36 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, lH), 7.13-7.19 (m, 2H), 6.84 (d, ~ = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 6.17 (s, lH), 4.72 (s, 2H), 3.98-4.08 (m, 4H), 3.25 (br s, lH), 2.90 (t, J = 5.8 Hz, 2H), 2.76 tt, ~ = 5.8 Hz, 2H), 2.60-2.68 (m, 4H), 2.45-2.55 (m, 4H), 1.78-1.85 (m, 4H), 1.55-1.65 (m, 4H), 1.38-1.46 (m, 2H).
Part B. 3-~4-~2-(1-Piperi~inyl)ethoxy~henyl]-methyl]-2-~4-~2-(1-~yrrolidinyl)ethoxy]phenyl]benzo-~b~thioph~no-6-met~ol Dioxalate.
~N
O (C2H202)2 ~ ~N
Triethylsilane (0.946 m~, 5.92 mmol) and trifluoroacetic acid (O.652 mL, 8.46 mmol) were added consecutively to a stirred solution of a(3)-r4-[2-(1-piperidinyl)ethoxy]-phenyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy3phenyl]benzo[b]-thiophene-3,6-dimethanol (Part A) (496 mg, 0.846 mmol) in dry 1,2-dichloroethane (5 mL) at 0 ~C under argon atmosphere, and the resultant solution was stirred at 0 ~C for 6 h. After dilution with THF (25 mL), the mixture was washed with saturated aqueous NaHCO3 (15 m~) and the aqueous layer was extracted with 'l'~ (15 mL). The combined organic layers were washed with brine l15 mL), dried over MgSO4, filtered, and concentrated. The gummy residue was chromatographed on silica [gradient TEA/i-PrOH (1:2) 0-4% in THF] to isolate 110 mg 123%) of the free base as a gum. The free ~ase was then ; 30 dissolved in EtOAc (5 mL) and treated with a solution of oxalic acid (39.9 mg, 0.443 mmol) in EtOAc (5 mL) to form a CA 02236007 l998-04-27 W 097/25033 PcT~us96/l799s white suspension. After filtration and drying, 120 mg (83%) of the title compound was obtained as a white solid.
mp 102.0-106.0 ~C; IR (KBr) 3410 (br), 2700 (br), 1725 cm~l;
lH N~IR (DMSO-d6) ~ 1.40-1.50 (m, 2H), 1.60-1.70 (m, 4H), Y
1.85-1.95 (m, 4H), 3.00-3.18 (m, 4H), 3.22-3.40 (m, 6H), 3.45-3.53 (m, 2H), 4.15 (s, 2H), 4.18-4.25 (m, 2H), 4.25-4.35 (m, 2H), 4.55 (s, 2H), 6.82 (d, ~ = 8.3 Hz, 2H), 6.98 (d, ~ -8.3 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 10 lH), 7.43 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.2 Hz, lH),7.84 (s, lH), 8.60 (br s, 4H); FDMS m/e 571 (M+-C4H3Og); Anal.
Calcd for C3gH46N2OllS: C, 62.38; H, 6.17; N, 3.73; S, 4.27.
Found: C, 62.63; H, 6.36i N, 3.91; S, 4.07.
F _ 1~ 33 Preparation of 6-Hydroxy-3-~6-[2-(1-~ ~olidinyl)-ethoxy]pyrid-3-ylmothyl~-2-Z4-~2-(1-pyrroliainyl)-ethoxy]phenyl]benzo ~b~ thiophene Dioxalate.
~o~N
HO ~ "'~" N ~ 2 C2H2~4 Part A. 6-~ethoxy-2-14-~2-(1-~ ~lidinyl)ethoxy]-phenyllbenzo ~b] thio~hsn-3-yl 6-Chlo ~id-3-yl Ketone.
~ Cl MeO ~ "~_,N ~
The title compound was prepared from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and 6-chloronicotinic acid in 51% yield (based on 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo [b] thiophene) by essentially following the proceedures described in Example 1, Part C.
-Part B. 6-MQthoxy-2-[4-~2-(l~lolidinyl)ethoxy~-phenyl3bonzol~b]thiophon-3-yl 6-~2-(1-Pyrrolidinyl)-~thoxy~pyrid-3-yl Ketone.
0~ ~ Nf~
MeO~ ~ ~,N~
The title compound was prepared in 84% yield :Erom 6-methoxy-2-[4-[2~ pyrrolidinyl)ethoxy]phenyl]benzo [b] -thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) and 1-(2-hydroxyethyl)pyrrolidine by essentially Eollowing the procedures described in Example 9, Part B.
FDMS 572 (M+l; 100); Anal. Calcd for C33H37N304S: C, 69.33;
H, 6.52; M, 7.35. Found: C, 6g.10; H, 6.76; N, 7.08.
Part C. 6-~othoxy-3-16-[2-(1-~yrrolidinyl)ethoxyl-pyrid-3-ylmethyl]-2-[4-~2-(1-~yrrolidiny].)Qthoxy~-phe~yllbenzo~b]thio~h~ Dioxalate Hemih~dr~t~.
~ 0~ N~
MeO /~ N~ 2 C2H204 0~~
The title was prepared in 3796 yield :Erom 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo [b] thiophen-3-yl 6-[2-(l-pyrrolidinyl)ethoxy]pyrid-3-yl ketone (Part B) by essentially f~ollowing the procedure described in Example 3, Part E.
W O 97/25033 PCT~US96/17995 FDMS 558 (M+l; 100); Anal. Calcd ~or C33H39N3O3~. 2C2H2~4- 0-5 H2O: C, 59.51; H, 5.94i N, 5.63. Found: C, 59.39; H, 5.76 N, 5.76.
Part D. 6-Hyaroxy-3-~6-t2-(1-~yrroli~inyl)-ethoxy]pyria-3-ylmethyll-2-~4-12-(1-pyrrolidinyl)-othoxyl~henyl]benzo~blthiophene Dioxalat~.
The title compound was prepared in 59% yield from 6-methoxy-3-~6-[2-(1-pyrrolidinyl)ethoxy~pyrid-3-ylmethyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene ~Part C~ by essentially following the procedure described in Example 1, Part D.
lH NMR (DMSO-d6) ~ 7.88 (d, J = 1.8 Hz, lH), 7.43-7.32 (m, 4H), 7.23 (d, J = 2.1 Hz, lH), 7.07 (d, J = 8.4 Hz, 2H), 6.78 (dd, J = 8.4 and 2.1 Hz, lH), 6.71 (d, J = 8.6 Hz, lH), 4.42 (t, ~ = 4.9 Hz, 2H), 4.30 (t, J = 4.6 Hz, 2H~, 4.09 (s, 2H), 3.53 (t, J = 4.3 Hz, 2H), 3.46 (t, J = 4.6 Hz, 2H), 2.50-2.33 ~m, 8H), 1.96-1.73 (m, 8H); FDMS: 544 (M + l; 100).
- _le 34 Pre~aration o~ 6-Hydroxy-3-14~ olidinyl)-methyl] benzyl]-2-[4-~(1-pYrrOlidinyl)methyl]l?hen bQnzolblthiophene Dioxa}ate.
HO~V
2(c2H2~4) Part A. 1-Bromo-4-[(1-~ loli~inyl)methylJb~nzene.
Br ~ N
Pyrrolidine (20.0 mL, 0.240 mole) was added to a stirred solution of 4-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous CH2C12 (20 mL) at 0 ~C under nitrogen. The resultant solution was allowed to stir at room temperature CA 02236007 l998-04-27 W O 97/2~033 PC~nJS96/~7995 for 1 h. The reaction mix~ure was diluted with EtOAc (150 mL) before it was washed with half-saturated aqueous NaHCO3 (50 mL). After drying over MgSO4, filtration, and concentration, the oily residue was chromatographed on silica [20% EtOAc in hexanes, then 10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 9.02 g of the benzyl pyrrolidine (94%) as an oil.
IR (neat) 2966,1488 cm-l; lH NMR (CDC13) ~ 1.79 (br s, 4H), 2.49 (br s, 4H), 3.57 (s, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H);
~?art B. 2-DimethylA ;~-6-m~thoxybonzo[blthiophen-3-yl 4- ~ y olidinyl)methyl3phenyl Kston~.
MeO ~
4-(Chloromethyl)benzoyl chloride (105 mg, 0.558 mmol) was added to a stirred solution of 2-dimethylamino-6-methoxybenzo[b]thiophene (105 mg, 0.507 mmol) in chlorobenzene (1 mL) under nitrogen. The resultant mixture was heated in an oil bath at 110 ~C for 2.5 h. The mixture was cooled to 0 ~C, treated with pyrrolidine (5 mL), then allowed to stir at room temperature for 2 h. After dilution with THF (20 mL), the mixture was washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 2~-40% EtOAc in hexanes, then 0-10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 148 mg (74%) of the ketone as a foam.
IR (neat~ 2957, 1625, 1603 cm~ ; H MMR (CDC13) ~ 1.83 (br s, 4H), 2.53 (br S, 4H), 2.87 (s, 6H), 3.69 (s, 2H), 3.83 (s, 3H), 6.81 (dd, J = 9.0 and 3.0 Hz, lH), 7.12 (d, J = 3.0 Hz, lH), 7.36 (d, J = g.0 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2H), '7.82 (d, J = 8.1 Hz, 2H); FDMS m/e 394 (M~).
W 097/2~033 PCTAJS96/17995 Part C. 6-Mothoxy-2-[4-~(1-~ Lolidinyl)methyl3-~henyl]benzotblthiophen-3-yl 4-[(1-Pyrrolidinyl)-m~thyl]phonyl Ketono.
MeO ~ ~
The aryl bromide of Part A (146 mg, 0.608 mmol) was added to a stirred suspension o~ magnesium ribbons (13.9 mg, O.570 mmol) in anhydrous THF (2 mL) under argon atmosphere, ~ollowed by the addition of a small iodine crytal. The resultant mixture was heated in an oil bath at 60-65 ~C for 2 h to form a homogeneous Grignard solution. The Grignard solution was cooled to room temperature before it was added to a stirred solution of the benzothiophene of Part B (150 mg, 0.380 mmol) in anhydrous THF (2 mL) at 0 ~C under argon atmosphere. The resultant mixture was stirred at 0 ~C ~or 1.5 h, then guenched with saturated aqueous NH4Cl (3 mL).
After extraction with EtOAc (15 mL x 2), the combined organic layers were dried over MgSO4, ~iltered, concentrated, and chromatographed on silica [gradient 0-4% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 170 mg (88%) of the trisubstituted benzothiophene as a ~oam.
IR (neat) 2964, 1647, 1603 cm-l; lH NMR (CDC13) ~ 1.77 (br s, 8H), 2.40-2.50 (m, 8H), 3.52 (s, 2H), 3.55 (s, 2H), 3.91 (s, 3H), 7.05 (dd, J = 8.9 and 2.3 Hz, lH), 7.17 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.32 (d, ~ = 8.1 Hz, 2H), 7.34 ld, J = 2.3 Hz, lH), 7.65 (d, J = 8.9 Hz, lH), 7.70 (d, J =
8.2 Hz, 2H); FDMS m/e 510 (M+).
Part D. 6-Mothoxy-3-t4~ r lolidinyl)m~thyll ~
benzyll-2-14-~(1-pyrrolidinyl)methyllphenyl]benzo-lb}thio~hene.
W O 97/25033 PCT~US96/17995 MeO ~ ~
DIBAL-H (0.911 mL, 1 M in toluene) was added to a stirred solution of the ketone of Part C (310 mg, 0.607 mmol) in anhydrous CH2C12 (4 mL) at 0 ~C under nitrogen atmosphere, and the resultant solution was stirred at 0 ~C for 40 min.
The reaction mixture was treated sequentially with MeOH (0.5 mL) and saturated aqueous Rochelle's salt solution (10 mL), and then the two-layered solution was stirred vigorously at room temperature for 1 h. A~ter extraction with EtOAc (50 mL), the organic layer was dried over MgSO4, ~iltered, and concentrated to yield 280 mg of the corresponding alcohol.
The above alcohol was dissolved in anhydrous CH2C12 (3 mL) and cooled down to 0 ~C be~ore it was sequentially treated with Et3SiH ~0.611 mL, 3.83 mmol) and TFA (0.421 mL, 15 5.46 mmol). The resultant mixture was stirred at 0 ~C for 1 h. After cautious treatment with saturated aqueous NaHCO3 (8 mL), the mixture was allowed to warm to room temperature and extracted with EtOAc (15 mL x 2). The com~ined organic layers were dried over MgSO4, filtered, concentrated, and 20 chromatographed on silica [gradient 0-4% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 220 mg (81%) o~ the corresponding methylene compound as a foam.
IR (neat) 2963, 1603 cm~l; lH NMR (CDCl3) ~ 1.75-1.87 (m, 25 8H), 2.45-2.60 (m, 8H), 3.57 (s, 2H), 3.64 (s, 2H), 3.87 (s, 3X), 4.24 (s, 2H), 6.90 (dd, J = 8.9 and 2.4 Hz, lH), 7.09 (d, ~ = 8.0 Hz, 2H), 7.21 (d, ~ = 8.0 Hz, 2H), 7.33 (d, ~ =
2.4 Hz, lH), 7.35 (d, J = 8.2 Hz, 2H), 7.39 (d, ~ = 8.9 Hz, lH), 7.45 (d, ~ = 8.2 Hz, 2H); FDMS m/e 496 (M+).
Part E. 6-Hy~roxy-3-14- r (~ o~ nyl)m~thyl~ -- benzyll-2-t4-[(1-~yrrolidinyl)methyllphenyl]bQnzo-lblthiorhe~e Dioxalate.
W O 97/25033 PCT~US96/17995 AlCl3 (354 mg, 2.66 mmol) was added to a stirred solution of the methoxy benzothiophene (220 mg, 0.443 mmol) in anhydrous CH2C12 (5 mL) at room temperature under nitrogen atmosphere. The resultant suspension was stirred for 3-5 min before it was treated with EtSH (0.2g5 mL, 3.99 mmol), and the mixture was stirred for an additional 35 min. After dilution with THF (15 mL), the mixture was cooled to 0 ~C and sequentially treated with saturated aqueous NaHC03 (15 mL) and saturated aqueous Rochelle's salt solution (10 mL). The two~layered solution was stirred vigorously for 70 min. The organic layer was separated and the aqueous layer was extracted with THF (25 mL x 2). The combined organic layers were dried over MgSO4, filtered, concentra~ed, and chromatographed on silica [gradient 0-4% EtOH/Et3M (2/1) in THF/hexanes (1/1)] to give 205 mg (96%) of the hydroxy benzothiophene as a foam.
A solution of oxalic acid (76.5 mg, 0.850 mmol) in EtOAc (4 mL) was added dropwise to a stirred solution of the above hydroxy benzothiophene in EtOAc (4 mL). The resultant w~ite suspension was filtered and the white solid was dried at 8Q
~C under vacuum to provide 240 mg (85%) of the dioxalate.
IR (neat) 3400-2500 (br), 1721, 1600 cm-l; lH NMR (CDC13) ~
1.75-1.95 (m, 8H), 2.95-3.20 (m, 8H), 4.17 (s, 2H), 4.21 (s, 2H), 4.26 (s, 2H), 6.81 (dd, ~ - 8.7 and 2.1 Hz, lH), 7.11 (d, J = 7.9 Hz, 2H), 7.28 (d, 3 = 2.1 Hz, lH), 7.35 (d, J =
7.9 Hz, 2H), 7.37 (d, ~ = 8.7 Hz, lH), 7.50 (d, J = 8.1 Hz, 2H), 7.56 (d, ~ = 8.1 Hz, 2H); FDMS m/e 483 (M+1-2C2H2O4);
Anal. Calcd for C31H34N20S 1.8C2H204: C, 64.46; H, 5.88i N, 4.34. Found: C, 64.17; H, 5.92; N, 4.47.
. ~le 35 Pre~aration of 6-Hydroxy-2-[4-~(4-morpholinyl)methyl]-phenyl]b~nzo[blthiophen-3-yl 4-~(1-Pyrrolidinyl~-methyl]phenyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 N~
2(c2H2o4) Part A. 4-l(4-Bromophenyl)methyl]morpholine~
Br ~ N-Following the procedure o~ Example 34, Part A, the benzyl morpholine was obtained as an oil in 100~ yield.
IR (~3r) 2803, 1487, 1111 cm-l; lH NMR (CDC13) ~ 2.43 (t, J =
4.5 Hz, 4H), 3 45 (s, 2H), 3.71 (t, J = 4.5 Hz, 4H), 7.22 (d, .J = 8.1 Hz, 2H), 7.45 (d, ~ = 8.1 Hz, 2H); FDMS m/e 255 (M+, 79Br) and 257 (M+, 81Br); Anal. Calcd for CllH14BrNO: C, 51.58; H, 5.51; N, 5.47. Found: C, 51.77; H, 5.66; N, 5.68.
Part B. 6-MQthoxy-2-[4-~(4-morpholinyl)methyl]-phenyllbenzo~b~thio~hen-3-yl 4-~(1-Pyrrolidinyl)-methyl]phenyl Ketone.
MeO ~ N~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the above aryl bromide as a foam in 88% yield.
IR (neat) 2954, 1649, 1602 cm-l; lH MMR (CDC13) ~ 1.77 ~r s, 4H), 2.35 (br s, 4H), 2.40 (br s, 4H), 3.39 (s, 2H), 3.56 (s, 2H), 3.68 (t, J = 4.2 Hz, 4H) 3.92 (s, 3H), 7.02 (dd, J = 8.7 and 2.1 Hz, lH), 7.14-7.37 (m, 7H), 7.64 (d, 8.7 Hz, lH), 7.70 (d, 7.8 Hz, 2H); FDMS m/e 527 (M+l).
CA 02236007 l998-04-27 Part C. 6-Hydroxy-2-~4-[(4-mOrpholinyl)methyll-phenyllbenzo[blthiophen-3-yl 4-~(1-Pyrrolidinyl)-methyl]phe~yl Ketone Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy ketone was obtained as a yellowish solid in 55% t yield.
IR (KBr) 3420 (br), 2990 ~br), 2830-2200 (br), 1641, 1608 cm~1; 1H N ~ (DMSO-d6) ~ 1.79 (br s, 4H), 2.37 (br s, 4H), 2.53 (br s, 4H), 3.39 (s, 2H), 3 .60 (s, 2H), 3 .68 (t, ~ - 4.2 Hz, 4H), 6.40 (dd, ~ = 8.7 and 2.1 Hz, lH), 6.69 (d, ~ = 2.1 Hz, lH), 7.12 (d, ~J = 8.1 Hz, 2H) 7.21-7.25 (m, 4H), 7.43 (d, ~J = 8.7 Hz, lH), 7.67 (d, J = 7 .8 Hz, 2H); FDMS m/e 513 (M~1-2C2H204 ) -~ ple 36 Pr~paration of 6-Hydroxy-2-[4-[(4-morpholinyl)methyl~-phenyl]-3-t4-t(1-pyrrolidinyl)mQthyl3benzyl]-benzotb]thio~hone Dioxalate.
HOJ ~ - N~> o 2 0 2 (c2H204 ~
Part A. 6-Methoxy-2-t4-t(4-morpholinyl)methyl]-phenyl]-3-~4-t(1-~yrrolidinyl)~ethyllbenzyll-benzo~b~thiophene.
MeO ~ ~- o Following the procedure of Example 34, Part D, the methoxy benzothiophene was obtained from the above ketone as a ~oam in 57% yie~d.
IR (neat) 2958, 1603 cm-1; lH NMR (CDC13) ~ 1.76-1. 80 (m, 4H), 2.37-2.50 (m, 8H), 3.53 (s, 2H), 3.57 (s, 2H), 3.73 (t, W O 97/2~033 PCTAUS96/17995 ~ = 4.8 Hz, 4H) 3.87 (s, 3H), 4.25 (s, 2H), 6.90 (dd, J = 8.7 and 2.4 Hz, lH), 7.10 (d, ~ = 8.1 Hz, 2H), 7.18-7.41 (m, 6H), 7.45 (d, J = 8.1 Hz, 2H); FDMS m/e 513 (M+l).
Part B. 6-Hydroxy-2-[4-1(4-morpholinyl)methyl]-~henyl]-3-14-[(1-pyrroli~inyl)methyl]bonzyl~-b~nzo Cb] thiophene Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy benzothiophene salt was obtained as a white solid in 57% yield.
IR (KBr) 3445 (br), 2950, 2840-2220 (br), 1720, 1630, 16Q0 Cm-1; 1H NMR (DMSO-d6) ~ 1.88 (br s, 4H), 2.56 (br s, 4H), 3.13 (br s, 4H3, 3.61 (br s, 4H), 3.70 (s, 2H), 4.22 (br s, 4H), 6.79 (dd, J = 8.4 and 2.0 Hz, lH), 7.13 (d, ~ = 7.5 Hz, 2H), 7.27 (d, ~ = 2.0 HZ , lH), 7.34-7.44 (m, 7H); FDMS m/e 499 (M~1-2C2H2O4); Anal. Calcd for C31H34N2O2S-2C2H2O4: C, 61.93; H, 5.64; N, 4.13. Found: C, 62.09; H, 5..77; N, 3.96.
_le 37 Preparation of 3-[3-Bromo-4-c(l-~y ~olidinyl)-methyl]benzyl]-6-hydroxy-2-14-t2-(4-morpholinyl)-Qthoxy~phQnyl]benzo~blthiophe~s Dioxalato.
~ N-~
HO ~ ~ o ~ N
2(caH2~4) Part A.Mothyl 3-Bromo-4-C(~ oli~inyl)methyl~-benzo~to.
Br MeO2C~N
AIBN ~79 mg) was added to a stirred suspension o~ methyl 3-bromo-4-methylbenzoate (11.0 g, 48.0 mmol) and NBS (10.3 g, 57.6 mmol) in CC14 (400 m~), and the resultant mixture was W O 97/25033 PCTnUS96/17995 heated to reflux for 2 h. After cooling to room temperature, the mixture was diluted with hexanes (200 mL) before it was filtered and concentrated to give 14.7 g (crude yield 100%) of methyl 3-bromo-4-(bromomethyl)benzoate.
Part of the crude dibromide (14.7 g) was dissolved in anhydrous CH2C12 (60 mL). The solution was cooled to 0 ~C
and treated with pyrrolidine (9.96 mL, 119 mmol), then it was allowed to stir at room tem.perature for 2 h. The reaction mixture was diluted with EtOAc (500 mL), washed with half-saturated a~ueous NaHCO3 (100 mL), dried over MgSO4, filtered, and concentrated to give an oily residue. The crude product was chromatographed on silica [gradient 0-10 EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 6.45 g of the pyrrolidinyl ester (45%) as an oil.
IR ~neat) 2953, 1728, 1602 cm 1; lH NMR (CDCl3) ~1.82 (br s, 4H), 2.61 (br s, 4H), 3.77 (s, 2H), 3.92 (s, 3H), 7.59 (d, J
- 8.0 Hz, lH), 7.95 (dd, ~ = 8.0 and 1.4 Hz, lH), 8.20 (d, = 1.4 Hz, lH); FDMS m/e 297 (M+, 79Br) and 299(M~, 81Br).
Part B. 3-Bromo-4-[(1-~l~lidinyl)methyl~benzoic Acid Hydrochloride.
Br H02C~N ~Cl LioH (32.4 mL, 1 N) was added to a stirred solution of the above ester (6.45 g, 21.6 mmol) in THF (75 mL) / MeOH (25 mL), and the resultant solution was heated in an oil bath at 50 ~C for 3 h. After cooling to room temperature, the solution was treated in portions with 5 N HCl (22 mL), and then concentrated at 50 ~C under vacuum to give 8.20 g (crude yield 99%) of the benzoic acid as a white solid contAminAted with LiCl.
IR (KBr) 3397 (br), 2924, 2679-2000 (br), 1713, 1634, 1464 cm~l;lH NMR (DMSO-d6) ~1.94 (br s, 4H), 2.95-3.70 (m, 4H), CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 4.54 (s, 2H), 7.92 (d, J = 8.1 Hz, lH), 8.10 (s, lH), 8.12 (d, ~ = 8.1 Hz, lH).
-Part C. 6-Nethoxy-2-[4-[2-(4-morpholinyl)ethoxy]-phenyllbQnzo~b~thiophene.
MeO ~ ~ N J
Cs2CO3 (4.89 g, 15.0 mmol) was added to a stirred solution of 2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene (1.10 g, 4.29 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (3.20 g, 17.2 mmol) in anhydrous DMF (10 mL).
The resultant suspension was heated in an oil bath at 75 ~C
~or 4 h. A~ter cooling to room temperature, the mixture was diluted with EtOAc (60 mL), washed with half-saturated a~ueous NaCl solution (20 mL), dried over MgSO4, filtered, and concentrated to give a solid residue. Chromatography on silica [gradient 0-15% EtOH/Et3N (2/1) in THF/hexanes (1/1)]
provided 1.43 g of the ether (90%) as a solid.
IR (KBr) 2940, 1606 cm~l; lH NMR (CDCl3) ~2.61 (t, ~ = 4.6 Hz, 4H), 2.84 (t, J = 5.7 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.84 (s, 3H), 4.17 (t, ~ = 5.7 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.98 (dd, J = 8.6 and 2.2 Hz, lH), 7.30 (d, J = 2.2 Hz, lH), 7.35 (s, lH), 7.60 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, lH); FDMS m/e 369 (M~).
Part D. 3-Bromo-4-1(1-~y~ olidinyl)methyllphenyl 6-Methoxy-2-~4-[2-(4-mor~holinyl~Qthoxy~phenyl]-bonzolb~thiophen-3-yl Ketone.
Br MeO ~ O ~ N J
Oxalyl chloride (1.11 mL, 12.7 mmol) was added to a stirred suspension of the above benzothiophene (812 mg, 2.53 mmol) in anhydrous ClCH2CH2Cl (6 mL), ~ollowed by the WO 97/25033 PCT~US96tl7995 addition o~ 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 6 h, then it was concentrated to dryness under vacuum at 50 ~C.
To the crude benzoyl chloride suspended in anhydrous CH2C12 (5 mL) was added a solution o~ the benzothiophene of Part C above (624 mg, 1.69 mmol) in anhydrous CH2C12 (10 mL).
The mixture was cooled to 0 ~C, treated with AlCl3 (1.35 g, 10.1 mmol), and stirred for 1 h. THF (10 mL) was added to the mixture at 0 ~C, followed by the slow, sequential additions of saturated aqueous NaHCO3 (30 mL) and saturated aqueous Rochelle's salt solution (10 mL). Then the two-layered solution was stirred vigorously for 70 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (25 mL), dried over MgS04, ~iltered, concentrated, and chromatographed on silica [gradient 0-20% EtOH/Et3N (2/1) in THF/h~n~ (1/1)] to give 695 mg (65%) of the ketone as a foam.
IR (neat) 2961, 1645, 1606 cm~l; lH NMR (CDC13) Sl.80 (br s, 4H), 2.52-2.57 (m, 8H), 2.76 (t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.72-3.89 (m, 4H), 3.91 (s, 3H), 4.04 (t, ~ = 5.7 Hz, 2H), 6.75 (d, ~ = 8.7 Hz, 2H), 7.20 (dd, ~ = 8.9 and 2.3 Hz, lH), 7.25-7.30 (m, 2H), 7.34 (d, ~ = 2.3 Hz, lH), 7.38 (d, ~
= 7.9 Hz, lH), 7.62 (dd, ~ = 7.9 and 1.6 Hz, lH), 7.68 (d, J
= 8.9 Hz, lH), 7.91 (d, ~ = 1.6 Hz, lH); FDMS m/e 634 (M+, 79Br) and 636(M+, 81Br).
Part E. 3-~3-Rromo-4-~ r y olidinyl)methyl~benzyl]-6-methoxy-2-[4-[2-(4-morpholinyl)ethoxy]~henyljbenzo-~b~thiophene. Br MeO ~ ~J~
W O 97/25033 pcTrus96ll7995 Following the procedure of~ Example 34, Part D, the corresponding methylene compound was obtained as a foam in 86% yield.
IR (neat) 2958, 1608 cm~l; FDMS m/e 621 (M+l, 79Br) and 623 (M+l, 81Br) Part F. 3-13-Bromo-4-t(1-~Y ~olidinyl)mQthyllben 6-hyaroxy-2-l4-l2-(4-morpholinyl)ethoxylphen benzo~b~thiorhs~e Dioxalate.
Following the procedure o~ Example 34, Part E, the h~droxy benzothiophene salt was obtained as a white solid in 55% yield.
~DMS m/e 607 (M+l, 79Br) and 609 (M~l, 81Br).
Example 38 Proparation o~ 6-Hydroxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl3-2-[4-[2-(4-morpholinyl)-ethoxyl~hQnyl]benzolblthiophone Dioxalate.
Me ~ N~
HO ~ O ~ N~J~
2tc2H2~4) Part A. 6-Methoxy-3-[3-mQthyl-4-1(1-~y lolidinyl)-methyl]b~nzyll-2-[4-12-(4-mor~holinyl)Qthoxy]phenyl]-benzolblthiophene.
Me ~ N~
MeO ~ O ~ N ~
A sealed tube cont~;n;n~ a stirred mixture of the aryl ~romide o~ Example 37, Part E, (283 mg, 0.456 mmol), -- tetramethlytin (0.316 mL, 2.28 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (16 mg, 0.014 mmolj in o-xylene (5 mL) was heated in an oil bath at 155 ~C for 1 h. A black CA 02236007 l998-04-27 W 097/25033 PCT~US96/17sss precipitate was formed. The mixture was cooled to room temperature and subjected to chromatography on silica [gradient 0-2096 EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 94 mg (37%, low yield attributed to spill) o~ the corresponding aryl methyl compound as a foam.
IR (neat) 2957, 1608 cm~l; lH NMR (CDC13) ~ 1.78 (br s, 4H), 3.3Q (s, 3H), 2.54-2.61 (m, 8H), 2.82 (t, LJ = 5.7 Hz, 2H), 3.57 (s, 2H), 3.75 (t, ~J = 4.5 Hz, 4H), 3.87 (s, 3H), 4.14 (t, .J = 5.7 Hz, 2H), 4.18 (s, 2H), 6.88-6.96 (m, 4H), 7.18 (d, J = 7.9 Hz, lH), 7.32-7.44 (m, 5H); FDMS m/e 556 (M+).
Part B. 6-Hydroxy-3-13-methyl-4-~ olidinyl)-methyl]benzyll-2-~4-12-(4-morpholinyl)ethoxy]~henyl]-benzo ~b] thiophene Dioxalate.
Following the procedure of Example 34, Part E, the hydroxy benzothiophene salt was obtained as a white solid in 55% yield.
20 IR (KBr) 3455 (br), 2970, 2840-2220 (br), 1723, 1630 (br), 1610 cm~ H NMR (DMSO-d6) ~ 1.79-1.89 (m, 4H), 2.27 (s, 3H), 2.63-2.71 (m, 4H), 2.90-3.12 (m, 6H), 3.55-3.63 (m, 4H), 4.13-4.24 (m, 6H), 6.88-7.04 (m, 5H), 7.28-7.39 (m, 5H); FDMS
m/e 543 (M+l).
Exa~le 39 Preparation of 6-Hydroxy-2-~4-~2-(1-~ olidinyl)-othyl]phenyllbenzo[blthiophen-3-yl 3-Methyl-4-~
olidinyl)mQthyl3phenyl Ketone Dioxalate.
Me HO
2(c2H204) Part A. l-Bromo-4-~2-(1-~ olidinyl)ethyl~benzene.
=
W O 97/25033 PCT~US96/1799 _ -145-Br ~ ~
Methanesulfonyl chloride (2.12 mL, 27.4 mmol) was added to a stirred solution of 4-bromophenethyl alcohol (5.00 g, 24.9 mmol) and anhydrous pyridine (2.21 mL, 27.4 mmol) in anhydrous CH2C12 (25 mL) at 0 ~C under nitrogen atmosphere.
Upon the completion of the addition the mixture was allowed to stir at room temperature for 8 h. Then the reaction mixture was cooled to 0 ~C and treated with pyrrolidine ~10 4 mL, 124 mmol). After stirring at room temperature ~or 2 h, the mixture was diluted with EtOAc (120 mL), washed with half-saturated NaHCO3 (30 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-10%
EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 5.37 g (85~) of the substituted pyrrolidine as an oil.
IR (CHC13) 2933, 1489 cm-l; lH NMR (CDC13) ~ 1.80 (br s, 4H), 2.56 (br s, 4H), 2.64-2.80 (m, 4H), 7.10 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H); FDMS m/e 253 (M+, 79Br) and 255 (M+, 81Br) .
Part B. 2-Dimethyl~ i~-6-~methoxy~benzo[b]thiophen-3-yl 3-Methyl-4-1(1-~ L~lidinyl)methyl]phenyl Ketone.
Me MeO ~ N~
Oxalyl chloride (2.57 mL, 29.5 mmol) was added to a stirred suspension of 3-methyl-4-[(1-pyrrolidinyl)methyl]-benzoic acid hydrochloride (1.76 g, 5.90 mmol) in anhydrous ClCH2CH2Cl (12 mL), followed by the addition of 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 6 h, then it was concentrated to dryness under vacuum at 50 ~C.
To the crude benzoyl chloride obt~l n~ and suspended in anhydrous chlorobenzene (10 mL) was added 2-dimethylamino-6-W O 97/25033 PCTrUS96/17995 methoxybenzo[b]thiophene (1.02 g, 4.92 mmol. The resultant mixture was heated in an oil bath at 110 ~C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL), washed with saturated NaHCO3 (25 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-10% EtOH/Et3N (2/1) in THF/hexanes (1/1)3 to give 1.50 g (75%) o~ the ketone as a foam.
IR (CHCl3) 2950, 1647, 1601 cm-l; lH NMR (CDC13) ~ 1.81 (br s, 4H), 2.39 (s, 3H), 2.56 (br s, 4H), 2.89 (s, 6H), 3.65 (s, 2H), 3.83 (s, 3H), 6.80 (dd, J = 9.0 and 2.4 Hz, lH), 7.12 (d, J = 2.4 Hz, lH), 7.32 (d, J = 9.0 Hz, lH), 7.39 (d, J =
8.1 Hz, lH), 7.63 (d, J = 8.1 Hz, lH), 7.69 (s, lH); FDMS m/e 408 (M+); Anal. Calcd for C24H2gN2O2S: C, 70.56; H, 6.91i N, 6.86. Found: C, 70.75; H, 7.15; N, 6.91.
Part C. 6-Methoxy-2-t4-[2-(1-~y~l~lidinyl)ethyl]-phenyl]benzo~b]thiophen-3-yl 3-Methyl-4-[(1-~lidinyl)mQthyl]~henyl Keton~.
Me MeO ~ N~
Following the procedure of Example 34, Part C, thetrisubstituted benzothiophene was obtained ~rom the aryl bromide of Part A above and the amino benzothiophene of Part B above as a foam in 96~ yield.
IR (CHC13) 2964, 1647, 1603 cm~l; lH NMR (CDC13) ~ 1.75-1.82 (m, 8H) 2.25 (s, 3H), 2.44 (br s, 4H), 2.51-2.61 (m, 6H), 2.71-2.76 (m, 2H), 3.53 (s, 2H), 3.90 (s, 3H), 6.99 (dd, J =
8.7 and 2.1 Hz, lH), 7.05 (d, J = 8.1 Hz, 2H), 7.23 (d, J =
7.8 Hz, lH), 7.29-7.34 (m, 3H), 7.52 (d, J - 7.8 Hz, lH), 7.58 (s, lH), 7.60 (d, J - 8.7 Hz, lH); FDMS m/e 538 (M~);
Anal. Calcd for C34H3gN2O2$: C, 75.80; H, 7.11; N, 5.20.
Found: C, 75.67; H, 7.10; N, 5.25.
, CA 02236007 l998-04-27 Part D. 6-Hydroxy-2-[4-12-(1-~yrrolidinyl)ethyl3-phenyl]benzolblthiophen-3-yl 3-Methyl-4-t( pyrroli~inyl~methyll~henyl K~tone Dioxalate.
Following the procedure of Example 34, Part E, the title compound was obtained as a yellowish solid in 77% yield.
IR (KBr) 3420 (br), 2970, 2850-2300 (br), 1721, 1641, 1607 cm~l; lH NMR (DMSO-d6) ~.1.83 (br s, 4H), 1.88 (br s, 4H), 10 2.26 (s, 3H), 2.81-2.91 (m, 6H), 3.21 (br s, 6H), 4.07 (s, 2H), 6.88 (dd, J = 8.7 and 2.1 HZ, lH), 7.17 (d, J = 8.0 Hz, 2H), 7.26 (d, ~J = 8.0 Hz, 2H), 7.33-7.39 (m, 3H), 7.46 (d, ~
8.7 Hz, lH), 7.54 (s, lH); FDMS m/e 525 (M+-2C2H2O4); Anal.
Calcd for C33H36N2O2S-2C2H204: C, 63.05; H, 5.72; N, 3.97.
15 Found: C, 63.24; H, 6.02; N, 4.22.
Exam~le 4~
Preparation of 6-Hydroxy-3-t3-methyl-4-t(1-~ lO-liainyl)methyl]benzyl~-2-t4-12-(1-pyrrolidinyl)Qthyll-phQnyl3benzotb~thiophQne Dioxalat~.
Me HO~--VN~
2(c2H2o4) Part A. 6-Methoxy-3-[3-m~thyl-4-[(1-~ ~.olidinyl)-ethyllbenzyl~-2-14-t2-(1-pyrrolidinyl)QthyllphQnyl]-benzotb]thiophen~.
Me MeO ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 39, Part C, as a foam in 67% yield.
CA 02236007 l998-04-27 W 097/25033 PCTAJS96/l79s~
I~ tKBr) 2953, 1601 cm-l; lH N ~ (CDCl3) ~ 1.77 (br s, 4H3, 1.83 (br s, 4H), 2.29 (s, 3H), 2.51 (br s, 4H), 2.60 rbr s, 4H), 2.70-2.75 (m, 2H), 2.85-2.88 (m, 2H), 3.54 (s, 2H), 3.88 (s, 3H), 4.20 (s, 2H), 6.88-6.95 (m, 3H), 7.17 (d, ~ = 7.8 Hz, lH), 7.24 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 2.1 Hz, lH), 7.38-7.45 (m, 3H); FD~S m/e 524 (M+); Anal. Calcd for C34H40N2OS: C, 77.82; H, 7.68; N, 5.34. Found: C, 78.03; H, 7.58; N, 5.54.
Part B. 6-Hydroxy-3-[3-methyl-4-[(1-~olidinyl)-methyl~benzyll-2-[4-12-(1-~yrrolidinyl)othyl~phenyl~-bonzolb~thio~hene Dioxalate.
Me HO ~ N
2(c2H2O4) Following the procedure of 33xample 34, Part D, the hydroxy benzothiophene salt was obtained as a white solid in 73% yield.
IR (KBr) 3420 (br), 2976, 2830-2230 (br), 1722, 1613 cm-l; lH
N~IR (DMSO-d6) ~ 1.81-1.91 (m, 8H), 2.26 (s, 3H), 2.95-3.11 (m, 6H), 3.19-3.35 (m, 6H), 4.15 (s, 2H), 4.17 (s, 2H), 6.79 (dd, J = 8 .6 and 2.0 Hz, lH), 6.89 (d, J = 8.4 Hz, lH), 6.99 (s, lH), 7.26 (d, J = 2.0 Hz, lH), 7.29-7.43 (m, 6H); FDMS
m/e 511 (M~1-2C2H204); Anal. Calcd for C33H3gN20S 2C2H20~: C, 64.33; H, 6.13; N, 4.06. Fourld: C, 64.42; H, 6.40; N, 4.11.
Exaunplo 41 Preparation of 6-Hydroxy-2-[4-12-(1-~1~olidinyl~-ethyl]phenyl~benzo[b~thiophen-3-yl 3-Methoxy-4-~(1-pyrrolidinyl)methyl~phenyl Ketone Dioxalate.
-W O 97/25033 PCT~US96/17995 -14g -OMe HO ~ N~
2(c2H2~4) Part A. Methyl 3-Methoxy-4-~ oli~lnyl)methyl]~
b~nzoate.
OMe MeO2C~N
Following the procedure of Example 37, Part A, the substituted pyrrolidine was obtained ~rom methyl 3-methoxy-4-methylbenzoate as an oil in 65% yield.
I3~ (CEIC13) 2954, 1716 cm-l; 1H NMR (CDC13) ~ 1.95 (br s, 4H), 2.89 (br s, 4H), 3.91 (s, 3H), 3.92 (s, 3H), 3.98 (br t, J =
6.8 Hz, 2H), 7.56 (s, lH), 7.61-7.67 (m, 2H); FDMS m/e 249 (M+).
Part B. 3-Methoxy-4~ oli~inyl)methyl]benzoic 15 Acia Hy~rochloride.
OMe H02C~N HCl Following the procedure of Example 37, Part B, the acid was obtained from the above ester as a yellowish solid in 65%
crude yield.
H NMR (DMSO-d6) ~1.89-1.94 (br s, 4H), 3.01-3.05 (br s, 2H), 3.26-3.34 (br s, 2H), 3.88 (s, 3H), 4.32 (s, 2H), 7.53 (s, lH), 7.54 (d, .J = 7.7 Hz, lH), 7.70 (d, IJ = 7.7 Hz, lH); FDMS
m/e 235 (M+).
r Part C. 6-Benzyloxy-2-(dimethylamino)benzolb~thio-~hen-3-yl 3-Methoxy-4-[(1-pyrrolidinyl)methyl~phenyl KetonQ.
W O 97/2~033 PCTfUS96/17995 OMe BnO~
Following the procedure of Example 39, Part B, the ketone was obtained from the above acid and 6-benzyloxy-2-dimethylaminobenzo[b]thiophene as a foam in 81% yield.
IR (CHC13) 2970, 1621, 1600 cm-l; lH NMR (CDC13) ~ 1.85 (br 5, 4H), 2.70 (br s, 4H), 2.89 (s, 6~I), 3.80 (s, 2H), 3.88 (s, 3H), 5.08 (s, 2H), ~.89 (dd, ~ = 8.9 and 2.5 Hz, lH), 7.20 (d, ~ = 2.3 Hz, lH), 7.33-7.47 (m, 9H); FDMS m/e 500 (M+).
Part D. 6-Bonzyloxy-2-14-[2-(~-~y olidinyl)ethyll-phenyl~bonzolblthiophen-3-yl 3-Methoxy-4-1(1-~olidinyl)~ethyl]phonyl Ketone.
OMe BnO~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the dimethylamino compound of Part C as a foam in 81% yield.
IR (CHCl3) 2965, 1648, 1601 cm~l; lH NMR (CDCl3) ~ 1.77-1.82 (m, 8H), 2.52 (br s, 4H), 2.60 (br s, 4H), 2.61-2.67 (m, 2H), 2.75-2.80 (m, 2H), 3.63 (s, 2H), 3.80 (s, 3~), 5.16 (s, 2H), 7.06 (d, J = 8.1 Hz, 2 + lH superimposed), 7.25-7.50 (m, llH), 7.61 (d, ~ = 8.9 Hz, lH); FDMS m/e 631 (M+l).
Part E. 6-Hydroxy-2- 14-12-(1-1?YrrolidinYl)ethyl]-phenyl]benzorb]thioph~n-3-yl 3-Methoxy-4-[(1-~y~ ol~dinyl)methyll~h~nyl Kotone Dio~alat~.
To a stirred solution of the above benzyloxy benzothiophene (440 mg, 0.698 mmol) in THF (8 mL) under nitrogen atmosphere were se~uentially added 10~ Pd/C (440 mg) CA 02236007 l998-04-27 W~97/25033 P ~ AUSg6~79g5 and 25% aqueous HC02NH4 (2 mL). The resultant mixture was stirred under a balloon nitrogen atmosphere ~or 7 h. After ~ filtration, the ~iltrate was diluted with EtOAc (50 mL), washed with half-saturated NaCl (15 mL), dried over MgSO4, filtered, concentrated, and chromatoyraphed on silica [gradient 0-20% EtOH/TEA (2/1) in THF/hexanes (1/1)] to give 225 mg (60~) of the hydroxy benzothiophene as a foam.
A solution of oxalic acid (64.2 mg, 0.712 mmol) in EtOAc (6 mL) was added dropwise to a stirred solution of the hydroxy benzothiophene (175 mg, 0.323 mmol) in THF (4 mL).
The resultant white suspension was filtered and the white solid was dried at 60 ~C under vacuum to provide 213 mg (91%) of the corresp~n~'ng dioxalate.
IR (neat) 3450 (br), 2964, 2830-2220, 1719, 1640, 1607 cm-1;
1H NMR (DMSO-d6) ~ 1.83-1.88 (br s, 8H), 2.83-2.93 (m, 6H), 3.18 (br s, 6H), 3.75 (s, 3H), 4.06 (s, 2H), 6.90 (dd, J =
8.8 and 2.2 Hz, lH), 7.15-7.39 (m, 8H), 7.43 (d, ~ = 8.8 Hz, lH); FDMS m/e 541 (M~1-2C2H204); Anal. Calcd for C33H36N2O3S-2C2H2O4: C, 61.66; H, 5.59; N, 3.89. Found: C, 61.91; H, 5.69; N, 4.00.
ExamplQ 42 PrQparation of 6-Hy~roxy-3-~3-methoxy-4- r (1-~yrrolidinyl)methyl]benzyl~-2-[4-[2-(1-~yrrolidinyl)-Qthyl]ph~nyllb~nzo[b]thiophQnQ Dioxalate.
OMe HO
2(c2H2~4) Part A. 6-Benzyloxy-3-t3-m~thoxy-4-~(1-~y~ oli~inyl)-m~thyl]b~nzyl~-2-[4- r 2-(1-~yrrolidinyl)ethyl]phenyll-benzorb]thiophene.
CA 02236007 l998-04-27 W 097/25033 PCT~USs6/l7sss ~152-OMe BnO ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 41, Part D as a foam in 62% yield.
IR (CHC13) 2966, 1601 cm 1; lH NMR (CDC13) ~ 1.82 (br s, 8H), 2.60 (br s, 8H), 2.68-2.75 (m, 2H), 2.72-2.95 (m, 2H), 3.68 (s, 5H, OCH3 and CH2), 4.22 (s, 2H), 5.13 (s, 2H), 6.64 (s, lH), 6.71 (d, J = 7 .5 Hz, lH), 6.98 (dd, J = 8.5 and 2.0 Hz, lH), 7.23 (br s, 2H), 7.30-7.50 (m, 10H); FDMS m/e 616 (M+).
Anal. Calcd for C40H44N2o2s: C, 77.88; H, 7.19; N, 4.54.
Found: C, 77.93; H, 7.22; N, 4.61.
Part B. 6-Hydroxy-3-~3-methoxy-4-[(1-p~ r Lolidinyl) ~
15 m~thyllb~nzyl]-2-~4-12-(1-pyrrolidinyl~ethyl~phenyl]-b~nzolb~thio~hene Dioxalate.
Following the procedure of Example 41, Part E, the title hydroxy benzothiophene salt was obtained from the benzyl ether as a white solid in an overall 65% yield.
IR (KBr) 3420 (br), 2980, 2830-2240 (br), 1720, 1613 cm~l; lH
NMR (DMSO-d6) ~ 1.86-1.93 (m, 8H), 2.96-3.01 (m, 2H), 3.06-3.21 (m, 4H), 3.25-3.50 (m, 6H), 3.70 (s, 3H), 4.14 (s, 2H), 4.20 (s, 2H), 6.60 (d, J = 7.9 Hz, lH), 6.81 (dd, J = 8.7 and 25 2.1 Hz, lH), 7.26 (d, J = 8.2 Hz, 2 + lH superimposed), 7.36 (d, J = 8.2 Hz, 2H) 7.42-7.46 (m, 3H); FDMS m/e 527 (M+l-2C2H204); Anal. Calcd for C33H3gN2O2S-1.7C2H2O4: C, 64.31; H, 6.14; N, 4.12. Found: C, 64.25; H, 6.42; N, 4.02.
Example 43 Pr~paration o~ 6-Hyaroxy-2-t4-t2-~1-t(5)-2-hydroxymethyl]~yrrolidinyl]ethyl]~henyl~benzotb]--CA 02236007 l998-04-27 W O 97/25033 PCTnJS96/l7995 thiophon-3-yl 3-M~thoxy-4- e ( 1-pyrrolidiny:L)methyl3-phenyl Ketone Dioxalate.
OMe 2(c2H2O4) OH
Part A. l-Bromo-4-[2-(triisopro~ylsilyloxy)ethyl]-benzene.
Br ~ O-TIPS
Triisopropylsilyl tri~luoromethanesulfonate (35.1 mL, 130 mmol) was added to a stirred solution o~ 4-bromophenethyl alcohol (20.2 g, 100 mmol) and anhydrous triethylamine (27.8 mL, 200 mmol) in anhydrous CH2C12 (200 mL) at room temperature under nitrogen atmosphere. The resultant mixture was stirred for 3 h. A~ter dilution with EtOAc (200 mL), the mixture was washed with a mixed aqeous solution o~ saturated NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica (gradient 0-10%
EtOAc in hexanes) to give 33.5 g (94%) of the silyl ether as an oil.
IR (CHCl3) 2944, 148g cm~l; lH NMR (CDC13) ~1.03 (br s, 3H), 20 1.39 (br s, 18H), 2.81 (t, J = 6.8 Hz, 2H), 3.86 (t, J = 6.8 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H);
FDMS m/e 356 (M+, 79Br) and 358 (M+, 81Br).
~?art B. 6-Benzyloxy-2-t4-(2-hydloxyethyl)~hQnyl]-25 benzo~blthiophen-3-yl 3-Melthoxy-4-~(l-pyrroli~linyl)-rlethyl]phenyl K~tone.
OMe ; BnO
OE~
CA 02236007 l998-04-27 W O 97/2~033 PCTrUS96/17995 The above silyl ether (571 mg, 1. 60 mmol) was added to a stirred suspension of magnesium ribbons (36. 4 mg, 1.50 mmol) in anhydrous THF (2 mL) under argon atmosphere, followed by the addition o~ a small iodine crystal. The mixture was heated in an oil bath at 60-65 ~C for 2 h to form a homogeneous Grignard solution. The Grignard solution was cooled to room temperature before it was added to a stirred solution o~ the compound o~ Example 41, Part C (500 mg, 1.00 mmol) in anhydrous THF (4 mL) at 0 ~C under argon atmosphere.
The resultant mixture was stirred at 0 ~C for 1.5 h, then quenched with saturated aqueous NH4Cl (5 mL). After extraction with EtOAc (25 mL x 2), the combined organic layers were dried over MgSO4, filtered, and concentrated to give a gummy residue (597 mg).
The residue was dissolved in anhydrous THF (5 mL) and treated with tetrabutylammonium fluoride (1.20 mL, 1 M in THF) at room temperature under nitrogen atmosphere. A~ter stirring ~or 1.5 h, the mixture was concentrated under vacuum and chromatographed on silica [gradient 0-30% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 395 mg (68%) of the alcohol as foam.
IR (CHCl3) 2960, 1646, 1601 Gm-1; 1H NMR (CDC13) ~ 1.80 (br s, 4H), 2.54 (br s, 4H), 2.75 (t, J = 6.2 Hz, 2H), 3.59 (s, 2H), 3.74 (t, ~ = 6.2 Hz, 2H), 3.79 (s, 3H), 5.18 (s, 2H), 7.05 (d, J = 8.1 Hz, lH), 7.09-7.50 (m, 13H), 7.74 (d, ~ =
8.g Hz, lH); FDMS m/e 578 (M+1); Anal. Calcd for C36H3sNO4S:
C, 74.84; H, 6.11; N, 2.42. Found: C, 7S.02; H, 6.34; N, 2.50.
Part C. 6-Benzyloxy-2-~4-~2-11-~(S)-2-hydroxymethyl]-~yrroli~inyllethyl]phenyl~benzo~blthio~hen-3-yl 3-Methoxy-4-~ olidinyl)mQthyl]PhQn~l Ketone.
W 097/25033 PCT~US96/17995 OMe ~3nO ~ ~
OH
Methanesulfonyl chloride (0.420 mL, 5.43 mmol) was added to a stirred solution of the above alcohol (2.09 g, 3.62 mmol) in anhydrous pyridine (5 mL) at 0 ~C under nitrogen atmosphere, and the reaction mixture was allowed to stir at room temperature for 2 h. (S)-Prolinol (1.25 mL, 12.7 mmol) was added and the resultant mixture was heated at 70 ~C ~or 2 h. After dilution with EtOAc (120 mL), the mixture was washed with half-saturated NaHCO3 (30 mL), dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-25% EtOH/Et3N (2/1) in THF/hexanes (1/1)~ to give 2.01 g (84%) of the substituted pyrrolidine a foam.
IR (neat) 3355 (br), 2958, 1646, 1600 cm~l; lH MMR (CDCl3) 1.63-2.19 (m, 8H), 2.25-2.80 (m, 8H), 2.87 (t, ~ = 7.7 Hz, 2H), 3.15-3.58 (m, 4H), 3.44 (dd, ~ = 11.5 and 3.6 Hz, lH), 3.60 (dd, J = 11.5 and 3.6 Hz, lH), 3.62 (s, 2H), 3.80 (s, 3H), 7.04-7.08 (m, 3H), 7.23-7.47 (m, llH), 7.62 (d, ~ - 9.0 Hz, lH); FDMS m/e 661 (M+l).
Part D. 6-Hydroxy-2-~4-12-~ (~)-2-hydroxymethyl]-]pyrrolidinyl]Qthyl]phenyl~b~nzo~b]thioph~n-3-yl 3-M~thoxy-4-[(1-pyrrolidinyl)mothyl]phenyl Ketone ~Dioxalate.
Following the procedure of Example 41-E, the title salt was obtained ~rom the above methoxy benzothiophene as a yellowish solid in an overall 6% yield. The free base of the title compound was unstable.
lH NMR (CD30D) ~ 1.75-2.25 (m, 8H), 2.82-3.05 (m, 2H), 3.15-3.23 (m, 4H), 3.38-3.91 (m, 6H), 3.80 (s, 3H), 4.01-4.13 ~m, W O 97/25033 PCTrUS96/17995 lH), 4.28 (s, 2H), 6.92 (br d, J = 6.3 Hz, lH), 7.03-7.37 (m, 8H), 7.56 (m,lH); FDMS m/e 571 (M+l).
~ e 44 Preparation of 6-Hydroxy-3-t3-methyl-4-~1-[(S)-2-mothoxymethyl]pyrrolidinyl~methyl~benzyll-2-~4-12-(1-pyrrolidinyl)ethoxy]phenyl]benzotb]thiophene Dioxalate.
Me HO ~ O ~'N~e 2~c2H2~4~
Part A. Methyl 3-Bromo-4-~ (S)-2-methoxymethyl]-~yrrolidinyl]methyl]benzoate.
Br MeO2C~
OMe Following the procedure of Example 37, Part A, the substituted pyrrolidine was obtained from methyl 3-bromo-4-methylbenzoate and (S)-2-(methoxymethyl)pyrrolidine as an oil in 6396 yield.
IR (neat) 2950, 1727 cm-l; FDMS m/e 341 (M~, 79Br) and 343 (M+, 81Br); Anal. Calcd for ClsH20BrNo3: C, 52.64; H, 5.89;
N, 4.09. Found: C, 52.91; H, 5.93; N, 3.85.
Part B. 3-Bromo-4-[[1-1(5)-2-methoxymethyl]-~yrrolidinyl]msthyl~benzoic acid hydrochloride.
Br H02C~, Cl OMe Following the procedure of Example 37, Part B, the acid was obtained from the above ester as a white solid in.l00%
yield.
CA 02236007 l998-04-27 W 097/25033 pcTrus96~I799s lH NMR (DMSO-d6) ~ 1.60-1.78 (m, lH), 1.80-2.05 (m, 2H), 2.08-2.22 (m, lH), 3 .10-3. 50 (m, 2H), 3.29 (s, 3H), 3 .60-3.65 (m, lH), 3.75-3.95 (m, 2H), 4.46 ~br d, J = 13.4 Hz, lH), 4.76 (d, ~T = 13.4 Hz, lH), 7.93 (d, J = 8.0 Hz, lH), 8.03 (d, LJ = 8.0 Hz, lH), 8.12 (S, lH), 11.15 (br s, lH), 13.55 (br S,lH).
Part C. 3-Bromo-4-t~ (S)-2-methoxymethyl~-~yrrolidinyl]methyl]~henyl 2-Dimethyl~ ; no- 6 -mothoxybenzo[b]thio~hen-3-yl Ketone.
Br MeO ~ N~'OMe Following the procedure oi~ Example 39, Part B, the ketone was obtained :Erom the above acid as a foam in 75%
yield.
IR (neat) 1626, 1544 cm-l; FDMS m/e 516 (M+, 79Br) and 518 (M+, 81Br); Anal. Calcd for C2sH2gBrN2O3S: C, 58.03; H, 5.65;
N, 5. 41. Found: C, 58.15i H, 5.40; N, 5.29.
Part D. 3-Bromo-4-~[1-~($)-2-methoxymethyll-~yrrolidinyllmothyllphenyl 6-Methoxy-2-[4-~2-~1-~yrrolidinyl)ethoxy~phenyl]benzo~b]thioph~n-3-yl Ketone.
Br MeO ~ oN~ 'N~ e Following the procedure o~ Example 3 4, Part C, the trisubstituted benzothiophene was obtained from the above benzothiophene and the corresponding aryl bromide as a foam in 95% yield.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 IR (neat) 2962, 1645, 1606 cm-l; FDMS m/e 662 (M+, 79Br) and 664 (M+, 81Br); Anal. Calcd for C3sH3gBrN204S: C, 63.34; H, 5.92; N, 4.22. Found: C, 63.18; H, 5.84; N, 4.44.
Part E. 3-c3-Bromo-4-lll-[(s)-2-methoxymethyl]-pyrrolidinyl]methyllb~nzyll-6-methoxy-2-14-~2-(1-~yrrolidinyl)ethoxyl~hQnyl]benzo~b~thiophQn~.
MeO ~ N~
Following the procedure oE Example 34, Part D, the methylene compound was obtained from the above ketone as a foam in 7g% yield.
IR (neat) 2963, 1607 cm-l; FDMS m/e 648 (M+, 79Br) and 650 (M+, 31Br); Anal. Calcd for C3sH41BrN203S: C, 64.71; H, 6.36;
15 N, 4.31. Found: C, 64.93; H, 6.42; N, 4.35.
Part F. 6-Methoxy-3-t3-methyl-4-ttl-1(5)-2-methoxymethyllpyrroli~inyl]m~thyl~benzyl]-2-14-~2-(1-~yrrolidinyl)othoxylphQnyllb~nzotblthiophene.
Me ~ ~OMe MeO' ~ ~
Following the procedure of Example 38, Part A, the aryl methyl compound was obtained ~rom the above aryl bromide as a foam in 85% yield.
25 IR (neat) 2962, 1608 cm~l; FDMS m/e 584 (M+) and 585 (Mtl);
Anal. Calcd for C36H44N203S: C, 73.94; H, 7.58; N, 4.79.
Found: C, 73.84; H, 7.42; N, 4.50.
Part G. 6-Hy~roxy-3-13-methyl-4~ (S)-2-mothoxymothyl]pyrroli~inyl]mothyl]benzyl]-2-~4-~2-(1-_ -159-pyrroliainyl)ethoxylphenyl~benzo~b]thiophene Dioxalate .
Following the procedure of Example 34, Part D, a mixture of the free bases of the compounds of this example and the following example were obtained from the above dimethoxy compound. Following conversion to the dioxalate, the title compound was obtained as a white solid in a 2-step yield of 19%.
10 IR (KBr) 3450-2500 (br), 1718, 1609 cm 1; FDMS m/e 571 (M+l-2C2H2O4); Anal. Calcd for C3sH42N2O3S 2C2H2O4: C, 62.39; H, 6.18; N, 3.73. Found: C, 62.61; H, 6.02; N, 3.72.
Examplo 45 15 Preparation of 6-Hy~roxy-3-[3-methy~-4-[tl-[(5~-2-hydroxymethyl]~yrroliainyl~m~thyllbenzyll-2-14-12-(1-~yrrolidinyl)ethoxy~henyll~enzolblthioph~ne Dioxalate.
Me HO f' ~ N~O>
2(CaH2O4) Following separation of the free base in Part ~ of the above example, the dihydroxy compound was converted into the title dioxalate which was obt~; n~ in a white solid in a 2-step yield of 33%.
25 IR (KBr) 3400-2500 (br), 1721, 1609 cm~l; FDMS m/e 557 (M+l-2C2H2O4); Anal. Calcd for C34H4QN2O3S 1.6C2H2O4: C, 62.39; H, 6.18; N, 3.73. Found: C, 62.61; Il, 6.02i N, 3.72.
>
~v~ 1~ 46 30 Preparation of 6-Hy~lroxy-2-1:4-t2-(1-~r~lolidinyl)-othoxy]phenyl]benzolb]thi.ophen-3-yl 3-Methyl-4-~(4-mor~holinyl)methyl~honyl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 Me N
~~~
2(c2H2~4) Part A. Methyl 3-Bromo-4-~(4-morpholinyl)meth~l]-b~zoat~- Br MeO2C~N~
~0 Following the procedu~e of Example 37, Part A, the substituted morpholine was obtained from methyl 3-bromo-4-methylbenzoate and morpholine as an oil in 53% yield.
IR (neat) 2953, 1727 cm~l; lH NMR (CDCl3) ~ 2.48-2.60 ~m, 10 4H), 3.63 (s, 2H), 3.70-3.80 (m, 4H), 3.93 ~s, 3H), 7.59 (d, J = 8.0 Hz, lH), 7.95 (d, J = 8.0 Hz, lH), 8.23 (s, lH); FDMS
m/e 313 (M+,79Br) and 315 (M+,81Br); Anal. Calcd for C13H16BrNO3: C, 49.70; H, 5.13; N, 4.46. Found: C, 49.42; H, 4.98; N, 4.55.
Par~ B. 3-Bromo-4-[(4-~orpholinyl)methyl]benzoic Acid Hydrochloride.
~ Br H02C~--N~l ~0 Following the procedure of Example 37, Part B, the acid was obtained ~rom the above ester as a white solid in 100 yield.
lH NMR (DMSO-d6) ~ 3.25 (br s, 4H), 3.88 (br s, 4H), 4.51 ~s, 2H), 7.93 (d, ~ = 8.Q Hz, lH), 8.12 (s, lH), 8.19 (br d, J =
8.0 Hz, lH).
PCT~US96/17995 W O 97nso33 Part C. 3-Bromo-4-~(4-morpholinyl)methyl~phonyl 2-Dimothylamino-6-methoxybenzo~b]thioph~n-3-yl Ketone.
Br ~~
MeO ~ N' Following the procedure o~ Example 39, Part C, the ketone was obtained from 2-dimethyl~m,no-6-methoxybenzo[b]thiophene and the above acid as a foam in 80%
yle~
IR (neat) 1622, 1540 cm~l; lH NMR (CDC13) ~ 2.52-2.60 (m, 4H), 2.89 ~s, 6H), 3.65 (s, 2H), 3.72-3.80 (m, 4H), 3.83 (s, 3H), 6.84 (dd, ~ = 8.9 and 2.4 Hz, lH), 7.13 (d, ~ = 2.4 Hz, lH), 7.39 (d, ~ = 8.9 Hz, lH), 7.58 (d, ~ = 8.0 Hz, lH), 7.77 (dd, ~ = 8.0 and 1.4 Hz, lH), 8.05 (d, ~ = 1.4 Hz, lH); FDMS
m/e 488 (M+,79Br) and 490 (M+,81Br).
I?art D. 3-Bromo-4-~(4-morpholinyl)methyl]ph~nyl 6-Methoxy-2-l4-~2-(1-pyrrolidinyl)ethoxy]phenyll-b~nzo~b]thio~hen-3-yl K~tonQO
Br ~ N
MeO ~ o ~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obt;~;n~ from the corresponding aryl bromide and the above benzothiophene as a foam in 80~ yield.
25 IR (neat) 2959, 1622, 1598 cm-l; FDM~ m/e 635 (M+l, 79Br) and 637 (M+l, 79Br).
Part E. 6-M~thoxy-2-[4-~2-(1-pyrrolidinyl)ethoxy]-~henyl]benzo~blthio~hQn-3-Yl 3-Methyl-4- r ( 4-mor~holinyl)m~thyl]phenyl K~tono.
Me MeO ~
Following the procedure of Example 34, Part E, the aryl methyl compound was obtained from the above aryl bromide as a foam in 76% yield.
IR (neat) 2958, 1643, 1603 cm-1; FDMS m/e 570 (M+).
Part F. 6-Xydroxy-2-14-12-(1-~y olidinyl)~thoxy]-phenyl~ benz o 1 b lthiol?hen-3-yl 3-Mothyl-4-[(4-morpholinyl)methyl]phenyl Ketono Dioxalato.
Following the procedure o~ Example 34, Part E, the salt of the hydroxy benzothiophene was obtained from the above methoxy ben~othiophene as a yellowish solid in a 2-step yield of 69%.
IR (KBr) 3400-2500 (br), 1725, 1639 cm-l; FDMS m/e 557(M+1-2C2H204); Anal. Calcd for C33H36N204S 2C2H204: C, 60.32; H, 5.47; N, 3.80. Found: C, 60.60; H, 5.53; N, 4.01.
Exam~le 47 Preparation of 3-l3-Bromo-4-l(4-mor~holinyl)meth benzyll-6-hydroxy-2-14- r 2-(1-~yrrolidinyl)ethoxy}-~honyl~benzo[bl thio~hene Dioxalate.
Br ~ N
HO ~ o ~ N~
2(C2H2O4) Part A. 3-[3-Bromo-4-t(4-morpholinyl)methyl]benzyl]-6-methoxy-2-14-12-(1-pyrrolidinyl)othoxy]phenyl}-bQnzolb] thiophone-W O 97/25033 PCTnJS96/1799 Br ~ N
MeO ~ ~ N~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone of Example 46, Part A as a foam in 84% yield.
IR (neat) 2958, 1608 cm~l; FDMS m/e 621 (M+1,79Br) and 623 (M~1,81Br); Anal. Calcd for C33H37BrN2O3S: C, 63.76; H, 6.00;
N, 4.51. Found: C, 63.50; H, 5.82; N, 4.38.
Part s. 3-13-sromo-4-1(4-morpholinyl)m~thyl]bQnzyl~-G-hydroxy-2-14-12-(1-pyrrolidinyl)ethoxylph~nyl]-benzolb]thiorhs~e Dioxalate.
Following the procedure of Example 34, Part E, the title hydroxy benzothiophene salt was obtained ~rom the above methoxy benzothiophene as a white solid in 66% yield.
IR (KBr) 3400-2500 (br), 1721, 1607 cm-l; FDMS m/e 607 (M+l-2C2H204,79Br) and 609 (M+1-2C2H204,81Br); Anal. Calcd for C32H35BrM2O3S 1.5C2H2O4: C, 56.61i H, 5.16; N, 3.77. Found: C, 56.70; H, 5.13; N, 3.95.
~ Y~ _le 48 Preparation of 6-Hydroxy-3 t3-methyl-4-[(A-morpholinyl)methyllbQnzyll-2-14-12~ pyrroli~inyl)-~thoxy]phenyl]bonzo lb] thiophene Dioxalate~
Me HO~o~ON~
2(c2H2o4) Part A. 6-Methoxy-3-13-methyl-4-1(4-morpholinyl)-methyl]b~nzyl]-2-14-12-(1-~yrrolidinyl)ethoxyl-~henyl]benzo tb] thiophene.
W O 97/25033 PCTnJS96/17995 Me MeO~O~N~>
Following the procedure o~ Example 38, Part A, the aryl methyl compound was obtained ~rom the aryl bromide of Example 47, Part A as a foam in 91% yield.
IR (neat) 2957, 1608 cm~l; FDMS m/e 556 (M+).
Part B. 6-Hy~roxy-3-13-methyl-4-1(4-morpholinyl)-m~thyllbQnzyll-2-14- r2 - ( 1-~yrroli~inyl)ethoxy]-phenyl]benzo~b]thiophQne Dioxalate.
Following the procedure of Example 34, Part E, the titlehydroxy benzothiophene salt was obtained ~rom the above methoxy benzothiophene as a white solid in a 2-step yield o~
79%.
IR (KBr) 3400-2500 (br), 1722, 1610 cm-l; FDM~ m/e 543 (M~-2C2H2O4); Anal. Calcd ~or C33H3gN2O3S 1.5C2H2O4: C, 63.79; H, 6.10; N, 4.13. Found: C, 63.92; H, 6.15; N, 4.31.
~YA _le 49 Preparation of 6-Hy~oxy-2-14-[2-(1-~ olidinyl)-~thoxy]~henyl]bQnzo[b]thiophen-3-yl 3-Methoxy-4-1(4-morpholinyl)methyl]phenyl Ketone Dioxalate.
OMe HO ~ N~
2(c2H2~4) Part A. Methyl 3-Methoxy-4-(4-mor~holinyl)benzoate.
OMe Meo2c~<~?
Following the procedure of Example 37, Part A, the substituted morpholine was obtained from methyl 4-methyl-3-methoxybenzoate and morpholine as an oil in 79% yield.
IR (neat) 2953, 1723, 1582 cm 1; FDMS m/e 265 (M+); Anal.
>
Calcd for C14HlgNO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.11; H, 7.20; N, 5.50.
Part B. 3-Methoxy-4-(4-morpllolinyl)benzoic Acid Hydrochloride.
OMe H02C~N~l ~0 Following the procedure of Example 37, Part B, the acid was obtained from the ester as a white solid in 100~ yield.
1H NMR (DMSO-d6) ~ 3.05 (br s, 2H), 3.15-3.25 (m, 2H), 3.85 (s, 2H), 3.87 (s, 5H, OCH3 and CH2), 4.29 (s, 2H), 7.52 (s, lH), 7.53 (d, J = 8.0 Hz, lH), 7.77 (d, J = 8.0 Hz, lH), 11.65 (br s, lH), 13.15 (br s, lH).
Part C. 6-BQnzyloxy-2-(dimethyl~ Q) benzolb~-thiophen-3-yl 3-Methoxy-4-~(4-mor~holinyl)methyl~-phenyl Ketone.
OMe ~ N
BnO ~ N' ~
Following the procedure of Example 39, Part B, the ketone was obtained from 6-benzyloxy-2-(dimethyl~m; no) -benzo~b]thiophene and the above acid as a foam in 81% yield.
IR (neat) 2954, 1625, 1600 cm 1; FDMS m/e 516 (M+); Anal.
Calcd for C30H32N2O4S: C, 69.74; H, 6.24; N, 5.42. Found: C, '70.03; H, 6.47; N, 5.44.
CA 02236007 l998-04-27 W 097/25033 PCT~USg6/l7995 Part D. 6-Benzyloxy-2-[4-[2-(1-~ ~olidinyl)ethoxy~-phenyl]benzotb~thiophen-3-yl 3-Methoxy-4-[(4-mor~holinyl)methyl~phenyl Ketone.
OMe BnO ~ O ~ M~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained from the corresponding aryl bromide and the above benzothiophene as a foam in 88% yield.
10 IR (neat) 2961, 1651 cm-li FD~qS m/e 662 (M+) and 663 (M+l);
Anal. Calcd for C40H42N2OsS: C, 72.48; H, 6.39; N, 4.23.
Found: C, 72.47; H, 6.35; N, 4.43.
Part E. 6-Hydroxy-2-14-[2-(l-~y ~olidinyl~ethoxyl-15 phenyl~benzolb~thiophen-3-yl 3-Methoxy-4-[(4-morpholinyl)methyllphenyl Ketone Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 74% yield.
IR (KBr) 3400-2500 (br), 1722, 1633, 1606 cm~l; FDMS m/e 573 (M+1-2C2H2O4); Anal. Calcd for C33H36N2OsS-2.3C2H2O4: C, 57.91; ~I, 5.25; N, 3.59. Fotm d: C, 57.93; H, 5.37; M, 3.78.
~Y~ _ le 50 Pre~aration of 6-Hydroxy-3-[3-methoxy-4-[(4-morpholinyl)methyl]benzyl]-2-[4-[2-(1-~yrrolidinyl?-ethoxy~phenyl~benzo[b]thio~he~e Dioxalate.
OMe ~ N ~
HO ~ M~>
2(C2H2O4) W O 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-3-[3-methoxy-4-[(4-morpholinyl)-m~thyl]bQnzyl~-2-[4-~2-(1-pyrrolidinyl)ethoxy]ph~nyl]-benzolb]thiophene.
OMe N
BnO ~ O ~ ON~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone of Example 49, Part D as a ~oam in 82% yield.
IR (neat) 2961, 1609 cm-l; FDMS m/e 649 (M+1); Anal. Calcd for C40H44N2O4S: C, 74.04; H, 6.84; N, 4.32. Found: C, 74.30;
H, 7.18; N, 4.34.
Part B. 6-Hydroxy-3-C3-methoxy-4-~(4-morpholinyl)-methyllbQnzyll-2-14-~2-(1-~yrrolidinyl)ethoxy~ph~nyl3-bonzotb~thiophon~ Dioxalate.
Following the procedure of Example 41, Part E, the salt o~ the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 90% yield.
IR (KBr) 3400-2500 (br), 1613 cm-l; FDMS m/e 559 (M+1-2C2H2O4); Anal. Calcd ~or C33H3gN2O~S-1.4C2H2O4: C, 62.79; H, 6.01; N, 4.09. Found: C, 62.73; H, 5.93; N, 4.04.
Example 51 Preparation of 6-Hydroxy-2-~4-~2-~ olidinyl~-ethyl]phenyl~benzolb]thiophen-3-yl 3-Methoxy-4-~(4-morpholinyl)mQthyl]phenyl RQtone Dioxalate.
OMe 2(C2H2O4) WO 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-2-t4-12-(1-~ olidinyl)ethyll-phenyllbenzotblthiophQn-3-yl 3-Nethoxy-4-1(4-morpholinyl)methyl]phenyl ~etone.
OMe BnO~
Following the procedure of Example 34, Part C, the trisubstituted benzothiophene was obtained ~rom the aryl bromide of Example 39, Part A and the ketone o~ Example 49, Part C as a foam in ~1% yield.
IR (neat) 3400 (br), 2959, 1651, 1600 cm-1; FDMS m/e 646 (M+); Anal. Calcd for C40H42N2O4S: C, 74.27; H, 6.54; N, 4.33. Found: C, 74.09; H, 6.74i N, 4.38.
Part B. 6-Hydroxy-2-~4-t2-(1-pyrrolidinyl)ethyl3-phenyllbenzo[blthiophen-3-yl 3-Methoxy-4-~(4-morpholinyl)methyl~henyl Ketone Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 83% yield.
IR (KBr) 3400-2500 (br), 1718, 1645 cm-1; FDMS m/e 557 (M+1-2C2H204); Anal. Calcd for C33H36N204S-2C2H204: C, 60.32; H, 5.47; N, 3.80. Found: C, 60.06; H, 5.43; N, 4.00.
r-- _,le 52 Preparation of 6-Hy~roxy-3-[3-methoxy-4-~(4-mor~holinyl)methyllbenzyl]-2-14-12-(1-pyrroli~inyl)-ethyllphenyl~benzo~b]thiophene Dioxalate.
OMe HO ~ /
2(c2H2~4) W O 97/25033 PCT~US96/17995 Part A. 6-Benzyloxy-3-r3-methoxy-4-1(4-m4rpholinyl)-m~thyl]benzyl]-2-[4-~2-(1-pyrrolidinyl)ethyllphenyl]-~onzo[b]thiophQno.
OMe BnO ~ ~
Following the procedure of Example 34, Part D, the methylene compound was obtained ~rom the ketone o~
Example 51, Part A as a :Eoam in 100% yield.
IR (neat) 2957, 1600 cm-l; FDMS m/e 632 (M+); Anal. Calcd 10 for C40H44N2O3S: C, 75.92; H, 7.01; N, 4.43. Found: C, 75.93;
H, 7.00; N, 4.39.
Part B. 6-Hydroxy-3-[3-methoxy-4-~4-morpholinyl)-mQthyl]~Qnzyl~-2-14-12-(1-pyrrolidinyl)~thyl~h~nyll-15 benzo[blthiophene Dioxalate.
Following the procedure o~ Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 83% yield.
20 IR (KBr) 3400-2500 (br), 1719, 1612 cm-l; FDMS m/e 543 (M+l-2C2H2O4); Anal. Calcd for C33H3gM2O3S 1.7C2H2O4: C, 62.83; H, 6.00; N, 4.03. Found: C, 62.72; H, 6.05; N, 4.16.
Fxample 53 25 Pr~paration of 6-Hydroxy-2-t4-[2-[1-[~5)-2-hydroxymethyl]pyrrolidinyllethyl]phenyl]b~nzo[bl-~hiophen-3-yl 3-Methoxy-4-1(~-morpholinyl)methyll-phenyl Ketono DioxalatQ.
CA 02236007 l998-04-27 OMe ~ N
HO
2(C2H2O4) OH
Part A. 6-Benzyloxy-2-[4-(2-hydroxyethyl)phenyl]-benzolblthiophen-3-yl 3-Methoxy-4-l(4-morpholinyl) methyll~henyl Ketone.
OMe ~ N ~
BnO ~ OH
Following the procedure of Example 43, Part A, the trisubstituted benzothiophene was obtained ~rom the ketone of Example 49, Part C as a foam in an overall 95% yield.
10 IR (neat) 3424 (br), 2936, 1647, 1600 cm~l; FDMS m/e 593 (M+); Anal. Calcd for C36H3sNOsS: C, 72.83; H, 5.94; N, 2.36.
Found: C, 72.66; H, 5.g5; N, 2.59.
Part B. 6-Benzyloxy-2-~4-~2-~ (5)-2-hydroxymethyl]-~yrrolidinyl~ethyl]~henyl]benzorb]thiophen-3-yl 3-Methoxy-4-[(4-mor~holinyl)methyl]~henyl ~etone.
OMe ~ N
BnO
OH
Following the procedure of Example 43, Part B, the substituted prolinol was obtained from the above alcohol and (S)-prolinol as a foam in an overall 43% yield.
IR (neat) 3389 (br~, 2954, 1654, 1600 cm-l; FDMS m/e 677 (M~l); Anal. Calcd for C41H44N20sS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.78; H, 6.46; N, 4.14.
CA 02236007 l998-04-27 WO 97/25033 PCT/USg6/17995 Part C. 6-Hydroxy-2-~4-[2-~1-1(5)-2-hydroxymethyl]-pyrrolidinyl~ethyllphenyl]benzolblthiophen-3-yl 3-Mothoxy-4-~14-morpholin~l)methyllph~nyl K~tone Dioxalate.
Following the procedure of Example 41, Part E, the salt o~ the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a yellowish solid in an overall 65% yield.
IR (KBr) 3377 (br), 3400-2500 (br), 1718, 1638, 1609 cm-l;
FDMS m/e 587 (M+1-2C2H2O4). Anal. Calcd for C34H38N205S 1.4C2H204: C, 62.01; H, 5.77; N, 3.93. Found: C, 61.99; H, 5.80; N, 4.12.
_le 54 Pr~p~ration of 6-Hydroxy-2-~4-[2-~ (g)-2-hydroxymethyllpyrroliainyl]ethyllphenyl}-3-~3-methoxy-4-~(4-morpholinyl)mothyllbenzyl]benzo~blthiophene ~ioxalate.
OMe ~<
~N--HO J~,~
2 (c2H2o4) OE
Part A. 6-Benzyloxy-2-~4-l2~ (5)~2-hYdrOXYmethYll-pyrrolidinyllQthyl~phenyll-3-~3-methoxy-4-~( 4-morpholinyl)methyllbenzyllbQnzo~blthiopheno.
OMe ~<
~ N
BnO
OH
$ 25 Following the procedure o~ Example 34, Part D, the methylene compound was obtained ~rom the above ketone as a ~oam in 88% yield.
W O 97/25033 PCT~US96/17995 IR (neat) 3390 (br), 2955, 1600 cm~l; FDMS m/e 663 (M+l).
Anal. Calcd for C41H46N204S: C, 74.29; H, 6.99; N, 4.23.
Found: C, 74.40; H, 6.97; N, 4.18.
Part B. 6-Hydroxy-2-14-l2-~ (s)-2-hydroxymethyl3 ~yrrol i~inyl 1 ethyllphenyl}-3-[3-methoxy-4-~4-morpholinyl)methyllbenzyl]benzo{blthioPhene Dioxalate.
Following the procedure o~ Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 73% yield.
IR (KBr) 3376 (br), 3400-2500 (br), 1719, 1612 cm-l; FDMS
m/e 573 (M+1-2C2H2O~]. Anal. Calcd for C34H40N2O4S-l-2C2H2O4:
C, 64.22; H, 6.28; N, 4.11. Found: C, 64.01; H, 6.10; N, 3.97.
_le 55 Preparation o~ 6-Hyaroxy-2-[4-~2-tl-l(R)-2-hydroxy-methyl]pyrrolidinyl]ethyllphenyllb~nzotb]thiophen-3-yl 3-MQthoxy-4-[(4-morpholinyl)m~thyllphenyl KetonQ
Dioxalate.
OMe HO
2(C2H2O4) ~OH
Part A. Preparation of 6-Benzyloxy-2-[4-12-tl-~(R)-2 hydroxymethyllpyrrolidinyllethyllphenyllbenzolblthio-phen-3-yl 3-Methoxy-4-[(4-morpholinyl)methyl]phenyl KQ tone.
CA 02236007 l998-04-27 OMe BnO ~ l ~ ¦
OH
Following the procedure of Example 43, Part C, the substituted prolinol was obtained from the alcohol of Example 53, Part A and (R)-prolinol as a foam in an overall 4896 yield.
IR (neat) 3378 (br), 29S6, 1648, 1600 cm-li FDMS m/e 677 (M+l). Anal. Calcd for C4lH44N2OsS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.96; H, 6.32; N, 4.20.
Part B. 6-Hydroxy-2-14-t2-11-t(R)-2-hydroxymethyl}-~yrrolidinyl~ethyl~phenyl]benzotb]thiophen-3-yl 3-Methoxy-4-[(4-morpholinyl3mothyl]phenyl Ketone Diox~latQ .
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a yellowish solid in an overall 63% yield.
IR (KBr) 3384 (br), 3400-2500 (br), 1719, 1638, 1607 cm-l;
FDMS m/e 587 (M+1-2C2H2O4). Anal. Calcd for C34H3gN2OsS-1.4C2H2O4: C, 62.01; H, 5.77; N, 3.93. Found: C, 61.73; H, 5.90; N, 4.14.
_le 56 Pr~paration o:E 6-Hy~lroxy-2-t4-~2-~ (~)-2-hydroxymethyl~pyrroli~inyl~ethyl]phenyl]-3-13-methoxy-4-[(4-morpholinyl)methyl]benzyllbenzolb]thiophene Dioxalate.
CA 02236007 l998-04-27 W 097125033 PCT~US96/17995 OMe ~ N
HO ~
2(C2H2O4) ~OH
Part A. 6-Benzyloxy-2-~4-12-tl-~(R)-2-hyaroxy~ethyl]-~yrrolidinyl]ethyllphenyl]-3-~3-methoxy-4-1(4-mor~holinyl)methyl~benzyl}benzo[b]thiophene.
OMe BnO ~ ~
OH
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone o~ Example 55, Part A as a :Eoam in 83% yield.
IR (neat) 3426 (br), 2955, 1600 cm~l; FDMS m/e 663 (M+l).
Anal. Calcd for C41H46N2O4S: C, 74.29; H, 6.99; N, 4.23.
Found: C, 74.29; H, 6.98; N, 4.33.
Part B. 6-Xydroxy-2-~4-r2-~ (R)-2-hydroxymethyl]-pyrrolidinyl]ethyl]~henyl~-3-~3-methoxy-4-t(4-morpholinyl)msthyl]benzyl]bonzo~b]thio~hene Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained ~rom the above benzyl ether as a white solid in an overall 77% yield.
IR (KBr) 3401 (br), 3400-2500 (br), 1718, 1612 cm-l; FD~S m/e 573 (M+l-2C2H2O4). Anal. Calcd ~or C34H40N2O4S 1~5C2H2O4: C, 62.79; H, 6.12; N, 3.96. Found: C, 62.68; H, 5.88; N, 4.13.
Exam~le 57 Prep~ration of 3,5-Dimethoxy-4-[(1-~y~ olidinyl)-methyl~phenyl 6-Hydroxy-2-~4-t2-(1-pyrrolidinyl)-Qthoxyl~henyl3benzo~blthiophen-3-yl Ketone.
OMe HO ~ Oe~ N~
2(H2C2O4) ~?art A. Nethyl 3,5-Dimetho~cy-4-l(l-~yllolidinyl) methyl3benzoate.
OMe MeOac ~ N~
OMe Following the procedure o~ Example 37, Part A, the .substituted pyrrolidine was obtained from methyl 3,5-dimethoxy-4-methylbenzoate and pyrrolidine as an oil in 51%
yield.
IR (KBr) 2964, 1721 cm~l; FDMS m/e 279 (M+~. Anal. ~alcd for ClsH21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.56; H, 7.65; N, 5.04.
P~rt B. 3,5-Dimethoxy-4-~(1-~y~ olidinyl)methyl~-~benzoic Acid Hydrochloride.
OMe HO2C ~ N~
OMe Following the procedure o~ Example 37, Part B, the acid was obt~; n~ ~rom the above ester as a white solid in 100%
yield.
lH NMR (DMSO-d6) ~1.80-2.00 (m, 4H), 3.00 (br s, 2H), 3.32 (br s, 2H), 3.86 (s, 6H), 4.20 (s, 2H), 7.20 (s, 2H).
CA 02236007 l998-04-27 Part C. 6-Benzyloxy-2-(dimethylamino)benzoCb]thio-~h~n-3-yl 3,5-Dimethoxy-4-[(1-pyrrolidinyl)methyl]-~henyl Ketono.
OMe ~ , OMe ~
Following the procedure of Example 39, Part C, the ketone was obtained from 6-benzyloxy-2-(dimethyl~m;no)-benzo[b]thiophene and the above acid as a foam in 71% yield.
IR (neat) 2957, 1625, 1601 cm~l; FDMS m/e 530 (M+).
Part D. 6-Benzyloxy-2-14-12-(1-~ lolidinyl)ethoxy~-phenyl]benzoCb~thiophen-3-yl 3,5-Dimothoxy-4-~(1-olidinyl)methyl]~h~nyl ~etone.
OMe BnO ~ OeN~ N~
Following the procedure of Example 34, Part C, the ketone was obtained from the corresponding aryl bromide and the above ketone as a foam in 88% yield.
IR (neat) 2957, 1647, 1606 cm-l; FDMS m/e 677 (M~l). Anal.
Calcd for C41H44N2OsS: C, 72.75; H, 6.55; N, 4.14. Found: C, 72.55; H, 6.76; N, 4.19.
Pa~t E. 3,5-Dimethoxy-4-~( 1-~r,olidiny})~ethyl~-phenyl 6-Hydroxy-2-C4-c2~ y~rolidinyl)eth phenyll bonzorb]thiophen-3-yl Keton~.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a yellowish solid in an overall 70% yield.
W O 97/25033 PCT~US96/17995 IR (KBr) 3450-2500 (br), 1720, 1643 cm-l; FDMS m/e 587 ~M+l-2C2H2O4). Anal. Calcd for C34H3gN2OsS-2C2H2O4: C, 59.52; H, ~ 5.52; N, 3.65. Found: C, 59.71; H, 5.78; N, 3.56.
Examl?le 58 Prep~ration of 3-13,5-DimQthoxY-4-~(l-~y ~olidinyl)-methyl]benzy$~-6-hydroxy-2-{4-[2-(1-pyrrolidinyl)-~thoxy]~henyl]benzo~ b] thiophene Dioxalate.
OMe HO~oeN~>
2(C2HaO4) Part A. 6-Benzyloxy-3-13,5-~imethoxy-4-~
~yrrolidtnyl)methyl]benzyl]-2-[4-12-(1-pyrrolidinyl)-~thoxy]phQnyl]benzolb]thiophene.
OMe BnO'C~Oe~>N~>
Following the procedure of Example 34, Part D, the methylene compound was obtained from the ketone of Example 57, Part D as a foam in 79% yield.
IR (neat) 2961, 1606 cm-l; FDMS m/e 663 (M+l). Anal. Calcd for C41H46N2O4S: C, 74.29; H, 6.99; N, 4.23. Found: C, 74.48;
H, 7.15; N, 4.37.
Part B. 3-l3~5-Dimethoxy-4-l(l-~yl oli~inyl)methyl]-benzyl]-6-hydroxy-2-14-~2-(l~yrroli~inyl)Qthoxy]-phenyl]benzo lb] thiophene Dioxalate.
Following the procedure of Example 41, Part E, the salt of the hydroxy benzothiophene was obtained from the above benzyl ether as a white solid in an overall 71% yield.
CA 02236007 l998-04-27 W O 97/25033 PCT~US96tl7995 IR (KBr) 3450-2500 ~br), 1721, 1609 cm-l; FDMS m/e 573 (M~l-2C2H2O4). Anal. Calcd for C34H40N2o4s-2c2H2o4: C, 60.63; H, 5.89; N, 3.72. Found: C, 60.92i H, 6.11; N, 3.94.
E:xample 59 Preparation of (1)-6-Hydroxy-3-t4-[[tran~-2-(l-~yrrolidinyl)cyclohexylloxylbenzyll-2-~4-~2-(1-pyrrolidinyl)etho~y~pheny}]b~nzo~b]thiophene Dioxalat~.
o""~
HO~ 2C~H204 ~
~art A. 6-Methoxy-2-[4-~2-(1-pyrroliainyl)ethoxy~-~henyl]b~nzo~b~thiop~en-3-yl 4-Fluorophanyl Ketone.
F
MeO~ ~
To 671.4 mg of 6-metho~-2-[4-[2-(1-pyrrolidinyl)-15 ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 10 mL
of l,2-dichloroethane was added 1.114 g o~ AlC13 at 0 ~C, followed by dropwise addition of 0.30 mL o~ 4-:Eluorobenzoyl chloride. The deep red solution was stirred at 0 ~C ~or 1 h and then at 0 to 15 ~C ~or 19 h. The reaction was quenched 20 by pouring the reaction mixture into 50 mL of ice-cold 2.0 N
NaOH solution. The mixture was then extracted with 3x100 mL
of EtOAc which was washed with 50 mL oi~ H20 and brine.
Combined organic layers were dried over MgSO4, concentrated, and puri:Eied by ~lash chromatography with 5 v/v % (10% conc W O 97/25033 PCT~US96/17995 NH40H in MeOH) in CH2C12 to give 826.4 mg (92%) of the product ketone as viscous oil.
;
FDMS 475 (M+); Anal Calcd for C2gH26FN03S: C, 70.71i H, 5.51; N, 2.94. Found: C, 70.75; H, 5.58; N, 3.15.
Part B. (I)-6-Methoxy-2-[4-[2-(l-~yrrolidinyl)-ethoxylph~nyl~b~nzo~b~thioph~n-3-yl 4- 11 tranB-2 Pyrrolidinyl)cyclohexyl~oxy~henyl Ketone.
Q
o",~
MeO ~ ~ ~ N
~
To a suspension of ca. 60 mg of NaH (60% oil dispersion) in 2.0 mL of freshly distilled THF was added 330.9 mg of (~)trans-2-(l-pyrrolidinyl)cyclohexanol in 2.0 mL of THF at room temperature. The mixture was heated at reflux for 45 min, cooled down to room temperature, and then to this was added 0.90 mL of 1.086 M of the fluoride (Part A). The mixture was heated at reflux for 24 h, cooled down, and then the reaction was quenched with 20 mL of H2O. The mixture was extracted with 3x50 mL of EtOAc which was washed with 25 mL
of brine. The combined extracts were dried over MgSO4, concentrated, and purified by flash chromatography with 40:5:55 THF-Et3N-hexanes to afford 349.9 mg (57%) of the product along with 49.0 mg (10%) of recovered fluoride.
mp 39-47 ~C; FDMS 624.9 (M+), 500.8 (base); Anal. Calcd for C3gH44N2O4S: C, 73.05; H, 7.10; N, 4.48. Found: C, 73.01;
H, 7.25; N, 4.21.
Part C. (~)-6-Hydroxy-3-~4~tr~n~-2~
pyrroliainyl)cyclohoxyl]oxy~b~nzyl~-2- r4 r2- (l-W O 97/25033 PCT~US96/17995 pyrroli~inyl)ethoxy]phenyl~benzotb]thiophQne Dioxalate.
The title compound was prepared in 36% yield for ~our steps from the ketone (Part B) by essentially following the procedures detailed in Example 21, Parts A-C.
mp >105 ~C (decomp?); FDMS 597.1 (M+l); Anal. Calcd for C37H44N2O3S 2~5c2Hao4: C, 61.38; H, 6.01i N, 3.41. Found:
C, 61.63; H, 5.77; N, 3.01.
~ Yr l~ 60 Pr~paration of ( + ) - 6-Hy~roxy-3-14-lltrans-2-(hexahydro-lH-azepin-1-yl)cyclohexyl]oxY]benzyl]-2-t4-[2-(l-~yrrolidinyl)ethoxy]ph2nyl]benzo lb] thiophene Dioxalate.
C~
,13'~"'~
HO~ ~ 2C2 ~~4 Part A. (+)-6-Methoxy-2-t4-12-(1-pyrroli~inyl)-~thoxy]phenyl]benzo tb] thiophen-3-yl 4-[ltrans- a -(Hexahydro-lH-azepin-1-yl)cyclohexyl]oxy]~henyl KQtonQ.
o~ ""~
MeO ~ ~
CA 02236007 l998-04-27 The title compound was prepared in 54% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl] 4-fluorophenyl ketone and (+)-trans-2-(hexahydro-lH-azepin-l-yl)cyclohexanol by essentially 5 ~ollowing the procedures detailed in Example 59, Part B.
mp 43.5-51.5 ~C; FDMS 653.1 (M+l); Anal. Calcd i~or C40H4gN2O4S: C, 73.59; H, 7.41; N, 4.29. Found: C, 73.61;
H, 7.61; N, 4.07.
Part B. (I)-6-Hydroxy-3-~4-t~tr~n3-2-(hexahydro-lH-azel?in-l-yl)cyclohexyl]oxy]bQnzyl] -2- ~4- t2- (1-pyrrolidinyl)ethoxy~phenyllbenzo[b~thiophQne Dioxalate.
The title compound was prepared in 29% yield ~or four steps from the ketone (Part A) by essentially following the procedures detailed ~n Example 21, Parts A-C.
mp >114 ~C (decomp?); FDMS 625.1 (M~l); Anal. Calcd for C39H48N203S 2.5C2H204: C, 62.18; H, 6.28; N, 3.30. Found:
C, 62.02; H, 6.28; N, 3.12.
r~ le 61 Pr~arntion o~ (I)-6-Hydroxy-3-[4-t~trans-2-(imidazol-25 1-yl)cyclohexyl~oxylbenzyl~-2-14-t2-(1-pyrrolidinyl)-ethoxylphenyl]benzotb~thiophene Dioxalate.
N~
N
,~o b HO~-- 2(~2HZO4 1 Part A. (~)-tran~-2-(Imidazol-1-yl)cycloh~YAnol.
CA 02236007 l998-04-27 W 097/25033 PCTrUS96/17995 ~182-N
H~b A mixture of 20.18 g of imidazole, 81.95 g of K2CO3, and 20.0 mL of cyclohexene oxide in ca. 200 mL of H20 was stirred at room temperature for l9 h, at l00 ~C (bath temp.) for 7 h, and then at room temperature overnight. The mixture was extracted with 3x500 mL of EtOAc and 500 mL of CH2Cl2. The organic layers were washed with 2x300 mL, of H20 and 300 mL of brine. Combined organic layers were dried over MgSO4 and concentrated. The crude product was crystallized from EtOAc to yield 8.57 g (26%) oi~ the crystalline solid.
mp 127-131 ~C; FDMS 167 (M~l); Anal Calcd for CgH14N2O 0.22H20: C, 63.~i2; H, 8.55; N, 16.46. Found: C, 63.63; H, 8.30; N, 16.11.
Pa~t B. (l)-6-Methoxy-2-14-[2-(l-~yrrolidinyl)-ethoxy]~henyl]bQnzotb]thioph~n-3-yl 4- 1 ~ tr~ns- 2 -(Imidazol-l-yl)cyclohexyl~oxy]phenyl Ketone.
N ~
o~~ b Meof ~ ~
The title compound was prepared in 71% yield from 6-methoxy-2-[4-[2-(l-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl~ 4-fluorophenyl ketone and (+)-trans-2-(imidazol-l-yl)cyclohexanol (Part A) by essentially following the procedures detailed in Example 59, Part B.
W O 97/25033 PCTnUS961I7995 mp 68-78 ~C; FDMS 622 4 (M+1); Anal Calcd for C37H3gN304S-0.35NH40H: C, 70 09i H, 6.48; N, 7.40 Found:
C, 69.75i H, 6.14i N, 7.03 P~rt C. (+)-6-Hydroxy-3-14-[[trans-2-(imidazol-1-yl)cyclohexyl~oxy]b~nzyl3-2-14-t2-(1-pyrroliainyl)-~thoxy~phenyllbenzolblthiorhe~e Dioxalate.
The title compound was prepared in 81~ yield for four steps from the ketone ~Part B) by essentially following the procedures detailed in Example 21, Parts A-C.
mp >103 ~C (decomp?); FDMS 594 (M+1); Anal. Calcd for C36H3gN303S-2.1C2H204-l.lC4HgO2: C, 60.89; H, 5.96; N, 4.78.
Found: C, 60 49; H, 5.59; N, 4.95.
-~1Q 62 Preparation of (+)-6-Hydroxy-3-t4-r[trans-2-(4-morpholinyl)cyclohexyl]oxy]b~nzyll -2-l4- 12-(1-pyrrolidinyl)ethoxy]~henyl]benzo l b~ thio~hene Dioxalate.
'~"'~
~_ 2C2 ~4 Part A. (+)-6-Methoxy-2-14-[2-(1-~yrrolidinyl)-Qthoxy~phQnyl~benzot b~ thio}~hen- 3 -yl 4-lttr~ns-2-(4-Morpholinyl)cyclohexyl]oxy]phenyl Keton~.
W O 97/25033 PCT~US96/17995 o N
~ob MeO ~ ~
The title compound was prepared in 80% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo-[b]thiophen-3-yl] 4-fluorophenyl ketone and (+) -trans-2- (4-morpholinyl)cyclohexanol by essentially following the procedures detailed in Example 59, Par~ B.
mp 50-57 ~C; FDMS 640.6 IM+); Anal. Calcd for C3gH44N2OsS 0.14CH2Cl2: C, 70.18; H, 6.84; N, 4.29. Found:
C, 70.20; H, 6.82; N, 4.35.
Part B. (1)-6-Hydroxy-3-14-lltrans-2-(4~morpholinyl) cyclohexyl]oxy]b~nzyl]-2-14-lZ-(l-~yrrolidinyl)-~thoxy]phenyl]b~nzo~blthiop~s~ Dioxalate.
The title compound was prepared in 72% yield for ~our steps from the ketone (Part A~ by essentially following the procedures detailed in Example 21, Part A-C.
mp ~110 ~C (decomp?); FDMS 613.4 (M+1); Anal Calcd for C37H44N2O4S 2.3C2H204 l.lC4HgO2: C, 60.26; H, 6.31; N, 3.06.
Found: C, 59.88; H, 5.94; N, 3.00.
le 63 Preparation o~ 6-Hydroxy-2-~4-~2-(1-~yrrolidinyl)-~thoxy~phenyl~benzolb]thiophen- 3-yl~ 3 -D~ethoxy-4-[ltran~-2-(l-pyrrolidinyl)cyclohQxyl~oxy]phenyl Ketone Dioxalate.
CA 02236007 l998-04-27 Wo 97/25033 PCT/US96rl7995 C~
OMe N
~0",~
HOJ~ 2C~ 2~4 Part A. 3-Methoxy-4-~trans-2~ ~yrrolidinyl)-cyclohexyl]oxylbenzoic Acid.
~) OMe N~
H02CJ~
The title compound was prepared in 96% f~or two steps from methyl vanillate similarly as described in Example 20, Parts B and C.
lH NMR (CDCl3) d 7 . 68 (m, 2H), 7 . 17 (d, J = 8 . 8 Hz, lH), 4 . 80 10 (m, lH), 3.88 (s, 3H), 3.63 (m, 2H), 3.35 (m, 2H), 3.11 (m, lH), 2 .35-1.25 (m, 12H).
Part B. (~)-6-Benzyloxy-2-[4-~2-(1-pyrrolidinyl)-~thoxy]phenyl]benzo~b]thio~hen-3-yl 3-Mothoxy-4-15 ~ ~ trans-2-(1-pyrroli~inyl)cyclohexylloxy]phQnyl Ke t onQ .
OMe N
~,o""~
The title compound was prepared in 43 % yield :Eor two steps from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene by 20 essentially following the procedures outlined in Example 41, W O 97/25033 PCT~US96/17995 Part C (but using thionyl chloride to form the acid chloride) and Example 81, Part E.
mp 50-54 ~C; FDMS 731.8 (M+1); Anal. Calcd for C4sHsoN2OsS:
C, 73.94; H, 6.90; N, 3.83. Found: C, 73.73; H, 6.96; N, 4.00.
Part C. (1)-6-Hy~roxy-2-[4-t2-~1-pyrrolidinyl)-othoxy3phenyl3benzotb]thiophen-3-yl 3-Methoxy-4-[ltr~n~-2-(l-pyr olidinyl)cyclohexylloxylphenyl KQtone Dioxalate.
The title compound was prepared in 12% yield for two steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl~ethoxy]-phenyl]benzo[b]thiophen-3-yl [3-methoxy-4-[[trans-2-(1-pyrro-lidinyl)cyclohexyl]oxy]phenyl] ketone (Part B) by essentially following the procedures described for debenzylation and oxalate salt formation in Example 81, Part I.
FDMS 641.3 (M+1); Anal. Calcd for C38H44N205S 2C2H204: C, 61.45; H, 5.89; N, 3.41. Found: C, 61.27; H, 5.77; N, 3.40.
~Yr ~le 64 Preparation of (t)-6-Hydroxy-3-[3-methoxy-4- r ~tran~-2-(1-pyrrolidinyl)cyclohexyl~oxy]benzyl]-2-14-r2-(1-pyrrolidinyl)ethoxylphenyl]benzolblthiophene Dioxalate.
OMe Q
b HO~ 2C ~204 The title compound was prepared in 59~ yield for four steps from (+)~6-benzyloxy-2-[4-[2-(1-pyrrolidinyl~ethoxy]-phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-[[trans-2-(1-W O 97/25033 PCT~US96~17g95 pyrrolidinyl)cyclohexyl]oxy]phenyl ketone (Example 63, Part B) by essentially following the procedures outlined in Example 85, Part B.
FDMS 627.3 (M+l); Anal. Calcd for ~38H46M2o4s-2c2H2o4: C, 62.52; H, 6.25; N, 3.47. Found: C, 62.73; H, 6.18; N, 3.43.
_1~ 65 Preparation o~ 6-Hyaroxy-3-[3-hy~roxy-4-~trans-2-10 (1-pyrrolidinyl)cyclohexyl]oxy]benzyl]-2-~4-~2-(1-~pyrroliainyl)ethoxylphenyllb~nzolblthio~hene.
OH ~
~,0""~
HO ~ ~
The title compound was prepared in 29% yield from (+)-6-hydroxy-3-[3-methoxy-4-[~trans-2-(1-pyrrolidinyl3cyclohexyl]-oxy]benzyl~-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophene (free base of Example 64) by essentially following the procedure outlined in Example 21, Part B.
FDMS 613.3 (M+l).
_1~ 66 Preparation o~ (1)-6-Hydroxy-2-~4-~2-(l-pyrroliainyl)-ethoxy~phenyl]benzo~b~thiophen-3-yl 3-Fluoro-4-[~trans-2-(1-~yrroliainyl)cyclohexyl]oxylphenyl Ketone Dioxalato.
W O 97~033 PCTAUS96/17995 F ~
0~ "~ ~
HO ~ C,H204 Part A. 6-Benzyloxy-2-(dimethyl~i~o)benzotblthi phen-3-yl 3,4-Difluorophenyl Ketone.
~ F
0~
~f 0~ \
The title compound (oil) was prepared in g5% yield from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene and 3,4-difluorobenzoyl chloride by essentially ~ollowing the procedure outlined in Example 81, Part C.
FDMS 423 (M+); Anal. Calcd for C24H1gF2NO2S: C, 68.07; H, 4.52; N, 3.31. Found: C, 68.36; H, 4.75; N, 3.37.
Part B. (~)-6-Benzy}oxy-2-[4-t2-(1-pyrrolidinyl)-ethoxy3~henyl]benzolb~thiophen-3-yl 3-~luoro-4-lttran~-2-(l-pyrrolidinYl)cyclohexyl3oxylphon Ketone.
=
W O 97/25033 PCT~US96/17995 The title compound was prepared in 67~ yield for two steps from 6-benzyloxy-2-(dimethylamino)benzo[b3thiophen-3-yl 3,4-difluorophenyl ketone (Part A) similarly as described in Example 59, Part B and Example 81, Part E.
mp 47-51 ~Ci FDMS 719 (M+l); Anal. Calcd for C44H47FN2O4S:
C, 73.51; H, 6.59; N, 3.90. Found: C, 73.28; H, 6.71; N, 4.01.
Part C. (_)-6-H~droxy-2-14-~2-(1-pyrrolidinyl)ethoxy~-phenyl]bQnzolb~thiophen-3-yll 3-Fluoro-4-Cltrans-2-( ~y lolidinyl)cyclohexyl]oxy]phenyl Ketone Dioxalate.
The title compound was obtained in 81% for two steps ~rom the ketone (Part B) via debenzylation and oxalate salt formation as described in Example 81, Part I.
FDMS 629.3 (M+l); Anal. Calcd for C37H41FN2O4S-2C2H204: C, 60.88; H, 5.61; N, 3.46. Found: C, 60.97; H, 5.70; N, 3.59.
R~A _le 67 Preparation of (_)-6-Hydroxy-3-13-fluoro-4-[[tran~-2-(l-~yrroli~inyl)cyclohexylloxy]benzyl]-2-14-12-(1-pyrrolidinyl)ethoxy]phenyllbanzo~b]thiophena Dioxalate.
F N
~¢~~"'~
HO~ 2c2H2O4 ~
The title compound was prepared in 66% yield for four steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl 3-fluoro-4-[[trans-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl ketone (Example 66, W O 97/25033 PCT~US96/17995 Part B) using similar procedures to those of Example 85, Part B.
mp >111 ~C (decomp.?); FDMS 614.8 (M+); Anal. Calcd for C37H43FN203S 2C2H2O4: C, 61.95; H, 5.96; N, 3.52. Found:
C, 61.81; H, 6.16; N, 3.38.
~r rle 68 Preparation of (~)-6-Hydroxy-2-[4-[2-(1-~yrrolidinyl)-ethoxy]~henyl]b~nzolblthiophen-3-yl 3-Fluoro-4-lltran~-2-(l-~iperidyl)cyclohexylJoxyl~h~nyl Ketona Dioxalate.
F N
o~~ b ~ ~r~ ~4 The title compound was prepared in 13% for four steps from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3,4-difluorophenyl ketone (Example 66, Part A) using similar methods to those of Example 66, Parts B and C.
FDMS 643.4 (M~1); Anal. Calcd for C3gH43FN2O4S-2C2H2O4: C, 61.30; H, 5.76; N, 3.41. Found: C, 61.57; H, 5.74; N, 3.59.
~xample 69 Praparation of (~)-6-Hydroxy-3-[3-fluoro-4-~trans-2-(1-pi~eridyl)cyclohoxylloxyJb~nzyll-2-~4-~2-(1-pyrro-lidinyl)ethoxy3phenyllbenzo~blthiophene Dioxalate.
W O 97~5033 PCTfUS96/1~995 F ~ ~
HO N
The title compound was prepared in 62% ~or three steps from (+)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 3-fluoro-4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy]phenyl ketone (an intermediate ln thepreparation of Example 68) using procedures similar to those o~ Example 85, Part B.
FDMS 629.4 (M+l); Anal. Calcd for C38H45FN203S-2C2H204 1.1C4H80: C, 62.74; H, 6.56; N, 3.15.
Found: C, 63.14; H, 6.27; N, 2.92.
F.~ pl~ 70 Preparation of (I)-6-Hydroxy-3-~4-[[tran~-2-(l-pyrrolidinyl)cyclohexyl]oxyl-3-(trifluoromethyl)-benzyll-2- r4- ~2-(1-~yrrolidinyl)ethoxy]phenyllbQnzo-~blthiophene Dioxalate.
~,o"~
HO~ 2C H~04 Part A. 6-BQnzyloxy-2-(~imethyl~ ;~o)benxo~blthiophen-3-yl 4-Fluoro-3-(tri~luoromethYl)phenyl Ketone.
W O 97/2~033 PCT~US96/17995 ~ F
¢~ 0~
The title compound was prepared in 93% yield from 6-benzyloxy-2-(dimethylamino~benzo[b]thiophene and 4-fluoro-3-(trifluoromethyl)benzoyl chloride by essentially ~ollowing the procedure outlined in Example 81, Part C, and Example 85, Part B.
mp 164-167 ~C; F~MS 473 (M+); Anal. Calcd for C2sH19F4NO2S:
C, 63.42; H, 4.04; N, 2.96. Found: C, 63.65; H, 4.17; N, 2.81.
Part B. (~)-6-Hydroxy-3-[4-lltran~-2-(l-pyrrolidinyl)-cyclohexyl~oxy~-3-(trifluoromethyl)-benzyl]-2-l4-l2-(1-pyrroliainyl)ethoxy]phonyllb~nzo-[blthio~ s Dioxalate.
The title compound was prepared in 41% for six steps ~rom 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 4-fluoro-3-(trifluoromethyl~phenyl ketone (Part A) using similar procedures to those of Example 66, Parts B and C.
mp >124 ~C (decomp?); FDMS 665.2 (M+1); Anal. Calcd for C38H43F3N203S-2C2H204: C, 59.71; H, 5.61; N, 3.32. Found:
C, 59.48; H, 5.55; N, 3.44.
~ le 71 Preparation o~ 6-Hydroxy-5-methoxy-3-[4-[[tra~s-2-~1-pyrrolidinyl)cyclohexyl]oxy]benzyl]-2-[4-12-(1-~yrroli~inyl)~thoxy~phenyl]benzolb~thiophene ~ioxalate.
W V 97/25033 PCT~US96/17995 o ~ 'O
MeO ~ 2CZ~2O4 Part A. 6-Benzyloxy-2-dimethylr-in~-5-m~thoxy-benzolblthiophene.
MeO~ /
The title compound was prepared in 17% for two steps from 4-benxyloxy-3-methoxybenzaldehyde and N,N-dimethylthioformamide using similar procedures to those of Example 81, Parts A and B.
mp 140-142 ~C; FDMS 313 (M+); Anal. Calcd for C1gH1gNO2S: C, 68.98; H, 6.11; N, 4.47. Found: C, 68.81; H, 6.32i N, 4.17.
Part B. (~)-6-Hydroxy-5-methoxy-3-l4-[[tran~-2-(1-pyrroli~inyl)cyclohexyl]oxy]benzyl3-2-{4-l2-(1-pyrroli~inyl)ethoxy~phenyl~bsnzo[blthiophQne Dioxalate.
The title compound was prepared in 37~ for seven steps from 6-benzyloxy-2-dimethyl~m; no-5-methoxybenzo[b]thiophene ~Part A) using procedures similar to those of Example 70, Parts A and B.
mp >100 ~C (decomp?)i FDMS 627 (M+1~; Anal. Calcd for C38H46N2o4s 2~4C2H204 0~6C4H802: C, 60.49; H, 6.31; N, 3.07.
Found: C, 60.11; H, 6.11; N, 3.43.
CA 02236007 l99X-04-27 ~ le 72 Pre~aratlon of (+)-5-Methox~-2-~4-[2-(1-~rrolidinyl)-ethoxy~phenyl~benzorb~thiophen-3-yl 4-~trans-2-(1-Pipe~idyl)cyclohex~rl]oxyl3;~henyl Ketone Dioxal~te.
~ob MeO~ Z CzH2O4 Part A. 5-Meth~yL~lLzo[b]thiophene.
MeO~[~>
5-Bromobenzo[b]thiophene was prepared in quantitative yield for two steps from 4-bromobenzenethiol and bromoacetaldehyde dimethyl acetal as described in the preparation of 4- and 6-methoxybenzo [b] thiophene (see Example g2, Part A): mp 40-43.5 ~C; FDMS 212.1 (M-1); Anal. Calcd for CgHsBrS-0.10C7HgOS: C, 46.01; H, 2.57i S, 15.53. Found:
C, 46.19; H, 2.49; S, 15.79.
To a solution of 1.8 g of 5-bromobenzo [bJ thiophene in 2 mL of anhydrous DM~ and 1 mL of MeOH was added 686 mg of NaOMe. The mixture was heated to 110 ~C (bath temp), and 121 mg of CuBr was added. The brown suspension was heated at 110 ~C for ~2 h and at -145 ~C for 30 min. The reaction was ~uenched with ca. 50 mL of H20 and the mixture was extracted with 100 mL of Et20 (2x), EtOAc (lx), and CH2C12 (lx). The organic layers were washed with 50 mL of brine, combined, dried over MgSO4, concentrated, and flash chromatographed with 3% Et2O-hexanes to afford 894.5 mg (64%) of the title compound along with 168.8 mg (9.4~) of 5-bromobenzo[b]-thiophene.
W O 97/Z5033 PCTnJS96/17995 mp 39-41.5 ~C; FDMS 164.2 (M+); Anal. Calcd for CgHgOS O.llH2O: C, 65.04; H, 4.98; S, 19.29. Found: C, 65.07; H, 4.95; S, 18.96.
Part B. 5-Methoxybenzolb]thiophene-2-boronic Acid.
MeO ~ B(OH)2 The title compound was prepared in 50% yield by essentially following the procedures in Example 1, Part A
from 5-methoxybenzo[b]thiophene (Part A).
mp 226-228 ~C; FDMS 569; Anal. Calcd for CgHgBO3S: C, 51.96; H, 4.36. Found: C, 51.85; H, 4.15.
Part C. 5-Methoxy-2-[4-[2-(1-~y oli~inyl)~thoxy~-phenyllbenzolb]thiophene.
MeO~_O
The title compound was prepared in 47% yield by essentially following the procedures in Example 1, Part B, from 5-methoxybenzo[b]thiophene-2-boronic acid (Part B) and 1-(2-(4-bromophenoxy)ethyl)pyrrolidine.
mp 123-126 ~C; FDMS 353 (M+); Anal. Calcd for C21H23N02S:
C, 71.36; H, 6.56; N, 3.96. Found: C, 71.07; H, 6.44; N, 4.01.
Part D. 4-Fluorophenyl 5-Methoxy-2-14-12-(1-~y~ r 0-lidinyl)ethoxy]phenyl~benzolb]thiophen-3-yl Ketone.
~ ~ F
0~
MeO~_ O
W O 97/25033 PCT~US96/17995 The title compound was prepared by essentially following the procedure detailed in Example 1, Part C, from 5-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part C) and 4-~1uorobenzoyl chloride. The crude product was purified by flash chromatography (silica gel, 55:42:3 THF-hexanes-Et3N) to afford 2.11 g (4.44 mmol, 71%) of a yellow semi-solid.
FDMS 475 (M+); Anal. Calcd for C2gH26FNo3s: C,70.72; H, 5.51; N, 2.95. Found: C, 70.50; H, 5.49; N, 2.83.
Part E. (+)-5-M~thoxy-2-14-12~ oliainyl)-~thoxyl~henyl]benzo~b]thiophQn-3~yl 4-t[tran~-2-(1-Piperidyl)cyclohexyl]oxy~phenyl K tone.
o~~"'~
MeO~ ~ _O
To a slurry of NaH (530 mg, 13.2 mmol, 60% dispersion in mineral oil) in 28 mL of anhydrous DMF was added dropwise 1.61 g (8,77 mmol) of (i)-trans-2~ piperidyl)cyclohexanol (Example 20, Part A) in 7 mL of DMF at room temperature over a period of 20 min. A heat gun was applied to the reaction mixture to facilitate alkoxide formation. Slow evolution of hydrogen gas was observed. The slurry was stirred at room temperature for 1 h, and to this was added the 4-fluorophenyl ketone (2.09 g, 4.39 mmol) (Part D) in 8 ml of DMF via a c~nnllla over 10 min period at room temperature. The slurry immediately turned reddish orange. The reaction was carried to completion by stirring overnight (18 h). The reaction was then quenched at 0 ~C with slow addition of 75 mL of H20.
The mixture was taken up in EtOAc and partitioned. The a~ueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over MgSO4 after washing with 300 mL of brine and then concentrated under reduced pressure. The residue was purified by PrepLC (40:57:3 THF-hexanes-Et3N) to afford 2.24 g (3.51 mmol, 80%) of a yellowish white foam.
mp 63-66 ~C; FDMS 639 (M+); Anal. Calcd for C3gH46N2O4S: C, 73.32; H, 7.26; N, 4.38. Found: C, 73.03; H, 7.38; N, 4.20.
Part F. (+)-5-Methoxy-2-t4--~2-(1-~y~ olidinyl)-~thoxy]phenyl~benzo~b~thio~h~n-3-yl 4-[ltran~-2-(1-- Piperidyl)cyclohexyl]oxy]ph~nyl Ketone Oxalate.
The title compound was prepared in 97% from the ketone (Part E) by essentially following the procedure outlined in Example 21, Part C.
mp 144-147 ~C; FDMS 639.3 (M+); Anal. Calcd for C39H48N2O3S 2.64C2H2O4: C, 60.67; H, 5.90; N, 3.20. Found:
C, 60.66; H, 5.89; N, 3.24.
Example 73 Preparation of (+)-5-M~thoxy-3-[4- r ~trang-2- (1-~iperiayl)cycloh~xyl]oxy~benzyl~-2-~4-~2-(1-pyrro-lidinyl)ethoxy~phenyl]benzo~b]thiophene Dioxalate.
~ob Me~ 0 2 c2H2~4 I ~
The free base of the compound was prepared in 69~ yield from the ketone (Example 72, Part E) by essentially following the procedures detailed in Example 21, Part A. The title compound was prepared by essentially following the procedure outlined in Example 21, Part C.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 Free base: mp 53-56 ~C; FDMS 625 (M+).
Dioxalate: mp 139-145 ~C; FDMS 625 (M+); Anal. Calcd ~or C39H48N2O3S 2.OC2H2O4: C, 64.16; H, 6.51; N, 3.48. Found:
C, 63.88; H, 6.57; M, 3.41.
le 74 Preparation of (+)-5-Hydroxy-3- t4- C ~trans-2- (1-pip~ridyl)cyclohexyl]oxylbQnzyl]-2-{4-[2-(1-pyrro-lidinyl)ethoxyl~h~nyllbenzolb]thiophene Dioxalate.
[~
~,o",~
HO ~ o 2 c~H2O4 Part A. (+)-5-Hydroxy-3-t4-~tran~-2- (l-piperidyl)-cyclohoxylloxy]b~nzyl] -2 - ~4-~2-~1-pyrrolidinyl)-ethoxy~phenyl~benzorb]thiophene.
~o",~
HQ ~ O
1~
The title compound was prepared in 89% yield ~rom the methoxybenzo[b]thiophene (free base o~ Example 73) by essentially following the procedures detailed in Example 21, Part B.
W O 97~5033 PCTnJS96/17995 mp 103-106 ~C; FDMS 610 (M+); Anal. Calcd for C3gH46N203S-1.48H20: C, 71.59; H, 7.74; N, 4.39. Found: C, 71.59; H, 7.44; N, 4.32.
Part B. ~+)-5-Hydroxy-3-t4-~[~rans-2-(1-piperidyl)-cyc lohexyl 1 oxy 1 benzyll-2-[4-12-(1-pyrrolidinyl)-ethoxy~phenyl] benzo lb] thiop~s~e Dioxalate.
The title compound was prepared from the free base by essentially following the procedures detailed in Example 21, Part C.
mp 172-176 ~C (dec); FDMS 611 (M+); Anal. Calcd for C38H46N203S 2C2H204 1.5H20: C, 61.67; H, 6.53; N, 3.42.
Found: ~, 61.41; H, 6.21; N, 3.40.
~ xampl~ 75 Preparation of (+)-7-Hy~roxy-2-~4-~2-(1-~ ~oliainyl)-ethoxy]phenyl~benzo~blthiophQn-3-yl 4-~tr~ns-2-(1-Piperiayl) cyclohexyll oxylphenyl Retone Dioxalate.
~~"'0 ~ 2 c2H~o4 Part A. 2-Methoxybenzenethioacetaldehyae Diethyl Acetal.
~~~
MeO O~_~-The title compound was prepared in 90% crude yield from 2-methoxybenzenethiol by essentially following the procedures detailed in Graham, S.L., et. al. J. Med. Chem . 1989, 32, 2548-2554.
W O 97/2~033 PCT~US96/17995 -200~
Part B. 7-Methoxybenzo [b] thiophene.
MeO
To a biphasic mixture of polyphosphoric acid (PPA; 64.1 g) and 600 mL of dry chlorobenzene heated to re~lux at 140 ~C
was added dropwise 2-methoxybenzenethioacetaldehyde diethyl acetal (Part A) (30.0 g, 117 mmol) in 75 mL of chlorobenzene over a period of 1.5 h. The dark green biphasic mixture was stirred at re~lux for an additional 1.5 h. The reaction mixture was cooled to room temperature and the organic layer was decanted off the PPA layer. The PP~ layer was cooled to O ~C and diluted with 500 mL of H20. This aqueous layer was extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with 200 mL o~ brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified using a PrepLC with a gradient elution (0 to 7~ Et2O
in hexanes) to afford 10.3 g (63.1 mmol, 54%) of a green oil.
FDMS 164 (M+); Anal~ Calcd for CgHgOS 0.06CH2C12: C, 64.27;
H, 4.83. Found: C, 64.15; H, 4.81.
Part C. 7-Nethoxybenzo~b]thiophene-2-boronic Acid.
~ B(OH)2 MeO
The title compound was prepared in 44% yield (51% SM
recovery) by essentially following the procedures in Example 1, Part A from 7-methoxy[b]benzothiophene (Part B).
mp 272-275 ~C; FDMS 569; Anal. Calcd for CgHgBO3S: C, 51.96;
H, 4.36; N, 0.00. Found: C, 51.71; H, 4.15; N, 0.00.
Part D. 7-Methoxy-2-t4-[2-(1-~ olidinyl)ethoxy]-phenyl]benzotb~thiophene.
W O 97t25033 PCT~US96/17995 N
MeO ~
The title compound was prepared in 31% yield by essentially following the procedures outlined in Example 1, Part B from 7-methoxybenzo[b~thiophene-2-boronic acid (Part C).
mp 88-90 ~C; FDMS 353 (M+); ~nal. Calcd for C21H23MO2S: C, 71.36; H, 6.56; N, 3.96. Found: C, 71.17; H, 6.58; N, 3.83.
Part E. 7-Hydroxy-2-~4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]bQnzolb]thiophone.
~o OH
The title compound was prepared by essentially following the procedures outlined in Example 21, Part B from 7-methoxy-benzo[b]thiophene (Part D) and recrystallized ~rom EtOAc-hexanes to af~ord 944 mg (2.78 mmol, 56%) of light orange needle-like crystals.
mp 180-183 ~C; FDMS 339 (M+); Anal. Calcd ~or C20H21NO2S 0.3H2O: C, 69.66; H, 6.31; N, 4.06. Found: C, 69.62; H, 6.21; N, 4.46.
Part F. 3-(4-Fluoro~henyl)carbonyl-2-~4 [2-(1-pyrrolidinyl)~thoxylphenyl]benzo~b~thiophQn-7-yl 4-Fluoro}~enzoate.
WO 97/25033 PCT~US96/17995 ~F
-- N
0~0 ~ ' F
To a slurry of 7-hydro~-2- r4-~2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene (Part E) (244 mg, O.808 ~nol) in 5.0 mL of anhydrous dichloroethane was added 4-fluorobenzoyl chloride (105 IlL, O.888 ~mnol) at room temperature. The white slurry was stirred at room temperature for 3 h to form the int~l~me-l;ate ester. The reaction was then cooled to O ~C and another 105 ,UL (0.888 mmol) of 4-fluorobenzoyl chloride was added, followed by 10 addition of aluminum chloride (431 mg, 3.23 mmol) which turned the slurry into a dark red homogeneous solution. The reaction was slowly warmed to room temperature over 2 h and then stirred for 2.5 days. The reaction mixture was then poured into 20 mL of ice-cold 2.0 N NaOX solution. The 15 mixture was then taken up in EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgS04 and concentrated under reduced pressure. The residue was purified by ~lash chromatography (silica gel, 496(10% NH40H in MeOH)/CH2Cl2) to afford 408 mg (.700 mmol, 87%) of an off-white foam.
mp 64-68 ~C; FDMS 583 (M+); Anal. Calcd for C34H27F2N04S 0.08CH2Cl2: C, 69.33; H, 4.64i N, 2.37. Found:
C, 69.36; H, 4.61; N, 2.01.
Part G. 4-Fluorophenyl 7-Hyaroxy-2-14-~2-(l-~y o-lid~nyl)ethoxyl~henyl~benzo[blthiophen-3-yl Ketone.
~ N
OH ~
To a slurry of NaH (14.4 mg, 0.171 mmol, 60% dispersion in mineral oil) in 0.5 mL of anhydrous THF (or DMF) was added (+3-trans-2-(1-piperidyl)cyclohexanol in 0.5 mL of THF (or DMF) via a cannula. The reaction mixture was warmed with a heat gun to initialize the alkoxide formation and then stirred at room temperature for 2 h. The slurry was cooled to 0 ~C and to this was added dropwise 4-fluorobenzoate (Part F) (100 mg, 0.171 mmol) in 0.5 mL of THF (or DMF). The reaction was stirred at 0 ~C for 1 h and then allowed to warm to room temperature while stirring for 45 min. The reaction was quenched at 0 ~C with 15 mL of H20. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 70:27:3 THF-hexanes-Et3N) to afford 67.9 mg (.147 mmol, 86%) of a brown solid.
mp 138-142 ~C, FDMS 462 (M+); Anal. Calcd for C27H24FN03S-0.57H20: C, 68.73; H, 5.37i N, 2.97. Found: C, 68.95; H, 5.66; N, 3.30.
Part H. (+)-7-Hydroxy-2-~4-12-(1-~ olidinyl)-ethoxylphenyllbenzolblthiophen-3-yl 4 - [ 1 trans- 2-(1-Pil?e-idyl)cyclohexyl30xy]phenyl Ketone Dioxalate.
The free base of the title compound was prepared in 18%
yield by essentially following the procedures in Example 72, Part E, from 4-fluorophenyl ketone (Part G) and (+)-tra~s-2-(1-piperidyl)cyclohexanol (Example 20 Part A). The dioxalate was then prepared by essentially following procedures in Example 21, Part C from the ~ree base.
W O 97/2~033 PCT~US96/17995 FDMS 625 (M+)i Anal. Calcd for C38H44N2O~S 2 5C2H204 3 2H2~
C, 56.91; H,6.15; N, 3.09. Found: C, 56.61; H, 5.80; N, 3.47.
~Y~ _le 76 Pruparation of (+) -6-Hy~roxy-3-[4- r ltrang-2- (1-piperidyl)cyclopentyl3Oxy]benzyl]-2-14-r2-(1-pyrro-li~inyl)Qthoxylph~nyllbenzolblthiophene Dioxalate.
~~"'~ ' H0~ 2 C2H2~4 Part A. (+)-trans-2-(1-Pi~eridyl)cyclopentanol.
~I0,~2 The title compound was prepared in 81% yield from cyclopentene oxide and piperidine ~y essentially following the procedures outlined in Example 20, Part A.
FDMS 169.1 (M+); Anal. Calcd for CloHlgNO 0.24H20: C, 69.19;
H, 11.31; N, 8.07. Found: C, 69.19; H, 11.40; N, 8.21.
Part B. (+)-6-Methoxy-2-[4-t2-(1-~yrrolidinyl)-ethoxyJ~henylJbenzo[b]thio~hQn-3-yl 4-1~(+)-tr~n~-2-(1-Piperidyl)cyclo~entyl~oxy]~henyl X~ton~.
0~' "'C~>
MeO ~ ~
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 72, Part E, ~rom 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+)-trans-2-(1-piperidyl)-cyclopentanol (Part A).
mp 68-72 ~C; FDMS 625 (M+); Anal. Calcd for C3gH44N2O4S: C, 73.05; H, 7.10; N, 4.48. Found: C, 73.27; H, 6.96; N, 4.30.
Part C. (+)-6-Methoxy-3-14-[[trans-2-(1-pip~ridyl~-cyclopentylloxy~benzyl]-2-[4-12-(1-pyrrolidinyl)-~thoxy~ phenyllbenzo[b~thiophQne.
~o",~
MeOJ~ ~
The title compound was prepared in 57% yield from theketone (Part B) by essentially following the procedures detailed in Example 21, Part A.
mp 61-64 ~C; FDMS 611 (M+); Anal Calcd for C3gH46N2O3S O.39H20: C, 73.87; H, 7.63; N, 4.53. Found: C, 73.85; H, 7.53; N, 4.83.
-20~-Part D. (~)-6-Hydroxy-3-t4-[[tran~-2~ piperidyl)-cyclopentyl30xy]bQnzyll-2-~4-~2-(l-pyrrolidinyl)-~thoxy~phenyllbenzo~b]thiophene Dioxalat~.
The free base of title compound was prepared in 79%
yield ~rom the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
The title compound was prepared by essentially following 10 the procedures detailed in Example 21, Part C.
mp 1~5-150 ~C; FDMS 597 (M+); Anal. Calcd for C37H44N2O3S 2.1C2H2O4 1.6H2O: C, 60.74; H, 6.36; N, 3.44.
Found: C, 60.41; H, 6.46; N, 3.37.
~r ~le 77 Proparation o~ (+)-3-[4-~rtran~-2-(Di~thylamino)-Cyclohexyl]oxylbQnzyl]-6-hydroxy-2-14-~2-(1-pyrro-lidinyl)ethoxylphQnyl3benzo~b3thio~hQnQ Dioxalate.
NJ
,~o b 2 C2H2~4 HO ~ ~
Part A. (~)-tran~-2-(Diethylamino)cycloh~Y~nol.
~J
HO", ~
The title compound was prepared from N,N-diethylamine and cyclohexene oxide by essentially following the procedures 25 outlined in Example 20, Part A. s CA 02236007 l998-04-27 FDMS 171 (M+, base); Anal. Calcd ~or CloH21NO 0~26CH2Cl2: C, 63.73; H, 11.22; N, 7.24. Found: C, 63.80; H, 11.35; N, 7.52.
Part B. (+) -4-rrtran~-2-(Die~thylamino)cyclohexyl]-oxylph~nyl 6-Methoxy-2-[4-~2-(1-pyrroli~inyl)Qthoxy]-~henyl3benzo~blthio~hen-3-yl Ketone.
NJ
o~~ b MeO~ ~ ~
The title compound was prepared in 67~ yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy~phenyl]benzo[b]thiophen-3-yl ketone (Fxample 59, Part A) and (+)-trans-2-(diethyl ~mi no)-cyclohexanol (Part A).
FDMS 627 (M+); Anal. Calcd for C3gH46N2O4S: C, 72.81; H, 7.40; N, 4.47. Found: C, 73.06; H, 7.44; N, 4.6S.
Part C. (+)-3-[4-rttranJ-2-~Diethylamino)cyclohexyl]-oxy]benzyl~-6-methoxy-2-~4-~2-(1-pyrrolidinyl)ethoxy]-~henyl]benzotb3thio~hene.
NJ
~~"'~
MeO~ ~
CA 02236007 l998-04-27 W 097/25033 PCT~US96tl7995 The title compound was prepared in 79% yield from the ketone (Part B) by essentially ~ollowing the procedures detailed in Example 21, Part A.
5 FDMS 613 (M+); Anal. Calcd for C3gH4gN2O3S: C, 74.47; H, 7.89; N, 4.57. Fourld: C, 74.49; H, 8.18; N, 4.66.
Part D. (i) -3- [4- t [trans-2- (Diethylamino)cyclohexyl]-oxylbenzyl~-6-hyaroxy-2-~4-~2-(l-~yrroliainyl)eth phenyl]benzo[b~thiophene.
NJ
~~"'~
HO ~
The title compound was prepared in 73% yield ~rom the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
mp 95-100 ~C; FDMS 599 (M+); Anal. Calcd for C37H46N2O3S 0.2CH2C12: C, 72.55; H, 7.59; N, 4.55. Found C, 72.21; H, 7.59; N, 4.87.
Part E. (~)-3-[4-t[tr~n~-2-(DiethYl~ ;~o)cyclohQxyl]-oxy~benzrll-6-hyaroxy-2-14-t2~ ~yrrolidinyl)ethoxy~-phenyl]benzo~blthiophene Dioxalate.
The title compound was prepared from the ~ree base (Part D) by essentially following the procedures detailed in 25 Example 21, Part C.
mp 143-146 ~C; FDMS 599 (M+); Anal. Calcd for C37H46N2O3S 2.0C2H204 1.8H20: C, 60.64; H, 6.66i N, 3.45. t Found: C, 60.63; H, 6.31; N, 3.26.
W O 97/25033 PCT~US96/17995 Pro~aration of (+)-3-{4-ltci~-2-(Dimethylamino)-cyclohexyl30xy]benzyl]-6-hyaroxy-2-14-12-(l-pyrro-li~inyl)ethoxy]~henyl]benzolb]thiophene Dioxalate.
O
/ 2 c2H204 ~
Part A. (+)-4-~cis-2-(Dimethylamino)cyclohoxyloxy]-~h~nyl 6-Methoxy-2-~4-12-(1-~rrrol~dinyl)Qthoxy]-phenyllbonzolblthiophen-3-yl Ketone.
N
~~~~
MeO~~ ~
The title compound was prepared in 71% yield by essentially following the procedures outlined in Example 72, Part E, ~rom 4-~luorophenyl 6-methoxy-2-[4-[2~
pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+) -cis-2- (dimethylamino)-cyclohexanol.
mp 61-64 ~C; FDMS 5g9 (M+); Anal. Calcd ~or C36H42N2O4S: C, 72.21; H, 7.07; N, 4.68. Found: C, 72.15; H, 7.30; N, 4.64.
Part B. (+)-3-[4-l[ci~-2-(DimQthylamino)ayclohexyl~-oxylbenzyll-6-methoxy-2-14-12-(1-pyrrolidinyl)ethoxy]-phenyl]benzolb]thiophone.
CA 02236007 l998-04-27 N
~~b MeO ~ ~
The title compound was prepared in 57% yield from the ketone (Part A) by essentially following the procedures detailed in Example 21, Part A.
FDMS 585 (M+); Anal. Calcd for C36H44N203S 0.27CH40: C, 73.41; H, 7.66; N, 4.72. Found: C, 73.62i H, 7.74; N, 4.32.
Part C. (+) -3- t4- C lcis-2- (Dimethylamino)cyclohexyl]-10 oxy3benzyl3 -6-hydroxy-2-l4-[2-( 1-pyrrolidinyl)ethoxy3-phenyl]benzolblthiophene.
N
,~ob HO ~ N
The title compound was prepared in 75% yield from the methoxybenzo[b]thiophene (Part B) by essentially following the procedures detailed in Example 21, Part B.
mp 95-98 ~C; FDMS 571 (M+); Anal. Calcd for C35H42N2O3S: C, 73.65; H, 7.42; N, 4.91. Found C, 73.39; H, 7.63; N, 4.78.
Part D. (+)-3-14-~lcis-2-(Dimethylamino)cyclohexyl]-oxy3benzyl3-6-hy~roxy-2-14-12-(1-pyrrolidinyl)ethoxy]-phenyllbenzo~b3thiophene Dioxalate.
The title compound was prepared from the free base (Part C) by essentially following the procedures detailed in Example 21, Part C.
CA 02236007 l998-04-27 mp 103-106 ~C (dec.); FDMS 571 (M+); Anal. Calcd for 35H42N203S 2 0C2H204 1.7H20: C, 59.94; H, 6.37; N, 3.58.
Found: C, 59.81; H, 6.09; N, 3.44.
~ Y~ _le 79 Preparation of (+)-3-14-lltrans-2-(Dimethylamino)-cyclohexylloxylbenzyll-6-hydroxy-2-14-12-(1-pyrro-lidinyl)ethoxy]phenyl]~enzolb]thiophene Dioxalate.
N
~0".~
HO~ ~ C2H2~4 Part A. (~)-trans-2-(DimQthylamino)cyclohe~ol.
HO" ~
To a solution of cyclohexene oxide (3.64 mL, 36.0 mmol) in 30 mL of dry methanol was added dropwise 2.0 M
dimethylamine in THF ~15.0 mL, 30.0 mmol). The reaction mixture was stirred at 0 ~C for 4 h. The solution was then warmed to room temperature and stirred for 18 h. The reaction mixture was then concentrated under reduced pressure to afford 1.11 g (26% crude yield) of the crude product which was used in the following reaction without purification.
Part B. (+)-4-l[trans-2-(Dimethylamino)cyclohexyl]-oxy]phenyl 6-Methoxy-2-14-12-(1-pyrrolidinyl)ethoxy3-phenyl~benzo~b]thiophen-3-yl Ketone.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 N
o~~ b ~eo ~ ~
The title compound was prepared in 77% yield by essentially i~ollowing the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl3benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (+)-trans-2-(dimethylamino)cyclohexanol (Part A).
mp 65-70 ~C; FDMS 599 (M+); Anal. Calcd for C36H42N204S: C, 72.21; H, 7.07; N, 4.68. Found: C, 71.98; H, 6.96; N, 4.44.
Part C. (+)-3-[4-[[tr~n~-2-(Dimothylamino)-cyclohQxylJoxy]benzyl]-6-methoxy-2-~4-12-(1-pyrroliainyl)othoxy~henyllbenzolb]thiophene.
N
~o",~
MeO ~ ~ ~ N
~
The title compound was prepared in 66% yield ~rom the ketone (Part B) by essentially following the procedures detailed in Example 21, Part A.
mp 58-61 ~C, FDMS 585 (M+); Anal. Calcd ~or C36H44N203S: C, 73.94; H, 7.58; N, 4.79. Found: C, 74.19; H, 7.55; N, 5.07.
Part D. (+)-3-[4-l~tr~ns-2-(Dimethylamino)-cycloh~xyl30xy]b~nzyl3-6-hy~roxy-2-[4-12-(1-pyrrolidinyl)ethoxy]phenylJbonzo[b]thiophene.
-wa, 97/2S033 PCT/US96/1799~;
~o"~
HO ~ ~
The title compound was prepared in 77% yield from the methoxybenzo[b]thiophene (Part C) by essentially following the procedures detailed in Example 21, Part B.
mp 97-102 ~C; FDMS 571 (M+); Anal. Calcd ~or C3sH42N2O3S O.l9CH2C12: C, 72.01; H, 7.28; N, 4.77. Found C, 72.04; H, 7.32; N, 4.43.
Part E. (+)-3-~4-~[tr~ns-2-(Dimethylamino)cyclo-hexylloxy]benzyl]-6-hy~roxy-2-14-~2-(1-pyrro-lidinyl)ethoxyl-phenyllbenzo~b]thiophe~e Dioxalate.
The title compound was prepared from the free base (Part D) by essentially following the procedures detailed in Example 21, Part C.
mp 104-106 ~C (dec.); FDMS 571 (M+); Anal. Calcd ~or C35H42N203S 2.0C2H204 1.2H20: C, 60.44; H, 6.41; N, 3.51.
Found: C, 60.07; H, 6.26; N, 3.21.
~ .~A _ le 80 Preparation of (+)-7-Hydroxy-3-[4-~trans-2-(1-piperi~yl)cyclohoxylloxy]benzyll-2-14-~2-(1-pyrro-li~inyl)ethoxylphenyllbenzo~blthiophene Dioxalate.
W o 97/25033 PCT~US96/17995 ~,o",~
~_ :2 C2H204 OH
Pa~t A. 4-Fluorophenyl 7-~ethoxy-2-14-~2-(1~
lidinyl)ethoxylphenyl]bQnzo ~blthiop~en-3-yl KetonQ.
I~F
~~
~ N
MeO ~
To a suspension of powdered KOH (177 mg, 3.15 mmol) in 1.6 mL of dry DMSO was added 4-fluorophenyl 7-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (350370) (Example 75, Part G) (364 mg, .788 mmol) at room temperature. The reaction mixture turned orange in color.
To the alkoxide was added slowly methyl iodide (49 ~L, .79 mmol) over a period of 15 min. The reaction mixture was then stirred for 1.5 h. Another portion of MeI (20 ~L, .32 mmol) was added, stirred for 1.5 h., followed by another addition of 20 ~L (0.32 mmol) of MeI and stirring for an additional 30 min at room temperature. The rection mixture was then poured into 20 mL of H20. This mixture was extracted with CH2C12 (3 x 20 mL). The combined organic layers were washed with H20 (5 x 10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 4%[10~ NH40H in MeOH]/CH2C12) to afford 108 mg (.226 mmol, 29%) of a white foam.
FDMS 475 (M+); Anal. Calcd for C2gH26FNO3S: C, 70.71; H, 5.51; N, 2.94. Found: C, 70.48; H, 5.77; N, 2.72.
W O 97/2~033 PCT~US96/17995 Part B. (+)-7-Methoxy-2-[4-12-(1-~yl r olidinyl)-ethoxy]phenyl]benzolb]thiophen-3-yl 4-lttrans-2-(1-Pip~ridyl)cyclohoxyl~oxy~ph3nyl Ketone.
o b ~ N
MeO ~
The title compound was prepared in 7496 yield by essentially following the procedures outlined in Example 72, Part E, from the 4-fluorophenyl ketone (BZ4-GCY-222) (Part A) and (+)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
mp 66-69 ~Ci :~DMS 639 (M+); Anal. ~alcd for C36H46N2O4S:
C, 73.32i H, 7.26i N, 4.38. Found: C, 73.60; H, 7.53i N, 4.65.
Part C. (+)-7-Methoxy-3-[4-lltr~ns-2-(1-piperidyl)-~yclohexyl]oxy]benzyl]-2-14-12-(1-pyrroli~inyl)-ethoxy]phenyl]benzo[b~thioph~ne Dioxalate.
~o b ~ 2 C2H2O4 MeO ~
The free base of the title compound was prepared in 6396 20 yield from the ketone (Part B) by essentially following the procedures detailed in Example 21, Part A. The title compound was prepared by essentially following the procedures outlined in Example 21, Part C from the i~ree base obtained.
W O 97n5033 PCT~US96/17995 --216-- r FDMS 625 (M+), Anal. Calcd for C3gH4gN203S-2.1C2H204 1.4H20.
C, 61.83; H, 6.61; N, 3.34. Found: C, 61.49i H, 6.58; N, 3.44.
Part D. (+)-7-~yaroxy-3-t4-[ttrans-2-(1-~iperidyl)-cyclohexyl]oxy~benzyl~-2-l4-r2-(1-pyrrolidinyl)-ethoxy~phenyllbenzotb~thio~hene Dioxalate.
~ e ~ree base of the title compound was prepared in 7 6%
yield from the methoxybenzothiophene (free base of Part C) by essentially following the procedures detailed in Example 21, Part B. The title compound was prepared b~ essentially following the procedures outlined in Example 21~ Part C from the free base obtained.
FDMS 611 (M+); Anal. Calcd for C38H46N2o3s~2 ~OC2H204 3.3H20:
C~ 59~35i H, 6~71; N, 3~30~ Found: C, 59~33; H~ 6~66; N, 3 ~45 ~
R~-q 1~ 81 Preparation of (+)-3-14-[[tran~-2-(Dimethylamino)-¢yclohexylloxy]-3-methoxyb~nzrl~-6-hydroxy-2-t4-t2-(1-pyrrolidinyl)ethoxylphenyl~benzo[b~thio~hene Dioxalate.
~ N
,~o b HO~ ~ 2 C2H2O4 Part A. 4-Benzyloxy-~-hyaroxy-N,N-(dimethyl)phenyl-thioacetamida.
W O 97/25033 PCT~US96117995 OH
~ N~
o~ S
To a solution of distilled diisopropylamine (22.9 mL, 175 mmol) in 400 mL of anhydrous THF at -78 ~C was added 1.6 M n-butyllithium in hexanes (100 mL, 160 mmol) over a period o~ 45 min. The mixture was stirred at -78 ~C ~or 1.5 h. To the solution was c~nn~ ted over a period of 1 h a solution of 4-benzyloxybenzaldehyde ~30.9 g, 146 mmol) and N,N-dimethylthioformamide (13.7 mL, 160 mmol) in 100 mL of distilled THF. The reaction mixture was stirred at -78 ~C
for 16 h. The reaction was then ~enched with 500 mL o~
saturated NH4Cl solution. The mixture was extracted with EtOAc (3 x 1 L), and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was then recrystallyzed from EtOAc/hexanes to afford 20.0 g (66.5 mmol, 46%) of an off-white solid.
mp 104-107 ~C; FDMS 301 (M+); Anal. Calcd for C17HlgNO2S: C, 67.75; H, 6.35i N, 4.65. Found: C, 67.61i H, 6.37; N, 4.57.
]?art B. 6-Benzyloxy-2-(dimethylAmino)benzo[b~-thiophene.
~ ~ N
To a solution of thioacetamide (Part A) (500 mg, 1.66 mmol) in 65 mL of dry dichloroethane at room temperature was added dropwise methanesulfonic acid (0.54 ml, 8.3 mmol). The red reaction mixture was stirred ~or 1.5 h and then poured into 10 mL of saturated aqueous NaHCO3 solution, followed by addition of 3 mL of H2O, and stirred vigorously. The layers W O 97~5033 PCTrUS96/17995 were separated and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 10%
Et2O/hexanes) to afford 327 mg (1.15 mmol, 70%) of a white solid.
mp 78-81 ~C; FDMS 283 (M+)i Anal. Calcd for C17H17NOS: C, 72.05i H, 6.05; N, 4.94. Found: C, 72.22; H, 6.15; N, 4.89.
Part C. 6-Benzyloxy-2-(dimethylamino)benzo~b~thio-phQn-3-yl 3,4-Dimethoxyph~nyl Xetone.
o~o\
0~ \
To a solution of 3,4-dimethoxybenzoyl chloride (1.250 g, 6.231 mmol) in 18 mL of chlorobenzene was added 6-benzylo~y-2-(dimethylamino)benzo[~]thiophene (Part B) (1.059 g, 3.738 mmol). The dark blue reaction mixture was then heated to 110 ~C and stirred for 17 h by which time the solution turned to brown. The brown solution was then quenched at 0 ~C with 30 mL of saturated aqueous NaHCO3 solution and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with 200 mL with brine, dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 50:50 EtOAc-hexanes) to afford 1.265 g (2.826 mmol, 76%) of a yellow foam.
mp 69-72 ~C; FDMS 447 (M+); Anal. Calcd for C26H2sNO4S: C, 69.78; H, 5.63; N, 3.13. Found: C, 69.93; H, 5.77; N, 3.25.
Part D. 4-~2-(1-~yl~olidinyl)ethoxy]~hQnyl Ma~nosium Bromid~.
W O 97/25033 PCT~US96/17995 BrMg ~
To a solution of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine in 24.1 mL o~ freshly distilled THF was added 293 mg of magnesium turnings. The mixture was heated at reflux for 3 h or until all the magnesium was consumed to afford ~24.1 mL of 0.48 M Grignard reagent solution.
l?art E. 6-Renzyloxy-2-~4-[2-~ olidinyl)ethoxy]-l?henyl]bQnzo~b~thiophen-3-yl 3,4-DimethoxyphQnyl l~eto~e.
~<
~~o\
o~o ~ ~\
To the dimethylaminobenzo[b]thiophenyl ketone (Part C) (1.237 g, 2.763 mmol) in 30 ml of freshly distilled THF was added dropwise 0.48 M 4-[2-(1-pyrrolidinyl)ethoxy]phenyl magnesium bromide in THF (Part D) (8.63 mL, 4.14 mmol) at 0 ~C. The resultant bright red solution was stirred at 0 ~C
for 2 h 15 min. The reaction was quenched at 0 ~C with 30 mL
of saturated aqueous NH4Cl solution. The mixture was diluted with 15 mL of H20 and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and then purified by flash chromatography (silica gel, 60:37:3 THF-hexanes-Ft3N) to afford 1.507 g (2.538 mmol, 92%) of a yellow foam.
mp 74-77 ~C; FDMS 593 (M+); Anal. Calcd for C36H3sNOsS: C, 72.83; H, 5.94; N, 2.36. Found: C, 72.91; H, 5.94; N, 2.62.
., CA 02236007 l998-04-27 W 097/2~033 PCT~US96/17sss P~rt F. 6-Benzyloxy-2-~4-[2-(1-~y olidinyl)ethoxyl-phenyl~b~nzo~b]thiophen-3-yl 4-Hydroxy-3-~ethoxyphenyl KQtone .
O~ OH
0~ ~0 ~ ~\
To the 3,4-dimethoxyphenyl ketone (Part E) (1.496 g, 2. 519 mmol) in 15 ml of dry DMF was added sodium thioethoxide (848 mg, 10.1 Imnol), and the reaction mixture was stirred at 80 ~C for 3h. The mixture was then cooled to 0 ~C and quenched with 15 mL of saturated aqueous NH4Cl solution.
This mixture was extracted with CHC13 (3 x 150 mL). The combined organic layers were washed with 450 mL of H20 and 150 mL o~ brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromato~raphy (silica gel, 696[1096 NH40H in MeOH]/CH2C12) to 15 afford 1.251 g (2.159 r~nol, 86%) o~ a yellow foam.
FDMS 579 (M+); Anal. Calcd for C3sH33NOsS: C, 72.52; H, 5. 74; N, 2.42. Found: C, 72.63; H, 5.73; N, 2.64.
P~rt G. (+)-6-Benzyloxy-2-~4-~2-(1~ olidinyl)-ethoxy]~henyl~benzo~b~thiophen-3-y} 4-[tr~n~-2-(Dimethyl~ ;~o)cyclohoxyl]oxy-3-methoxyPhenyl Ketone.
O N
o~-~ b J~O
~ ~ ..
W O 97/25033 PCTnJS96~7995 The title compound was prepared in 93~ yield by essentially following the procedures outlined in Example 20, Part B from the phenol (Part F) and (+)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A).
mp 66-69 ~C; FDMS 705 (M+); Anal. Calcd for C43H48N205S-0.62NH50: C, 71.08; H, 7.09; N, 5.05. Found: C
'70.88; H, 6.76; N, 4.65.
:Part H. (+)-6-Benzyloxy-a~[4-~ltrans-2-(~imethyl-;~o)cycloh~xyl30xy~-3-m~thoxyphenyll-2-C4-12-(l-~yrroli~inyl)ethoxy~phcnyl~benzo[b]thio~hene-3-methanol.
O N
HO ~
0~\ ~
The title compound was prepared in by essentially following the procedures outlined in Example 31, Part B from the ketone ~Part G). The crude product was purified by flash chromatography (silica gel, 10%[10% NH40H in MeOH]/ CH2Cl2) to afford 418 mg (.591 mmol, 69%) of a white foam.
FDMS 708 (M+l); Anal. Calcd for C43H50N205S 0.22CH2C12: C, 71.54; H, 7.12; N, 3.86. Found: C, 71.52; H, 7.31; N, 4.06.
Part I. (+)-3-l4-[ltrans-2-(DimethylA ;~o)cyclohexyl~-oxy] -3-methoxybenzyl3-6-hydroxy-2-C4-C2-(l-pyrroli-dinyl)~thoxylphenyl~benzo1b~thiophene Dioxalate.
The 6-benzyloxy protected title compound was prepared from the disubstituted methanol (Part H) by essentially following procedures outlined in Example 31, Part C. A
slurry o~ the crude (+3-6-benzyloxy-3-[4-l[trans-2-(dimethylamino3cyclohexyl]oxy]-3-methoxybenzyl] -2-~4-l2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b~thiophene (374 mg, .542 mmol) and Pd/C (10%, 375 mg) in 5.4 mL of a 1:1 mixture of THF-EtOH was stirred under positive hydrogen pressure (from balloon) for 19 h. The reaction mixture was filtered through a pad of diatomaceous earth and washed with THF. The filtrate was then concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%[10% NH40H
in MeOH]/CH2C12) to afford 200 mg (.333 mmol, 61~ from alcohol) of an off-white foam. The title compound was then prepared by essentially following the procedures outlined in Example 21, Part C from the free base.
mp 167 ~C (dec.); FDMS 601 (M+); Anal. Calcd for 15 C36H44N2O4S 1.83C2H204: C, 62.22; H, 6.27; N, 3.66. Found:
C, 62.26; H, 6.40; N, 3.28.
r~ le 82 Preparation of (+)-4-~t~ans-2-(Dimothyla~i~o)-cyclohexyl~ox~l -3-methoxyphenyl 6-Hydroxy-2-14- r2- (l-pyrroli~inyl)ethoxy]phenyl]benzorb]thiophen-3-yl Ketone Dioxalate.
o N
o~~ b HO ~ 2 C2H2O4 The title compound was prepared from the free base (Example 81, Part G) by essentially following the procedures outlined in Example 81, Part I and Example 21, Part C.
mp 170 ~C (dec.); FDMS ~15 (M+); Anal. Calcd for C36H42N20sS 1.82C2H204: C, 61.15; H, 5.91; N, 3.60. Found:
C, 61.12; H, 6.05; N, 3.66.
W O 97/25033 PCTnUS96~1799S
~r le 83 Pr~paration Of 3-~3-Chloro~4~ r oliainyl) ~
methyllbenzyll-2-~4-~2-(1-pyrrolidinyl)ethoxy~phenyl3-b~nzo~blthio~hene Dioxalate.
Cl N
~_ :Z C2H2~4 ~
Part A. M~thyl 4-~ - -thyl-3-chlore~e~70ate.
Cl O Br The title compound was prepared in 56% yield by essentially following the procedure outlined in the first part of Example 37, Part A, from methyl 3-chloro-4-methylbenzoate.
FDMS 264 (M+); Anal. Calcd for CgHgBrClO2: C, 41.02; H, 3.06. Found: C, 41.10; H, 3.10.
Part B. Methyl 3-Chloro-4-[(1-~r~olidinyl)methyl~-benzoate.
Cl MeO ~
The title compound was prepared in 44~ yield by essentially following the procedures outlined in the second part of Example 37, Part A, from methyl 4-bromomethyl-3-chlorobenzoate (Part A).
F FDMS 253 (M+); Anal. Calcd ~or C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.24; H, 6.11; N, 5.53.
W O 97/25033 PCTrUS96/17995 Part C. 3-Chloro-4-1(1-~ ~olidinyl)methyl~benzoic Acid cl HO~--~
The title compound was prepared in 72% crude yield by essentially following the procedures outlined in Example 20, Part C, from methyl 3-chloro-4-[~1-pyrrolidinyl)methyl]-benzoate (Part B). This compound was used without purification.
Part D. 3-Chloro-4-t(l-~ olidinyl)methyl]phenyl a- t4-t2-(1-~yrroli~inyl)Qthoxy]~hQnyllbenzolblthio-phen-3-yl Ketono Dioxal~te.
N ~
2 c2H2~4 ~~ ~
The free base of the title compound was prepared in 55%
yield by essentially following the procedures outlined in Example 1, Part C from 2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene (Example 4, Part A) and 3-chloro-4-[(l-pyrrolidiny)lmethyl]benzoic acid (Part C). The title compound was then prepared by essentially following the procedures outlined in Example 21, Part, C from the free base.
mp 97-102 ~Ci FDMS 544 (M-l); Anal. Calcd for C32H33ClN2O2S 2.0C2H2O4: C, 59.62; H, 5.14; N, 3.86. Found:
C, 59.41; H, 5.28; N, 3.90.
Part E. 3-~3-Chloro-4-t(l-~ lolidinyl)methyl]-benzyl]-2-t4-[2-(1-~yrrolidinyl)ethoxy]phonyl3-benzotb3thiophene Dioxalate.
W O 97/25033 PCT~US96/17995 The ~ree base o~ the title compound was prepared in 57%
yield by essentially following the procedures in Example 21, Part A from the ketone (~ree base o~ Part D). The title compound was prepared by essentially following the procedures outlined in Example 21, Part C from 3-r3-chloro-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene.
mp 126-130 ~C dec.; FDMS 531 (M+); Anal. Calcd ~or C32H3sClN2OS 2.0C2H2O4: C, 60.80; H, 5.53i N, 3.94. Found:
C, 60.63; H, 5.81; N, 3.87.
Exam~le 84 Preparation of 3-[3-~hloro-4-~ olidinyl3methyll-bonzyl~-6-hydroxy-2-14-12-(1-~yrroliainyl)ethoxyl-~henyllbenzo ~b~ thio~hene Dioxalate.
2 c2H2~4 HO ~ ~ N
Part A. 6-Benzyloxy-2-(dimethylr ;~o)benzo ~b~ thio-phen-3-yl 3-~hloro-4-t(1-pyrrolidinyl)methyl]phenyl Retone. Cl ~Nl~>
\
The title compound was prepared in 93% yield by essentially ~ollowing the procedures outlined in Example 41, Part C (but using thionyl chloride to ~orm the acid chloride) W O 97/25033 PCTrUS96/17995 ~rom 6-benzyloxy-2-(dimethylamino~benzo[b]thiophene (Example 81, Part B) and 3-chloro-4-[(1-pyrrolidinyl)methyl]benzoic acid (Example 83, Part C).
FDMS 504 (M-l); Anal Calcd. ~or C2gH29ClN2O2S: C, 68.96; H, 5.79; N, 5.55. Found: C, 69.00; H, 5.62; M, 5.55.
Part B. 6-Benzyloxy-2-[4-[2-(1-~ lolidinyl)ethoxyl-phQnyllbsnzolblthio~hen-3-yl 3-Chloro-4-1(l-~y ~olidinyl)methyl]phenyl Ketone.
N~
0~
The title compound was prepared in 94% yield by essentially following the procedures in Example 81, Part E, ~rom 4-[2-(l-pyrrolidinyl)ethoxy]phenyl magnesium bromide (Example 81, Part D) and 6-benzyloxy-2-(dimethyl ~m; nQ) -benzo[b]thiophen-3-yl 3-chloro-4-[(1-pyrrolidinyl)methyl]-phenyl ketone (Part A).
FDMS 651 (Mt).
Part C. 3-Chloro-4-[(1-pyrrollainyl)methyl3~henyl 6-Hydroxy-2-[4-[2-(1-~yrrolidinyl)ethoxy~phenylJ-benzo~b~thiophen-3-yl Ketone Dioxalate.
Cl N
HO~ ~ C2H2~4 CA 02236007 l998-04-27 The :Eree base of the title compound was prepared in 71%
yield by essentially following the procedures outlined in Example 81, Part I from the ketone. The title compound was prepared by essentially ~ollowing the procedure outlined in Example 21, Part C.
mp 174-178 ~C; FDMS 561 (M+); Anal. Calcd for C32H33ClN2O3S 1.75~2H2O4: C, 59.33; H, 5.12; N, 3.78.
Found: 59.33; H, 5.27; N, 3.90.
Part D. 3-13-Chloro-4-t(l-~Ylloli~inYl)m~thYll-benzyl]-6-hydroxy-2-14-12-(1-pyrroli~inyl)ethoxy]-phenyl]benzolblthiophene DioxalatQ.
The free base o:E the title compound was prepared in 38%
yield by essentially following the procedures outlined in Example 21, Part A, from the above ketone (Part C). The title compound was then prepared ~y essentially following the procedures outlined in Example 21, Part C.
FDMS 547 ~M+); Anal. Calcd for C32H3sClN2O2S 1.66C2H204: C, 60.90; H, 5.54; N, 4.02. Found: C, 60.90; H, 5.72; N 3.99.
_ 1Q 85 Preparation of (+)-6-Hyaroxy~3-[3-methoxy-4-l[trans-2-(1-pi~eri~yl)cyclohQxyl]oxy]benzyl]-2-[4-1i2-(1-pyrro-li~inyl)ethoxy3phenyl~bQnzotb3thio~hQne Dioxalate.
o Q
~o"~
HO~o 2 c2H204 Part A. (+)-6-Benzyloxy-2-14-12-(1-~y lolidinyl)-~thoxy]ph~nyl]bonzolb]thiophQn-3-yl 3-Methoxy-4-l[tran~-2-(l-piperidyl)cyclohexyl]oxy]phenyl Ketone.
W O 97~5033 PCTrUS96/17995 o~ ~
o~~"'~
o~~
,~
The title compound was prepared in 72% yield by essentially following the procedures outlined in Example 20, Part B, from 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-~l 4-hydroxy-3-methoxyphenyl ketone (Example 81, Part F) and (+)-trans-2-(1-piperidyl)-cyclohexanol (Example 20, Part A).
FDMS 746 (M+); Anal. Calcd for C46Hs2N20sS-0.19CH2C12: C, 72.89; H, 6.94; N, 3.68. Found: C, 72.84; H, 6.98; N, 4.03.
Part B. (+)-6-~ydroxy-3-13-methoxy-4-~tr~ns-2-(1-pi~eridyl)cyclohexyl]oxylbenzyll-2-t4-12-(1-pyrro-lidinyl)ethoxyl~honyllbonzo[b]thiophQne Dioxalate.
The free base of the title compound was prepared in 46%
yield by essentially following the procedures outlined in Example 21, Part A and Example 81, Part I from the ketone (Part A). The tîtle compound was then prepared by essentially following the procedure outlined in Example 21, Part C.
mp 167-171 ~C (dec.); FDMS 641 (M+~; Anal. Calcd for C3gH4gN204S-1.88C2H204: C, 63.39; H, 6.44; N, 3.46. Found:
C, 63.39; H, 6.61; N, 3.27.
~ Y~ _le 86 Preparation of (i)-6-xydroxy-2-14-[2-(1-~ olidinyl)-ethoxy]phenyl]benzo~b]thiophen-3-yl 3-Methoxy-4-~ttrans-2-(1-~iperidyl)cyclohexy]loxylphenyl Ketone Dioxalat~.
o~
" ~~ '~
HO~o C2H204 The free base of the ~itle compound was prepared in 41%
yield by essentially following the debenzylation procedure in Example 81, Part I, ~rom the ketone (Example 85, Part A).
The title compound was then prepared by essentially following the procedures in Example 21, Part C.
mp 151-155 ~Ci FDMS 655 (M~); Anal. Calcd for C3gH46N20sS-1.76C2H204: C, 62.79; H, 6.14; N, 3.44. Found:
C, 62.56; H, 6.54; N, 3.31.
_le 87 Preparation of (+)-3-[~tran~-2-(Dimethylamino)-cyclohexylloxy~isoxazol-5-yl 6-Hydroxy-2-14-[2-( ~yrrolidinyl)ethoxylphenyllbenzorb]thioph~n-3-yl Ketone Dioxalate.
--N
3¢~N 2 c2H2~4 P~rt A. (+)-Methyl 3-Eltran~-2-(Dimethylamino) cyclohexyl]oxyli~oxazolo-5-carboxylate.
., WO 97/2~033 PCTAJS96/17995 - N
~,o~
MeO
The title compound was prepared in 73% yield ~y essentially following the procedures outlined in Example 20, Part B ~rom methyl 3-hydroxyisoxazole-5-carboxylate and (+)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A) ~DMS 268 (M~); Anal. Calcd ~or Cl3H20N2o4: C, 58.19; H, 7.51; N, 10.44. Found: C, 58.31; H, 7.51; N, 10.54.
Part B. (~)-3-~[trans-2-(Dimethylamino)cyclohexyl~-oxylisoxazolQ-5-carboxylic Acid.
o~
~ ~ ,N
HO
The title compound was prepared by essentially following the procedures outlined in ~xample 20, Part C, from the ester (Part A).
Part C. (~)-6-Benzylox~-2-(dimQthyl~;~o)benzo[b]-thiophen-3-yl 3- r [trans-2-(Dimethylamino)cyclohexyl~-oxyli~oxazol-5-yl KetonQ.
- N
01~
O ~ ,N
0~ \
~
W O 97/25033 PCTnJS96/17995 The title compound was prepared in 92% yield by essentially following the procedures outlined in Example 84, - Part A from the isoxazole-5-carboxylic acid (Part B) and 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (Example 81, Part B).
FDMS 519 (M+); Anal. Calcd for C29H33N304S-0.52H20: C, 65.84i H, 6.49; N, 7.94. Found: C, 65.87; H, 6.12; N, 7.56.
Part D. (~)-6-Benzyloxy-2-~4-~2-(1-~y ~oliainyl)-othoxylphenyl~benzolblthio~hen-3-yl 3-1ltran~-2-(Dimethylamino)cyclohexyllo~yl isoxazol-~-yl Ketone.
- N
~ ~ ~ N ~
The title compound was prepared in 77% yield by essentially following the procedures outlined in Example 81, Part E from the ketone (Part C) and 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl magnesium bromide (Example 81, Part D).
FDMS 666 (M+).
2~
Part E. (+)-3-1ltrans-2-(Dimethylamino) cyclohexyll-oxy]isoxazol-5-yl 6-Hydroxy-2- 14-[2- ~1-pyrrolidinyl)-~thoxy]~hQnyl]benzolblthio~hQn-3-yl Ketone Dioxalato.
The ~ree base of the title compound was prepared in 51%
yield by essentially following the debenzylation procedure outlined in Example 81, Part I from the ketone (Part D). ~he title compound was prepared by essentially following the procedures in Example 21, Part C.
W O 97/2~033 PCT~US96/17995 FDMS 576 (M+).
Example 88 Prsparation of 3-~4-~(DimQthyl~;no)methyl]-3-methoxybQnzyl]-6-hydroxy-2-t4-12-(1-pyrrolidinyl)-~thoxy]phenyl~benzo~b]thiophsne Dioxalate.
o N -~ I
HO ~ ~ N
Part A. 4-Allyloxy-~-hydroxy-N,N-dimethylphenyl-thioacetamide.
qH
~ N~
o~ S
The title compound was prepared in 70% yield by essentially ~ollowing the procedure in Example 81, Part A
from 4-allyloxybenzaldehyde.
FDMS 251 (M+).
Part B. 6-Allyloxy-2-(dimethylamino)benzo[b~thiophene.
The title compound was prepared in 49% yield by essentially following the procedures outlined in Example 81, Part B from the thioacetamide (Part A).
FDMS 233 (M+); Anal. Calcd for C13HlsNOS: C, 66.92; H, 6.48;
N, 6.00. Found: C, 66.76i H, 6.54; N, 5.82.
Part C. Methyl 4-(Dimethyl~-;no)methyl-3-methoxy-- henzoate.
MeO~ N
The title compound was prepared in 77% yield by essentially following the procedure outlined in Example 37, Part A from methyl 4-bromomethyl-3-methoxybenzoate (see Example 37, Part A) and dimethylamine.
FDMS 223 (M+); Anal. Calcd. for C12H17N03: ~, 64.55; H, 7.67; N, 6.27. Found: C, 64.52; H, 7.68; N, 6.43.
Part D. 4-(DimethylA ;no)methyl-3-methoxybenzoic Acid.
H~ ' N
o The crude title compound (+30% NaCl by weight) was prepared by essentially following the procedures outlined in Example 20, Part C from the methyl benzoate (Part C).
Part E. 6-Allyloxy-2-(dimQthyl~ ino)benzo~b~thiophen-3-yl 4-(Dimethylamino)methyl 3-methoxyphenyl Ketone.
o~
N--~N
J
The title compound was prepared in 73% yield (23% SM
recovered) by essentially following the procedures outlined in ~xample 84, Part A from 6-allyloxy-2-(dimethylamino)benzo-[~]thiophene (Part B) and 4-(dimethylamino)methyl-3-methoxybenzoic acid (Part D).
FDMS 424 (M+); Anal. Calcd for C24H28N2O3S: C, 67.90; H, 6.65; N, 6.60. Found: C, 68.18; H, 6.77; N, 6.81.
Part F. 6-Allyloxy-2-[4-r2-(1-pyrrolidinyl)ethoxy]-~hen~l]benzo~b]thiophen-3-yl 4-(Dimethyl~ ;~o)mothyl-3-mothoxyphonyl Ketone.
0~/
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 81, Part E from the ketone (Part E) and 4-[2-(1-pyrrolidinyl)-ethoxy]phenyl magnesium bromide (Example 81, Part D).
FDMS 570 (M~); Anal. ~alcd for C34H3gN2O4S: C, 71.55; H, 6.71; N, 4.91. Found: C, 71.30; H, 6.85; N, 4.89.
Part G. 3-E4-(Dimothylamino)mQthyl-3-methoxybenzyl}
6-hydroxy-2-l4-~2-(1-pyrrolidinyl)ethoxy~phenyl]-bonzoEb~thio~hene Dioxalate.
Deoxygenation of the ketone (Part F) was accomplished in 57% crude yield by essentially following the procedures outlined in Example 21, Part A.
The ~ree base of the title compound was prepared by stirring a slurry of the above crude product (139 mg, .250 mmol), 10% Pd/C (150 mg), and p-toluenesulfonic acid monohydrate (105 mg, .551 mmol) in 3 mL o~ a 5:1 mixture of MeOH-THF solution at re~lux ~or 22 h. The reaction was ~uenched with 3.5 mL of saturated a~ueous NaHCO3 solution, CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 stirred vigorously for 15 min, and then concentrated to dryness under reduced pressure. The residue was taken up in - 200 mL of THF and stirred vigorously for 30 min. The slurry was ~iltered through a pad of diatomaceous earth and washed with THF. The filtrate was concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%~10% NH40H in Me0H~/CH2Cl2) to afford 66.7 mg (.129 mmol, 52%) of a light brown foam. The title compound was prepared by essentially following the procedures outlined in Example 21, Part C.
FDMS 517 (M+); Anal. Calcd for C31H36N203S 2 OC2H2o4 0~7H2o-l-2c4Hgo2 (Hygroscopic): C, 58.65; H, 6.31; N, 3.44. Found: C, 58.27; H, 6.31; N, 3.41.
_ 1~ 89 Pr~paration of 2-14- r2- (Dimethylamino)ethoxy]phenyl]-3-~4-(dimethylamino)methyl-3-methoxybenzyl]-6-hyaroxy-benzolb]thiophene Dioxalate.
o ,~f7-HO~ N--Part A. 12-(4-Chlorophe~o~y)ethyl]dimethyl~ ;ne.
o Cl ~
N--The title compound was prepared in 61% yield (26% SM
recovered) by essentially following the procedure outlined in Example 34, Part A from 2-bromoethyl 4-chlorophenyl ether and dimethylamine.
FDMS 199 (M+); Anal. Calcd for C1oH14ClN0: C, 60.15; H, 7.07; M, 7.01. Found: C, 59.88; H, 7. 03; N, 7. 22.
CA 02236007 l998-04-27 W O 97/2~033 PCT~US96/17995 Part B. Pro~aration of 4-~2-(DimothylA-ino)ethoxy]-~honyl Magnesium Chloride.
g ~
N--To the chlorobenzene (Part A) in 23.6 I~ oi~ ~reshly distilled THF was added 216 mg of magnesium turnings and a catalytic amoun~ o~ iodine crystals. The mixture was heated at reflux for 3 6 h or until all the magnesium was consumed to af~ord ~23.6 mL, o:E 0.3 8 M Grignard reagent solution as a milky white suspension.
Part C. 6-Allyloxy-2-[4-~2-(dimethylamino)Qthoxy]-~henyll ben z o [ b] thi ophen-3-yl 4-(Dim~thylamino)methyl-3-methoxyphenyl Ketono.
o~3~ N--~J
The title compound was prepared in 80% yield by essentially ~ollowing the procedures outlined in Example 81, Part E ~rom the ketone (Example 88, Part E) and the Grignard reagent (Part B).
FDMS 544 (M+); Anal. Calcd ~or C32H36N2O4S: C, 70.56; H, 6.66i N, 5.14. Found: C, 70.33; H, 6.73; N, 5.10.
Part D. 2-[4-[2-(DimethYl~ ;no)ethoxy]phenyll-3-C4-~dimethylamino)methyl-3-methoxybenzyl3-6-hydroxy-b~nzoCblthiopheno Dioxalat~.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/1799 Deoxygenation of the ketone (Part C) was accomplished in 46% by essentially following the procedures outlined in ~ Example 21, Part A.
The ~ree base of the title compound was prepared in 45%
yield by essentially following the procedures outlined in Example 88, Part G. The title compound was then prepared by essentially following the procedure outlined in Example 21, Part C.
FDMS 491 (M+); Anal. Calcd for C2gH34N203S 2.0C2H204 1.06C4HgO2 (Hygroscopic): C, 58.54i H, 6.13; N, 3.67. Found: C, 58.62; H, 6.39; N, 3.79 Example 90 Preparation of 2-[4-[2-(Dim~thy}~ ;no)ethoxy]phenyl]-6-hydroxybonzo[blthiophen-3-yl 4-(Dimethylamino)-methyl-3-methoxyphenyl Ketone Dioxalate.
o~
N -0~ 1 HO~ ~3~ 2 C2H204 The free base of the title compound was prepared in 37%
yield by essentially following the procedures outlined in Example 88, Part G from 6-allyloxy-2-[4-[2-(dimethylamino)-ethoxy]phenyl]benzo[b]thiophen-3-yl 4-(dimethylamino)methyl-3-methoxyphenyl ketone (Example 89, Part C). The dioxalate was then prepared by using the procedures from Example 2~, Part C from the free base.
FDMS 505 (M+); Anal. Calcd for C29H32N2O4S 2 ~C2H2~4 C, 57.89; H, 5.30; N, 4.09. Found: C, 57.75; H, 5.47; N, 4.13.
..
W O 97/25033 PCT~US96/17995 ~Y;' _ 1~3 91 PrQparation of 4-(Dim~thylamino)methyl-3-methoxy-phenyl 6-Hydroxy-2-C4-l2-(l-~yrrolidinyl)ethoxy3 phenyl]bQnzo[blthiophen-3-yl Ketone Dioxalate.
o ~f HO~o 2 c2H2o4 <
The free base of the title compound was prepared in 81 yield by essentially following the procedures outlined in Example 88, Part G ~rom 6-allyloxy-2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl 4-(dimethylamino)methyl-3-methoxyphenyl ketone (Example 88, Part F). The dioxalate was then prepared by using the procedures ~rom Example 21, Part C from the free base.
FDMS 531 (M+); Anal. Calcd for C31H34N204S-2.0C2H204: C, 59.15; H, 5.39; N, 3.94. Found: C, 58.96; H, 5.73; N, 4.00.
Example 92 Preparation of (+)-4-Hydroxy-3-14-C[trans-2-~l-piperi~yl)cyclohexylloxylbenzyll-2-[4-C2-(l~pyrro-lidinyl)ethoxy]~henyl]benzo [b3 thiophene Dioxalate.
OH ~ o", b ~ o 2 C2H2~4 Part A. 4-Methoxybenzo ~b3 thiophene an~ 6-Methoxy-b~nzo lb3 thiophene.
W O 97/25033 PCT~US96/17995 ,. -239-OMe MeOJ~
To a mixture of 25.10 g of 3-methoxybenzenethiol and 19.2 ml, of bromoacetaldehyde dimethyl acetal in 200 mL of acetone was added 27 g of K2CO3 in one portion at room temperature. The white suspension was stirred vigorously at room temperature for 2 h. The mixture was filtered with thorough ethereal rinse. The filtrate was concentrated, taken up in 500 mL of Et20, and washed with 300 mL of H20, 0.5 N KOH, H2O, and brine. The washings were back extracted with Et2O (3 x 500 mL). Combined organic layers were dried over MgSO4 and concentrated to afford 37. 46 g (quantitative) of the crude 3-methoxybenzenethioacetaldehyde dimethyl acetal.
To a heated biphasic solution of 53.9 g of PPA in ca.
500 mL of chlorobenzene at 14S ~C (bath temp.) was added dropwise 18.44 g of the crude acetal in ca. 100 mL of chlorobenzene over 4.5 h period. The dark green biphasic solution was heated at reflux with vigorous stirring for another 2 h. After cooling to room temperature, the organic layer was separated, concentrated, taken up in 500 mL of EtOAc, and washed with 300 mL of H2O and brine. The PPA
layer was dissolved in ca. 1.0 L of H2O and extracted with EtOAc (4 x 500 mL). The extracts were washed with 300 mL of H2O and 1:1 mixture of saturated aqueous NaHCO3 and brine.
Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with hexanes to yield 2.40 g of 4-methoxybenzo[b] thiophene and 7.96 g of 6-methoxybenzo [b] -thiophene (78% total) which were cleanly separated.
4-methoxybenzothiophene: FDMS 164.0 (M+); Anal. Calcd for CgH8OS: C, 65.82i H, 4.91; S, 19.52. Found: C, 66.01; H, 4.90i S, 19.60.
6-methoxybenzothiophene: FDMS 164.0 (M+).
W O 97/25033 PCT~US96/17995 Part B. 4-Methoxybenzolb]thiophene-2-boronic Acid.
OMe ~ B (OH)2 The title compound was prepared in 62~ yield by essentially ~ollowing the procedures in Example 1, Part A
from 4-methoxybenzothiophene (Part A).
mp 267-270 ~C; FDMS 570.
Part C. 4-Methoxy-2-~4-~2-~ t oli~inyl)ethoxy]-phenyl~benzolb]thioph~ne.
OMe The title compound was prepared in 53% yield by essentially following the procedures outlined in Example 1, Part B from 4-methoxybenzo[b]thiophene-2-boronic acid (Part B).
FDMS 353 (M+).
Part D. 4-Hydroxy-2-[4-C2~ ~y~lolidinyl)ethoxy~-phonyl]benzolb]thiophono.
OH
~~
The title compound was prepared by essentially following the procedures outlined in Example 21, Part B from the methoxybenzo[b]thiophene (Part C). Recrystallization from 25 EtOAc-hexanes afforded 712 mg (2.09 mmol, 38%) of off-white needle-like crystals.
CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 mp 191-193 ~C; FDMS 339 (M+); Anal. Calcd for C20H2lNo2s-o~l7H2o: C, 70.13; H, 6.28; N, 4.09. Found: C, ~ 69.81; H, 6.10; N, 3.85.
Part E. 2-14-[2-(1-~y ~olidinyl)Qthoxy]phenyl~-benzolb]thiophen-4-yl 4-Fluorobenzoate.
A mixture of 4-hydroxybenzo[b]thiophene (Part D) (607 mg, 1.79 mmol) and 4-fluorobenzoyl chloride (233 ~L, 1.97 mmol) in 10 mL of anhydrous dichloroethane was stirred at room temperature for 18 h. Another portion of 4-~luorobenzoyl chloride (166 ~L, 1.48 mmol) was added and the reaction mixture was stirred for 3 days. A third portion of acid chloride (233 ~l, 1.97 mmol) was added and the mixture was stirred for an additional 4 h. The reaction was then quenched with 25 mL of satd. NaHC03 soln, and the mixture was extracted (3 x 100 mL) with EtOAc. The combined organic layers were washed with 100 mL of brine, dried over MgS04, concentrated under reduced pressure, and ~lash chromatographed (silica gel, 5%[10% NH40H in MeOH]/CH2Cl2) to afford 699 mg (1.51 mmol, 85~) of a white solid.
FDMS 461 (M+); Anal. Calcd for C27H24FN03S 0.16NHsO: C, 69.42; H, 5.35; N, 3.48. Found: C, 69.40; H, 5.30; N, 3.65.
Part F. 3-(4-Fluorophenyl)carbonyl-2-~4-12-(1-Pyrrolidinyl)ethoxy]phenyl~benzo~b]thiophen-4-yl 4-Fluorobonzo~te.
x W O 97/25033 PCT~US96/17995 F
0 0~
To a solution of 4-fluorobenzoate ~Par~ E) (683 mg, 1.48 mmol) in 10.0 mL of anhydrous dichloroethane was added 4-fluorobenzoyl chloride (192 ~L, 1.63 mmol) at room temperature. The reaction mixture was cooled to 0 ~C, and aluminum chloride (789 mg, 5.92 mmol) was added which turned the slurry into a dark red homogeneous solution. The reaction mixture was slowly warmed to room temperature and then stirred ~or 24 h. Another portion of aluminum chloride (395 mg, 2.94 mmol) and 4-fluorobenzoyl chloride (95 ~L, .80 mmol) were added, and the reaction mixture was stirred at room temperature for another 24 h. The reaction mixture was then poured into 25 mL of ice-cold saturated aqueous NaHCO3 solution. The mixture was taken up in EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (4 x 150 mL). The combined organic layers were washed with 100 mL of brine, dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (MPLC, silica gel, 40:57:3 THF-hexanes-Et3N) to afford 193 mg (.331 mmol, 22%) of white foam.
mp 58-63 ~C; FDMS 583 (M+); Anal. Calcd ~or C34H27F2NO4S: C, 69.97; H, 4.66; N, 2.40. Found: C, 70.37; H, 5.00; N, 2.30.
Part G. (+)-4-~ydroxy-2-t4-12-(1-1?yrrolidinyl)-~thoxyl~henyl]bQnzo[~thiophen-3-yl 4-l[trans-2-(1-PipQridyl)cyclohexyl]oxy]phenyl Ketone.
W O 97/25033 PCT~US96/17995 OH ~
.. ~~
The title compound was prepared in 32% yield by essentially following the procedures in Example 75, Part G, from the 4-~1uorobenzoate (Part F) and (+)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
FDMS 625 (M+); Anal. Calcd for C38H44N2O4S 2-5C2H2~4 3- 2 C, 56.91; H,6.15; N, 3.09. Found: C, 56.61; H, 5.80; N, 3.47.
~art H. (+)-4-Hydroxy-3- 14- ~ ~trans-2- ( l-piperidyl)-cyclohexyl]oxy]benzyl]-2 - ~4 - 12 - ( l-pyrrolidinyl)-~sthoxy~phcnyl~bonzorb~thiophon~.
OH ~
~ N
The title compound was prepared in 24% yield by essentially following the procedures outlined in Example 21, Part A from the ketone (Part G).
FDMS 610 (M+).
Part I. (+)-4-Hydroxy-3- ~4- ~ l trans-2- ( l-piperidyl)-cyclohexyl~oxy]benzyl] -2- ~4- ~2- ( l-pyrrolidinyl)-ethoxy]phenyl]benzolb]thiophone Dioxalate.
W O 97/25033 PCT~US96/17995 The title compound was prepared by essentially ~ollowing the procedure outlined in Example 21, Part C from the ~ree base (Part H).
FDMS 611 (M+); Anal. Calcd for C3gH46N2O3S 2.1C2H204 3.3H20:
C, 58.98; H, 6.66; N, 3.26. Found: C, 58.70i H, 6.32; N, 3.28.
~,~r _ le 93 Preparation of 5-Methoxy-3-E3-methoxy-4~
pyrrolidinyl)methyllbenzyl~-2-14- r2- (l-pyrrolidinyl)-ethoxy]phQnyllbenzolblthiophene Dioxalate.
~ N ~
Part A. 5-Mothoxy-2-~4-~2-(1-pyrrolidi~yl)ethoxy]-phenyl]benzolb]thiophen-3-yl 3-Methoxy-4~
~yrroli~inyl)methyl]phenyl Ketone Dioxalat~.
~_ z c2H2~4 <~
The free base of the title compound was prepared in 37%
yield by essentially ~ollowing the procedures outlined in Example 41; Part C ~rom 5-methoxy-2-[4-[2-(l-pyrrolidinyl~-ethoxy]phenyl]benzo[b]thiophene (Example 71, Part C) and 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoic acid (Example 41, Part B). The title compound was prepared by essentially CA 02236007 l998-04-27 W 097/25033 PCT~US96117995 following the procedures outlined in Example 21, Part C from the free base.
-FDMS 571 (M+); Anal. Calcd for 5 C34H38N2O4S-2.0C2H204-0.48C4H802: C, 60.46; H, 5.83; N, 3.53. Found: C, 60.57; H, 6.08; N, 3.58 Part B. 5-Methoxy-3-[3-methoxy-4-(1-~1lolidinyl-methyl)benzyl]-2-14-12-(1-pyrrolidi~yl)ethoxy]phenyl]-benzo~b]thiophene Dioxalate.
I~he free base of the title compound was prepared in 68%yield by essentially following the procedures in Example 21, Part A from the free base of ketone (Part A). The title compound was prepared by essentially following the procedures in Example 21, Part C from the free base.
Free base: FDMS 557 (M+); Anal. Calcd ~or C34H40N2O3S: C, 73.35; H, 7.24; N, 5.03. Found: C, 73.49; H, 7.12; N, 5.03.
Dioxalate: FDMS 557 (M+); Anal. Calcd for C34H40N2O3S 1-7c2H2o4 0-5C4H8o2 C, 62-77i Found: C, 62.63; H, 6.73; N, 3.97.
~ le 94 Preparation of 1-12- 12-Fluoro-4- 112-14-12- (1-pyrro-li~inyl)ethoxy]phenyl~benzolb]thiophen-3-yl]methyl~-l?h9~oxy]ethyl]~yrrolidine Dioxalate.
A O'' ~ -'N
W O 97~5033 PCT~US96/17995 Part A. 3~4-Difluoro~henyl 2-L4-12-(1-Pyrrolidinyl)-ethoxy]phenyl~benzolb]thiophen-3-yl Ketone.
~'o ~ ~N ~
A slurry oE 3.23 g (10 mmol) o:E 2- [4-[2-(1-pyrro-lidinyl)ethoxy)phenyl]benzo[b]thiophene in 50 mL of 1,2'dichloroethane was treated with 1.76 g (10 mmol) of 3,4-di~luorobenzoyl chloride at 0 ~C. The mixture was protected ~rom light and 4.4 mL (40 mmol) TiC14 was added dropwise. The reaction was stirred at 0 ~C for 5 h at which time it was quenched by carefully pouring it into 400 mL o~
saturated aqueous NaHCO3. To this was added EtOAc (200 mL), and the two layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give a crude oil which was puri~ied by chromatography (sio2; 2%
MeOH in CHCl3) to afford 1.7 g (3.7 mmol; 37%) of the ketone as a VlSCOUS oil.
lH NMR (CDCl3) ~ 7.87-7.75 (m, 2H), 7.63-7.56 (m, lH), 7.48-7.31 (m, 3H), 7.30-7.25 (m, 2H), 7.03-6.94 (m, lH), 6.79-6.75 (m, 2H), 4.1 (t, 2H), 2.8 (t, 2H), 2.7-2.5 (m, 4H), 1.84-1.80 (m, 4H); FDMS 463 (M+); Anal. Calcd for C27H23F2N02S-1-08C~C13: C, 56.93; H, 4.1i N, 2.36. Found: C, 56.90; H, 4.05; N, 2.45.
Part B. 3-Fluoro-4-C2-t~ r Loli~inyl) ethoxy~phenyl 2-14-12-(1-Pyrroli~inyl)othoxyphenyllb~nzolb~thio~hen-3-yl ~etono.
W O 97/25033 PCTnUS96/17995 ~, A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was rinsed with hexanes and dried under reduced pressure. To this was added 30 mL o~ dry THF, followed by 1.1 g (9.8 mmol) of 1-(2-hydroxyethyl)pyrrolidine. After gas evolution had ceased, a solution of 2.27 g (4.90 mmol) of the 3,4-difluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]-benzo[~]thiophen-3-yl ketone in 30 mL of THF was added. The reaction was stirred under a nitrogen atmosphere for 3 h at ambient temperature after which it was poured into a mixture of 100 mL of brine and 60 mL of EtOAc. The layers were separated and the aqueous layer was extracted with 30 mL of EtOAc. The combined organic layer was washed with brine (2 X
100 mL), dried over Na2S04, and concentrated under reduced pressure to give 3.2 g of an oil. This was purified twice by chromatrography (SiO2i 50/45/5% THF/Hex/Et3N; tllen 5% CHCl3 in MeOH) to afford 1.6 g (2.9 mmol; 58~) of the desired compound as a viscous oil.
20 1H NMR (CDC13) ~ 7.87-7.84 (m, lH), 7.69-7.66 (m, lH), 7.58-7.54 (m, lH), 7.50-7.47 (m, lH), 7.38-7.26 (m, 3H), 6.81-6.75 (m, 4H), 4.15 (t, 2H), 4.06 (t, 2H), 2.91-2.86 (m, 4H), 2.62-2.61 (m, 8H), 1.82-1.77 (m, 8H); FDMS 461 (M-97), 559 (M+l);
Anal. Calcd for C33H3sFN2O3S 1.45CHCl3: C, 56.54; H, 5.02; N, 25 3.83. Found: C, 56.45; H, 5.0; N, 3.87.
100 mg was converted to the dioxalate salt.
~ Anal. Calcd for C33H3sFN2O3S 2 C2H2O4-1 H2O: C, 58.72; H, 5.46; N, 3.70. Found: C, 58.46; H, 5.06; N, 3.32.
W O 97/25033 PCTnUS96/17995 Part C. 1-12-~2-Fluoro-4~1~2-~4-~2-(1-pyrrolidinyl)-Qthoxy]phenyl]benzo~b]thio~hen-3-yl]~ethyl]phenoxy~-othylJ~y r lolidine Dioxalate.
A solution of 1.1 g (2 mmol) of 3-fluoro-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-~1-pyrrolidinyl)ethoxy-phenyl]benzo[b]thiophen-3-yl ketone in 25 mL of THF at 0 ~C
was treated with 10 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 30 min and was ~uenched by the addition of 5 mL of EtOAc and concentrated in vacuo. The resulting residue was immersed in an ice bath, then cautiously treated with 10 mL of TFA, followed by 186 mg (5 mmol) of NaBH4. The reaction was stirred ~or 2 h, then evaporated in vacuo. The residue was taken up in 50 mL of 5 N NaOH and extracted with CH2C12 (2 X 30 mL). The combined extracts were dried over Na2SO4 and evaporated in vacuo to give 900 mg of an oil. Purification by chromatography (MPLC
Sio2; 60/35/5 THF/Hex/TEA) afforded 135 mg (0.25 mmol, 12%) o~ the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
lH NMR (CDC13) ~ 7.95-7.85 (m, lH), 7.75-7.7 (m, lH), 7.6-7.65 (m, lH), 7.55-7.5 (m, lH), 7.45-7.38 (m, 4H), 7.05 (s, lH), 6.85-6.8 (m, 2H), 5.05 (s, 2H), 4.20 (t, 2H), 4.1 (t, 2H), 3.0-2.9 (m, 4H), 2.7-2.6 (m, 8H), 1.8-1.9 (m, 8H); Anal.
Calcd for C33H37FN202S-1.65 C2H2O4: C, 62.89; H, 5.86; N, 4.04. Found: C, 62.93; H, 6.05; N, 4.00.
Example 95 Preparation of 1-~2-~4-~2-~4-12-(1-~y r olidinyl)-ethoxy]p~enyl~benzo~blthiophen-3-yllmethyll-2-tri~luoromethylphenoxy]ethyl]pyrrolidine Dioxalate.
WO 97/25033 PCTn~S96/17995 N ~ 2C2HaO4 ~ ~N ~
Part A. 4-Fluoro-3-trifluoromethylphenyl 2-~4-~2-(1-Pyrroli~inyl)~thoxy~ph~nyl~b~nzo[b]thiophen-3-yl ~tone.
J
"~--'N
~
A slurry o~ 8 g (38.4 mmol) of 4-fluoro-3-trifluoromethyl benzoic acid in 30 mL of dichloromethane and 2 drops of DMF
was treated with 6.70 mL (76.9 mmol) of (COCl)2 and the mixture was stirred at ambient temperature for 4 h. The resulting solution was evaporated in vacuo, and the residual oil was distilled under reduced pressure to yield 7.2 g (31.8 mmol, 83%) of the acid chloride as a colorless oil.
A solution of 3.38 g (10.45 mmol) of 2-[4-[2-(1-pyrro-lidinyl)ethoxy)phenyl]benzo[b]thiophene was dissolved in 200 mL of 1,2-dichloroethane and treated with 2.4 g (10.45 mmol) of the above acid chloride at 0 ~C The reaction was protected ~rom light and 4.4 mL (39.8 mmol) TiC14 was added dropwise. The reaction was stirred at ambient temperature for 4 h at which time it was quenched by carefully pouring it into 500 mL of saturated aqueous NaHCO3. EtOAc (400 mL) was added and the two layers were separated. The a~ueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give an oil which was purified by chromatography (sio2i 78/20/2% Hex/THF/Et3N) to afford 3.64 g (7.1 mmol; 68%) of the ketone as a solid.
lH NMR (CDC13) ~ 7.95-7.85 (m, 3H), 7.45-7.35 (m, 3H), 7.30-7.2 (m, 2H), 7.1-7.00 (m, lH), 6.79-6.72 (m, 2H), 4.05 (t, 2H), 2.85 (t, 2H), 2.7-2.5 (m, 4H), 1.85-1.75 (m, 4H); FDMS
514 (M+1); Anal. Calcd for C2gH23F4NO2S: C, 65.89; H, 4.51;
N, 2.73. Found: C, 65.75; H, 4.68; N, 2.78.
Part B. 2-[4-[2-(1-Pyrroliainyl)ethoxyphenyl]-:benzo~b]thiophen-3-yl 4-~2-(1-Pyrrolidinyl)ethoxy]-3-tri:~luorophenyl Ketone.
''"--'N ~
A 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol) was rinsed with hexanes and dried under reduced pressure. To this was added 25 mL of dry DMF followed by 1.35 g (11.7 mmol) 1-(2-hydroxyethyl)pyrrolidine. After gas evolution had ceased, a solution of 3 g (5.8 mmol) of 4-fluoro-3-trifluoromethylphenyl 2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophen-3-yl ketone in 30 mL of DMF
was added. The reaction was stirred under a nitrogen atmosphere overnight at ambient temperature, after which it was poured into a mixture of 100 mL of brine and 60 mL of EtOAc. The layers were separated and the a~ueous layer was extracted with 30 mL of EtOAc. The combined organic layer was washed with brine (2 X 100 mL), dried over Na2SO4, and concentrated under reduced pressure to 3.8 g of an oil. This was purified by chromatrography (SiO2; 5% MeOH/1~ NH40H in WO 97/25033 PCT/US96~1799~;
CHC13) to afford 3.07 g (5 mmoli 87%) of the named compound as a viscous oil.
-FDMS 609 (M+1) 5412 mg was converted to the dioxalate salt.
lH NMR (DMSO-d6) ~ 8.1 (d, lH), 8.0-7.9 (m, 2H), 7.65 (d, lH), 7.5-7.4 (m, 2H), 7.4-7.3 (m, 2H), 7.15 (d, lH), 6.9-7.0 (d, 2H), 4.55 (bs, 4H), 4.55-4.4 (m, 2H), 4.2-4.3 (m, 2H), 3.4-3.6 (m, 4H); 3.1-3.3 (m, 8H), 1.8-1.95 (m, 8H); Anal.
Calcd for C34H3sF3N2O3S 1.5C2H2O4: C, 59.75; H, 5.15; N, 3.77. Found: C, 59.61; H, 5.16; N, 3.80.
Part C. 1-12-[4-[[2-[4-[2-(1-Pyrrolidinyl)ethoxy~-phenyllbenzolb]thio~hen-3-yllmethyl~-2-trifluoro-methyl~henoxy3ethyl~ olidine Dioxalate.
A solution of 1 g (1.64 mmol) of the 2-[4-[2-(1-pyrro-lidinyl3ethoxyphenyl]benzo[~]thiophen-3-yl 4-[2-(1-pyrro-lidinyl)ethoxy]-3-trifluorophenyl ketone in 30 mL of THF at 0 ~C was treated with 9 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 1 h and was quenched by the addition of 5 mL of EtOAc and concentrated in vacuo. The resulting residue was immersed in an ice bath then cauiously treated with 10 mL of TFA followed by 124 mg (3.30 mmol) of NaBH4. The reaction was stirred for 2 h then evaporated in vacuo. The residue was partitioned between saturated a~ueous NaHCO3 (25 mL) and CHCl3 (50 mL). The layers were separated and the aqueous layer was extracted with CHCl3 (3 X 30 mL).
The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 1.1 g of an oil. Purification by chromatography (SiO2; 2% MeOH in CHCl3) afforded 353 mg (0.59 mmol 36%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
1H NMR (Free Base-CDCl3) ~ 7.84-7.81 (m, lH), 7.48-7.45 (m, lH), 7.4-7.31 (m, 3H), 7.31-7.15 (m, 2H), 7.15-7.11 (m, lH), 6.93-6.98 (m, 2H), 6.82 (d, lH), 4.2 (s, 2H), 4.15-4.1 (m, 4H), 2.95 (t, 4H); 2.65-2.55 ~m, 8H), 1.85-1.75 (m, 8H);
Anal. Calcd for C3gH41F3N2O1oS: C, 58.91; H, 5.33; N, 3.62.
Found: C, 58.80; H, 5.27; N, 3.57.
~.YA _ le 96 Preparation of 3-Nitro-4-~2-(1-~lidinyl)ethoxy]-phenyl 2-14-~2-(1-~y lolidinyl)ethoxyphenyl]benzo~b]-thiophen-3-yl Ketone Dioxalate.
q N ~ 2C~H204 ~ 'N
~/
Part A. Methyl 3-Nitro-4-~2-(1-y~lLolidinyl)ethoxyl-bonzoate ~yarochlori~e.
N~ "~o, ~HCl A mixture of 32 g (162.4 mmol) of methyl 4-hydroxy-3-nitrobenzoate, 51.13 g (194.9 mmol) of triphenylphosphine, 22.45 g (194.9 mmol) of 1-(2-hydroxyethylpyrrolidine), and 600 mL of CH2C12 was cooled to 0 ~C and treated with 33.95 g of (194.9 mmol) diethyl azodicarboxylate. The cooling bath was removed and the reaction was stirred at ambient temperature for 16 h. It was concentrated to dryness under reduced pressure, mixed with 200 mL of CHC13 and filtered.
The filtrate was chromatographed (sio2; 3% MeOH in CHCl3) to give 14.63 g of product still contA~;nAted with methyl 4-hydroxy-3-nitrobenzoate. It was dissolved in 200 mL of EtOAc and treated with HCl gas for 2 min. The resulting W097/25033 PCT~Sg6/17995 solid was filtered to yield 11.81 g (36 mmol, 22%) of the HCl salt of the named product.
-1H NMR (DMSO-d6 ) ~ 10 . 85-11 (bs, 1H), 8.45 (d, 1H), 8.25 (dd, lH), 7.58 (d, lH), 4.65 (t, 2H), 3.9 (s, 3H), 3.7-3.55 (m, 4H), 3.05-3.4 (m, 2H); 2.1-1.8 (m, 4H); FDMS 294 (M+); Anal.
Calcd for C14HlgN2Os-HCl: C, 50.84; H, 5.79; N, 8.47. Found:
C, 50.84; H, 5.70; N, 8.62.
Part B. 3-Nitro-4-[2-(1-pyrrolidinyl)ethoxy]benzoic A~id Hydrochloride.
''"~'o ~ OH
~HCl NO2 Methyl 3-nitro-4-E2-(1-pyrrolidinyl)ethoxy]benzoate (5.9 g, 20 mmol) was mixed with 60 mL o~ 5 N aqueous HCl and refluxed 16 h. It was mixed with toluene/EtOH and concentrated under reduced pressure to dryness. The resulting solid was tritrated with hot EtOAc to afford 5.7 g (18 mmol, 90%) of the benzoic acid hydrochloride.
20 1H NMR (DMSO-d6) ~ 8.36 (d, lH), 8.22(dd, lH), 7.45 (d, lH), 4.21 (t, 2H), 3.65-3.4 (m, 5H), 3.0-3.2 ~m, 3H), 2.1-1.7 (m, 4H); FDMS 280 (M+); Anal. Calcd ~or C13H16N2Os HCl 0.11toluene: C, 50.60; H, 5.50; N, 8.47.
Found: C, 50.60; H, 5.51; N, 8.57.
Part ~. 3-Nitro-4-12-(1-~ Lolidinyl)ethoxylphenyl a - t4-12-(1-Pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl Ketone Dioxalate.
A mixture of 2 g (6.3 mmol) of 3-nitro-4-[2-(1-pyrro-30 lidinyl)ethoxy]benzoic acid hydrochloride, 20 mL of SOCl2, 50 A- mL of 1,2-dichloroethane and 2 drops of DMF was heated at reflux for 16 h then evaporated in vacuo to dryness. The resulting solid was dissolved in 50 mL o~ 1,2-dichloroethane W097/25033 pcT/us96ll7sss -254~
and concentrated under reduced pressure. It was redissolved in 50 mL of 1,2-dichloroethane and treated sequentially with a solution of 2 g (6.2 mmol) of 2-[4-[2-(1-pyrrolidinyl)- ~
ethoxy]phenyl]benzo[b]thiophene in 150 mL of 1,2-dichloroethane and 3.3 g (24.7 mmol) of AlC13 at 0 ~C. The reaction was protected from light and stirred at 0 ~C ~or 5 h at which time it was quenched by carefully pouring it into 200 mL of vigorously stirred saturated aqueous NaHCO3. A
solution of 200 mL of EtOAc and 400 mL o~ THF was addea and the mlxture was filtered through diatomaceous earth and the two layers were separated. The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to gi~e an oil which was purified by chromatography (sio2; 10~ MeOH
in CHC13) to afford 1.26 g (2.2 mmol; 36%) of the desired compound as an oil. A sample of 200 mg was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free Base-CDCl3) ~ 8.17 (d, lH), 7.93 (dd, lH), 7.87 (dd, lH), 7.81-7.78 (m, lH), 7.41-7.38 (m, 2H), 7.31-7.27 (m, 2H), 6.93 (d, lH), 6.78-6.75 (m, 2H), 4.22 (t, 2H), 4.04 (t, 2H), 2.92 (t, 2H), 2.86 (t, 2H), 2.61-2.58 (m, 8H~, 1.81-1.76 (m, 8H); FDMS 586 (M+l); Anal. Calcd for C33H35N305S-2C2H204:
C, 58.03; H, 5.13; N, 5.49. Found: C, 58.30; H, 5.13; N, 5.74.
_le 97 Proparation o~ 3-Amino-4- r2- (l-pyrrolidinyl)ethoxy}-phenyl 2-[4-~2-(1-Pyrrolidinyl)e'choxyphenyl]-30 bonzo[}~ thiophen-3-yl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 ~>
~ ~N ~ 2C2H204 A solution o~ 3-nitro-4-[2-(l-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone (O.57 g 1 mmol) in 10 mL of EtOH and 10 mL of HOAc was hydrogenated in a shaken hydrogenation apparatus ~or 60 h with 0.5 g of 5% Pd/C and an initial hydrogen pressure of 4.1 bar. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to an oil. This was partitioned between 10 mL of saturated aqueous NaHC03 and a 70/30 mixture of EtOAc and MeOH. The organic layer was dried over Na2S04 and concentrated in vacuo to an oil which was purified by chromatrography (siO2; 5% MeOH/1% NH40H in CHC13) to afford 0.26 g (0.47 mmol; 47%) o~ the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
lH NMR (Free Base-CDCl3) ~ 7.82-7.79 (m, lH), 7.57-7.55 (m, lH), 7.37-7.30 (m, 2H), 7.29-7.26 (m, 3H), 7.12-7.08 (m, lH), 6.78-6.75 (m, 2H), 6.58 (d, lH), 4.07 (t, 2H), 4.04 (t, 2H), 4.00 (bs, 2H), 2.88-2.81 (m, 4H), 2.59-2.55 (m, 8H), 1.79-1.74 (m, 8H); FDMS 556 (M+l); Anal. Calcd ~or C33H37N303S-0.6C2H204-1.8 MeOH: C, 56.69; H, 5.87; N, 4.95.
Found: C, 55.98i H, 5.88; N, 5.24 F.YA 1~ 98 Pre~ration of 1-12-[2-Nitro-4-112-14-12-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl3-methyl]p~oxy]ethyl]pyrroli~ine Dioxalate.
W O 97/25033 PCT~US96/17995 ~ 2 c ~H2o4 A solution of 5.7 g (9.7 mmol~ of 3-nitro-4-~2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy-phenyl]benzo[b~thiophen-3-yl ketone in 200 mL of CH2C12 at 0 ~C was treated with 49 mL of 1 M DIBAL-H in hexanes. The reaction was stirred at 0 ~C for 1 h then concentrated in vacuo to an oil. The resulting residue was immersed in an ice bath then cautiously treated with 25 mL of TFA dropwise, followed by 736 mg (19.5 mmol) of NaBH4. The reaction was stirred for 30 min then evaporated in vacuo . The residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (300 mL). Aqueous 5 N NaOH (50 mL) was added, and the layers were separated. The a~ueous layer was extracted with EtOAc (3 X 100 mL). The combined organic layers were dried over Na2SO4 and evaporated in ~acuo to give 8 g o~ an oil Purification by chromatography (sio2i 2~ MeOH in CHCl3) af~orded 3.1 g (5.4 mmol 56%) of the title compound as an oil which was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free Base-CDC13) ~ 7.85-7.82 (m, lH), 7.62 (d, lH), 7.46-7.43 (m, lH), 7.38-7.29 (m, 4H), 7.20 (dd, lH), 6.97-6.91 (m, 3H), 4.22 (s, 2H), 4.19-4.12 (m, 4H), 2.92 (t, 4H), 2.65-2.60 (m, 8H), 1.84-1.76 (m, 8H); FDMS 572 (M+l); Anal.
Calcd ~or C33H37N3O4S-2C2H2O4: C, 59.11; H, 5.50; N, 5.59.
Found: C, 59.40; H, 5.46; N, 5.87 W O 97/25033 PCr~US96/17995 ~rle g g Preparation of l-t2-[2-A ;no-4-[t2-t4-[2~(1-- ~yrroli~inyl)ethoxy]phonyl~benzotb~thiophen-3-yl]-methyl]phenoxy]ethyl~pyrroli~ine Dioxalate.
N ~
O~ 'N 2C2H204 ~
The title compound was prepared in 36% yield from 1-[2-[2-nitro-4-[[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b3thiophen-3-yl]methyllphenoxy]ethyl]pyrrolidine by essentially following the procedure detailed ~or the preparation of Example 97.
Anal. Cal~d for C33H3gN302S 2C2H204 0.95 MeOH: C, 60.59; H, 6.27; N, 5.59. Found: C, 60.62; H, 6.12; N, 5.30 ~Y~ _le 100 Preparation of 3-Bromo-4-t2-(1-pyrroli~inyl)ethoxy]-phenyl 2-{4-t2-(1-Pyrrolidi~yl)ethoxyphenyl]benzotb]-thiophen-3-yl Ketone Dioxalate.
N
" "-'N ~ 2C2H20~
Part A. 3-Bromo-4-methoxyph~nyl 2-(4-Methoxyphenyl)-benzo~b]thiophen-3-yl Keton~.
W O 97/25033 PCT~US96/17995 ~ 3 A slurry of 13.35 g (58 mmol) o~ 3-bromo-4-methoxybenzoic acid in 120 mL of 1,2-dichloroethane and 1 mL of DMF was treated with 8.4 mL (116 mmol) of SOC12 and the mixture was heated at re~lux Eor 16 h. The resulting solution was evaporated in vacuo to an oil which was mixed with 50 mL o~
1,2-dichloroethane and reconcentrated under reduced pessure.
A solution of the above oil in 120 mL o~ 1, 2 -dichloro-ethane was treated with 13.86 g (58 mmol) of 2-[4-methoxy)-phenyl]benzo[b]thiophene. The mixture was cooled to 0 ~C,protected ~rom light and treated with 25 mL (228 mmol) of TiC14 dropwise. The reaction was stirred at 0 ~C for 3 h at which time it was quenched by the care~ul addition o~ 100 mL
of saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with saturated a~ueous NaHCO3.
It was dried over Na2SO4 and evaporated in vacuo to give 28 g of a solid which was purified by chromatography (SiO2; 50%
CHC13 in Hex) to afford 17.13 g (37.81 mmol; 65%) of the ketone as a solid.
H MMR (CDCl3) ~ 8.03 (d, lH), 7.88-7.85 (m, lH), 7.72-7.67 (m, 2H), 7.38-7.33 (m, 4H), 6.81-6.71 (m, 3H), 3.88 (s, 3H), 3.76 (s, 3H).
P~rt B. 3-Bromo-4-hydroxyphenyl 2-(4-Hyd oxy~henyl)-benzo ~b~ thio~hen-3-yl Ketone .
W O 97~5033 PCTAUS96/17995 ~ OH
A 0 ~C solution of 6.5 g (14.3 mmol) of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone in 300 mL of dichloromethane was treated with 15.3 g (115 mmol) o~ AlCl3, followed by 17 mL (230 mmol) of ethanethiol.
The cold bath was removed and the reaction was stirred at ambient temperature for 3.5 h. The reaction mixture was cooled to 0 ~C and poured into cold water. The layers were separated and the a~ueous layer was extracted with EtOAc (2 X
150 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 5.9 g (13.9 mmol, 97%) of an oil which crystallized out when mixed with CH2C12.
lH NMR (DMSO-d6) ~ 11.4 (bs, 2~), 8.1-8.05 (m, lH), 7.8 (d, lH), 7.62-7.5 (m, 2H), 7.45-7.35 (m, 2H), 7.25 (d, 2H), 6.85 (d, lH), 6.75 (d, 2H); FDMS 425.8 (M+l).
Part C. 3-Bromo-4-~2-(1-~yrrolidinyl)ethoxy]phenyl 2-~4-12-(1-Pyrrolidinyl)ethoxyphenyl~benzo[b]thiophen-3-yl Ketone Dioxalate.
A solution of 1 g (2.4 mmol) of the above bis-hydroxy-benzothiophene in 25 mL of DMF was treated with 1.6 g (9.6 mmol) of l-(2-chloroethyl)pyrrolidine hydrochloride followed by 4.7 g (14.4 mmol) of Cs2C03. The mixture was heated to 85 ~C for 16 h at which time it was cooled and poured into 100 ~L of brine and extracted with EtOAc (3 X 50 mL). The combined organic layers were dried over MgSO4 and evaporated to give 1.1 g of an oil which was purified by radial chromatography (sio2; 60:35:5 hexanes-THF-TEA) to afford 0.68 g (1.1 mmol; 46~) of an oil. The oil was converted to the dioxalate salt according to the method of Example 1, Part C.
1H NMR (Free Base-CDCl3) ~ 8.31 (d, lH), 7 84 (dd, lH), 7.71-7.68 (m, lH), 7.65 (dd, lH), 7.38-7.32 (m, 3H), 6.98 (s, lH), 6.8-6.77 (m, 2H), 6.69 (d, lH),4.13 (t, 2H), 4.05 (t, 2H), 2.93 (t, 2H), 2.86 (t, 2H), 2.67-2.57 (m, 8H), 1.81-1.76 (m, 8H); FDMS 619 (M+).
~le 101 Preparation of 1-~2-~2-Bromo-4-[~2-~4-~2-~1-pyrrolidinyl)~thoxy~phQnyl~bQnzo~b~thiophQn-3-yl]-methyl~phe~ry]~thyl~ olidine Dioxalate.
N ~
o 2C2H2O4 ~ ~N ~
To a solution of 83 mg (2.20 mmol) of LAH in 20 mL of dry THF was added dropwise a solution o~ 0.68 g (1.1 mmol) of 3-bromo-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone in 15 mL o~ dry THF at 0 ~C. The reaction was stirred at ambient temperature for 2 h then quenched with 5 mL of EtOAc and poured into 100 mL of brine. The mixture was extracted with 150 mL o~ 20% MeoH in EtOAc. The extracts were dried over MgSO4 and concentrated to 537 mg of an oil.
The resulting oil was mixed with 10 mL of TFA, cooled to 0 ~C and treated with 65 mg (1.73 mmol) o~ NaBH4. The cooling bath was removed and the reaction was stirred for 16 h. It was evaporated in vacuo and partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (30 mL). The layers were separated and the a~ueous layer was extracted with EtOAc (3 X 20 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to give 450 mg o~ an oil. Purification by chromatography (SiO2; 1% MeOH/0.5~
CA 02236007 l998-04-27 WO 97/25033 PCTfJSg6/17995 NH40H in CHCl3) afforded 122 mg (0.2 mmol 23%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Par~ C.
FDMS 605 (M+).
~ Y~rle 102 Preparation of 1-[2-12-MQthoxy-4-~2-[4-12-(1-pyrrolidin~l)ethoxy~ph~nyl]b~nzo~b~thioph~n-3-yl]-methyllphenoxylethyl~yrroli~ ne Dioxalate.
'' " ~'N
Part A. Methyl 3-~ethoxy-4 12-(1-~. olidinyl)-Qthoxy] benzoatQ .
The substituted pyrrolidine was prepared in 94% yield from methyl 4-hydroxy-3-methoxybenzoate and K2C03 by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR (CDC13) ~ 7.63 (d, lH), 7.53 (s, lH), 6.9 (d, lH), 4.2 (t, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.96 (t, 2H), 2.64-2.61 (m, 4H), 1.85-1.75 (m, 4H); FDMS 279 (M+).
Part B. 3-~ethoxy-4-12-(1-~yrrolidinyl)ethoxy]benzoic Acid Hydrochloride.
W O 97/25033 PCT~US96/1799 N~ " ~o ~ OH
~HCl OCH3 The benzoic acid hydrochloride was prepared in 63% yield from methyl 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]benzoate by essentially following the procedure detailed for the preparation of Example 96, Part B.
H N ~ (DMSO-d6) ~ 11.27 (bs, 2H), 7.57 (d, lH), 7.55 (5, lH), 7.12 (d, lH), 4.44 (t, 2H), 3.82 (s, 3H), 3.5 (bs, 4H), 3.1 (bs, 2H); 1.98 (bs, 2H), 1.89 (bs, 2H); Anal. Calcd for C14HlgNO4 HCl: C, 55.72; H, 6.68; N, 4.64. Found: C, 56.01;
H, 6.88i N, 4.70.
Part C. 3-Methoxy-4-[2-~1-pyrrolidinyl)ethoxy~phenyl 2-~4-~-(1-Pyrrolidinyl)etho~yphenylbenzol~thiophen-3-yl Ketono.
~ ~N ~
The ketone was prepared in 33% yield from 3-methoxy-4-[2-(l-pyrrolidinyl)ethoxy]benzoic acid hydrochloride by essentially following the procedure detailed for the preparation of Example 96, Part C.
1H MMR (Free Base-CDCl3) ~ 7.86-7.83 (m, lH), 7.67-7.64 (m, lH), 7.49 (d, lH), 7.38-7.26 (m, 5H), 6.8-6.76 (m, 2H), 6.67 (d, lH), 4.12 (t, 2H), 4.06 (t, 2H), 3.83 (t, 3H), 2.94 (t, W O 97~5033 PCTnJS96/t7995 2H), 2.88 (t, 2H), 2.62-2.58 (m, 8H), 1.81-1.76 (m, 8H); FDMS
570 (M+).
., Part D. 1-[2-~2-M~thoxy-4-l~2-[4-~2-(1-pyrrolidinyl)-ethoxy]phenyl]benzotb]thiophen-3-yllmethyl]phenoxyJ-ethyl~pyrrolidinQ Dioxalat~.
The title compound was prepared in 10~ yield from 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzorb]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
H NMR (Free Base-CDC13) ~ 7.98-795 (m, lH), 7.64-761 (m, lH), 7.50 (d, 2H), 7.36-7.33 (m, 2H), 7.12 (d, 2H), 6.87-6.84 (m, 2H), 6.51 (d, lH), 6.2 (bs, 4H), 4.34 (t, 2H), 4.20 (s, 2H), 4.16 (t, 2H), 3.68 (s, 3H), 3.5 (t, 2H), 2.86 (t, 2H), 2.67-2.57 (m, 8H), 2.0-1.9 (m, 8H); FDMS 557 (M+l); Anal.
Calcd for C34H40N2O3S 2C2H2O4: C, 61.94; H, 6.02; N, 3.80.
Found: C, 62.23; H, 6.09; N, 3.89.
~ Y~ _le 103 Preparation of 3-Hydroxy-4-C2-(~ olidinyl)-Qthoxy~phenyl 2-[4-~2-(1-Pyrrolidinyl)ethoxyphenyl]-benzotb]thiophQn-3-yl Ketone Dioxalate.
OH
M ~ 2C2H2O4 ''"--'N
The title compound was prepared in 83% yield from 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-~4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part B.
Anal. Calcd for C33H36N204S 2C2H204 1.25H20: C, 58.53; H, 5.64; N, 3.69. Found: C, 58.42; H, 5.27; N, 3.86.
Example 104 Preparation of 1-[2-c2-Hy~roxy-4-[[2-~4-l2-(l-pyrrolidinyl)ethoxylphQnyllb~nzolblthiophan-3-yll-methyl]ph~noxy]ethyll~y olidine Dioxalat~.
OH
¦ ~ ~ N ~ 2C2H2O4 ''~'~'N ~
The title compound was prepared in 29% yield from 3-hydroxy-4- [2- (1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[~]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 95, Part C.
FDMS 541.9; Anal. Calcd for C33H3gN203S-1.75C2H204: C, 62.6;
H, 5.97; N, 4.00. Found: C, 62.44; H, 6.09; N, 4.11.
~Yr~ 1Q 105 Pr~l?aration of 3-Propyl-4-[2-(1~ olidinyl)ethoxy]-phenyl 2-t4-12-(1-Pyrrolidinyl)ethoxyphenyl]-benzolblthio~hen-3-yl Ketono Dioxalate.
N ~ 2C2H204 ''~'--'N ~
W O 97/25033 PCT~US96/1799 Part A. 2-(4-Methoxyphenyl)benzolb~thiophen-3-yl 4-M~3thoxy-3-propylphenyl Ketone.
O
' 3 A mixture of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl ketone (1 g, 2.2 mmol), tetrapropyltin ~1.6 g, 5.5 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) and toluene (20 mL) was heated in a sealed tube at 130 ~C for 18 h. The mixture was concentrated under reduced pressure, mixed with 30 mL of diethyl ether and stirred vigorously with 30 mL saturated aqueous KF for 2 h.
The layers were separated and the organic layer was dried over MgSO4 then concentrated to dryness. Purification by chromatography (sio2; 45~ ClCH2CH2Cl in Hex) afforded 0.88 g (2.1 mmol 96%) of the propyl compound as a solid.
FDMS 416 (M+); Anal. Calcd for C26H24O3S H2O: C, 71.86; H, 6.03. Found: C, 71.46; H, 5.82.
Part B. 2-(4-Hydroxyphenyl)benzo[b]thiophen-3-yl 4-Hydroxy-3-propylphenyl Ketone.
o~
OH
The named compound was prepared in quanitative yield from 2- ~4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxy-3-propyl-W O 97/25033 PCT~US96/17995 phenyl ketone by essentially following the procedure detailed ~or the preparation o~ Example 100, Part B.
FDMS 388 (M+); Anal. Calcd for C24H2003S-0.72CHCl3: C, 62.69;
H, 4.44. Found: C, 62.58; H, 4.4.
Part C. 3-~ o~yl-4-12-(1-~y olidinyl)ethoxylphenyl 2-14-[2-(1-Pyrrolidinyl)Qthoxyphenyl]b~nzo[blthioph~n-3-yl Ketone Dioxalate.
The title compound was prepared in 69% yield from 3-propyl-4-hydroxyphenyl 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR ~Free base-CDCl3) ~ 7.86-7.83 (m, lH), 7.67-7.58 (m, 3H), 7.38-7.32 (m, 4H), 6.79-6.76 (m, 2H), 6.66 (d, lH), 4.09 (t, 2H), 4.03 (t, 2H), 2.89 (t, 2H), 2.85 (t, 2H), 2.62-2.59 (m, 8H), 2.51-2.46 (m, 2H), 1.79-1.65 (m, 8H), 1.52-1.44 (m, 2H~, 0.84 (t, 3H); FDMS 583 (M~l); Anal. Calcd ~or C36H42N203S-2C2H204-0.15CCl4: C, 71.66; H, 6.99; N, 4.62.
Found: C, 71.85; N, 7.23; N, 4.23.
~.Y~m~le 106 Pr~aration of 3-Ethyl-4-t2-(1-~ olidinyl)ethoxyl-phenyl 2-t4-t2-(1-Pyrrolidirlyl)ethoxyphenyl]-bcnzolb]thiophQn-3-yl Ketone Dioxalate.
2C~H~04 "~'--'N ~
Part A. 3-Ethyl-4-methoxyphenyl 2-(4-Methoxy~henyl)-~nzolb]thiophQn-3-yl K~tone.
O ~
The ethyl compound was prepared in 45% yield ~rom 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone and tetraethyltin by essentially following the procedure detailed for the preparation of Example 105, Part A.
Anal. Calcd for C25H22O3S: C, 74.6; H, 5.51. Found: C, 74.9;
N, 5.65.
~?art B. 3-Ethyl-4-hyd~y~henyl 2-(4-Hydroxyphenyl)-benzolb]thiophQn-3-yl Ketone.
~ OH
~\>~
OH
The named compound was prepared in 96% yield from 3-ethyl-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b~thiophen-3-yl ketone by essentially following the procedure detailed ~or the preparation of Example 100, Part B.
FDMS 374 (M+); Anal. Calcd ~or C23HlgO3S 0.lCHC13: C, 71.81;
H, 4.72. Found: C, 71.92; M, 4.81.
P2lrt C. 3-Ethyl-4-t 2-(1~ lidinyl) ethoxylphenyl a -14-l2-(l-Pyrrolid~inyl)etho:cyphenyllbenzo[blthiophen 3-yl Ketone Dioxalate.
W O 97/25033 PCT~US96/17995 The title compound was prepared in 42% yield from 3-ethyl-4-hydroxyphenyl 2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part C.
lH NMR (Free base-CDC13) ~ 7.91-7.88 (m, lH), 7.73-7.62 (m, 3H), 7.43-7.35 (m, 4H), 6.82 (d, 2H), ~.71 (d, lH), 4.15 (t, 2H), 4.09 (t, 2H), 2.95 (t, 2H), 2.90 (t, 2H), 2.67-2.55 (m, 10H), 1.9-1.84 (m, 8H), 1.13 (t, 3H); FDMS 569 (M+l); Anal.
Calcd for C3sH40N2O3S 2C2H2O4: C, 62.55; H, 5.92; N, 3.74.
Found: C, 62.33; H, 5.85; N, 3.74.
~ ~le 107 Preparation of 3-Butyl-4-t2-(1-pyrrolidinyl)ethoxy]-phenyl 2-~4-~2-(1-Pyrrolidinyl)ethoxyphenyl]-benzo ~b~ thiol?hen-3-yl Ketone.
~ ~N ~
Part A. 3-Butyl-4-methoxy~henyl 2-(4-Methoxyphenyl)-benzo ~b] thiophen-3-yl Ketone.
The butyl compound was prepared in 49% yield from 3-bromo-4-methox~phenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone and tetrabutyltin by essentially following the CA 02236007 l998-04-27 W 097/25033 PCT~US96/17995 procedure detailed for the preparation of Example 105, Part A.
FDMS 430 (M+); Anal. Calcd for C27H2603S 0.25H20: C, 74.54;
H, 6.14. Found: C, 74.79; N, 6.32.
~.
Part B. 3-Butyl-4-hyd o~y~h9nyl 2-(4-Hydroxyph~nyl)-benzolblthio~hQn-3-yl KetonQ.
l ~ s\ ~7 ~
The named compound was prepared in 98g6 yield from of 3-butyl-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 100, Part B.
Anal. Calcd for C25H22O3S-0.5CHC13: C, 66.27; H, 4.91.
Found: C, 66.29; N, 4.84.
l?art C. 3-Butyl-4-~2-(1-~ lolidinyl)Qthoxylph~nyl a- ~4-12-(1-Pyrrolidinyl)ethoxyphenyl]benzo~blthiophen-3-yl Ketone.
The title compound was prepared in 49% yield from 3-butyl-4-hydroxyphenyl 2-( 4-hydroxyphenyl)benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed ~or the preparation of Example 100, Part C.
lH N ~ (Free base-CDC13) ~ 7.86-7.83 (m, lH), 7.67-7.58 (m, 3H), 7.38-7.32 (m, 4H), 6.79-6.76 (m, 2H), 6.66 (d, lH), 4.09 (t, 2H), 4.03 (t, 2H), 2.89 (t, 2H), 2.85 (t, 2H), 2.62-2.56 ~m, 8H), 2.50 (t, 2H), 1.94-1.78 (m, 8H~, 1.46-1.38 (m, 2H), 30 1.28-1.2 (m, 2H), 0.88 (t, 3H); FDMS 597 (M+l); Anal. Calcd for C37H44N203S-0.7Hex: C, 75.3; H, 8.25; N, 4.26. Found: C, 75.24; H, 7.90; N, 3. 87.
W O 97/25033 PCT~US96/17995 ~ . ~r-~.le 108 Preparation of 1-[2-12-Propyl-4-~[2-14- r2- (l-pyrrolidinyl)ethoxylphQnyllbenzolblthiophen-3-yll-mothyl] phenoxylethyllpyrroli~ine Dioxalate.
~< /J
''~'--'N ~
1 ~
The title compound was prepared in 56% yield from 3-propyl-4-[2-(1-pyrrolidinyl~ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo~b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
1H NMR (Free base-CDCl3) ~ 7.84-7.81 (m, lH), 7.54-7.51 (m, lH), 7.44-7.42 (m, 2H), 7.32-7.24 (m, 3H), 6.96-6.93 (m, 2H), 6.87-6.84 (m, lH), 6.71-6.68 (m, lH), 4.18 (s, 2H), 4.14 (t, 2H), 4.05 (t, 2H), 2.94-2.87 (m, 4H), 2.63-2.58 (m, 8H), 2.53 (t, 2H), 1.84-1.77 (m, 8H), 1.59-1.51 (m, 2H), 0.89-0.86 (m, 3H); FDMS 569 (M+1); Anal. Calcd for C36H44N2o2s-l.75c2H2o4:
C, 65.7; H, 6.74; N, 3.78. Found: C, 65.g9; N, 6.54; N 3.71.
Example 109 Preparation of 1-[2-[2-Ethyl-4-[12-[4-[2-(1-pyrrolidinyl)ethoxyl~hQnyllbenzo[b]thiophen-3-yll-mcthylll?honoxy]ethyl]pyrroli~ine Dioxalate. t W O 97/25033 PCT~US96/17995 O/--O" "--'N ~
The title compound was prepared in 56% yield from 3-ethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2~(1-pyrrolidinyl~ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially following the procedure detailed for the preparation of Example 101.
lH NMR (Free base-CDC13) ~ 7.84-7.81 (m, lH), 7.55-7.51 (m, lH), 7.45-7.41 (m, 2H), 7.30-7.28 (m, 3H), 6.97-6.93 (m, 2H), 6.87-6.83 (m, lH), 6.73-6.68 (m, lH), 4.19 (s, 2H), 4.14 (t, 2H), 4.06 (t, 2H), 2.94-2.87 (m, 4H), 2.65-2.55 (m, lOH), 1.84-1.79 (m, 8H), 1.14 (s, 3H); Exact Mass Calcd for C35H42N202S: 555.3045. Found: 555 3057 1;!YA 16~ 110 Pre~aration of 1-[2-t2-Butyl 4-112-[4-~2-(1-~yrrolidinyl)ethoxy]phenyl~enzo[b]thiophen-3-yl]-m~thyl]~h~o~y~Qthyl~y olidine Dioxalate.
~ M ~ 2C2H204 ~
The title compound was prepared in 64% yield from 3-butyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyphenyl]benzo[b]thiophen-3-yl ketone by essentially ~ollowing the procedure detailed for the preparation o~ Example 101.
1H NMR (DMSO-d6) ~ 7.98-7.94 (m, lH), 7.58-7.5 (m, lH), 7.47 (d, 2H), 7.34-7.32 (m, 2H), 7.1 (d, 2H), 6.9 (s, lH), 6.8 (s, 2H) 4.5 (bs, 4H), 4.35 (t, 2H), 4.21 (t, 2H), 4.17 (s, 2H), 3.54-3.50 (m, 4H), 3.4-3.2 (m, 8H), 2.5-2.4S (m, 2H), 1.93-1.85 (m, 8H), 1.44-1.39 (m, 2H), 1.26-1.21 (m, 2H), 1.17 (t, 3H); FDMS S82 (M+1); Anal. Calcd for C37H46N202S-1-75C2H204:
C, 6S.7; H, 6.74; N, 3.78. Found: C, 65.99; N, 6.54; N 3.71.
lS ~ ~l~ 111 Preparation of 1- ~2-[2-Acetamido-4-~12-[4-[2-(1-p~rrolidinyl)~thoxylphenyl]benzoC b ] thi ophen-3- yl~-methyl~honoxy]othyl]pyrrolidine Dioxalate.
NHAc 1-[2-[2-Amino-4-[[2-[4-[2-~1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl]methyl]phenoxy]ethyl]pyrrolidine (178 mg,0.33 mmol3 was treated with 2 mL of acetic anhydride and 2 mL o~ pyridine. This was stirred at ambient temperature for 16 h and concentrated under reduced pressure.
The resulting oil was mixed with toluene and reconcentrated to dryness. Purification by chromatography (sio2i 95/5 THF/Et3N) afforded 70 mg (0.12 mmol 36%) of the title compound as an oil which was converted to the dioxalate salt according to the method of Example 1, Part C.
W O 97/25033 PC~US96/I7995 1H NMR (Free base-CDCl3) ~ 8.93 (s, lH), 8.33 (d, 1H), 7.82-7.79 (m, lH), 7.54-7.50 (m, lH), 7.46-7.43 (m, 2H), 7.28-7.24 (m, 2H), 6.96-6.93 (m, 2H), 6.73 (d, lH), 6.62 ~d, lH), 4.22 (s, 2H), 4.13 (t, 2H), 4.08 (t, 2H), 2.91 (t, 2H), 2.77 (t, 2H), 2.63-2.61 (m, 8H), 2.17 (s, 3H), 1.84-1.79 (m, 8H); FDMS
584 (M+l); Anal. Calcd for C3sH41N3O3S-2C2H2O4: C, 61.32; H, 5.94; N, 5.50. Found: C, 61.59; H, 5.98; N, 5.59.
- _le 112 Preparation o~ 2-~2-EthylA ;~-4-[~2-t4-~2-(1-pyrrolidinyl)ethoxy]phenyl]benzo~b]thiophen-3-yl~-m~thyllph~noxylethyll~yrrolidine Dioxalat~.
NHEt N
1-[2-[2-Acetamido-4-[[2-[4-~2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl3methyl~phenoxy]ethyl]pyrrolidine ~600 mg, 1.1 mmol) was dissolved in 20 mL of dry THF and added to a mixture of 20 mL of THF and 84 mg (2.2 mmol) of LAH. The reaction was heated at reflux for 3 h then quenched with 5 mL of EtOAc. To this was added 25 mL of saturated aqueous potassium sodium tartrate. The mixture was stirred ~or 30 min and extracted with EtOAc (3 X 30 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to 450 mg of an oil which was puri~ied by chromatrography (sio2; 5~ MeOH/1% NH40H in CHCl3) to a~ford 55 mg (0.1 mmol; 9%) of the title compound as an oil which was converted to- the dioxalate salt according to the method of Example 1, Part C.
W O 97/25033 PCT~US9G/1799 H NMR (Free base-CDCl3~ ~ 7.82-7.80 (m, lH), 7.59-7.55 ~m, lH), 7.47-7.44 (m, 2H), 7.29-7.27 (m, 2H), 6.96-6.93 (m, 2H), 6.62 (d, lH), 6.44 (d, lH), 6.34 (dd,lH), 4.22 (bs, lH), 4.17 (s, 2H), 4.13 (t, 2H), 4.07 (t, 2H), 3.05 (q, 2H), 2.94-2.86 (m, 4H), 2.65-2.59 (m, 8H), 1.84-1.77 (m, 8H), 1.21 (t, 3H);
FDMS 572 (M+3); Anal. Calcd ~or C3sH43N3O2S-2C2H204: C, 62.47; H, 6.32; N, 5.60. Found: C, 62.46; H, 6.19; N, 5.43.
~Y~ _le 113 Preparation of l-~-t2-Meth~sulfonamido-4-~t2-l4-l2 ~l-pyrrolidinyl)ethoxy]phenyl3benzolbJthio~hen-3-yll-methyl]phenoxylethyllpyrrolidin~ Dioxalate.
2C2H2O~
A solution of 1-[2-[2-amino-4-~[2-[4-[2-~1-pyrrolidinyl)ethoxy]phenyl~benzo[b]thiophen-3-yl]methyl]-phenoxy]ethyl]pyrrolidine (750 mg, 1.4 mmol) in 25 mL of CH2C12 at 0 ~C was treated with 159 mg (107 mL, 1.4 mmol) o~
methanesulfonyl chloride. The reaction was stirred at 0 ~C
for 8 h then concentrated under vaccuum. The residue was purified by chromatrography (sio2i 5% MeOH/1% NH40H in CHCl3) to afford 447 mg (0.72 mmol; 52%) of the title compound as an oil which was converted to the dioxalate salt according to the method o~ Example 1, Part C.
lH NMR (Free base-CDC13) ~ 7.84-7.81 (m, lH), 7.55-7.53 (m, lH), 7.52-7.41 (m, 3H), 7.30-7.27 (m, 3H), 6.98-6.94 (m, 2H), 6.85 (d, lH), 6.76 (dd,lH), 4.21 (s, 2H), 4.15 (s, 2H), 4.09 (t, 2H), 2.93 (t, 2H), 2.82 (s, 3H), 2.65-2.60 (m, 10H), 1.89-1.84 (m, 4H), 1.83-1.80 (m, 4H); FDMS 619 (M+); Anal.
W O g7/25033 PCT~US96/17995 _ -275-Calcd for C34H41N3O4S2 2C2H2O4 1H2O-0.lEtOAc: C, 55.79; H, 5.83; N, 5.08. Found: C, 56.01; H, 5.98; N, 4.71.
.
RYA _ le 114 Preparation of 1-[2-12-Phenylsulfonamido-4-~[2-[4-12-(1-pyrrolidinyl)ethoxylphenyl]benzolb]thiophen-3-yl]-methyl~henoxy3Qthyllpyrrolia.ine Dioxalate.
NHS02Ph This compound was prepared in 35% yield from phenylsulfonyl chloride and 1-[2-[2-amino-4-[[2-~4-[2-(1-pyrrolidinyl)ethoxy]phenyl]~enzo[b]thiophen-3-yl]methyl]-phenoxy]ethyl]pyrrolidine by essentially following the procedure detailed for the preparation of Example 113.
lH NMR (Free base-CDCl3) ~ 8.1 (bs, lH), 7.84-7.81 (m, lH), 7.58-7.54 (m, 2H), 7.49-7.35 (m, 5H), 7.31-7.21 (m, 4H), 6.98-6.95 (m, 2H), 6.72-6.78 (m, 2H), 4.17-4.12 (m, 4H), 3.92 ~t, 2H), 2.92 (t, 2H), 265-2.54 (m, 10H), 1.94-193 (m, 4H), 1.83-1.79 (m, 4H); FDMS 682 (M+1); Anal. Calcd for C39H43N3O4S2 1.5C2H204-0.2H20: C, 61.48; H, 5.70; N, 5.12.
Found: C, 61.25; H, 6.05; N, 4.97.
~r le 115 Pr~paration of 2-14-(2-~ ;n~Qthoxy)phenyl]-6-hy~Lroxy-3-~3-methyl-4-[(1-pyrroli~in~l)mQthyl]benzyl]-benzo~b]thiophQnQ Dioxalate.
W O 97/25033 PCT~US96/17995 ~0 1 ~ ' 0 ~ NH2 Part A. 4-(6-Methoxybenzo~b~thiophen-2-yl)phQnyl Trii~o~ropyl~ilyl Ether.
H3C0 ~ ,S ~
A solution of 6-methoxy-2-(4-hydroxyphenyl)benzo[b~-thiophene (16 g, 62.4 mmol) in 160 mL of dry DMF was treated with Et3N (12.6 g, 124.8 mmol) at 0 ~C. To this was added in a dropwise manner 28.7 g (93.6 mmol) of triisopropyl trifluoromethanesulfonate. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h before being poured into 200 mL of saturated aqueous NaHCO3 and 300 mL of brine. This was extracted with 10% EtOAc in hexanes (3 X 200 mL). The combined extracts were washed with brine (2 X 300 mL), dried over MgSO4 and concentrated under reduced pressure to give 32 g of an oil which was purified by chromatrography (sio2; 5~ EtOAc in Hexanes) to yield 12.3 g (29.8 mmol, 48%) of the silyl ether as a white solid.
FDMS 412 (M+); Anal. Calcd for C24H32O2SSi 0.65EtOAc: C, 68.50; H, 8.18. Found: C, 68.55; H, 8.16.
Part B. 6-Methoxy-2-[4-~(triisopropylsilyl)oxy]-25 phonyl]bQnzo~b~ thiophen-3-yl 3-Methyl-4-~ pyrro-lidinyl)methyl~ph~nyl Ketone wo 97/25033 PCT/US96/17995 H3CO ~
The ketone was prepared in 83% yield from the above benzothiophene, TiC14, and 3 -methyl-4-[(1-pyrro-lidinyl)methyl]benzoic acid hydrochloride by essentiallyfollowing the procedure detailed for the preparation of Example 96, Part C.
FDMS 613 (M~); Anal. Calcd for C37H47No3SSi- 0 .23CHC13: C, 10 69.5; H, 7.40; N, 2.18. Found: C, 69.43; H, 7.48; N, 2.34.
Part C. 2-(4-Hydoxyphenyl)-6-methoxybenzo~b]thiophen-3-yl 3-Methyl-4-~ olidinyl)methyl~phenyl Ketone.
H3 co 1 ' A solution of the above silyl ether (5.23 g, 8.5 mmol) in THF ~50 mL) was treated with a 1 M THF solution o~
tetrabutylammonium fluoride ( 8 .5 mL) at ambient temperature.
The reaction was stirred for 16 h, concentrated in vacuo, 20 mixed with CHC13 and purified by chromatography (sio2i 2.5%
MeOH in CHC13) to afford 3.8 g (8.3 mmol, 98%) of the phenoxy product as an oil.
W O 97~5033 PCTAJS96/17995 H NMR (Free base-CDC13) ~ 7.65 (d, lH), 7.53 (s, lH), 7.48 (d, lH), 7.32 (d, lH), 7.21-7.16 (m, 3H), 6.99-6.97 (m, lH), 6.57 (d, 2H), 5.75 (bs, lH), 3.89 (s, 3H), 3.59 (s, 2H), 2.6-2.5 (m, 4H), 2.25 (s, 3H), 1.85-1.78 (m, 4H).
Part D. 2-(4-Hydroxyphonyl)-6-methoxy-3-~3-methyl-4-C(l-pyrrolidinyl)mothyl]benzyl]benzo[b]thioph~ne.
H3CO ~
A solution of the above ketone (4 g, 8.7 mmol) in THF
(100 mL) was cooled to 0 ~C under N2 and treated with a 1 M
solution of LAH in THF (17.4 mL). The bath was removed and the reaction was stirred at ambient temperature ~or 2 h. It was quenched by the dropwise addition of 500 mL o~ H20 at 0 ~C, followed by 200 mL o~ EtOAc and 50 g diatomaceous ear~h.
The mixture was ~iltered, the layers were separated, and the organic layer was dried over MgSO4 and concentrated to give 4 g of the benzyl alcohol.
The foam was dissolved in 100 mL of ClCH2CH2Cl and cooled to 0 ~C under N2. The colorless solution was treated with 5.1 g (43.5 mmol) of Et3SiH and 10 g (87.4 mmol) o~ TFA. The reaction was stirred at 0 ~C for 1 h then ~uenched with 50 mL
of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with 100 mL o~ CH2C12. The combined organic layer was dried over MgSO4 and concentrated to an oil. Purification by chromatography (sio2; 65/30/5%
Hex/THF/Et3N) a~forded 3.5 g (7.9 mmol 91%) o~ the methylene compound as a ~oam.
lH NMR (Free base-DMSO-d6) ~ 7.55 (d, lH), 7.4 (d, lH), 7.36 (d, 2H), 7.1 (d, lH), 6.95-6.80 (m, 5H), 4.15 (s, 2H), 3.80 W O 97/25Q33 PCT~US96/17995 (s, 3H), 3.4 (s, 2H), 3.3 (bs, lH), 2.43-2.30 (m, 4H), 2.20 (s, 3H), 1.65-1.60 (m, 4H); FDMS 443 (M+).
,.
P~rt E. 6-Methoxy-3-13-methyl-4-1(1-yy r olidinyl)-methyl~benzyl]-2-~4-12-(phthalimido)Qthoxy]phenyl]-b~nzotb~thioph~ne.
H3COm~ G
The named compound was prepared in 29% yield from 2-(4-10 hydrox~phenyl)-6-methoxy-3-[3-methyl-4-[(1-pyrrolidinyl)-methyl]benzyl3benzotb]thiophene and hydroxyethylphthalimide by essentially following the procedure detailed for the preparation of Example 20, Part B.
15 FDMS 616 (M+); Anal. Calcd for C3gH36N204S-1.2H20: C, 71.49;
H, 6.06; N, 4.39. Found: C, 71.58; H, 6.10; N, 4.36.
Part F. 6-Hydroxy-3-[3-methyl-4-~ olidinyl)-methyl]benzyl]-2-14-12-(phthalimidyl)etho~y]phenyl]-20 blenzo lb] thiophene Dioxalate.
/~/~
J~o ~~
2C2H204 ~
W O 97/25033 PCT~US96/17995 This compound was prepared in 52% yield ~rom the above 6-methoxybenzo[b]thiophene by essentially ~ollowing the procedure detailed for the preparation of Example 1, Part D.
lH NMR (~ree base-CDC13) ~ 7.88-7.84 (m, 2H), 7.74-7.71 (m, 2H), 7.34-7.29 (m, 2H), 7.19-7.15 (m, 2H), 7.1 (d, lH), 6.92 (s, lH), 6.88-6.84 (m, 3H), 6.41-6.37 (m, lH), 4.24 (t, 2H), 4.14-4.10 (m, 3H), 3.61 (s, 2H), 2.69-2.61 (m, 6H), 2.27 (s, 3H), 1.80-1.79 (m, 4H); FDMS 603 (M+l).
Part G. 2-14-(2-~ ;noethoxy)phenyl]-6-hydroxy-3-~3-methyl-4-~ yrrolidinyl)methyl]benzyll-benzolb]thiophene Dioxalate.
A mixture of the above phthalimide (0.4 g, 0.66 mmol) and 1 mL hydrazine hydrate in 50 mL o~ EtOH was heated at re~lux ~or 1 h then concentrated to dryness under reduced pressure.
The residue was mixed with 50 mL o~ 1 N aqueous NaOH and 50 mL of 10% MeOH in EtOAc. The layers were separated and the a~ueous layer was extracted with 25 mL of 10% MeOH in EtOAc.
The combined organic layer was dried over MgSO4, concentrated to dryness and purified by chromatrography (sio2; 5% MeOH, 1%
NH40H in CHC13) to af~ord 230 mg (0.49 mmol, 74%) of the title product as a solid which was converted to its dioxalate salt according to the method o~ Example 1, Part C.
1H NMR (Free base-CDC13) ~ 8.3 (s, lH), 7.39 (d, lH), 7.37-7.2 (m, 3H), 7.05 (d, lH), 7.0 (d, 2H), 6.85 (s, lH), 6.82-6.7 (m, 2H), 4.08 (s, 2H), 3.94 (t, 2H), 3.41 (s, 2H), 3.34 (bs, 2H), 2.88 (t, 2H), 2.39-2.35 (m, 4H), 2.18 (s, 3H), 1.65-1.6 (m, 4H); FDMS 472 (M~).
- _le 116 Preparation of (R) -6-HYarOXY-2- r4- ~2-hydroxy-3-(1-~yrroli~inyl)pro~oxylphenyll-3-[3-methyl-4-~(1-~yrro-l idinyl)methyllbenzyl]benzolblthio~hene Dioxalate.
CA 02236007 l998-04-27 CH
HO ~ S
O ~ N
Part A. (2R)-2-E4-(Glycidyloxy)phenyl~-6-methoxy-3- r 3-methyl-4-l(l-~yrrolidinyl)methyl]benzyl~-benzo~b~thiophQne.
H3CO ~
O
A 60% dispersion o~ sodium hydride (141 mg,3.5 mmol) was rinsed with hexanes under a nitrogen atmosphere and dried under reduced pressure. To this was added a solution of the hydroxyphenylbenzo[b]thiophene of Example 115, Part C (1.3 g, 2.9 mmol) in 30 mL of dry DMF and stirred for 1 h at ambient temperature. The mixture was treated with (2R)-(-)-glycidyl-3-nitrobenzenesulfonate, then stirred for 16 h at ambient temperature. The reaction was poured into a mixture of 50 mL
o~ saturated aqueous NaHCO3, 100 mL of saturated aqueous NaCl and 100 mL of H20. It was extracted with EtOAc (3 X 100 mL).
The extracts were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified by chromatrography to give 1.2 g (2.4 mmol, 81%) o~ the product as an oil.
lH NMR (Free base-CDC13) ~ 7.45-7.38 (m, 5H), 7.33 (d, lH), 7.18 (d, lH), 6.97-6.88 (m, 3H), 4.23-4.18 (m, lH), 4.18 (s, 2H), 4.02-3.96 (m, lH), 3.88 (m, 3H), 3.55 (s, 2H), 3.39-3.37 W O 97n~033 PCT~US96/17995 (m, lH), 2.95-2.92 (m, lH), 2.79-2.71 (m, lH), 2.55-2.49 (m, 4H), 2.3 (s, 3H), 1.8-1.76 (m, 4H).
Part B. (R)-2-t4-[2-Hydroxy-3-(1-~ olidinyl)-}?ropo~ey]phenyll-6-m~thoxy-3-~3-methyl-4-~(1-~yrrolidinyl)methyl~benZyl]bQnZO~b]thiOphenQ.
~ C~
O ~ N
OH
The above (2R)-[(glycidyloxy)phenyl]benzo~b]thiophene (1.18 g, 2.4 mmol) was mixed with pyrrolidine (338 mg, 4.8 mmol) and MeOH (50 mL). The mixture was heated at reflux ~or 6 h, concentrated to an oil and purified by chromatrography (sio2; 30% THF/5% Et3N in hexanes) to afford 1 g of the named product as an oil.
Part C. (R)-6-Hydroxy-2-~4-~2-hydroxy-3-(1-pyrro-lidinyl)propoxylphenyl3-3-~3-methyl-4-[(1-pyrro-lidinyl)methyl]benzyl3benzo~blthiorhe~e Dioxalate.
The title compound was prepared in 61% yield from the above methoxybenzo[b]thiophene by essentially following the procedure detailed for the preparation of Example 115, Parts F and G.
1H NMR (DMSO-d6) ~ 7.4-6.7 (m, llH), 4.3-3.9 (m, 9H), 3.4-3.2 (m, 7H), 3.2-2.29 (m, 4H), 2.25 (s, 3H), 2.00-1.7 ~m, 10H);
FDMS 557 (Mtl).
W O 97/25033 PCTrUS96/17995 RYr~le 117 Preparation of 1-~2-t4-~E5-Fluoro-6-hydroxy-2-~4-l2-r ( l-pyrrolidinyl)e~hoxy]ph~nyl~benzo~b]thiophen-3-yl~-mothyl~phQnoxy~Qthyl~ Loli~lne Dioxalat~.
F~ = ,3~ 2 C H O
Part A. N,N-Dim~thyl-3-fluoro-4-mothoxy-a-hydroxy-phenylthioacetamide.
OH
F~ ,NMe2 MeO
A -78 ~C solution of 18.7 mL ~142.7 mmol) of diisopropylamine in 100 mL of THF was treated with 89.0 mL
(1.6 M in hexanes; 142.2 mmol) of n-BuLi. The reaction mixture was stirred at -78 ~C for 15 min and at 0 ~C for 0.5 h. After cooling back to -78 ~C, a solution of 20.0 g (129.7 15 mmol) of 3-fluoro-4-anisaldehyde and 12.2 mL (143.6 mmol) of N,N-dimethylthioformamide in 100 mL of THF was added slowly.
After complete addition, the reaction was stirred at -78 ~C
for 15 min and was quenched with a solution of 15 mL of HOAc in 100 mL of MeOH. The mixture was concentrated in vacuo and the residue was partitioned between 250 mL of saturated aqueous NaHCO3 and 250 mL of EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give 22.4 g of an oily 25 solid. Trituration with Et2O afforded 16.21 g ~66.6 mmol 51%) of the title compound as a light yellow solid.
Anal. Calcd for CllH14FNO2S: C, 54.30; H, 5.80; N, 5.76.
Found: C, 54.00; H, 5.86; N, 5.77.
W 097125033 PCT~US96/17995 Part B. 2-DimethylA ;~o-5-fluoro-6-methoxy-benzo ~bl thiophene .
MeO~ NMe2 A solution of 16.6 g (68.2 mmol) of N,N-dimethyl-3-fluoro-4-methoxy-2-hydroxyphenylthioacetamide (Part A) in 400 mL of CH2C12 was treated with 22.0 mL (339.0 mmol) of MeS03H
in a dropwise manner. The reaction was stirred at room temperature for 4 h, was cooled to 0 ~C, and was quenched by the careful addition of 500 mL of saturated aqueous NaHCO3.
The two layers were separated and the aqueous layer was extracted with EtOAc (5x200 mL). The combined organic layers were washed with 500 mL of saturated aqueous NaHCO3 and 500 mL of H2O, dried over Na2SO4, and filitered. Evaporation of the solvent in vacuo afforded 21.4 g of an oil which was purified by flash chormatography (sio2; gradient of 10% then 20% EtOAc in hexanes) to give 2.87 g (12.7 mmol; 19~) of the title compound as a light pink solid.
FDMS 225 (M+); Anal. Calcd for CllH12FNOS: C, 58.65; H, 5.37;
N, 6.22. Found: C, 58.37i H, 5.42; N, 6.17.
Part C. 2-Dimethyl~ ;~o-5-fluoro-6-methoxy-benzo ~b3 thiophene-3-yl 4-Nitrophenyl K~tono.
2 5 ~ ~ _ N02 A solution o~ 1.08 g (4.82 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene (Part B) in 15 mL of chlorobenzene was treated with 0.99 g (5.31 mmol) of 4-nitrobenzoyl chloride. The reaction was stirred at room temperature for 17 h and was diluted with 100 mL of EtOAc.
The solution was washed sequentially with 2 N aqueous NaOH (2 x 50 mL), H2O (50 mL) and brine (50 mL), then dried over W O 97/25033 PCTnUS96/1799S
Na2SO4, and filtered. Evaporation of the solvent in vacuo afforded 2.1 g of a dark solid which was purified by flash chromatography (sio2i gradient of 10% then 20~ then 40% EtOAc in hexanes) to give 0.27 g of starting material and 1.25 g ~3.34 mmoli 93% based on consumed starting màterial) of the title compound.
FDMS 374 (M+); Anal. Calcd for ClgHlsFN2O4S: C, 57.75i H, 4.04; N, 7.48. Found: C, 58.04i H, 3.98; N, 7.50.
Part D. 2-Dimethyl~ ;~o-5-fluoro-6-methoxy-h~nzo~b~thiophon-3-yl 4-~2-(1-Pyrrolidinyl)othoxy~-p~enyl Ketone.
~ o A mixture of 2.0 g (5.34 mmol) of 2-dimethylamino-5-~luoro-6-methoxybenzo~b]thiophene-3-yl 4-nitrophenyl ketone (Part C) and 1.4 g (60% dispersion in mineral oil; 35.0 mmol;
washed with hexanes) of NaH in 60 mL of DMF was treated with a solution of 3.75 mL (32.1 mmol) of 1-(2-hydroxyethyl)-pyrrolidine in 10 mL of DMF in such rate to control theeffervescence. After complete addition, the reaction was stirred at room temperature ~or 1 h and was quenched by the careful addition of 5 mL of MeOH. The mixture was diluted with 200 mL of EtOAc and was poured into 200 mL of H20. The two layers were separated and the organic phase was washed with H2O (2 x 100 mL) and brine (100 mL). The organic phase was dried over K2CO3, filtered, and concentrated in vacuo to give 5.21 g of an amber oil. Purification by flash - chromatography (sio2i gradient of 2% then 5% MeOH in CH2C12) afforded 2.10 g (4.74 mmoli 89%) of the title compound as a bright yellow oil.
W O 97/25033 PCT~US9~/17995 FDMS 442 (M+); Anal. Calcd for C24H27FN2O3S: C, 65.14; H, 6.15; N, 6.33. Found: C, 65.08; H, 6.43; N, 6.29.
Part E. 5-Fluoro-6-methoxy-2-~4-~2-(1-pyrrolidinyl)-ethoxy~phenyl]b~nzotblthio~?hQn-3-yl 4-~2-(1-ry ~-lidiny1)ethoxyl~h~nyl Ketone Dioxalat~.
MeO ~ ¦ J ~ ~ 2 C2H2O4 Magnesium turnings (69 gm; 2.84 mmol) were placed in a 3-neck round bottom e~uipped with a stir bar, nitrogen inlet, dropping funnel and reflux co~n~or and flame-dried under a stream of nitrogen. THF (5 mL) was added to the reaction vessel followed by a solution of 732 mg (2.71 mg) of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine and a small I2 crystal. The vessel contents were heated to mild reflux for 7 h at which time all the Mg had been consumed. The reaction was cooled to 0 ~C and was added via a cannula to a 0 ~C solution of 1.00 g (2.26 mmol) of 2-dimethylamino-5-fluoro-6-methoxy-benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) in 10 mL of THF. The mixture was stirred at 0 ~C for 16 h, was ~uenched with 10 mL of H20, and was acidified to pH 7-8 with 1 N a~ueous HCl. The mixture was extracted with CH2C12 (4 x 100 mL). The combined organic extracts were washed with H2O, dried over K2CO3, filtered, and concentrated in vacuo to give 1.53 g of an oil.
Purification ~y flash chromatography (sio2; 4:11:84 TEA/THF/hexanes) afforded 1.18 g (2.12 mmol; 78~) of the title compound as an oil. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 589 (M+1); Anal. Calcd for C34H37FN2O4S-2 C2H2O4: C, 57.22; H, 5.18i N, 3.51. Found: C, 57.48; H, 5.42; N, 3.54.
W O 97~5033 PCT~US96/17995 Part F. 5-Fluoro-6-hydroxy-2-[4-t2-(1-pyrrolidinyl)-r ethoxylphonyllbenzolb~thiophe~-3-yl 4-t2-~1-Pyrro-lidinyl)ethoxy]phenyl Ketone Dioxalat~.
HO ~ 2 C2H~O4 By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared in 61 yield starting from 5-fluoro-6-methoxy-2-[4-t2-~1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[2-(1-10 pyrrolidinyl)ethoxy]phenyl ketone (Part E). A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 575 (M+l); Anal. Calcd for C33H35FN2o4s-2 C2H2~4: C, 15 61.49; H, 5.44; N, 3.88. Found: C, 61.30; H, 5.67; N, 4.09.
~art G. 1-~2-~4-t15-Fluoro-6-Hydroxy-2-14-~2-(1-~yrrolidinyl)ethoxy~phenyl]benzo~blthiophQn-3-yll-methyl~phQnoxy~othyllpyrrolidine DioxalatQ.
The title compound was prepared in 64% yield from 5-fluoro-6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b~thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part F) by essentially following the procedure detailed in Example 3, Part E. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
- FDMS 561 (M+l); Anal. Calcd for C33H37FN2O3S 2 C2H2O4: C, 59.99; H, 5.58; N, 3.78. Found: C, 59.76; H, 5.67; N, 3.68.
W O 97/25033 PCT~US96/17995 ~Y~ _ le 118 Preparation of (+)-5-Fluoro-6-hydroxy-3-l4-lltrans-2-(l-pip~ridyl)cyclohexyl3Oxy]benzyl~-2-t4-r2-(1-pyrro-lidinyl)ethoxylphQnyllbenzolblthiophQne Dioxalate.
~ N ~
Part A. 2-Dimethyl~;~o-5-fluoro-6-methoxy-benzol~lthiophene-3-yl 4-lltrans-2-(l-Piperidyl) cyclohexyl~oxy~phonyl Ketone.
N""
Meo~
The title compound was prepared in 51% ~rom 2-dimethylamino-5-~luoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Example 117, Part C) and (i)-trans-2-(l-piperidyl)cyclohexanol b~ essentially following the procedure detailed in Example 117, Part D.
FDMS 510 (M+); Anal. Calcd ~or C2gH3sFN2O3S: C, 68.21; H, 6.91; N, 5.49. Found: C, 68.32; H, 7.18; N, 5.39.
Part B. (~)-5-Fluoro-6-methoxy-2-14-12-(l-y~ o-20 li~inyl)ethoxy]phQnyllbenzo[blthiophen-3-yl 4-lltrans-2-(1-Piperidyl)cyclohexyl]oxy~phenyl Ketone Dioxalate. t W O 97/25033 PCT~US96/17995 ~/~
N~", ~
~eO~O 2 C~Hz04 The title compound was prepared in 72% yield (based on consumed starting material) from 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-[[trans-2-(1-piperidyl)-cyclohexyl]oxy~phenyl ketone (Part A) by essentiallyfollowing the procedure detailed in Example 117, Part E. A
sample was converted to the dioxalate salt according to the method descri~ed in Example 1, Part C.
FDMS 657 (M+1); Anal. Calcd ~or C39H45FN204S 2 C2H2~4: C, 61.71; H, 5.90; N, 3.35. Found: C, 61.45; H, 6 07; N, 3.63.
Part C. (+)-5-Fluoro-6-hyaroxy-2-l4-~2-(1~ o-lidinyl)~thoxylphenyl]benzo~thioph~n-3-yl 4-~tra~-2-(1-Piperidyl)cyclohexyl]oxy]phenyl Ketone Dioxalate.
1~~
~ N"" ~
HO ~--O 2 C2H204 The title compound was prepared in 70% yield from (+)-~ 5-fluoro-6-methoxy-2-[4-[2~ pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 4-[[trans-2-(1-piperidyl)cyclohexyl]-oxy]phenyl ketone (Part B) by essentially following the procedure detailed in Example 1, Part D. A sample was W O 97/25033 PCT~US96/17995 -29~-converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 643 (M+l); Anal. Calcd for C3gH43FN2O4S 2 C2H2O4: C, 61.30; H, 5.76; N, 3.40. Found: C, 61.04; H, 5.84; N, 3.45.
Part D. (+)-5-Fluoro-6-hydroxy-3-14-[ltrans-2-(1-~iperidyl)cyclohexyl~Oxy]bQnzYll-2-l4-l2-(l-~yrr li~inyl)ethoxy~phenyl~benzoCblthioPhene Dioxalate.
The title compound was prepared in 70~ yield from (+)-5-fluoro-6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophen-3-yl 4-[[trans-2-(l-piperidyl)-cyclohe~rl]oxy]phenyl ketone (Part C) by essentially following the procedure detailed in Example 3, Part E. A
15 sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 629 (M+l); Anal. Calcd for C38H45FN2O3S 2 C2H2~4~
62.36; H, 6.11; N, 3.46. Found: C, 62.60; H, 6.11; N, 3.50.
FY~ le 119 Preparation of 1-~2-[4-CC2-[4-12-(1-~ olidinyl)-othoxy~henyl]bQnzofuran-3-yl]mQthyl]phenoxy~ethyl~-pyrroli~ine DioxalatQ.
~~ N~ 2 C2H2O4 ~ N~
Part A. 2-(4-MQthoxyphenyl)benzofuran.
OMe CA 02236007 l998-04-27 A solution of 46.0 g (0.39 mole) of benzofuran in 100 mL
of Et20 was treated with 0.40 mol (1.6 M in hexanes) of n-BuLi at such a rate as to keep the reaction temperature below 25 ~C. The mixture was stirred for 15 min and was added to a 10 ~C solution of 57.2 g (0.40 mole) of CuBr in 100 mL of Et20 at a rate so as to keep the reaction temperature below 10 ~C. The mixture was allowed to reach room temperature over 0.5 h an~ was treated with a solution of 93.6 g of iodoanisole in 300 mL of pyridine. The mixture was heated to 110 ~C for 3 h, allowing the Et20 to boil off.
The reaction mixture was concentrated in vacuo and the residue was dissolved in 3 L of EtOAc. The organic layer was washed several times with 2 N aqueous HC1 and once with H20, dried over MgSO4, and filtered. Concentration in vac~o afforded a residue which was recrystallized from MeOH to afford 44.5 g of the title compound as a solid.
mp 145-147 ~C.
Part B. 2-(4-Methoxyphenyl)benzofuran-3-yl 4-t2-(1-Py oli~inyl)ethoxy]phenyl K~tone.
~ O~ - N ~
The title compound was prepared in 79% yield from 2-(4-methoxyphenyl)benzofuran (Part A) and 4- [2- (1-pyrrolidinyl)-ethoxy]benzoic acid hydrochloride by essentially followingthe procedure detailed in Example 1, Part C.
- mp 92-95 ~C; FDMS 441 (M+);
L'art C. 2-(4-Hydroxyphenyl)benzofuran-3-yl 4-~2-(1-Pyrroliainyl)Qthoxy]phQnyl K~tone.
W O 97/2~033 PCT~US96/17995 By essentially following the procedures described in Example 1, Part D, the title compound was prepared in 81%
yield from 2-(4-methoxyphenyl)benzofuran-2-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part B).
FDMS 427 (M+); Anal. Calcd for C27H2sNO4: C, 75.86; H, 5.89;
N, 3.38. Found: C, 75.59i H, 5.96; N, 3.47.
Part D. 2-C4-~2-(1-~y~ olidinyl)Qthoxy3phenyl~-benzo~uran-3-yl 4-~2-(1-Pyrrolidinyl)ethoxy]phenyl K~tone Dioxalate.
~ O~'-'N ~ 2 C2HaO4 ~~>
By essentially following the procedure described in Example 3, Part D, the title compound was prepared in 76%
yield from 2-(4-hydroxyphenyl)benzo~uran-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D) and 1-(2-chloroethyl)pyrrolidine hydrochloride. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 525 (M+l). Anal. Calcd ~or C33H36N204-2 C2H2O4 C, 63.06; H, 5.72 N, 3.98. Found: C, 62.66 H, 5.75; N, 4.06.
WO 97/25033 PCT~US96/17995 Part E. 1-[2-[4-~t2-t4-~2-(1-pyrrolidinyl)ethoxy]-phcnyl~benzofuran-3-yl~methyl~phenoxy3ethyl]-olidine Dioxalate.
By essentially following the procedure detailed in Example 3, Part E, the title compound was prepared in 82%
yield from 2-[4-~2- (l-pyrrolidinyl)ethoxy]phenyl]benzofuran-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part D). A
s~mple was converted to the dioxalate salt according to the method described in Example 1, Part C.
FDMS 511 (M+l); Anal. Calcd for C33H3gN2O3-2 C2H2O4-H2O C, 62.70; H, 6.26 N, 3.95. Found: C, 62.83 H, 6.13; N, 3.98.
Ex~mpla 120 Preparation of N-[4-l6-Hyaroxy-3-l~3-methyl-4-[(1-~yrroliainyl)methyl~phenyllmethyl]~enzolb~thiphQn-2-yl]ph~nyl]-a-(l-pyrrolidinyl)acetamide Dioxalate.
Me __~
~ 1.7 C~H2O4 Part A. N-(4-Bromophenyl)-a-chloroacetamide.
Br A mixture of 8. 60 g (0. 05 mol) of 4-bromoaniline, 10.60 g (0.10 mol) of Na2CO3, and 6.78 g (0.06 mol) of chloroacetyl chloride in 100 mL of acetone was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo, 25 and the residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to give 11.4 g of analytically pure title compound as light crystals.
FDMS 248 (M~); Anal. Calcd for CgH7BrClNO: C, 38.67; H, 2.84;
N, 5.64. Found: C, 38.45i H, 2.83; M, 5.56.
Part B. N-(4-Bromophenyl)-a-(l-Pyrrolidinyl)ac~tamido.
Br ~ ~ ~
A solution of 5.0 g (0. 02 mol) of N-(4-bromophenyl)-oc-chloroacetamide (Part A) and 5.05 mL (0.06 mol) of pyrrolidine in 100 mL of THF was stirred overnight at ambient temperature. The mixture was concentrated in vacuo and the residue was partitioned between H20 and EtOAc. The organic layer was separated, washed with H2O, dried over Na2SO4, ~iltered, and evaporated in vacuo to af~ord 5.74 g of analytically pure title compound as crystals.
mp 60-63 ~C; Anal. Calcd ~or C12H15BrN20: C, 50.90; H, 5.34;
N, 9.89. Found: C, 50.62; H, 5.39; N, 9.74.
\
Part C. N-~4-(6-Methoxybenzo[b~thiophen-2-yl)phenyl]-~-(l-pyrroliainyl)acetamide.
MeO ~ ~ N ~
By essentially ~ollowing the procedures described in Example 1, Part B, the title compound was prepared in 97%
yield from N-(4-bromophenyl)-a~ pyrrolidinyl)acetamide (Part B) and 6-methoxybenzo[b]thiophene-2-boronic acid ~Example 1, Part A).
IR (CHC13) 1684; FDMS 366 (M+).
W097/25033 PCT/US96/1799s Part D. N-t4-~6-Methoxy-3-~[3-methyl-4-~(1-pyrroli~linyl)methyl~phenyl~carbonyl]benzo[b]thiophQn-2-yllphenyl~ (1-pyrrolidinyl)acetamide :Dioxalzlte.
Me ~~~
N ~ 2 C2H204 MeOJ~ S>~
By essentially following the procedures described in Example 1, Part C, the title compound was prepared in 68%
yield ~rom the product o~ Part C and 3-methyl-4-~(1-pyrrolidinyl)methyl]benzoic acid. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
IR (CHC13) 1701, 1640; FDMS 567 (M+~. Anal Calcd for C34~37N303S-2 C2H204 C, 61.03; H, 5.53 N, 5.62. Found: C, 60.99 H, 5.72; N, 5.38.
Part E. N-14-[6-Eydroxy-3-~[3-methyl-4-[(1-pyrrolidinyl)methyl~phenyl]carbonyl]bQnzoLb]thiophen-a -yl lphenyl]-oc-(1-pyrroli~linyl)acetamide.
By essentially following the procedures described in Example 1, Part D, the title compound was prepared ~rom the product o~ Part D. A sample was converted to the oxalate salt according to the method described in Example 1, Part C.
FDMS 554 (M+l). Anal. Calcd ~or C33H3sN303S.1.7 C2H204 C, 61.86; H, 5.48 N, 5.95. Found: C, 62.15 H, 5.47; N, 5.78.
Part F. N-14-~6-Hydroxy-3-[[3-methyl-4-~(1-pyrrolidinyl)methyl]phenyl]methyl]benzo[b]thiophen-2-yl~phenyl]-oc-(1-pyrrolidinyl~acetamide Dioxalate.
By essentially ~ollowing the procedures described in Example 3, Part E, the title compound was prepared ~rom the W O 97~5033 PCTAUS96/17995 product of Part E above. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
IR (KBr) 1696, 1607; FDMS 540 (M+1). Anal. Calcd for C33H37N3O2S 1.7 C2H2O4 C, 61.86i H, 5.48 N, 5.95. Found: C, 62.15 H, 5.47; N, 5.78.
Example 121 10 Preparation of 1- ~2-C4-l3-~4- ~1-Ethy:L-2-(1-pyrro-lidinyl)ethoxyl~henyl~methyl3benzotb]thiophen-2-yl]-~henoxy~ethyll~y~olidine Dioxalate.
~ ~ ~ N ~
" "~'N ~
Pa~t A. 1-(1-~y olidinyl)butan-2-ol.
~ N ~
\J ~
A mixture of 2.6 mL (31.1 mmol) of pyrrolidine and 21.6 g ~156.3 mmol) of K2C03 in 100 mL of DMF was treated with 4.7 g (3.20 mL; 90~ tech. grade; 28.2 mmol) of 1-bromo-2-butanone and the reaction was stirred at ambient temperature for 2 h.
The mixture was filtered and concentrated in vacuo. The residue was taken up in 100 mL of 1 N aqueous HCl and the solution was washed with 100 mL of EtOAc. The aqueous layer was basi~ied to pH 13 with solid KOH and was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over K2CO3, filtered, and concentrated in va~uo to give 1.6 g of an oil. The oil was taken up in 100 mL of THF and the solution was treated with 860 mg (22~7 mmol) of LiAlH4 at room temperature for 3 h, and then quenched by the sequential addition of 60 mL of H20, 60 mL of 2 N a~ueous NaOH, and 60 W O 97/25033 PCTnJS96/17995 mL of H20 at O ~C. The mixture was filtered through diatomaceous earth, and the organic solvent was evaporated in vacuo . The aqueous layer was extracted with EtOAc (4xlOO
mL). The combined organic layers were dried over K2C03, filtered, and concentrated in vacuo to give 1.40 g of an oil.
Puriflcation by ~lash chromatography (SiO2; 3% MeOH in CHC13 saturated with NH40H~ afforded 0.95 g of the title compound as an oil.
FDMS 144 (M+l); Anal. Calcd for CgH17NO: C, 67.09; H, 11.96;
N, 9.78. Found: C, 67.34; H, 12.07; N, 10.08.
Part B. 4-~1-Ethyl-2-(1-~yllolidinyl)~thoxy]phenyl 2-[4-[2-~1-Pyrrolidinyl)ethoxy~phenyllbenzolb~thio-~hen-3-yl Ketone Dioxalat~.
I ~
~/
A O ~C mixture of 75.0 mg (1.88 mmol)of NaH and 550 mg (1.23 mmol) of 4-i~ luorophenyl 2-[4- [2-(l-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thien-3-yl ketone in 10 mL of DMF was treated with a solution of 190 mg (1.3 3 mmol) of the alcohol from Part A above in 5 mL of DMF at 60 ~C for 13 h. After cooling to room temperature, the mixture was poured into 100 mL o:~ brine and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H20 (2 x 100 mL) and brine (100 mL), dried over K2CO3, filtered, and concentrated in vacuo to give 780 mg of an oil. Purification by radial chromatography (sio2; 5% MeOH in CHC13 saturated with NH40H) afforded 210 mg (0.37 mmol; 30%) of the title compound as an oil. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
W O 97t2~033 PCT~US96/17995 FDMS 659 (M+l+C2H204); Anal. Calcd for C3sH40N203S.2 C2H204:
C, 62.55; H, 5.92; N, 3.74. Found: C, 62.32; H, 6.15; N, 3.51.
Part C. 1-~2-t4-[3-[~4-[1-Ethyl-2-~1-~yl olidinyl)-~thoxylphenyllmethyl]benzo~blthiophen-2-yl~phenoxyl-Qthyl]pyrrolidine Dioxalate.
A O ~C solution of the ketone from Part B (135 mg, 0.237 mmol) in 2 .5 mL of anhydrous THF was treated with DIBAL-H
(593 ~L, 0.593 mmol, 1.0 M solution in toluene) dropwise via a syringe. After 1 h at O ~C, the excess DIBAL-H was quenched with excess MeOH (approximately 1 mL). A solution o~ 5 mL of saturated NatK+ tartrate and 5 mL o~ EtOAc were added, and the biphasic mixture was vigorously stirred for 1.5 h at ambient temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was dissolved in 2.5 mL of 1,2-dichloroethane a~d Et3SiH (183 ~L, 2.37 mmol).
Upon cooling to O ~C, TFA (265 ~L, 1.66 mmol) was added in a dropwise fashion. A~ter 1.5 h, the reaction mixture was poured into 50 mL o~ saturated a~ueous NaHC03 solution. The a~ueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Ma2S04, filtered and concentrated in vacuo. Purification by radial chromatography (sio2; gradient 2.5% to 5% MeOH in CHC13, saturated with NH40H) af~orded 62 mg (0.112 mmol; 47%) o~ a yellow oil. The ~ree base was converted to the title dioxalate salt according to the conditions described in Example 1, Part C.
FDMS 555 (M+l); Anal. calcd ~or C3sH42N202S-2C2H20~: C, 63.74; H, 6.31; N, 3.81. Found: C, 63.52; H, 6.26; N, 3.73.
- _le 122 Preparation o~ 2-[4-[3-~4-~2-(1-~y oli~inyl)-butoxy]~phenyl~methyl]benzolb~thiophen-2-yl]-~henoxy]ethyllpyrrolidine Dioxalate.
CA 02236007 l998-04-27 W O 97/25033 PCT~US96/17995 I ~ 2 C2H2O4 Part A. 2-(1-~y~olidinyl)butanol.
G N J~-The title compound was prepared in 64~ yield for 2 steps from pyrrolidine and ethyl 2-bromobutyrate by essentially following the procedure detailed in Example 121, Part A.
FDMS 144 (M+l); Anal. Calcd for C8H17NO: C 67.09; H 11.96;
N 9.78. Found: C, 66.23; H, 11.36; N, 9.~8.
Part B. 4-~2-(1-Pyrrolidinyl)butoxy]phenyl 2-14-~2-(l-Pyrrolidinyl)Qthoxy]phQnyl]bQnzo~b]thiophen-3-yl Ketone Dioxalate.
~ 2 C2H2O4 The title compound was prepared in 59~ yield from the product of Part A and 4-fluorophenyl 2-[4-[2~
pyrrolidinyl)ethoxy]phenyl]benzo[b]thien-3-yl ketone by essentially following the procedure detailed in Example 121, Part B. A sample was converted to the dioxalate salt according to the method described in Example 1, Part C.
W O 97/25033 PCT~US96/17995 FDMS 569 (M~l); Anal. Calcd for C3sH40N2O3S 2 C2H2O4: C, 62.55; H, 5.92i N, 3.74. Found: C, 62.39; H, 5.80; N, 3.59.
Part C. 1-12-14-[3- r t4-12-(l-Pyrrolidinyl)but phenyllmethyl~ benzolb~thiophen-2-yl]phenoxy]ethyl]-pyrrolidine Dioxalate.
The title compound was prepared from the free base of the ketone ~rom Part C in 76% yield by essentially following the procedure described in Example 121, Part C.
FDMS 555 (M+l); Anal. calcd for C3sH42N2O2S-2C2H204: C, 63.74; H, 6.31; N, 3.81. Found: C, 63.64; H, 6.07i N, 3.70.
~xample 123 Pre~aration of 1-~2-~15-[6-Hydroxy-3-tl3-methoxy-4-l(l-pyrrolidinyl)methyl]phenyl]methyl]benzo ~b] thio-phen-2-yl~pyrid-2-yl]oxylethyl~yrrolidine Dioxalate.
~ ~
2 C2H2~~
Part A. 6-Benzyloxy-2-16-[2-(1-~y lolidinyl)ethoxy]-pyrid-3-yl~benzo~ b] thiophen-3-yl 3-Methoxy-4-~(1-~y olidinyl)methyl]phenyl Ketone.
CMe ~
~~,D ~ -~Q-~~ L
A -78 ~C solution o~ 5-bromopyrid-2-yl 2 pyrrolidinyl)ethyl ether (3.25 g, 12.0 mmol) in 40 mL o~
. . . . CA 02236007 1998-04-27 '.
DEIVIANDES OU BREVETS VOL~I~VIINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU C~ BREVFr COMPREND PLUS C)'UN TOME.
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Claims (40)
1. A method of inhibiting thrombin comprising using an effective amount of a thrombin inhibiting compound of formula I (or a pharmaceutically acceptable salt thereof) wherein A is 0, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen o~ sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)Rf or -NHS(O)2Rg in which Rf is hydrogen or (1-2C)alkyl and Rg is (1-2C)alkyl or phenyl;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
(a) x2 is imino, a direct bond, methylene, 0 or S;
j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexathyleneimino; or (b) x2 is imino, 0 or S; j is 1; k is 1; m is 1; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, 0 or S; j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, 0 or S; j is 0, 1; 2 or 3; k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -(CH2)n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(0)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, 0 or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or (2) X3 is imino, O or S; q is 0; r is 1; one R3 group is (1-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) X3 is -N(Rh)-; q is O; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
q is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino.
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen o~ sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)Rf or -NHS(O)2Rg in which Rf is hydrogen or (1-2C)alkyl and Rg is (1-2C)alkyl or phenyl;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
(a) x2 is imino, a direct bond, methylene, 0 or S;
j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexathyleneimino; or (b) x2 is imino, 0 or S; j is 1; k is 1; m is 1; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, 0 or S; j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, 0 or S; j is 0, 1; 2 or 3; k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -(CH2)n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(0)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, 0 or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or (2) X3 is imino, O or S; q is 0; r is 1; one R3 group is (1-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) X3 is -N(Rh)-; q is O; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
q is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino.
2. The method of Claim 1 wherein said compound is a compound of formula I in which A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitroyens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, 0 or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, 0 or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitroyens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, 0 or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, 0 or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
3. The method of Claim 2 wherein A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship; and A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent.
4. The method of Claim 2 wherein said compound is a compound of formula I in which A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Rj ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to X2;
A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, 0 or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, 0 or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A2 is para-phenylene which may bear a substituent Rj ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to X2;
A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is 0, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, 0 or S; j and k are both 0; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, 0 or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
5. The method of Claim 4 wherein A2 is para-phenylene or pyridine-2,5-diyl in which the 2-position is joined to X2; and A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3.
6. The method of Claim 4 wherein said compound is a compound of formula Ia wherein A is S, -CH=CH- or -CH2-CH2-;
D is CH, CRj or N in which Rj is methyl, hydroxy or methoxy;
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2a is methylene or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino;
X3a is methylene, imino, O, or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino or 1-imidazolyl.
D is CH, CRj or N in which Rj is methyl, hydroxy or methoxy;
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2a is methylene or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino;
X3a is methylene, imino, O, or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino or 1-imidazolyl.
7. The method of Claim 6 wherein D is CH or N;
and E is CH, CRe or N in which Re is (1-3C)alkyl or halo.
and E is CH, CRe or N in which Re is (1-3C)alkyl or halo.
8. The method of Claim 6 wherein A is S; D is CH;
E is CRe in which Re is methoxy; R5 is hydrogen; R6 is hydroxy; X1 is methylene; x2a is O; and the group NRaRb is pyrrolidino; x3a is O; and the two R3 groups together form a divalent radical -(CH2)s- in which s is 4 and which forms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
E is CRe in which Re is methoxy; R5 is hydrogen; R6 is hydroxy; X1 is methylene; x2a is O; and the group NRaRb is pyrrolidino; x3a is O; and the two R3 groups together form a divalent radical -(CH2)s- in which s is 4 and which forms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRCRd is pyrrolidino.
9. The method of Claim 1 wherein said compound is a compound of formula Ib wherein A is S, -CH=CH- or -CH2-CH2-;
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2b is a direct bond or O; Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or N in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2b is a direct bond or O; Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
10. The method of Claim 9 wherein A is S; G is CH
or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; X1 is methylene; x2b is a direct bond or 0; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; X1 is methylene; x2b is a direct bond or 0; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
11. The method as claimed in any one of the above Claims 1-7 and 9 wherein said compound is one in which X1 is methylene.
12. The method as claimed in any one of the above Claims 1-7 and 11 wherein said compound is one in which s is 4.
13. The method as claimed in any one of the above Claims 1-7, 9 and 11-12 wherein said compound is one in which A is S.
14. The method as claimed in any one of the above Claims 1-7, 9 and 11-13 wherein said compound is a compound of formula I in which R1 denotes a hydroxy substituent at the position corresponding to the 6-position of a benzo[b]thiophene or a compound of formula Ia or of formula Ib in which R5 is hydrogen and R6 is hydroxy.
15. The method of Claim 1 wherein said compound is (a) 1-[2-[[5-[6-hydroxy-3-[[3-methoxy-4-[(1-pyrrolidinyl)-methyl]phenyl]methyl]benzo [b] thiophen-2-yl]pyrid-2-yl]oxy]-ethyl]pyrrolidine, (b) 1-[2-[[5-[6-hydroxy-3-[[3-methyl-4-[(1-pyrrolidinyl)-methyl]phenyl]methyl]benzo [b] thiophen-2-yl]pyrid-2-yl]oxy]-ethyl]pyrrolidine, or (c) 6-hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene.
16. A novel compound of formula I (or a pharmaceutically acceptable salt thereof) wherein A is O, S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)Rf or -MHS(O)2Rg in which Rf is hydrogen or (1-2C)alkyl and Rg is (1-2C)alkyl or phenyl;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
(a) X2 is imino, a direct bond, methylene, O or S;
j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then X2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, 0 or S; j is 1; k is 1; m is 1; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, 0 or S; j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, 0 or S; j is 0, 1, 2 or 3; k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -(CH2) n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(0)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, 0 or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or (2) X3 is imino, 0 or S; q is 0; r is 1; one R3 group is (1-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) X3 is -N(Rh)-; q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group MRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
q is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; X1 is carbonyl; x2 is O; j and k are both 0, the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q- (CHR3-CHR3)r- is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino.
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, -NHCH2Rf, -NHC(O)Rf or -MHS(O)2Rg in which Rf is hydrogen or (1-2C)alkyl and Rg is (1-2C)alkyl or phenyl;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
(a) X2 is imino, a direct bond, methylene, O or S;
j is 0; k is 0; m is 1, 2, 3 or 4; provided that when m is 1, then X2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or (b) x2 is imino, 0 or S; j is 1; k is 1; m is 1; R2 is hydroxy; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (c) x2 is imino, 0 or S; j is 1; k is 1; m is 0; R2 is hydroxymethyl or methoxycarbonyl; and Ra and Rb are independently hydrogen or (1-3C)alkyl; or (d) x2 is imino, 0 or S; j is 0, 1, 2 or 3; k is 1;
m is 0 or 1; provided that j and m are not both 0; R2 and Ra together form a diradical -(CH2) n- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and Rb is hydrogen or (1-3C)alkyl; or (e) x2 is -NH-C(0)-; j is 0; k is 0; m is 1; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; and (1) X3 is a direct bond, methylene, imino, 0 or S;
q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently hydrogen or (1-4C)alkyl or the group NRCRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or (2) X3 is imino, 0 or S; q is 0; r is 1; one R3 group is (1-5C)alkyl and the other R3 group is independently hydrogen or (1-5C)alkyl; and Rc and Rd are independently hydrogen or (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (3) X3 is imino, O or S; q is 0, 1 or 2; r is 1;
one R3 group is hydrogen and the other R3 group together with the group Rc forms a divalent radical -(CH2)t- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and Rd is hydrogen or (1-3C)alkyl; or (4) X3 is -N(Rh)-; q is 0; r is 1; the R3 group on the carbon bonded to X3 and the group Rh together form a diradical -(CH2)3-; the other R3 group is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group MRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or (5) X3 is ethene-1,2-diyl or ethyne-1,2-diyl;
q is 1; r is 0; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; X1 is carbonyl; x2 is O; j and k are both 0, the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q- (CHR3-CHR3)r- is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino.
17. The novel compound of formula I (or pharmaceutically acceptable salt thereof) of Claim 16 in which A is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a methyl, hydroxy or methoxy substituent;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl, (1-2C)alkoxy or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRCRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
18. The novel compound of formula I (or pharmaceutically acceptable salt thereof) of Claim 17 wherein A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship; and A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent.
19. The novel compound of formula I (or pharmaceutically acceptable salt thereof) of Claim 17 wherein A is S, -CH=CH- or -CH2-CH2-;
A2 is para-phenylene which may bear a substituent Rj ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to X2;
A3 is para-phenylene which may bear a substituent Rj ortho to the group X3 and Rj is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
A2 is para-phenylene which may bear a substituent Rj ortho to the group x2 and Rj is methyl, hydroxy or methoxy or A2 is pyridine-2,5-diyl in which the 2-position is joined to X2;
A3 is para-phenylene which may bear a substituent Rj ortho to the group X3 and Rj is (1-3)alkyl, (1-2C)alkoxy or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then x2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino or morpholino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl.
20. The novel compound of formula I (or pharmaceutically acceptable salt thereof) of Claim 19 wherein A2 is para-phenylene or pyridine-2,5-diyl in which the 2-position is joined to X2; and A3 is para-phenylene which may bear a substituent Re ortho to the group X3 and Re is (1-3)alkyl or halo or A3 is pyridine-2,5-diyl in which the 2-position is joined to X3.
21. The compound (or pharmaceutically acceptable salt thereof) as claimed in Claim 19 which is a compound of formula Ia wherein A is S, -CH=CH- or -CH2-CH2-;
D is CH, CRj or N in which Rj is methyl, hydroxy or methoxy;
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2a is methylene or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino;
X3a is methylene, imino, O, or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino or 1-imidazolyl;
provided that the compound is not one in which A is S; D is CH; E is CH; R5 is hydrogen, R6 is hydrogen, hydroxy or methoxy; X1 is carbonyl; X2a is O; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; X3a is O; each R3 is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino or hexamethylenemino.
D is CH, CRj or N in which Rj is methyl, hydroxy or methoxy;
E is CH, CRe or N in which Re is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
x1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
x2a is methylene or O; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino;
X3a is methylene, imino, O, or S; and each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)s- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino or 1-imidazolyl;
provided that the compound is not one in which A is S; D is CH; E is CH; R5 is hydrogen, R6 is hydrogen, hydroxy or methoxy; X1 is carbonyl; X2a is O; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; X3a is O; each R3 is hydrogen; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino or hexamethylenemino.
22. The compound (or pharmaceutically acceptable salt thereof) of Claim 21 wherein D is CH or N; and E is CH, CRe or N in which Re is (1-3C)alkyl or halo.
23. The compound (or pharmaceutically acceptable salt thereof) of Claim 21 wherein A is S; D is CH; E is CRe in which Re is methoxy; R5 is hydrogen; R6 is hydroxy; X1 is methylene; X2a is O; and the group NRaRb is pyrrolidino; X3a is O; and the two R3 groups together form a divalent radical -(CH2)s- in which s is 4 and which forms a trans-1,2-cyclohexanediyl group; and Rc and Rd are each methyl or the group NRcRd is pyrrolidino.
24. The compound (or pharmaceutically acceptable salt thereof) as claimed in Claim 16 which is a compound of formula Ib wherein A is S, -CH=CH- or -CH2-CH2-;
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or M in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2b is a direct bond or O; Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
G is CH, CRk or N in which Rk is methyl, hydroxy or methoxy;
M is CH, CRm or M in which Rm is (1-3C)alkyl, (1-2C)alkoxy or halo;
R5 is hydrogen, halo, methyl, hydroxy or methoxy;
R6 is hydrogen, hydroxy or methoxy;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2b is a direct bond or O; Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino or piperidino; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino or morpholino.
25. The compound (or pharmaceutically acceptable salt thereof) of Claim 24 wherein A is S; G is CH
or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; x1 is methylene; X2b is a direct bond or O; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRcRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
or N; M is CH, CRm or N in which Rm is methyl, methoxy, chloro or bromo; R5 is hydrogen; R6 is hydroxy; x1 is methylene; X2b is a direct bond or O; the group NRaRb is pyrrolidino; and Rc and Rd are each methyl or the group NRcRd is 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino or morpholino.
26. The compound (or pharmaceutically acceptable salt thereof) as claimed in any of the above Claims 16-22 or 24 wherein X1 is methylene.
27. The compound (or pharmaceutically acceptable salt thereof) as claimed in any of the above Claims 16-22 or 26 wherein s is 4.
28. The compound (or pharmaceutically acceptable salt thereof) as claimed in any of the above Claims 16-22, 24 or 26-27 wherein A is S.
29. The compound (or pharmaceutically acceptable salt thereof) as claimed in any of the above Claims 16-22, 24 or 26-28 wherein said compound is a compound of formula I in which R1 denotes a hydroxy substituent at the position corresponding to the 6-position of a benzo[b]thiophene or a compound of formula Ia or of formula Ib in which R5 is hydrogen and R6 is hydroxy.
30. The novel compound (or pharmaceutically acceptable salt thereof) of Claim 16 wherein said compound is (a) 1-[2-[[5-[6-hydroxy-3-[[3-methoxy-4-[(1-pyrrolidinyl)-methyl]phenyl]methyl]benzo[b]thiophen-2-yl]pyrid-2-yl]oxy]-ethyl]pyrrolidine, (b) 1-[2-[[5-[6-hydroxy-3-[[3-methyl-4-[(1-pyrrolidinyl)-methyl]phenyl]methyl]benzo[b]thiophen-2-yl]pyrid-2-yl]oxy]-ethyl]pyrrolidine, or (c) 6-hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene.
31. An acid additon salt of a novel compound of formula I as claimed in any of Claims 16-30 made with an acid which affords a pharmaceutically acceptable anion.
32. A pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a novel compound of formula I (or a pharmaceutically acceptable salt thereof) as claimed in any of the above Claims 16-31.
33. A process for preparing a novel compound of formula I (or a pharmaceutically acceptable salt thereof) as claimed in any of Claims 16-31 which is selected from:
(A) for a compound of formula I in which X1 is ethene-1,1-diyl, methylenation of a corresponding compound of formula I in which X1 is carbonyl;
(B) for a compound of formula I in which X1 is methylene, reductive removal of the hydroxy group of a corresponding alcohol of formula II;
(C) for a compound of formula I in which A is O or S and X1 is carbonyl, acylation of a corresponding compound of formula III
with an activated derivative of a corresponding acid of formula IV;
HOOC-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd IV
(D) for a compound of formula I in which A is -CH=CH-, selective dehydrogenation of a corresponding compound in which A is -cH2-cH2-;
(E) for a compound of formula I in which A is -CH2-CH2- and X2 is carbonyl, condensation of a corresponding compound of formula V
with a corresponding reagent of formula VI;
Br-Mg-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb VI
(F) for a compound of formula I in which X1 is O, cross coupling a corresponding compound of formula VII
with a corresponding boronic acid of formula VIII;
(HO)2B-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb VIII
(G) for a compound of formula I in which X1 is O
or S, treatment of a corresponding organolithium compound of formula IX
with a corresponding disulfide of formula X;
(-S-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd)2 X
(H) for a compound of formula I in which R1 or a substituent on A2 or A3 is hydroxy, removal of the O-methyl group of a corresponding compound of formula I in which R1 or a substituent on A2 or A3 is methoxy;
(I) for a compound of formula I in which X2 is O
or S, alkylation at X2 of a corresponding compound of formula XI
in which X2 is O or S with a corresponding compound of formula XII
L-(CH2)j-(CHR2)k-(CH2)m-NRaRb XII
in which L denotes a leaving group;
(J) for a compound of formula I in which X3 is O
or S, alkylation at X3 of a corresponding compound of formula XIII
in which X3 is O or S with a corresponding compound of formula XIV
L-(CH2)q-(CHR3-CHR3)r-NRcRd XIV
in which L denotes a leaving group;
(K) for a compound of formula I in which X2 and X3 are O or S and in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb is the same as -(CH2)q-(CHR3-CHR3)r-NRcRb, dialkylation of a compound of formula XV
with a compound of formula XII;
(L) for a compound of formula I in which R1 is carbamoyl, aminolysis of a corresponding intermediate compound of formula I in which R1 is a lower alkoxy-carbonyl group;
(M) for a compound of formula I in which R1 or a substituent on A3 or the value of -X3-(CH2)q-(CHR3-CHR3)r-NRcRb is aminomethyl, reduction of an intermediate compound corresponding to a compound of formula I but in which R1 is cyano or of a corresponding compound of formula I in which a substituent on A3 is cyano or of an intermediate compound corresponding to a compound of formula I but in which -X3-(CH2)q-(CHR3-CHR3)r-NRcRb is cyano;
(N) for a compound of formula I in which R1 or R2 is hydroxymethyl, reduction of a corresponding intermediate compound of formula I in which R1 or R2 is a lower alkoxy-carbonyl group;
(O) for a compound of formula I in which A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 and X3 is O, displacement of the leaving group L of a corresponding compound of formula XVI
with an alkali metal alkoxide of an alcohol of formula XVII;
HO-(CH2)q-(CHR3-CHR3)r-NRcRd XVII
(P) for a compound of formula I in which A3 bears a (1-4C)alkyl substituent, substitution of the bromo group of a corresponding compound of formula I in which A3 bears a bromo substituent;
(Q) for a compound of formula I in which X1 is carbonyl, condensation of a corresponding organolithium compound of formula IX with a derivative of a corresponding acid of formula IV which will provide a ketone upon condensation;
(R) for a compound of formula I in which X1 is carbonyl, condensation of a corresponding organolithium compound of formula XVIII
Li-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd XVIII
with a derivative of a corresponding acid of formula XIX
which will provide a ketone upon condensation;
(S) for a compound of formula I in which A is -CH=CH- and X1 is methylene, elimination of water from a corresponding compound of formula II in which A is -CH2-CH2-;
(T) for a compound of formula I in which A is S and X1 is carbonyl, condensation of a compound of formula XXV
with a corresponding reagent of formula VI;
(U) alkylation of an amine of formula HNRaRb with a compound of formula XXVI
wherein L is a leaving group, or for a compound of formula I in which R2 is OH, wherein L and R2 form an epoxide;
(V) alkylation of an amine of formula HNRcRd with a compound of formula XXVII
wherein L is a leaving group;
(W) for a compound of formula I in which X1 is carbonyl and X3 is imino, O, S or -N(Rh)-, substitution of the group Z wherein Z is fluoro or nitro of a ketone of formula XXVIII
using a compound of formula XXIX, H-X3-(CH2)q--CHR3-CHR3)r-NRcRd XXIX
or a metal salt thereof;
(X) for a compound of formula I in which a substituent on A3 is amino, reduction of a corresponding compound of formula I in which a substituent on A3 is nitro;
(Y) for a compound of formula I in which a substituent on A3 is -NHC(O)Rf or -NHS(O)2Rg, substitution of the amino group of a corresponding compound of formula I in which a substituent on A3 is amino using an activated derivative of an acid of formula HOC(O)Rf or HOS(O)2Rg;
(Z) for a compound of formula I in which a substituent on A3 is -NHCH2Rf or a compound of formula I in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb terminates in -CH2-NRaRb, reduction of the amide of a corresponding compound of formula I
in which a substituent on A3 is -NHC(O)Rf or of an intermediate compound corresponding to a compound of formula I but in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb terminates in -C(O)NRaRb;
(AA) for a compound of formula I in which X3 is ethene-1,2-diyl, reduction of the triple bond of a corresponding compound of formula I in which X3 is ethyne-1,2-diyl;
and (AB) for a compound of formula I in which a substituent on A3 is cyano, substitution of the halo group of a corresponding compound of formula I in which a substituent on A3 is bromo or iodo;
whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group;
whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I
is required, it is obtained by reacting the basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure;
and wherein, unless more specifically described, the values of A, A2, A3, R1, R2, R3, Ra, Rb, RC, Rd, X1, X2, X3, j, k, m, q, and r are as defined in any of claims 16-31.
(A) for a compound of formula I in which X1 is ethene-1,1-diyl, methylenation of a corresponding compound of formula I in which X1 is carbonyl;
(B) for a compound of formula I in which X1 is methylene, reductive removal of the hydroxy group of a corresponding alcohol of formula II;
(C) for a compound of formula I in which A is O or S and X1 is carbonyl, acylation of a corresponding compound of formula III
with an activated derivative of a corresponding acid of formula IV;
HOOC-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd IV
(D) for a compound of formula I in which A is -CH=CH-, selective dehydrogenation of a corresponding compound in which A is -cH2-cH2-;
(E) for a compound of formula I in which A is -CH2-CH2- and X2 is carbonyl, condensation of a corresponding compound of formula V
with a corresponding reagent of formula VI;
Br-Mg-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb VI
(F) for a compound of formula I in which X1 is O, cross coupling a corresponding compound of formula VII
with a corresponding boronic acid of formula VIII;
(HO)2B-A2-X2-(CH2)j-(CHR2)k-(CH2)m-NRaRb VIII
(G) for a compound of formula I in which X1 is O
or S, treatment of a corresponding organolithium compound of formula IX
with a corresponding disulfide of formula X;
(-S-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd)2 X
(H) for a compound of formula I in which R1 or a substituent on A2 or A3 is hydroxy, removal of the O-methyl group of a corresponding compound of formula I in which R1 or a substituent on A2 or A3 is methoxy;
(I) for a compound of formula I in which X2 is O
or S, alkylation at X2 of a corresponding compound of formula XI
in which X2 is O or S with a corresponding compound of formula XII
L-(CH2)j-(CHR2)k-(CH2)m-NRaRb XII
in which L denotes a leaving group;
(J) for a compound of formula I in which X3 is O
or S, alkylation at X3 of a corresponding compound of formula XIII
in which X3 is O or S with a corresponding compound of formula XIV
L-(CH2)q-(CHR3-CHR3)r-NRcRd XIV
in which L denotes a leaving group;
(K) for a compound of formula I in which X2 and X3 are O or S and in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb is the same as -(CH2)q-(CHR3-CHR3)r-NRcRb, dialkylation of a compound of formula XV
with a compound of formula XII;
(L) for a compound of formula I in which R1 is carbamoyl, aminolysis of a corresponding intermediate compound of formula I in which R1 is a lower alkoxy-carbonyl group;
(M) for a compound of formula I in which R1 or a substituent on A3 or the value of -X3-(CH2)q-(CHR3-CHR3)r-NRcRb is aminomethyl, reduction of an intermediate compound corresponding to a compound of formula I but in which R1 is cyano or of a corresponding compound of formula I in which a substituent on A3 is cyano or of an intermediate compound corresponding to a compound of formula I but in which -X3-(CH2)q-(CHR3-CHR3)r-NRcRb is cyano;
(N) for a compound of formula I in which R1 or R2 is hydroxymethyl, reduction of a corresponding intermediate compound of formula I in which R1 or R2 is a lower alkoxy-carbonyl group;
(O) for a compound of formula I in which A3 is pyridine-2,5-diyl in which the 2-position is joined to X3 and X3 is O, displacement of the leaving group L of a corresponding compound of formula XVI
with an alkali metal alkoxide of an alcohol of formula XVII;
HO-(CH2)q-(CHR3-CHR3)r-NRcRd XVII
(P) for a compound of formula I in which A3 bears a (1-4C)alkyl substituent, substitution of the bromo group of a corresponding compound of formula I in which A3 bears a bromo substituent;
(Q) for a compound of formula I in which X1 is carbonyl, condensation of a corresponding organolithium compound of formula IX with a derivative of a corresponding acid of formula IV which will provide a ketone upon condensation;
(R) for a compound of formula I in which X1 is carbonyl, condensation of a corresponding organolithium compound of formula XVIII
Li-A3-X3-(CH2)q-(CHR3-CHR3)r-NRcRd XVIII
with a derivative of a corresponding acid of formula XIX
which will provide a ketone upon condensation;
(S) for a compound of formula I in which A is -CH=CH- and X1 is methylene, elimination of water from a corresponding compound of formula II in which A is -CH2-CH2-;
(T) for a compound of formula I in which A is S and X1 is carbonyl, condensation of a compound of formula XXV
with a corresponding reagent of formula VI;
(U) alkylation of an amine of formula HNRaRb with a compound of formula XXVI
wherein L is a leaving group, or for a compound of formula I in which R2 is OH, wherein L and R2 form an epoxide;
(V) alkylation of an amine of formula HNRcRd with a compound of formula XXVII
wherein L is a leaving group;
(W) for a compound of formula I in which X1 is carbonyl and X3 is imino, O, S or -N(Rh)-, substitution of the group Z wherein Z is fluoro or nitro of a ketone of formula XXVIII
using a compound of formula XXIX, H-X3-(CH2)q--CHR3-CHR3)r-NRcRd XXIX
or a metal salt thereof;
(X) for a compound of formula I in which a substituent on A3 is amino, reduction of a corresponding compound of formula I in which a substituent on A3 is nitro;
(Y) for a compound of formula I in which a substituent on A3 is -NHC(O)Rf or -NHS(O)2Rg, substitution of the amino group of a corresponding compound of formula I in which a substituent on A3 is amino using an activated derivative of an acid of formula HOC(O)Rf or HOS(O)2Rg;
(Z) for a compound of formula I in which a substituent on A3 is -NHCH2Rf or a compound of formula I in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb terminates in -CH2-NRaRb, reduction of the amide of a corresponding compound of formula I
in which a substituent on A3 is -NHC(O)Rf or of an intermediate compound corresponding to a compound of formula I but in which -(CH2)j-(CHR2)k-(CH2)m-NRaRb terminates in -C(O)NRaRb;
(AA) for a compound of formula I in which X3 is ethene-1,2-diyl, reduction of the triple bond of a corresponding compound of formula I in which X3 is ethyne-1,2-diyl;
and (AB) for a compound of formula I in which a substituent on A3 is cyano, substitution of the halo group of a corresponding compound of formula I in which a substituent on A3 is bromo or iodo;
whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group;
whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I
is required, it is obtained by reacting the basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure;
and wherein, unless more specifically described, the values of A, A2, A3, R1, R2, R3, Ra, Rb, RC, Rd, X1, X2, X3, j, k, m, q, and r are as defined in any of claims 16-31.
34. A process of Claim 33 selected from procedures (A)-(R) of Claim 33 which is a process for a novel compound of formula I wherein is S, -CH=CH- or -CH2-CH2-;
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then X2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; X1 is carbonyl; X2 is O; the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q-(CHR3-CHR3)r-is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group MRcRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino whereafter, for any of the procedures (A)-(R), when a pharmaceutically acceptable salt of a compound of formula I
is required, it is obtained by reacting the basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
A2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship;
A3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which heteroaromatic divalent radical the valences are in the 1,4- or 2,5- or 3,6- relationship and which divalent radical may bear a (1-3C)alkyl or halo substituent;
R1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
X1 is O, S, methylene, carbonyl or ethene-1,1-diyl;
X2 is a direct bond, methylene, O or S; j and k are both O; m is 1, 2, 3 or 4; provided that when m is 1, then X2 is a direct bond; and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino;
X3 is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X3 is a direct bond; each R3 is hydrogen or the two R3 groups together form a divalent radical -(CH2)S- in which s is 3 or 4; and Rc and Rd are independently (1-3C)alkyl or the group NRcRd is pyrrolidino, piperidino, morpholino, hexamethyleneimino or 1-imidazolyl;
provided that the compound is not one in which A is S; A2 is para-phenylene; A3 is para-phenylene; R1 denotes zero substituents on the benz-ring or R1 denotes a hydroxy or methoxy substituent at the 6-position of the benzo[b]thiophene ring; X1 is carbonyl; X2 is O; the group -(CH2)m- is ethylene; Ra and Rb are independently (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, morpholino or hexamethyleneimino; X3 is O; the group -(CH2)q-(CHR3-CHR3)r-is ethylene; and Rc and Rd are independently (1-3C)alkyl or the group MRcRd is pyrrolidino, piperidino, morpholino or hexamethyleneimino whereafter, for any of the procedures (A)-(R), when a pharmaceutically acceptable salt of a compound of formula I
is required, it is obtained by reacting the basic form of such a compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
wherein the values of A, A2, A3, R1, R2, R3, Ra, Rb, Rc, Rd, X1, X2, X3, j, k, m, q, and r are as defined in any of Claims 1-15.
36 The alcohol of Claim 35 wherein said compound is a compound of formula IIa wherein A, D, E, R3, R5, R6, Ra, Rb, RC, Rd, X2a, and X3a are as defined in any of Claims 6-8 for a compound of formula Ia.
37. The alcohol of Claim 35 wherein said compound is a compound of formula IIb wherein A, G, M, R5, R6, Ra, Rb, Rc, Rd, and X2b are as defined in any of Claims 9-10 for a compound of formula Ib.
38. The invention disclosed hereinbefore.
39. A novel compound of formula I substantially as hereinbefore described with reference to any of the Examples.
40. A process for preparing a novel compound of formula I substantially as hereinbefore described with reference to any of the Examples.
Applications Claiming Priority (4)
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|---|---|---|---|
| US712095P | 1995-10-31 | 1995-10-31 | |
| US60/007,120 | 1995-10-31 | ||
| US2825296P | 1996-10-09 | 1996-10-09 | |
| US60/028,252 | 1996-10-09 |
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|---|---|
| CA2236007A1 true CA2236007A1 (en) | 1997-07-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002236007A Abandoned CA2236007A1 (en) | 1995-10-31 | 1996-10-30 | Antithrombotic diamines |
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|---|---|
| US (3) | US6025382A (en) |
| EP (1) | EP0863755B1 (en) |
| JP (1) | JP2002500618A (en) |
| AT (1) | ATE284690T1 (en) |
| AU (1) | AU7725596A (en) |
| CA (1) | CA2236007A1 (en) |
| DE (1) | DE69634045T2 (en) |
| ES (1) | ES2233982T3 (en) |
| WO (1) | WO1997025033A1 (en) |
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| JP3157882B2 (en) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | New benzothiophene derivatives |
| US5371091A (en) * | 1992-08-31 | 1994-12-06 | Bristol-Myers Squibb Company | Heteroaromatic amine thrombin inhibitors |
| US6756388B1 (en) * | 1993-10-12 | 2004-06-29 | Pfizer Inc. | Benzothiophenes and related compounds as estrogen agonists |
| US5441965A (en) * | 1993-12-21 | 1995-08-15 | Eli Lilly And Company | Methods of inhibiting thrombin |
| US5510357A (en) | 1995-02-28 | 1996-04-23 | Eli Lilly And Company | Benzothiophene compounds as anti-estrogenic agents |
| US5523309A (en) * | 1995-03-10 | 1996-06-04 | Eli Lilly And Company | Benzofuran pharmaceutical compounds |
| CA2218756A1 (en) | 1996-10-25 | 1998-04-25 | Kristin Sue Marron | Substituted benzo¢b!thiophene compounds having activity as selective estrogen receptor modulators |
| US5929090A (en) | 1997-09-12 | 1999-07-27 | Eli Lilly And Company | 2-aryl-3-aminoaryloxynaphthy1 compounds, intermediates, compositions and methods |
-
1996
- 1996-10-30 JP JP52518397A patent/JP2002500618A/en not_active Withdrawn
- 1996-10-30 AT AT96940354T patent/ATE284690T1/en not_active IP Right Cessation
- 1996-10-30 ES ES96940354T patent/ES2233982T3/en not_active Expired - Lifetime
- 1996-10-30 AU AU77255/96A patent/AU7725596A/en not_active Abandoned
- 1996-10-30 WO PCT/US1996/017995 patent/WO1997025033A1/en active IP Right Grant
- 1996-10-30 EP EP96940354A patent/EP0863755B1/en not_active Expired - Lifetime
- 1996-10-30 CA CA002236007A patent/CA2236007A1/en not_active Abandoned
- 1996-10-30 DE DE69634045T patent/DE69634045T2/en not_active Expired - Fee Related
-
1997
- 1997-04-30 US US08/846,647 patent/US6025382A/en not_active Expired - Fee Related
-
1999
- 1999-05-14 US US09/312,593 patent/US6251921B1/en not_active Expired - Fee Related
- 1999-08-05 US US09/369,416 patent/US6265575B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US6265575B1 (en) | 2001-07-24 |
| ATE284690T1 (en) | 2005-01-15 |
| AU7725596A (en) | 1997-08-01 |
| EP0863755A1 (en) | 1998-09-16 |
| EP0863755B1 (en) | 2004-12-15 |
| DE69634045D1 (en) | 2005-01-20 |
| JP2002500618A (en) | 2002-01-08 |
| EP0863755A4 (en) | 1999-01-20 |
| WO1997025033A1 (en) | 1997-07-17 |
| ES2233982T3 (en) | 2005-06-16 |
| US6251921B1 (en) | 2001-06-26 |
| DE69634045T2 (en) | 2005-05-19 |
| US6025382A (en) | 2000-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |