WO2011137220A1 - Small molecule neuropeptide s antagonists for the treatment of addictive disorders, mood, anxiety and sleep disorders - Google Patents
Small molecule neuropeptide s antagonists for the treatment of addictive disorders, mood, anxiety and sleep disorders Download PDFInfo
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- WO2011137220A1 WO2011137220A1 PCT/US2011/034276 US2011034276W WO2011137220A1 WO 2011137220 A1 WO2011137220 A1 WO 2011137220A1 US 2011034276 W US2011034276 W US 2011034276W WO 2011137220 A1 WO2011137220 A1 WO 2011137220A1
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- QCEJTPCHYLGAJS-UHFFFAOYSA-N Cc(nc1[n]2cccc1)c2P(c1ccccc1)(c1ccccc1)=S Chemical compound Cc(nc1[n]2cccc1)c2P(c1ccccc1)(c1ccccc1)=S QCEJTPCHYLGAJS-UHFFFAOYSA-N 0.000 description 4
- JMQNVOCWVYLBNV-UHFFFAOYSA-N Cc([nH]c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S Chemical compound Cc([nH]c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S JMQNVOCWVYLBNV-UHFFFAOYSA-N 0.000 description 3
- 0 **(c1c(*)[n](*)c2*1cccc2)(c1ccccc1)c1ccccc1 Chemical compound **(c1c(*)[n](*)c2*1cccc2)(c1ccccc1)c1ccccc1 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N CCN(CC)CC Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- LNAATWIXDKSAQZ-UHFFFAOYSA-N Cc([n](CCc1ccccc1)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S Chemical compound Cc([n](CCc1ccccc1)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S LNAATWIXDKSAQZ-UHFFFAOYSA-N 0.000 description 2
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N NCc(cc1)ccc1F Chemical compound NCc(cc1)ccc1F IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 2
- FPHKOMPAHWNIOS-UHFFFAOYSA-N S=P(c1cnc2[n]1cccc2)(c1ccccc1)c1ccccc1 Chemical compound S=P(c1cnc2[n]1cccc2)(c1ccccc1)c1ccccc1 FPHKOMPAHWNIOS-UHFFFAOYSA-N 0.000 description 2
- NBWRKGNTIPMLEC-UHFFFAOYSA-N c(nc1[n]2cccc1)c2P(c1ccccc1)c1ccccc1 Chemical compound c(nc1[n]2cccc1)c2P(c1ccccc1)c1ccccc1 NBWRKGNTIPMLEC-UHFFFAOYSA-N 0.000 description 2
- UDXCUFNNQWAYPY-UHFFFAOYSA-N Cc([n](C(NCc(cc1)ccc1F)=O)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S Chemical compound Cc([n](C(NCc(cc1)ccc1F)=O)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S UDXCUFNNQWAYPY-UHFFFAOYSA-N 0.000 description 1
- DFRQCYBOSYQXCX-UHFFFAOYSA-N Cc([n](C(NCc1ccccc1)=O)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S Chemical compound Cc([n](C(NCc1ccccc1)=O)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=S DFRQCYBOSYQXCX-UHFFFAOYSA-N 0.000 description 1
- SWXCDXYMILWJBK-UHFFFAOYSA-N Cc([n](C)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=O Chemical compound Cc([n](C)c1c2cccc1)c2P(c1ccccc1)(c1ccccc1)=O SWXCDXYMILWJBK-UHFFFAOYSA-N 0.000 description 1
- BHNHHSOHWZKFOX-UHFFFAOYSA-N Cc1cc(cccc2)c2[nH]1 Chemical compound Cc1cc(cccc2)c2[nH]1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 1
- ADBHSOKUEXFGBH-UHFFFAOYSA-N O=C(NCc(cc1)ccc1F)[n]1c(cccc2)c2c(P(c2ccccc2)(c2ccccc2)=S)c1 Chemical compound O=C(NCc(cc1)ccc1F)[n]1c(cccc2)c2c(P(c2ccccc2)(c2ccccc2)=S)c1 ADBHSOKUEXFGBH-UHFFFAOYSA-N 0.000 description 1
- SNLLYSRKOQFTLF-UHFFFAOYSA-N OC(c1cnc2[n]1cccc2)(c1ccccc1)c1ccccc1 Chemical compound OC(c1cnc2[n]1cccc2)(c1ccccc1)c1ccccc1 SNLLYSRKOQFTLF-UHFFFAOYSA-N 0.000 description 1
- OKNMZMSLVXAEQF-UHFFFAOYSA-N S=P(c1c(-c2ccccc2)[nH]c2c1cccc2)(c1ccccc1)c1ccccc1 Chemical compound S=P(c1c(-c2ccccc2)[nH]c2c1cccc2)(c1ccccc1)c1ccccc1 OKNMZMSLVXAEQF-UHFFFAOYSA-N 0.000 description 1
- PZUFMDQPPKTAHD-UHFFFAOYSA-N S=P(c1c[nH]c2c1cccc2)(c1ccccc1)c1ccccc1 Chemical compound S=P(c1c[nH]c2c1cccc2)(c1ccccc1)c1ccccc1 PZUFMDQPPKTAHD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- NPS Neuropeptide S
- NPSR Neuropeptide S receptor
- TGR23 and vasopressin receptor-related receptor 1 (VRRl)
- VRRl vasopressin receptor-related receptor 1
- GPCR G-protein coupled receptor
- NPS acts as an agonist at the NPSR, causing dose dependent intracellular Ca ++ mobilization, as well as increasing adenylyl cyclase accumulation, as measured by cAMP assay. NPS signalling through its G-protein-coupled receptor is also implicated in asthma susceptibility.
- Neuropsychiatric disorders including, for example, mood, anxiety, eating, and sleep related disorders, as well as alcoholism and drug addiction are major causes of mortality and morbidity.
- Patient relapse into drug seeking and use, after an interval of sobriety, is a key component of the addictive syndrome, with approximately two-thirds of patients relapsing within 3 months of initiating abstinence.
- the present invention provides a compound of General Formula I:
- R ⁇ and R 2 are the same or different moieties and each are selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, heterocyclyl Ci-C 6 alkyl, Ci-C 6 alkylamino Ci-C 6 alkyl, C]-C 6 dialkylamino Ci-C 6 alkyl, C 6 - Ci4 aryl Ci-C 6 alkylamino Ci-C 6 alkyl, C]-C 6 alkylthio Cj-C 6 alkyl, C 6 -Ci 4 arylthio, C 6 -Ci4 aryl d-C 6 alkylthio d-C 6 alkyl, C C 6 alkylsulfonyl Ci-C 6 alkyl, C 6 -Ci 4 arylsulfonyl d-C 6 alkyl, C 6 -Cii
- Ci-C 6 alkyl C]-C6 alkylamino, di Ci-C alkylamino, di Ci-C 6 alkylamino Ci-C6 alkyl, thio Q-C6 alkyl, thio C 2 - C 6 alkenyl, thio C 2 -C 6 alkynyl, C -C 14 aryloxy, C 2 -C 6 acyloxy, thio C 2 -C 6 acyl, amido, sulphonamido, Ci-C alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono Ci-C 6 alkyl, carboxy
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein R] is selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyamino, C 6 - C] 4 aryl C]-C 6 alkenyl, C 6 -Ci 4 aryl CpC alkylamino alkoxy, and C 6 -Ci4 aryl C]-C 6 alkoxy, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R 2 is selected from the group consisting of H, Ci-C alkyl, C -Ci 4 aryl, and C 6 -Ci
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, C]-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -C] 4 aryl Ci-C 6 alkyamino, C 6 -Ci 4 aryl Ci-C alkenyl, C 6 -Cj 4 aryl Ci-C 6 alkylamino alkoxy, and C 6 -Ci 4 aryl Ci-C 6 alkoxy, wherein the aryl, or heterocyclyl moiety is substituted with one or more halo groups.
- Ri is selected from the group consisting of: H, C]-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -C] 4 aryl Ci-C 6 alkyamino, C 6 -Ci 4 aryl Ci-C alkenyl,
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the aryl, or heterocyclyl moiety of Ri is substituted with one or more fluoro groups.
- the present invention provides compounds having the following General Formula I:
- Ri is selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci4 aryl, C 6 -Ci 4 aryl C]-C 6 alkyl and C 6 -C)4 aryl Ci-C 6 alkenyl, wherein the aryl moiety is
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the compound is one of the following:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one of the above identified compounds of General Formula I, as set forth above, or a salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, and at least one other compound, salt, solvate, or stereoisomer thereof, suitable for use in treating a neuropsychiatric disorder.
- the compound suitable for use in treating a neuropsychiatric disorder is selected from the group consisting of the following drug classes: antipsychotics, antidepressants and anxiolytics.
- the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the neuropsychiatric disorders being treated by the methods of the present invention comprise pain, sleep, mood, anxiety, eating and addictive disorders.
- the anxiety disorders being treated by the methods of the present invention are selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder.
- the eating disorders being treated by the methods of the present invention are selected from the group consisting of: anorexia nervosa and bulimia.
- the addictive disorders being treated by the methods of the present invention are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction.
- the present invention provides a method of treating a Neuropeptide S Receptor related disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- Figure 1 is a depiction IC 5 0 inhibition curves for Examples 7, 8 and 9, showing inhibition of intracellular calcium (Ca ) production.
- Figure 2 is a depiction IC50 inhibition curves for Examples 7, 8 and 9, showing inhibition of cAMP production.
- Figure 3 is binding competition curves for Y 10 -NPS labeled with 1 5 I and
- NPSAs NPS antagonists
- the present invention provides a clinically useful treatment for alcohol and drug addiction.
- the NPSAs of the present invention will also be useful in these clinical areas.
- the present invention provides a compound of General Fonnula I:
- R ⁇ and R 2 are the same or different moieties and each are selected from the group consisting of: H, Cj-C alkyl, C 6 -Ci 4 aryl C]-C 6 alkyl, heterocyclyl Ci-C 6 alkyl, Ci-C 6 alkylamino Ci-C 6 alkyl, Ci-C 6 dialkylamino Ci-C 6 alkyl, C 6 - C[ 4 aryl C[-C 6 alkylamino Ci-C 6 alkyl, Ci-C 6 alkylthio Ci-C 6 alkyl, C -C 14 arylthio, C 6 -Ci 4 aryl C ⁇ -Ce alkylthio Ci-C 6 alkyl, C]-C 6 alkylsulfonyl C]-C 6 alkyl, C -Ci 4 arylsulfonyl Ci-C 6 alkyl, C 6 -Ci
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Rj is selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -Ci aryl Ci-C alkyamino, C 6 - Ci 4 aryl Ci-C 6 alkenyl, C 6 -Ci 4 aryl Ci-C 6 alkylamino alkoxy, and C 6 -Ci 4 aryl Ci-C 6 alkoxy, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R 2 is selected from the group consisting of H, Cj-C 6 alkyl, C6-Ci 4 aryl, and C 6 -Ci 4
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, Cj-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -C] 4 aryl Ci-C 6 alkyamino, C 6 -Ci 4 aryl Ci-C 6 alkenyl, C 6 -Ci 4 aryl Ci-C 6 alkylamino alkoxy, and C 6 -Ci 4 aryl C[-C 6 alkoxy, wherein the aryl, or heterocyclyl moiety is substituted with one or more halo groups.
- Ri is selected from the group consisting of: H, Cj-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -C] 4 aryl Ci-C 6 alkyamino, C 6 -Ci 4 aryl Ci-C 6 alken
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the aryl, or heterocyclyl moiety of R] is substituted with one or more fluoro groups.
- the present invention provides compounds having the following General Formula I:
- Ri is selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci 4 aryl, C 6 -Ci 4 aryl Ci-C 6 alkyl and C 6 -Ci 4 aryl Ci-C 6 alkenyl, wherein the aryl moiety is
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Rj is selected from the group consisting of: H, Ci-C 6 alkyl, C 6 -Ci 4 aryl, and C 6 -Ci4 aryl Ci-C 6 alkyl, wherein R 2 is selected from the group consisting of: H, and C
- the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the compound is one of the following:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one of the above identified compounds of General Formula I, as set forth above, or a salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, and at least one other compound, salt, solvate, or stereoisomer thereof, suitable for use in treating a neuropsychiatric disorder.
- the compound suitable for use in treating a neuropsychiatric disorder is selected from the group consisting of the following drug classes: antipsychotics, antidepressants and anxiolytics.
- the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the neuropsychiatric disorders being treated by the methods of the present invention comprise pain, sleep, mood, anxiety, eating and addictive disorders.
- the anxiety disorders being treated by the methods of the present invention are selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder.
- the eating disorders being treated by the methods of the present invention are selected from the group consisting of: anorexia nervosa and bulimia.
- the addictive disorders being treated by the methods of the present invention are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction.
- the present invention provides a method of treating a a Neuropeptide S Receptor related disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a method of binding a Neuropeptide S receptor in a host cell comprising contacting the Neuropeptide S receptor with an effective amount of a compound of General Fonnula I, as set forth above, or a salt, solvate, or stereoisomer thereof.
- the present invention provides a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, wherein the composition includes a pharmaceutically and physiologically acceptable carrier, in an amount effective for use in a medicament, preferably for use as a medicament for treating a neuropsychiatric disorder in a subject, preferably wherein the neuropsychiatric disorder comprises pain, sleep, mood, anxiety, eating and addictive disorders, or for use as a medicament for treating an anxiety disorder, preferably wherein the anxiety disorders are selected from the group consisting of: panic disorder, social phobia and obsessive- compulsive disorder, or for use as a medicament for treating an eating disorder, preferably wherein the eating disorders are selected from the group consisting of: anorexia nervosa and bulimia, or for use as a medicament for treating an addictive disorder, preferably wherein the addictive disorders are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders
- the present invention provides a compound of General Fonnula I, as set forth above, or salt, solvate, or stereoisomer thereof, wherein the
- composition includes a phamiaceutically and physiologically acceptable carrier, in an amount effective for use in a medicament, preferably for use as a medicament for treating a neuropsychiatric disorder in a subject, wherein the effective amount of the compound of General Formula I, or a salt, solvate, or stereoisomer thereof, administered to the subject is in a range of between about 0.001 mg/kg/day to about 1000 mg/kg/day, preferably, at least about 0.01 mg/kg/day to about 100 mg/kg/day, more preferably about 0.1 mg/kg/day to about 10 mg/kg/day, still more preferably about 0.5 mg/kg/day to about 5 mg/kg/day.
- the compounds of General Formula I can function as NPS receptor antagonists (NPSAs), and in conjunction with a pharmaceutically acceptable earner, are capable of being used in the treatment of NPS related disorders.
- NPSA NPS receptor antagonists
- the terms "NPSA” and “compounds of General Formula I, or a salt, solvate, or stereoisomer thereof are used interchangeably in the specification.
- the present invention also provides a method of treating a neuropsychiatric disorder in a subject, comprising administering to the subject, a
- the method of treating a neuropsychiatric disorder includes, but is not limited to, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders.
- the present invention provides a method for treating or suppressing the symptoms of eating disorders in a subject, comprising administering to a patient in need of treatment a therapeutically effective amount of at least one of the above identified compounds, and a pharmaceutically acceptable carrier.
- the eating disorders being treated by the compounds and methods of the present invention can include, for example, anorexia nervosa and bulimia.
- the method for treating or suppressing the symptoms of eating disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
- the present invention provides a method for treating or suppressing the symptoms of addictive disorders in a subject, including, for example, alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction, the method comprising administering to the patient, a therapeutically effective amount of at least one of the above identified compounds and a pharmaceutically acceptable carrier.
- the method for treating or suppressing the symptoms of addictive disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
- the present invention provides a method for treating or suppressing the symptoms of anxiety disorders in a subject, comprising administering to a patient in need of treatment a therapeutically effective amount of at least one of the above identified compounds, and a pharmaceutically acceptable carrier.
- the anxiety disorders being treated by the compounds and methods of the present invention can include, for example, panic disorder, social phobia or obsessive- compulsive disorder.
- the method for treating or suppressing the symptoms of anxiety disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
- the at least one other compound suitable for use in treating a neuropsychiatric disorder can include, for example, a compound from the classes of drugs known as antipsychotics, antidepressants and
- anxiolytics and other drugs known to be effective in treating a neuropsychiatric disorder.
- NPSAs and preparations that comprise NPSAs may be administered to subjects in effective dosages and by effective routes of administration to cause, for example, decreased arousal, decreased awakening, decreased alertness, decreased spontaneous movement, sleep, somnolence, sedation, normalized sleep patterns, normalized sleep stages, increased duration of sleep, bronchodilation, relaxation of bronchial smooth muscle and/or other effects as described herein.
- NPSAs including, e.g., compounds of General Formula I, as set forth above, and salts, solvates, and stereoisomers thereof
- preparations that comprise NPSAs are useful for treating neuropsychiatric disorders, including, for example, insomnia, sleep disorders, decreased duration of sleep or frequent awakening, disorders that cause excessive spontaneous movement, some behavioral disorders, bronchitis, obstructive pulmonary disease, asthma, allergic conditions and other disorders as described herein.
- hydrocarbon group of the "hydrocarbon group which may be substituted" represented by R ⁇ and R 2 may be exemplified by a straight-chained or cyclic hydrocarbons (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, a branched or straight-chain alkylamino, dialkylamino, or alkyl or dialkylaminoalkyl, or thioalkyl, thioalkenyl, thioalkynyl, aryloxy, thioaryl, thioheteroaryl, acyloxy, thioacyl, amido, sulphonamido, etc.), or the like.
- alkyl preferably include a C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like.
- C 1-6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- alkenyl preferably include C 2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1- methyl-2-propenyl, 2-methyl-l-propenyl, etc.) and the like.
- alkynyl preferably include C 2 . 6 alkynyl (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.) and the like.
- hydroxyalkyl embraces linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. Examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.
- alkenyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond.
- alkynyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon- carbon triple bond.
- alkoxy and “alkoxyalkyl” embrace linear or branched oxy- containing radicals having alkyl portions of one to about ten carbon atoms, such as a methoxy group.
- the "alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide haloalkoxy or haloalkoxyalkyl groups.
- alkylamino includes monoalkylamino.
- the term “monoalkylamino” means an amino, which is substituted with an alkyl as defined herein.
- Examples of monoalkylamino substituents include, but are not limited to, methylamino, ethylamino, isopropylamino, t-butylamino, and the like.
- dialkylamino means an amino, which is substituted with two alkyls as defined herein, which alkyls can be the same or different. Examples of dialkylamino substituents include dimethylamino, diethylamino,
- alkylthio alkenylthio
- alkynylthio group consisting of a sulphur atom bonded to an alkyl-, alkenyl- or alkynyl- group, which is bonded via the sulphur atom to the entity to which the group is bonded. Included within the NPSAs of the present invention are the tautomeric forms of the disclosed compounds, isomeric forms including diastereoisomers, and the pharmaceutically-acceptable salts thereof.
- pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
- the NPSAs of the present invention contain basic nitrogen atoms, and the described salts made in accordance with embodiments of the invention were generated by alkylation of the Ni nitrogen of a imidazo[l,2-a]pyridine.
- acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid, and such organic acids as maleic acid, succinic acid and citric acid.
- Other pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium, or with organic bases, such as dicyclohexylamine. All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid or base with the corresponding NPSAs of the present invention.
- Salts formed from free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
- inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
- the salts of the NPSAs should be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable
- pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maieic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maieic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- embodiments of the invention include hydrates of the NPSAs of the present invention.
- the term "hydrate” includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. Hydrates of the NPSAs of the present invention may be prepared by contacting the NPSA with water under suitable conditions to produce the hydrate of choice.
- compositions of the present invention comprise the compounds of the present invention, for example, the compounds of General Formula I, and/or their salts, solvates, or stereoisomers thereof, together with a
- NPSR related disorders including, for example, addictive disorders, anxiety disorders, eating disorders, obsessive compulsive disorders and social phobias.
- a method for treating NPSR-related disorders in a subject comprising administering to the subject, at least one NPSA of the present invention, or its salt, solvate, or stereoisomer thereof, in an amount effective to treat the NPSR related disorder in the subject.
- the present invention provides a method for blocking the endogenous agonist of an NPSR, by contacting the NPSR with an effective amount of at least one NPSA of the present invention, or its salt, solvate, or stereoisomer thereof, under conditions effective to cause the NPSA compounds to bind the NPSR.
- the binding of the at least one NPSA to the NPSR will inhibit the endogenous agonist of the NPSR, and initiate the suppression or treatment of symptoms of neuropsychiatric disorders in a subject, including, for example, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders.
- contacting means that the one or more NPSAs of the present invention are introduced into a sample having at least one NPSR, or NPSR complex, and appropriate enzymes or reagents, in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the at least one NPSA to the NPSR or an NPSR complex.
- Methods for contacting the samples with the NPSAs, and other specific binding components are known to those skilled in the art, and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
- NPSR Neuropeptide S receptor
- the host cell refers to any type of cell that can contain the NPSR.
- the host cell can be a eukaryotic cell, e.g., plant, animal, fungi, or algae, or can be a prokaryotic cell, e.g., bacteria or protozoa.
- the host cell can be a cultured cell or a primary cell, i.e., isolated directly from an organism, e.g., a human.
- the host cell can be an adherent cell or a suspended cell, i.e., a cell that grows in suspension.
- Suitable host cells are known in the art and include, for instance, DH5a E. coli cells, Chinese hamster ovarian cells, monkey VERO cells, COS cells, HEK293 cells, and the like.
- the host cell is preferably a eukaryotic cell, e.g., a CHO cell.
- the host cell is preferably a mammalian cell. Most preferably, the host cell is a human cell.
- the population of cells can be a heterogeneous population comprising the host cell comprising the NPSR.
- the population of cells can be a substantially homogeneous population, in which the population comprises mainly of host cells (e.g., consisting essentially of) comprising the NPSR.
- the population also can be a clonal population of cells, in which all cells of the population are clones of a single host cell comprising the NPSR.
- the term "contacting" means that the at least one NPSA of the present invention is introduced into a subject receiving treatment for a neuropsychiatric disorder, and the at least one NPSA is allowed to come in contact with the NPSR or NPSR complex in vivo.
- the subject referred to in the inventive methods can be any subject.
- the subject is a mammal.
- the term "mammal” refers to any mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Camivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order
- Anthropoids humans and apes.
- An especially preferred mammal is the human.
- the present invention provides a method of treating a subject having or displaying symptoms of neuropsychiatric disorders, including, for example, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders, the method comprising administering to the subject, a pharmaceutical composition comprising at least one NPSA, and at least one other compound suitable for use in treating a neuropsychiatric disorder, with a pharmaceutically acceptable carrier, in an effective amount to inhibit, suppress or treat symptoms of the neuropsychiatric disorder.
- a pharmaceutical composition comprising at least one NPSA, and at least one other compound suitable for use in treating a neuropsychiatric disorder, with a pharmaceutically acceptable carrier, in an effective amount to inhibit, suppress or treat symptoms of the neuropsychiatric disorder.
- the compounds suitable for use in treating a neuropsychiatric disorders in the present invention include, for example, drugs in the following classes: antipsychotics, antidepressants, anxiolytics and other classes of drugs known to those of skill in the art.
- antidepressant medications are well-known, and commonly used to treat depressive disorders, include, for example, selective serotonin reuptake inhibitors (SSRIs), tricyclics, and monoamine oxidase inhibitors (MAOIs).
- SSRIs selective serotonin reuptake inhibitors
- MAOIs monoamine oxidase inhibitors
- benzodiazepines such as diazepam, triazolam, midazolam, lorazepam, chlordiazepoxide, alprazolam, and other benzodiazepine-based medications.
- Typical antipsychotic drugs useful in the present invention include, for example, chlorporomazine, emonopride, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, pimozide, perphenazine, raclopride, remoxipride, spiperone, thioridazine, thiothixene, and trifluoperazine.
- Typical antipsychotics are believed to act by blocking dopaminergic receptors (dopamine receptor antagonists), primarily dopamine D 2 receptors, thereby reducing dopaminergic transmission in the brain. Examples of "atypical"
- antipsychotics useful in the present invention include, but are not limited to, asenapine olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, amisulpride, ziprasidone, and mirtazapine.
- Embodiments of the invention include a process for preparing pharmaceutical products comprising the NPS antagonist compounds.
- pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
- Pharmaceutical compositions formulated for particular applications comprising the NPSAs of the present invention are also part of this invention, and are to be considered an embodiment thereof.
- the term “treat,” as well as words stemming therefrom, includes preventative as well as disorder remitative treatment.
- the terms “reduce,” “suppress,” and “inhibit,” as well as words stemming therefrom, have their commonly understood meaning of lessening or decreasing. These words do not necessarily imply 100% or complete treatment, reduction, suppression, or inhibition.
- the pharmaceutical compositions of the present invention comprise the NPSAs of the present invention together with a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier can be any of those conventionally used, and is limited only by physico- chemical considerations, such as solubility and lack of reactivity with the active
- pharmaceutically acceptable carriers described herein for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active agent(s), and one which has little or no detrimental side effects or toxicity under the conditions of use.
- the carriers or diluents used herein may be solid carriers or diluents for solid formulations, liquid earners or diluents for liquid formulations, or mixtures thereof.
- Solid earners or diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
- pharmaceutically acceptable carriers may be, for example, aqueous or non-aqueous solutions, suspensions, emulsions or oils.
- non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include, for example, water, alcoholic/aqueous solutions, cyclodextrins, emulsions or suspensions, including saline and buffered media.
- oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish-liver oil, sesame oil, cottonseed oil, corn oil, olive, petrolatum, and mineral.
- Suitable fatty acids for use in parenteral formulations include, for example, oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
- Parenteral vehicles for subcutaneous, intravenous, intraarterial, or intramuscular injection
- parenteral vehicles include, for example, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
- Formulations suitable for parenteral administration include, for example, aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- Intravenous vehicles include, for example, fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
- sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
- water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
- the NPSAs of the present invention may further comprise, for example, binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),
- binders e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone
- disintegrating agents e.g., cornstarch, potato starch, alginic acid, silicon dioxide,
- croscarmelose sodium crospovidone, guar gum, sodium starch glycolate
- buffers e.g., Tris- HC1, acetate, phosphate
- additives such as albumin or gelatin to prevent absorption to surfaces
- detergents e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts
- protease inhibitors e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts
- surfactants e.g.
- sodium lauryl sulfate permeation enhancers
- solubilizing agents e.g., cremophor, glycerol, polyethylene glycerol, benzlkonium chloride, benzyl benzoate, cyclodextrins, sorbitan esters, stearic acids
- anti-oxidants e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole
- stabilizers e.g.,
- viscosity increasing agents e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum
- sweetners e.g., aspartame, citric acid
- preservatives e.g., thimerosal, benzyl alcohol, parabens
- lubricants e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate
- flow-aids e.g., colloidal silicon dioxide
- plasticizers e.g., diethyl phthalate, triethyl citrate
- emulsifiers e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
- polymer coatings e.g., poloxamers or poloxamines
- coating and film forming agents e.g., ethyl cellulose, acrylates, poly
- the choice of carrier will be determined, in part, by the particular NPSA, as well as by the particular method used to administer the NPSA. Accordingly, there are a variety of suitable formulations of the pharmaceutical compositions of the invention.
- the following formulations for parenteral, subcutaneous, intravenous, intramuscular, intraarterial, intrathecal and interperitoneal administration are exemplary, and are in no way limiting. More than one route can be used to administer the NPSAs, and in certain instances, a particular route can provide a more immediate and more effective response than another route.
- Suitable soaps for use in parenteral formulations include, for example, fatty alkali metal, ammonium, and triethanolamine salts
- suitable detergents include, for example, (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and
- amphoteric detergents such as, for example, alkyl- -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
- the parenteral formulations will typically contain, for example, from about 0.5% to about 25%o by weight of the NPSAs in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants, for example, having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight.
- HLB hydrophile-lipophile balance
- Suitable surfactants include, for example, polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
- the parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
- injectable formulations are in accordance with the invention.
- the requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)).
- the amount or dose of the NPSAs administered should be sufficient to effect, e.g., a therapeutic or prophylactic response, in the subject over a reasonable time frame.
- the dose will be determined by the efficacy of the particular NPSA and the condition of a subject, as well as the body weight of a subject to be treated.
- the dose of the NPSA also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular NPSA. Typically, an attending physician will decide the dosage of the NPSA with which to treat each individual subject, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, NPSA to be administered, route of administration, and the severity of the condition being treated.
- the dose of the NPSA can be between about 0.001 mg/kg/day to about 1000 mg/kg/day, preferably, at least about 0.01 mg/kg/day to about 100 mg/kg/day, more preferably, about 0.1 mg/kg/day to about 10 mg/kg/day, still more preferably, about 0.5 mg/kg/day to about 5 mg/kg/day.
- the dose of the NPSA administered to the subject is in a range of between about 0.1 mg/kg/day to about 10 mg/kg/day, preferably, at least about 0.5 mg/kg/day to about 4 mg/kg/day, more preferably, about 1 mg/kg/day to about 2 mg/kg/day, and most preferably about 1 mg/kg/day.
- the NPSA can be modified into a depot form, such that the manner in which the NPSA is released into the body to which it is administered is controlled with respect to time and location within the body (see, for example, U.S. Patent No. 4,450,150).
- Depot forms of NPSAs can be, for example, an implantable composition comprising the NPSA and a porous or non-porous material, such as a polymer, wherein the NPSA is encapsulated by or diffused throughout the material and/or degradation of the non-porous material.
- the depot is then implanted into the desired location within the body and the NPSAs are released from the implant at a predetermined rate.
- the NPSAs provided herein can be controlled release compositions, i.e., compositions in which the one or more NPSAs are released Over a period of time after administration.
- Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
- the composition is an immediate release composition, i.e., a composition in which all or substantially all of the NPSA is released immediately after administration.
- the NPSAs can be delivered in a controlled release system.
- the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration.
- a pump may be used.
- polymeric materials can be used.
- a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Design of Controlled Release Drug Delivery Systems, Xiaoling Li and Bhaskara R. Jasti eds. (McGraw-Hill, 2006)).
- the NPSA compositions of the present invention may also include incorporation of the active ingredients into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
- polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc.
- liposomes such as polylactic acid, polglycolic acid, hydrogels, etc.
- microemulsions such as polylactic acid, polglycolic acid, hydrogels, etc.
- Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
- NPSAs may be modified by, for example, the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline.
- the modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection, than do the corresponding unmodified compounds.
- Such modifications may also increase the NPSAs' solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
- the desired in vivo biological activity may be achieved by the administration of such polymer-compound adducts less frequently, or in lower doses than with the unmodified compound.
- reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as about 25 °C.
- All solvents were of anhydrous quality purchased from Aldrich Chemical Co. (Sigma-Aldrich, St. Louis, MO) and used as received. Commercially available starting materials and reagents were purchased from Aldrich and were used as received.
- the column used was a Phenomenex Luna CI 8 (5 micron, 30 x 75 mm) (Phenomenex, Torrance, CA) at a flow rate of 45 ml/min.
- the mobile phase consisted of acetonitrile (AcCN) and water (each containing 0.1%
- TFA trifluoroacetic acid
- Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA).
- Method 1 A 7 minute gradient of 4 to 100% AcCN (containing 0.025% TFA) in water (containing 0.05%> TFA) was used with an 8 minute run time at a flow rate of 1 ml/min.
- a Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C.
- Method 2 A 3 minute gradient of 4 to 100%> AcCN (containing 0.025% TFA) in water (containing 0.05% TFA) was used with a 4.5 minute run time at a flow rate of 1 ml/min.
- the TFA salt obtained was dissolved in DCM, treatment with excess HCl (4M in ethanol) and then concentration in vacuo (twice) to obtain the HCl salt 3- (diphenylphosphoryl) imidazo[l,2-a]pyridine, HCl (45 mg, 0.13 mmol, 31 % yield).
- reaction mixture was then diluted with toluene, and the precipitated solids (presumed to be Et 3 N and pyridium salts) were filtered off.
- the filtrate was concentrated and taken up in DCM. Hexanes were also added to cause further precipitation.
- the resulting solids were then filtered off.
- the mixture was adsorbed on silica gel and subjected purification by flash column chromatography (0 to 100% EtOAc/hexanes), to obtain a mixture of the required product and an unidentified impurity.
- Step 1 Preparation of 2-(4-fluorophenyl)imidazo[l,2-a]pyridine.
- 2-Bromo-l-(4- fluorophenyl)ethanone (1.15 g, 5.31 mmol) and pyridin-2-amine (500 mg, 5.31 mmol) in ethanol (10 ml) were heated in a microwave vessel at 150 °C for 30 minutes. The reaction was cooled, concentrated, diluted with dichloromethane, and washed with saturated aqueous NaHC0 3 .
- Step 2 Preparation of 3-(Diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l ,2-a]pyridine. Chlorodiphenylphosphine (2.22 g, 10.1 mmol) was dissolved in toluene (2.5 ml) and treated with iodotrimethylsilane (1.37 ml, 10.1 mmol) under nitrogen at room temperature for 45 minutes.
- Intracellular calcium was measured using a BD PBX NW calcium assay kit (BD Bioscience, Rockville, MD).
- a Chinese hamster ovary cell line (CHO) stably expressing the NPSR was generated using standard tissue culture methods for CHO cells known in the art. The cells were maintained in F12 medium containing 10 % FBS, 100 units/ml Penicillin, 100 aglm ⁇ Streptomycin, and 200 ⁇ g ml Geneticin (Invitrogen, Carlsbad, CA) at 37 °C, 5% C0 2 . Cells were seeded at 3 ⁇ /well with 1500 cells in black, tissue culture treated, clear bottom 1536-well plates (Greiner Bio-One, Monroe, NC).
- test compounds prepared in DMSO were then added using a pintool station (Kalypsys, San Diego, CA). Fluorescence was monitored over time as cells were challenged with EC 80 of agonists (80 nM NPS for NPSR or 1 nM vasopressin for Vasopressin Vlb receptor) in a FDSS-7000 detector (Hamamatsu, Bridgewater, NJ).
- the basal fluorescence signal was first recorded for 10 seconds at 1 Hz, followed by addition of 2 ⁇ agonist prepared in HBSS buffer supplemented with 0.1% BSA, and the antagonist response of compounds was recorded for another 170 seconds.
- the CCD binning was set to 2x2.
- the time-course fluorescence responses were expressed in terms of fluorescent change over background.
- the maximal fluorescent response was exported into a text file using the instrument's software data export utility. Concentration-response curves were fitted and EC 50 /IC 5 0S were calculated with the GraphPad Prism ® software (GraphPad, San Diego, CA), and are shown in Figure 1.
- Intracellular cAMP level was measured using LANCE cAMP detection kit (Perkin Elmer, Waltham, MA). After overnight incubation at 37 °C 5% C0 2 , CHO-NPSR cells were seeded at 4 ⁇ /well with 2000 cells in white, tissue culture treated 1536-well plates. The cells were then treated with the addition of ⁇ ⁇ of stimulation buffer (IX PBS buffer, 0.1 % BSA, 0.05% Tween-20, 500 ⁇ Ro 20-1724 (Sigma-Aldrich), EC80 of NPS) to each well, and then the cells were incubated at 37 °C, 5 % C0 2 for 30 minutes.
- stimulation buffer IX PBS buffer, 0.1 % BSA, 0.05% Tween-20, 500 ⁇ Ro 20-1724 (Sigma-Aldrich)
- D2 conjugated cAMP 1.25 ⁇ of D2 conjugated cAMP, and 1 ⁇ of cryptate conjugated anti-cAMP antibody were then added to the wells.
- D2 conjugated cAMP and cryptate conjugated anti-cAMP antibody were both prepared in cell lysis buffer according to the manufacturer's instructions. After 30 minutes, plates were then read in View Lux plate reader (Perkin Elmer, Waltham, MA) using the TRF detection mode optimized for HTRF.
- Y 10 -NPS labeled with 125 I was obtained from NEN Perkin Elmer (Boston, MA).
- competition binding assay increasing concentrations of unlabeled human NPS or NPSAs were used to compete with 0.15nM [ 125 I]Y 10 -NPS.
- Non-specific binding was determined in the presence of 1 ⁇ unlabeled NPS.
- CHO-NPSR cells were first seeded into 24-well plates and cultured until reaching about 95% confluence. Cells were then washed once with 1 ml PBS and incubated with radioligand with, or without compounds, in DMEM medium containing 0.1% bovine serine albumin, at room temperature for about 90 minutes.
Abstract
Disclosed are compounds of General Formula I: wherein R1, R2, R3, X and Y are described herein, as well as pharmaceutically acceptable salts, solvates, and stereoisomers thereof. Pharmaceutical compositions comprising such compounds, as well as methods of use, and treatment for neuropsychiatric disorders including pain, sleep, mood, anxiety, eating and addictive disorders, are also provided.
Description
SMALL MOLECULE NEUROPEPTIDE S ANTAGONISTS FOR THE TREATMENT OF ADDICTIVE DISORDERS, MOOD, ANXIETY AND SLEEP DISORDERS
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No.
61/328,900, filed on April 28, 2010, the entire contents of which are incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Neuropeptide S (NPS) is believed to affect arousal, wakefulness, propensity for movement, asthma and other allergic responses, stress associated with several anxiety disorders, and other physiological functions. NPS is the endogenous ligand for the
Neuropeptide S receptor (NPSR), which is also known as TGR23 and vasopressin receptor- related receptor 1 (VRRl) (Genbank accession no. BD183774, BD183814, BD183773). The NPSR is a G-protein coupled receptor (GPCR). NPS acts as an agonist at the NPSR, causing dose dependent intracellular Ca++ mobilization, as well as increasing adenylyl cyclase accumulation, as measured by cAMP assay. NPS signalling through its G-protein-coupled receptor is also implicated in asthma susceptibility.
[0003] Neuropsychiatric disorders including, for example, mood, anxiety, eating, and sleep related disorders, as well as alcoholism and drug addiction are major causes of mortality and morbidity. Patient relapse into drug seeking and use, after an interval of sobriety, is a key component of the addictive syndrome, with approximately two-thirds of patients relapsing within 3 months of initiating abstinence.
[0004] Therefore, there still exists a need to find improved treatments for
neuropsychiatric disorders.
BRIEF SUMMARY OF THE INVENTION
[0005] In accordance with an embodiment, the present invention provides a compound of General Formula I:
or a salt, solvate or stereoisomer thereof, wherein R\ and R2 are the same or different moieties and each are selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyl, heterocyclyl Ci-C6 alkyl, Ci-C6 alkylamino Ci-C6 alkyl, C]-C6 dialkylamino Ci-C6 alkyl, C6- Ci4 aryl Ci-C6 alkylamino Ci-C6 alkyl, C]-C6 alkylthio Cj-C6 alkyl, C6-Ci4 arylthio, C6-Ci4 aryl d-C6 alkylthio d-C6 alkyl, C C6 alkylsulfonyl Ci-C6 alkyl, C6-Ci4 arylsulfonyl d-C6 alkyl, C6-Ci4 arylsulfmyl Ci-C6 alkyl, hydroxy Ci-C6 alkyl, Ci-C alkoxy, C]-C6 alkoxy Ci- Ce alkyl, C3-C8 cycloalkyl, heterocyclyl, C6-C! 4 aryl, C6-C14 aryl Ci-C6 alkyl, C]-C6 alkylamino, di Ci-C alkylamino, di Ci-C6 alkylamino Ci-C6 alkyl, thio Q-C6 alkyl, thio C2- C6 alkenyl, thio C2-C6 alkynyl, C -C14 aryloxy, C2-C6 acyloxy, thio C2-C6 acyl, amido, sulphonamido, Ci-C alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono Ci-C6 alkyl, carboxy Ci-C6 alkyl, dicarboxy Ci-C6 alkyl, dicarboxy halo Ci-C6 alkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, alkylamino, dialkylamino, trialkylamino, guanidine, aldehydo, ureido, and aminocarbonyl, wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl, wherein X is selected from the group consisting of a phosphorous atom and a carbon atom, wherein when X=C, R3=hydroxyl, when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom, and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
[0006] In accordance with an embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein R] is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyamino, C6- C]4 aryl C]-C6 alkenyl, C6-Ci4 aryl CpC alkylamino alkoxy, and C6-Ci4 aryl C]-C6 alkoxy,
wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R2 is selected from the group consisting of H, Ci-C alkyl, C -Ci4 aryl, and C6-Ci4 aryl Ci-C6 alkyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl, wherein X is selected from the group consisting of a phosphorous atom and a carbon atom, wherein when X=C, R3=OH, wherein when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom; and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
[0007] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, C]-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyl, C6-C]4 aryl Ci-C6 alkyamino, C6-Ci4 aryl Ci-C alkenyl, C6-Cj4 aryl Ci-C6 alkylamino alkoxy, and C6-Ci4 aryl Ci-C6 alkoxy, wherein the aryl, or heterocyclyl moiety is substituted with one or more halo groups.
[0008] In a further embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the aryl, or heterocyclyl moiety of Ri is substituted with one or more fluoro groups.
[0009] In an embodiment, the present invention provides compounds having the following General Formula I:
wherein R\ and R2 are the same or different moieties and each comprise a hydrocarbon group which can be optionally substituted, R3 is either S, O, or OH, and X is either a phosphate
atom or a carbon atom, wherein when X=C, R3=OH; and when X=P, R3=S, or O, and wherein Y is either N or C, and pharmaceutically acceptable salts, solvates or stereoisomers thereof.
[0010] In a further embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, C6-Ci4 aryl C]-C6 alkyl and C6-C)4 aryl Ci-C6 alkenyl, wherein the aryl moiety is substituted with one or more halo groups, wherein R2 is selected from the group consisting of: H, Ci-C6 alkyl and C6-Q4 aryl, wherein R3=S, wherein X=P, and wherein Y=N.
[0011] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, Ci-C alkyl, C6-C14 aryl, and C6-Ci4 aryl Ci-C6 alkyl, wherein R2 is selected from the group consisting of: H, Ci-C6 alkyl and C6-C]4 aryl, wherein R3=S, wherein X=P, and wherein Y=N.
[0012] In yet another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Rj is selected from the group consisting of: H, Cj-C alkyl, C6-C14 aryl, and C6-Ci4 aryl CpC6 alkyl, wherein R2 is selected from the group consisting of: H, and Ci-C6 alkyl, wherein R3=S, wherein X=P, and wherein
Y=N.
[0013] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the compound is one of the following:
Example 27
xampe 40
[0014] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the above identified compounds of General Formula I, as set forth above, or a salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
[0015] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, and at least one other compound, salt, solvate, or stereoisomer thereof, suitable for use in treating a neuropsychiatric disorder. In an embodiment, the compound suitable for use in treating a neuropsychiatric disorder is selected from the group consisting of the following drug classes: antipsychotics, antidepressants and anxiolytics.
[0016] In accordance with an embodiment, the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier. In another embodiment, the neuropsychiatric disorders being treated by the methods of the present invention comprise pain, sleep, mood, anxiety, eating and addictive disorders. In an embodiment, the anxiety disorders being treated by the methods of the present invention are selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder. In a further embodiment, it is contemplated that the eating disorders being treated by the methods of the present invention are selected from the group consisting of: anorexia nervosa and bulimia.
[0017] It is contemplated that in a further embodiment, the addictive disorders being treated by the methods of the present invention are selected from the group consisting of:
alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction.
[0018] In accordance with an embodiment, the present invention provides a method of treating a Neuropeptide S Receptor related disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0019] Figure 1 is a depiction IC50 inhibition curves for Examples 7, 8 and 9, showing inhibition of intracellular calcium (Ca ) production.
[0020] Figure 2 is a depiction IC50 inhibition curves for Examples 7, 8 and 9, showing inhibition of cAMP production.
[0021] Figure 3 is binding competition curves for Y10-NPS labeled with 1 5I and
Examples 7, 30, and 32, depicting their relative binding affinity for the NPSR.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In accordance with the present invention, the development of the compounds of General Fonnula I, and their salts, solvates, and stereoisomers thereof, have activity as NPS antagonists (NPSAs), and the present invention provides a clinically useful treatment for alcohol and drug addiction. In addition, because mood, anxiety, eating, and sleep related behaviors are often closely linked with addictive processes, and are also affected by the NPS system, the NPSAs of the present invention will also be useful in these clinical areas.
[0023] In accordance with an embodiment, the present invention provides a compound of General Fonnula I:
or a salt, solvate or stereoisomer thereof, wherein R\ and R2 are the same or different moieties and each are selected from the group consisting of: H, Cj-C alkyl, C6-Ci4 aryl C]-C6 alkyl, heterocyclyl Ci-C6 alkyl, Ci-C6 alkylamino Ci-C6 alkyl, Ci-C6 dialkylamino Ci-C6 alkyl, C6- C[4 aryl C[-C6 alkylamino Ci-C6 alkyl, Ci-C6 alkylthio Ci-C6 alkyl, C -C14 arylthio, C6-Ci4 aryl C\-Ce alkylthio Ci-C6 alkyl, C]-C6 alkylsulfonyl C]-C6 alkyl, C -Ci4 arylsulfonyl Ci-C6 alkyl, C6-Ci4 arylsulfinyl C C6 alkyl, hydroxy Cj-C alkyl, Ci-C6 alkoxy, Ci-C6 alkoxy Ci- C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, C6-Ci4 aryl, C6-Ci4 aryl Q-C6 alkyl, C C6 alkylamino, di Ci-C6 alkylamino, di Ci-C6 alkylamino Cj-C6 alkyl, thio Ci-C6 alkyl, thio C2- C6 alkenyl, thio C2-C6 alkynyl, C6-Ci4 aryloxy, C2-C6 acyloxy, thio C2-C acyl, amido, sulphonamido, Ci-C6 alkyl, C2-C alkenyl, and C2-C6 alkynyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono Q-C6 alkyl, carboxy Ci-C6 alkyl, dicarboxy Cj-C6 alkyl, dicarboxy halo Ci-C6 alkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, alkylamino, dialkylamino, trialkylamino, guanidine, aldehydo, ureido, and aminocarbonyl, wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl, wherein X is selected from the group consisting of a phosphorous atom and a carbon atom, wherein when X=C, R3=hydroxyl, when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom, and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
[0024] In accordance with an embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Rj is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyl, C6-Ci aryl Ci-C alkyamino, C6- Ci4 aryl Ci-C6 alkenyl, C6-Ci4 aryl Ci-C6 alkylamino alkoxy, and C6-Ci4 aryl Ci-C6 alkoxy,
wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R2 is selected from the group consisting of H, Cj-C6 alkyl, C6-Ci4 aryl, and C6-Ci4 aryl C C6 alkyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy, wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl, wherein X is selected from the group consisting of a phosphorous atom and a carbon atom, wherein when X=C, R3=OH, wherein when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom; and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
[0025] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, Cj-C6 alkyl, C6-Ci4 aryl Ci-C6 alkyl, C6-C]4 aryl Ci-C6 alkyamino, C6-Ci4 aryl Ci-C6 alkenyl, C6-Ci4 aryl Ci-C6 alkylamino alkoxy, and C6-Ci4 aryl C[-C6 alkoxy, wherein the aryl, or heterocyclyl moiety is substituted with one or more halo groups.
[0026] In a further embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the aryl, or heterocyclyl moiety of R] is substituted with one or more fluoro groups.
[0027] In an embodiment, the present invention provides compounds having the following General Formula I:
wherein Rj and R2 are the same or different moieties and each comprise a hydrocarbon group which can be optionally substituted, R3 is either S, O, or OH, and X is either a phosphate
atom or a carbon atom, wherein when X=C, R3=OH; and when X=P, R3=S, or O, and wherein Y is either N or C, and pharmaceutically acceptable salts, solvates or stereoisomers thereof.
[0028] In a further embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, C6-Ci4 aryl Ci-C6 alkyl and C6-Ci4 aryl Ci-C6 alkenyl, wherein the aryl moiety is substituted with one or more halo groups, wherein R2 is selected from the group consisting of: H, Cj-C6 alkyl and C6-Ci4 aryl, wherein R3=S, wherein X=P, and wherein Y=N.
[0029] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Ri is selected from the group consisting of: H, C[-C6 alkyl, C6-Ci4 aryl, and C6-Ci4 aryl Ci-C6 alkyl, wherein R2 is selected from the group consisting of: H, C\-C alkyl and C6-Ci4 aryl, wherein R3=S, wherein X=P, and wherein Y=N.
[0030] In yet another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein Rj is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, and C6-Ci4 aryl Ci-C6 alkyl, wherein R2 is selected from the group consisting of: H, and C|-C6 alkyl, wherein R3=S, wherein X=P, and wherein Y=N.
[0031] In another embodiment, the present invention provides a compound of General Formula I, or a salt, solvate, or stereoisomer thereof, wherein the compound is one of the following:
Example 12
Example 13
Example 21
Example 22
Example 24
Example 25
[0032] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the above identified compounds of General Formula I, as set forth above, or a salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
[0033] In a further .embodiment, the present invention provides a pharmaceutical composition comprising a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, and at least one other compound, salt, solvate, or stereoisomer thereof, suitable for use in treating a neuropsychiatric disorder. In an embodiment, the compound suitable for use in treating a neuropsychiatric disorder is selected from the group consisting of the following drug classes: antipsychotics, antidepressants and anxiolytics.
[0034] In accordance with an embodiment, the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
[0035] In accordance with an embodiment, the present invention provides a method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier. In another embodiment, the neuropsychiatric disorders being treated by the methods of the present invention comprise pain, sleep, mood, anxiety, eating and addictive disorders. In an embodiment, the anxiety disorders being treated by the methods of the present invention are selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder. In a further
embodiment, it is contemplated that the eating disorders being treated by the methods of the present invention are selected from the group consisting of: anorexia nervosa and bulimia.
[0036] In a further embodiment, the addictive disorders being treated by the methods of the present invention are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction.
[0037] In accordance with an embodiment, the present invention provides a method of treating a a Neuropeptide S Receptor related disorder in a subject comprising administering a therapeutically effective amount of a compound of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
[0038] In accordance with another embodiment, the present invention provides a method of binding a Neuropeptide S receptor in a host cell comprising contacting the Neuropeptide S receptor with an effective amount of a compound of General Fonnula I, as set forth above, or a salt, solvate, or stereoisomer thereof.
[0039] In accordance with an embodiment, the present invention provides a compound of General Formula I, as set forth above, or salt, solvate, or stereoisomer thereof, wherein the composition includes a pharmaceutically and physiologically acceptable carrier, in an amount effective for use in a medicament, preferably for use as a medicament for treating a neuropsychiatric disorder in a subject, preferably wherein the neuropsychiatric disorder comprises pain, sleep, mood, anxiety, eating and addictive disorders, or for use as a medicament for treating an anxiety disorder, preferably wherein the anxiety disorders are selected from the group consisting of: panic disorder, social phobia and obsessive- compulsive disorder, or for use as a medicament for treating an eating disorder, preferably wherein the eating disorders are selected from the group consisting of: anorexia nervosa and bulimia, or for use as a medicament for treating an addictive disorder, preferably wherein the addictive disorders are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction, when administered to the subject in an effective amount.
[0040] In another embodiment, the present invention provides a compound of General Fonnula I, as set forth above, or salt, solvate, or stereoisomer thereof, wherein the
composition includes a phamiaceutically and physiologically acceptable carrier, in an amount
effective for use in a medicament, preferably for use as a medicament for treating a neuropsychiatric disorder in a subject, wherein the effective amount of the compound of General Formula I, or a salt, solvate, or stereoisomer thereof, administered to the subject is in a range of between about 0.001 mg/kg/day to about 1000 mg/kg/day, preferably, at least about 0.01 mg/kg/day to about 100 mg/kg/day, more preferably about 0.1 mg/kg/day to about 10 mg/kg/day, still more preferably about 0.5 mg/kg/day to about 5 mg/kg/day.
[0041] In a further embodiment, the compounds of General Formula I, as set forth above, or a salt, solvate, or stereoisomer thereof, can function as NPS receptor antagonists (NPSAs), and in conjunction with a pharmaceutically acceptable earner, are capable of being used in the treatment of NPS related disorders. As such, the terms "NPSA" and "compounds of General Formula I, or a salt, solvate, or stereoisomer thereof are used interchangeably in the specification.
[0042] In an embodiment, the present invention also provides a method of treating a neuropsychiatric disorder in a subject, comprising administering to the subject, a
therapeutically effective amount of at least one of the above identified compounds and a pharmaceutically acceptable carrier. In accordance with the present invention, the method of treating a neuropsychiatric disorder includes, but is not limited to, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders.
[0043] In another embodiment, the present invention provides a method for treating or suppressing the symptoms of eating disorders in a subject, comprising administering to a patient in need of treatment a therapeutically effective amount of at least one of the above identified compounds, and a pharmaceutically acceptable carrier. In accordance with the present invention, the eating disorders being treated by the compounds and methods of the present invention can include, for example, anorexia nervosa and bulimia. In accordance with the present invention, the method for treating or suppressing the symptoms of eating disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
[0044] In a further embodiment, the present invention provides a method for treating or suppressing the symptoms of addictive disorders in a subject, including, for example, alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders
associated with alcohol, tobacco and nicotine addiction, the method comprising administering to the patient, a therapeutically effective amount of at least one of the above identified compounds and a pharmaceutically acceptable carrier. In accordance with the present invention, the method for treating or suppressing the symptoms of addictive disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
[0045] In yet another embodiment, the present invention provides a method for treating or suppressing the symptoms of anxiety disorders in a subject, comprising administering to a patient in need of treatment a therapeutically effective amount of at least one of the above identified compounds, and a pharmaceutically acceptable carrier. In accordance with the present invention, the anxiety disorders being treated by the compounds and methods of the present invention can include, for example, panic disorder, social phobia or obsessive- compulsive disorder.
[0046] In accordance with the present invention, the method for treating or suppressing the symptoms of anxiety disorders in a subject may also include administering to the subject, a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the above identified compounds, and at least one other compound suitable for use in treating a neuropsychiatric disorder, and a pharmaceutically acceptable carrier.
[0047] In accordance with the present invention, in an embodiment, the at least one other compound suitable for use in treating a neuropsychiatric disorder can include, for example, a compound from the classes of drugs known as antipsychotics, antidepressants and
anxiolytics, and other drugs known to be effective in treating a neuropsychiatric disorder.
[0048] In an embodiment, NPSAs and preparations that comprise NPSAs may be administered to subjects in effective dosages and by effective routes of administration to cause, for example, decreased arousal, decreased awakening, decreased alertness, decreased spontaneous movement, sleep, somnolence, sedation, normalized sleep patterns, normalized sleep stages, increased duration of sleep, bronchodilation, relaxation of bronchial smooth muscle and/or other effects as described herein. Thus, NPSAs (including, e.g., compounds of General Formula I, as set forth above, and salts, solvates, and stereoisomers thereof) and preparations that comprise NPSAs, are useful for treating neuropsychiatric disorders,
including, for example, insomnia, sleep disorders, decreased duration of sleep or frequent awakening, disorders that cause excessive spontaneous movement, some behavioral disorders, bronchitis, obstructive pulmonary disease, asthma, allergic conditions and other disorders as described herein.
[0049] As used herein, including, e.g., General Formula I, the term "hydrocarbon group" of the "hydrocarbon group which may be substituted" represented by R\ and R2 may be exemplified by a straight-chained or cyclic hydrocarbons (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, a branched or straight-chain alkylamino, dialkylamino, or alkyl or dialkylaminoalkyl, or thioalkyl, thioalkenyl, thioalkynyl, aryloxy, thioaryl, thioheteroaryl, acyloxy, thioacyl, amido, sulphonamido, etc.), or the like. Among these, straight-chained or cyclic hydrocarbon having 1 to 16 carbon atoms are preferred.
[0050] As used herein, examples of the term "alkyl" preferably include a C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like.
[0051] As used herein, examples of the term "alkenyl" preferably include C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1- methyl-2-propenyl, 2-methyl-l-propenyl, etc.) and the like.
[0052] As used herein, examples of the term "alkynyl" preferably include C2.6 alkynyl (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.) and the like.
[0053] The term "hydroxyalkyl" embraces linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. Examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc. The term "alkenyl" embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond. The term "alkynyl" embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon- carbon triple bond. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals having alkyl portions of one to about ten carbon atoms, such as a methoxy group. The "alkoxy" or "alkoxyalkyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide haloalkoxy or haloalkoxyalkyl groups.
[0054] The term "alkylamino" includes monoalkylamino. The term "monoalkylamino" means an amino, which is substituted with an alkyl as defined herein. Examples of monoalkylamino substituents include, but are not limited to, methylamino, ethylamino, isopropylamino, t-butylamino, and the like. The term "dialkylamino" means an amino, which is substituted with two alkyls as defined herein, which alkyls can be the same or different. Examples of dialkylamino substituents include dimethylamino, diethylamino,
ethylisopropylamino, diisopropylamino, dibutylamino, and the like.
[0055] The terms "alkylthio," "alkenylthio" and "alkynylthio" group mean a group consisting of a sulphur atom bonded to an alkyl-, alkenyl- or alkynyl- group, which is bonded via the sulphur atom to the entity to which the group is bonded. Included within the NPSAs of the present invention are the tautomeric forms of the disclosed compounds, isomeric forms including diastereoisomers, and the pharmaceutically-acceptable salts thereof.
[0056] The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
[0057] The NPSAs of the present invention contain basic nitrogen atoms, and the described salts made in accordance with embodiments of the invention were generated by alkylation of the Ni nitrogen of a imidazo[l,2-a]pyridine. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid, and such organic acids as maleic acid, succinic acid and citric acid. Other pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium, or with organic bases, such as dicyclohexylamine. All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid or base with the corresponding NPSAs of the present invention.
[0058] Salts formed from free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
[0059] For use in medicines, the salts of the NPSAs should be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable
pharmaceutically acceptable salts of the compounds of the present invention include, for
example, acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maieic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
[0060] In addition, embodiments of the invention include hydrates of the NPSAs of the present invention. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. Hydrates of the NPSAs of the present invention may be prepared by contacting the NPSA with water under suitable conditions to produce the hydrate of choice.
[0061] In an embodiment, the pharmaceutical compositions of the present invention comprise the compounds of the present invention, for example, the compounds of General Formula I, and/or their salts, solvates, or stereoisomers thereof, together with a
pharmaceutically acceptable carrier.
[0062] The compounds and pharmaceutical compositions of the present invention are suitably used as therapeutic agents for NPSR related disorders including, for example, addictive disorders, anxiety disorders, eating disorders, obsessive compulsive disorders and social phobias. According to another embodiment of the present invention, a method is provided for treating NPSR-related disorders in a subject, comprising administering to the subject, at least one NPSA of the present invention, or its salt, solvate, or stereoisomer thereof, in an amount effective to treat the NPSR related disorder in the subject.
[0063] Accordingly, in a further embodiment, the present invention provides a method for blocking the endogenous agonist of an NPSR, by contacting the NPSR with an effective amount of at least one NPSA of the present invention, or its salt, solvate, or stereoisomer thereof, under conditions effective to cause the NPSA compounds to bind the NPSR.
Without being limited to any particular theory, it is believed the binding of the at least one NPSA to the NPSR will inhibit the endogenous agonist of the NPSR, and initiate the suppression or treatment of symptoms of neuropsychiatric disorders in a subject, including, for example, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders.
[0064] As defined herein, in one or more embodiments, "contacting" means that the one or more NPSAs of the present invention are introduced into a sample having at least one NPSR, or NPSR complex, and appropriate enzymes or reagents, in a test tube, flask, tissue
culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the at least one NPSA to the NPSR or an NPSR complex. Methods for contacting the samples with the NPSAs, and other specific binding components are known to those skilled in the art, and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
[0065] Another embodiment of the invention further provides a host cell comprising a Neuropeptide S receptor (NPSR). As used herein, the term "host cell" refers to any type of cell that can contain the NPSR. The host cell can be a eukaryotic cell, e.g., plant, animal, fungi, or algae, or can be a prokaryotic cell, e.g., bacteria or protozoa. The host cell can be a cultured cell or a primary cell, i.e., isolated directly from an organism, e.g., a human. The host cell can be an adherent cell or a suspended cell, i.e., a cell that grows in suspension. Suitable host cells are known in the art and include, for instance, DH5a E. coli cells, Chinese hamster ovarian cells, monkey VERO cells, COS cells, HEK293 cells, and the like. For purposes of testing or binding the NPSR with one of the compounds of the present invention, the host cell is preferably a eukaryotic cell, e.g., a CHO cell. For purposes of testing or screening the ability of the compounds to bind or antagonize the NPSR, the host cell is preferably a mammalian cell. Most preferably, the host cell is a human cell.
[0066] Also provided by an embodiment of the invention is a population of cells comprising at least one host cell described herein. The population of cells can be a heterogeneous population comprising the host cell comprising the NPSR. Alternatively, the population of cells can be a substantially homogeneous population, in which the population comprises mainly of host cells (e.g., consisting essentially of) comprising the NPSR. The population also can be a clonal population of cells, in which all cells of the population are clones of a single host cell comprising the NPSR.
[0067] In another embodiment, the term "contacting" means that the at least one NPSA of the present invention is introduced into a subject receiving treatment for a neuropsychiatric disorder, and the at least one NPSA is allowed to come in contact with the NPSR or NPSR complex in vivo.
[0068] The subject referred to in the inventive methods can be any subject. Preferably, the subject is a mammal. As used herein, the term "mammal" refers to any mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and
mammals of the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Camivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order
Anthropoids (humans and apes). An especially preferred mammal is the human.
[0069] In a further embodiment, the present invention provides a method of treating a subject having or displaying symptoms of neuropsychiatric disorders, including, for example, disorders related to pain, sleep, mood, anxiety, eating and addictive disorders, the method comprising administering to the subject, a pharmaceutical composition comprising at least one NPSA, and at least one other compound suitable for use in treating a neuropsychiatric disorder, with a pharmaceutically acceptable carrier, in an effective amount to inhibit, suppress or treat symptoms of the neuropsychiatric disorder.
[0070] The compounds suitable for use in treating a neuropsychiatric disorders in the present invention, include, for example, drugs in the following classes: antipsychotics, antidepressants, anxiolytics and other classes of drugs known to those of skill in the art.
[0071] Several types of antidepressant medications are well-known, and commonly used to treat depressive disorders, include, for example, selective serotonin reuptake inhibitors (SSRIs), tricyclics, and monoamine oxidase inhibitors (MAOIs).
[0072] Several types of medications for treatment of anxiety disorders (such as phobias, obsessive compulsive disorders) and seizure disorders include, for example, benzodiazepines, such as diazepam, triazolam, midazolam, lorazepam, chlordiazepoxide, alprazolam, and other benzodiazepine-based medications.
[0073] "Typical" antipsychotic drugs, useful in the present invention include, for example, chlorporomazine, emonopride, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, pimozide, perphenazine, raclopride, remoxipride, spiperone, thioridazine, thiothixene, and trifluoperazine. Typical antipsychotics are believed to act by blocking dopaminergic receptors (dopamine receptor antagonists), primarily dopamine D2 receptors, thereby reducing dopaminergic transmission in the brain. Examples of "atypical"
antipsychotics useful in the present invention include, but are not limited to, asenapine olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, amisulpride, ziprasidone, and mirtazapine.
[0074] Embodiments of the invention include a process for preparing pharmaceutical products comprising the NPS antagonist compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein. Pharmaceutical compositions formulated for particular applications comprising the NPSAs of the present invention are also part of this invention, and are to be considered an embodiment thereof.
[0075] As used herein, the term "treat," as well as words stemming therefrom, includes preventative as well as disorder remitative treatment. The terms "reduce," "suppress," and "inhibit," as well as words stemming therefrom, have their commonly understood meaning of lessening or decreasing. These words do not necessarily imply 100% or complete treatment, reduction, suppression, or inhibition.
[0076] In an embodiment, the pharmaceutical compositions of the present invention comprise the NPSAs of the present invention together with a pharmaceutically acceptable carrier. With respect to pharmaceutical compositions described herein, the pharmaceutically acceptable carrier can be any of those conventionally used, and is limited only by physico- chemical considerations, such as solubility and lack of reactivity with the active
compound(s), and by the route of administration. The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active agent(s), and one which has little or no detrimental side effects or toxicity under the conditions of use.
[0077] The carriers or diluents used herein may be solid carriers or diluents for solid formulations, liquid earners or diluents for liquid formulations, or mixtures thereof.
[0078] Solid earners or diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
[0079] For liquid formulations, pharmaceutically acceptable carriers may be, for example, aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include, for example, water, alcoholic/aqueous solutions, cyclodextrins, emulsions or suspensions, including saline and buffered media.
[0080] Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish-liver oil, sesame oil, cottonseed oil, corn oil, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include, for example, oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
[0081] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) include, for example, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Formulations suitable for parenteral administration include, for example, aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
[0082] Intravenous vehicles include, for example, fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Examples are sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
[0083] In addition, in an embodiment, the NPSAs of the present invention may further comprise, for example, binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),
disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide,
croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris- HC1, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., cremophor, glycerol, polyethylene glycerol, benzlkonium chloride, benzyl benzoate, cyclodextrins, sorbitan esters, stearic acids), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,
hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweetners (e.g., aspartame,
citric acid), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates), and/or adjuvants.
[0084] The choice of carrier will be determined, in part, by the particular NPSA, as well as by the particular method used to administer the NPSA. Accordingly, there are a variety of suitable formulations of the pharmaceutical compositions of the invention. The following formulations for parenteral, subcutaneous, intravenous, intramuscular, intraarterial, intrathecal and interperitoneal administration are exemplary, and are in no way limiting. More than one route can be used to administer the NPSAs, and in certain instances, a particular route can provide a more immediate and more effective response than another route.
[0085] Suitable soaps for use in parenteral formulations include, for example, fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include, for example, (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
[0086] The parenteral formulations will typically contain, for example, from about 0.5% to about 25%o by weight of the NPSAs in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants, for example, having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include, for example, polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
[0087] The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
[0088] Injectable formulations are in accordance with the invention. The requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)).
[0089] For purposes of the invention, the amount or dose of the NPSAs administered should be sufficient to effect, e.g., a therapeutic or prophylactic response, in the subject over a reasonable time frame. The dose will be determined by the efficacy of the particular NPSA and the condition of a subject, as well as the body weight of a subject to be treated.
[0090] The dose of the NPSA also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular NPSA. Typically, an attending physician will decide the dosage of the NPSA with which to treat each individual subject, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, NPSA to be administered, route of administration, and the severity of the condition being treated. By way of example, and not intending to limit the invention, the dose of the NPSA can be between about 0.001 mg/kg/day to about 1000 mg/kg/day, preferably, at least about 0.01 mg/kg/day to about 100 mg/kg/day, more preferably, about 0.1 mg/kg/day to about 10 mg/kg/day, still more preferably, about 0.5 mg/kg/day to about 5 mg/kg/day. In an alternate embodiment, the dose of the NPSA administered to the subject is in a range of between about 0.1 mg/kg/day to about 10 mg/kg/day, preferably, at least about 0.5 mg/kg/day to about 4 mg/kg/day, more preferably, about 1 mg/kg/day to about 2 mg/kg/day, and most preferably about 1 mg/kg/day.
[0091] Alternatively, the NPSA can be modified into a depot form, such that the manner in which the NPSA is released into the body to which it is administered is controlled with respect to time and location within the body (see, for example, U.S. Patent No. 4,450,150). Depot forms of NPSAs can be, for example, an implantable composition comprising the NPSA and a porous or non-porous material, such as a polymer, wherein the NPSA is
encapsulated by or diffused throughout the material and/or degradation of the non-porous material. The depot is then implanted into the desired location within the body and the NPSAs are released from the implant at a predetermined rate.
[0092] In one embodiment, the NPSAs provided herein can be controlled release compositions, i.e., compositions in which the one or more NPSAs are released Over a period of time after administration. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). In another embodiment the composition is an immediate release composition, i.e., a composition in which all or substantially all of the NPSA is released immediately after administration.
[0093] In yet another embodiment, the NPSAs can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration. In an embodiment, a pump may be used. In one embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Design of Controlled Release Drug Delivery Systems, Xiaoling Li and Bhaskara R. Jasti eds. (McGraw-Hill, 2006)).
[0094] The NPSA compositions of the present invention may also include incorporation of the active ingredients into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
[0095] In accordance with the present invention, NPSAs may be modified by, for example, the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. The modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection, than do the corresponding unmodified compounds. Such modifications may also increase the NPSAs' solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by the
administration of such polymer-compound adducts less frequently, or in lower doses than with the unmodified compound.
EXAMPLES
[0096] Unless otherwise stated, all reactions were earned out under an atmosphere of dry argon or nitrogen in dried glassware. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as about 25 °C. All solvents were of anhydrous quality purchased from Aldrich Chemical Co. (Sigma-Aldrich, St. Louis, MO) and used as received. Commercially available starting materials and reagents were purchased from Aldrich and were used as received.
[0097] Analytical thin layer chromatography (TLC) was performed with Sigma Aldrich TLC plates (5 x 20 cm, 60 A, 250 μηι) (Sigma-Aldrich). Visualization was accomplished by irradiation under a 254 nm UV lamp. Chromatography on silica gel was performed using forced flow (liquid) of the indicated solvent system on Biotage KP-Sil pre-packed cartridges and using the Biotage SP-1 automated chromatography system (Biotage AB, Uppsala, Sweden). Reverse phase preparative purification was performed on a Waters semi- preparative HPLC (Waters, Billerica, MA). The column used was a Phenomenex Luna CI 8 (5 micron, 30 x 75 mm) (Phenomenex, Torrance, CA) at a flow rate of 45 ml/min. The mobile phase consisted of acetonitrile (AcCN) and water (each containing 0.1%
trifluoroacetic acid (TFA)). A gradient of 10% to 50% AcCN over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220 nM).
[0098] 1H and 13C NMR spectra were recorded on a Varian Inova 400 MHz spectrometer (Varian Instruments, Palo Alto, CA). Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDC13 7.27 ppm, 77.00 ppm, DMSO-i 6 2.50 ppm, 39.51 ppm for Ή, 13C respectively). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br s= broad singlet, m = multiplet), coupling constants, and number of protons.
[0099] Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA). Method 1 : A 7 minute gradient of 4 to 100% AcCN (containing 0.025% TFA) in water (containing 0.05%> TFA) was used with an 8 minute run time at a flow rate of 1 ml/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C. Method 2: A 3 minute gradient of 4 to 100%> AcCN (containing
0.025% TFA) in water (containing 0.05% TFA) was used with a 4.5 minute run time at a flow rate of 1 ml/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 100 mm) was used at a temperature of 50 °C.
[0100] Purity determination was performed using an Agilent Diode Array Detector. Mass determination was performed using an Agilent 6130 mass spectrometer with
electrospray ionization in the positive mode (Agilent Technologies). Unless otherwise stated all compounds were >95% purity.
[0101] Molecular weight confirmation was confirmed using an Agilent Time-Of-Flight Mass Spectrometer. A 3 minute gradient from 4 to 100% AcCN (0.1 % formic acid) in water (0.1 % formic acid) was used with a 4 minute run time at a flow rate of 1 ml/minute. A Zorbax SB-C18 column (3.5 micron, 2.1 x 30 mm (Agilent Technologies), was used at a temperature of 50 °C. Confimiation of molecular formula was confirmed using electrospray ionization in the positive mode with the Agilent Masshunter software (version B.02).
EXAMPLE 1
[0102] The synthesis of 3-(diphenylphosphino)imidazo[l,2-a]pyridine is described below.
[0103] Chlorodiphenylphosphine (1.40 g, 6.35 mmol) and iodotrimethylsilane (1.27 g, 6.35 mmol) were mixed in toluene (4 ml) and stirred for about 2 hours. This mixture was transferred to a premixed solution of imidazo[l ,2-a]pyridine (500 mg, 4.23 mmol) and triethylamine (2.35 ml, 16.9 mmol) in pyridine (10 ml). The reaction was allowed to stir overnight, concentrated in vacuo, and concentrated with toluene (X2) to remove pyridine. The crude mixture was dissolved in dichloromethane (DCM) and purified by silica gel chromatography (0 to 100% ethyl acetate (EtOAc)/DCM) to provide 3-
(diphenylphosphino)imidazo [l ,2-a]pyridine (550 mg, 1.82 mmol, 43.0 % yield). 1H NMR (400 MHz, DMSO- ) δ ppm 6.94 (td, J=6.8, 1.4 Hz, 1 H), 7.36 (m, 12 H), 7.71 (m, 1 H),
8.16 (m, J=6.8, 2.1 , 1.1, 1.1 Hz, 1 H); LC/MS: Method 1 , retention time 4.500 min; HRMS (m/z) calculated for Ci9H,6N2P+ (M+H)+ 303.1046, found 303.1049.
EXAMPLE 2
[0104] The synthesis of 3-(diphenylphosphoryl) imidazo[l,2-a]pyridine, HCl is described below.
[0105] 3-(Diphenylphosphino)imidazo[l,2-a]pyridine (125 mg, 0.413 mmol) was dissolved in tetrahydrofuran (THF) and treated with excess 30% hydrogen peroxide (300 mg, 2.65 mmol). The reaction was stirred for 16 hours, then diluted with EtOAc and washed with water. The organic layer was dried (MgS04), filtered, concentrated, and purified by reverse phase HPLC. The TFA salt obtained was dissolved in DCM, treatment with excess HCl (4M in ethanol) and then concentration in vacuo (twice) to obtain the HCl salt 3- (diphenylphosphoryl) imidazo[l,2-a]pyridine, HCl (45 mg, 0.13 mmol, 31 % yield). 1H NMR (400 MHz, DMSO- 6) δ ppm 7.39 (m, 1 H), 7.63 (m, 4 H), 7.75 (m, 6 H), 7.87 (m, 1 H), 7.94 (s, 1 H), 8.00 (m, 1 H), 8.78 (d, J=6.8 Hz, 1 H); LC/MS: Method 1 , retention time 3.693 minutes; HRMS (m/z) calculated for Ci9Hi6N2OP (M+H)+ 319.0995, found 319.0995.
EXAMPLE 3
[0106] The synthesis of 3-(diphenylphosphorothioyl)imidazo[l ,2-a]pyridine, HCl is described below.
[0107] 3-(Diphenylphosphino)imidazo[l ,2-a]pyridine (125 mg, 0.413 mmol) was dissolved in THF and treated with excess sulfur (50 mg, 1.6 mmol). The reaction was stirred for 16 hours, then diluted with EtOAc and washed with water. The organic layer was dried
(MgS04), filtered, concentrated, and purified by reverse phase HPLC. The TFA salt obtained was dissolved in DCM, treatment with excess HC1 (4M in ethanol) and then concentration in vacuo (twice) to obtain the HC1 salt 3-(diphenylphosphorothioyl)imidazo[l ,2-a]pyridine,
HC1 (50 mg, 0.135 mmol, 33 % yield). 1H NMR (400 MHz, DMSO-<¾ δ ppm 7.19 (t, J=6.8 Hz, 1 H), 7.38 (br. s., 1 H), 7.66 (m, 7 H), 7.80 (m, 4 H), 7.89 (d, J=9.2 Hz, 1 H), 8.52 (d, J=6.7 Hz, 1 H); LC/MS: Method 1 , retention time 4.845 minutes; HRMS (m/z) calculated for Ci9Hi6N2PS (M+H)+ 335.0766, found 335.0771.
EXAMPLE 4
[0108] The synthesis -amino-l-(prop-2-ynyl)pyridinium, Br- is described below.
[0109] Pyridin-2-amine (9.5 g, 0.10 mol) and 3-bromoprop-l-yne (10 ml, 0.10 mol) were taken in ethanol (50 ml) and refluxed for 2 hours. The reaction was left to cool overnight. A light yellow solid precipitated out of the reaction. This was filtered via a Buchner funnel, washed with cold ethanol, and air dried to obtain 2-amino-l-(prop-2-ynyl)pyridinium, Br- (10 g, 47 mmol, 47 % yield). 1H NMR (400 MHz, DMSO- 6) δ ppm 3.82 (t, J=2.5 Hz, 1 H), 5.08 (d, J=2.5 Hz, 2 H), 6.95 (td, J=6.9, 1.4 Hz, 1 H), 7.1 1 (m, 1 H), 7.91 (ddd, J=8.9, 7.1, 1.7 Hz, 1 H), 8.17 (m, 1 H), 8.63 (br. s., 2 H).
EXAMPLE 5
[0110] The synthesis -methylimidazo[l ,2-a]pyridine is described below.
[0111] 2-Amino-l-(prop-2-ynyl)pyridinium bromide (6.0 g, 28 mmol) was mixed with copper(I) iodide (0.537 g, 2.82 mmol), PdCl2(PPh3)2 (0.495 g, 0.705 mmol) in DMF (50 mL), treated with triethylamine (12 ml, 87 mmol) and stirred overnight by which the light orange solution had turned brown. The reaction was concentrated, adsorbed on to silica gel and then
purified by flash silica gel chromatography (0 to 100% DCM/EtOAc), to provide 2- methylimidazo[l ,2-a]pyridine (2.69 g, 20.35 mmol, 72 % yield). 1H NMR (400 MHz, Chloroform-c δ ppm 2.46 (s, 3 H), 6.72 (m, 1 H), 7.1 1 (ddd, J=9.0, 6.8, 1.4 Hz, 1 H), 7.33 (s, 1 H), 7.54 (m, 1 H), 8.03 (dt, J=6.8, 1.2 Hz, 1 H).
EXAMPLE 6
[0112] The synthesis of 3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine is described below.
[0113] General Procedure A: Chlorodiphenylphosphine (3.89 ml, 26.4 mmol) and iodotrimethylsilane (5.29 g, 26.4 mmol) were stirred in toluene (10 ml) for 2 hours. This was added to a premixed solution of 2-methylimidazo[l ,2-a]pyridine (2.33 g, 17.6 mmol) and triethylamine (9.78 ml, 70.5 mmol) in pyridine (10.0 ml), and stirred 12 hours. Sulfur (0.565 g, 17.6 mmol) was added and stirred for another 6 hours. The reaction was concentrated, then concentrated again with toluene (to remove pyridine), and diluted with benzene. The solids (presumed to be triethylamine (Et3N) and pyridine salts) were filtered, and the filtrate, adsorbed over silica and subjected to purification by flash silica gel chromatography (0 to 75% EtOAc in DCM) to provide 3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2- ajpyridine (3.02 g, 8.67 mmol, 49.2 % yield). 1H NMR (400 MHz, DMSO- ) δ ppm 1.57
(m, 3 H), 6.96 (m, J=6.7, 6.7, 1.0, 0.7 Hz, 1 H), 7.44 (m, 1 H), 7.60 (m, 4 H), 7.68 (m, 3 H), 7.78 (m, 4 H), 8.35 (dt, J=6.8, 1.2 Hz, 1 H).
EXAMPLE 7
[0114] The synthesis of 3-(diphenylphosphorothioyl)-l,2-dimethyl-lH-imidazo[l,2- a]pyridin-4-ium, MeS04 ~ is described below.
[0115] General Procedure B: 3-(Diphenylphosphorothioyl)-2-methylimidazo[l ,2- ajpyridine (90 mg, 0.26 mmol) and dimethyl sulfate (0.05 ml, 0.52 mmol) were taken in dioxane (2 ml). The contents were heated in a sealed tube at 100 °C for 16 hours. The reaction was cooled and the solid obtained was filtered, washed with diethyl ether, and air dried to obtain 3-(diphenylphosphorothioyl)-l ,2-dimethyl-lH-imidazo[l ,2-a]pyridin-4-ium, MeS04 " (50 mg, 0.1 1 mmol, 41 % yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 3 H), 3.91 (s, 3 H), 7.54 (t, J=7.0 Hz, 1 H), 7.68 (td, J=7.6, 3.5 Hz, 4 H), 7.77 (m, 2 H), 7.87 (m, 4 H), 8.15 (t, J=8.3 Hz, 1 H), 8.39 (m, 1 H), 8.66 (d, J=6.8 Hz, 1 H); LC/MS: Method 1 , retention time 4.545 minutes; HRMS (m/z) calculated for C2iH20N2PS+ (M)+ 363.1079, found 363.1080.
EXAMPLE 8
[0116] The synthesis of 3 -(diphenylphosphorothioyl)-l -methyl- lH-imidazo[l ,2- a]pyridin-4-i " is described below.
[0117] 3-(Diphenylphosphorothioyl)imidazo[l ,2-a]pyridine (150 mg, 0.449 mmol) was reacted with dimethyl sulfate (0.086 ml, 0.897 mmol), according to General Procedure B, to obtain 3-(Diphenylphosphorothioyl)-l -methyl-lH-imidazo[l ,2-a]pyridin-4-ium, MeS04 " (70 mg, 0.15 mmol, 34 % yield). 1H NMR (400 MHz, DMSO- 6) δ ppm 4.02 (s, 3 H), 7.65 (m, 5 H), 7.77 (m, 2 H), 7.86 (m, 4 H), 8.08 (dd, J=2.0, 0.4 Hz, 1 H), 8.21 (m, 1 H), 8.3 (m, 1 H), 8.72 (m, 1 H); LC/MS: Method 1 , retention time 4.468 minutes; HRMS (m/z) calculated for C20Hi8N2PS+ (M)+ 349.0923, found 349.0925.
EXAMPLE 9
[0118] The synthesis of l -benzyl-3-(diphenylphosphorothioyl)-lH-imidazo[l ,2- a]pyridin-4-iu - is described below.
[0119] 3-Diphenylphosphorothioyl)imidazo[l ,2-a]pyridine (124 mg, 0.371 mmol) and (bromomethyl)benzene (0.055 ml, 0.463 mmol) were reacted according to General Procedure B, to obtain l -benzyl-3-(diphenylphosphorothioyl)-lH-imidazo[l ,2-a]pyridin-4-ium bromide (75 mg, 0.15 mmol, 40 % yield). 1H NMR (400 MHz, DMSO-t/6) δ ppm 5.73 (s, 2 H), 7.40 (m, 5 H), 7.67 (m, 5 H), 7.77 (m, 2 H), 7.89 (m, 4 H), 8.21 (ddd, J=9.2, 7.2, 1.2 Hz, 1 H), 8.29 (d, J=2.3 Hz, 1 H), 8.37 (m, 1 H), 8.75 (m, 1 H); LC/MS: Method 1 , retention time 5.069 minutes; HRMS (m/z) calculated for C26H22N2PS+ (M)+ 425.1236, found 425.1242.
EXAMPLE 10
[0120] The synthesis of 3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine, HC1 is described below.
[0121] 3-(Diphenylphosphino)-2-methylimidazo[l ,2-a]pyridine (209 mg, 0.660 mmol) was dissolved in THF (5 ml), treated with excess sulfur (200 mg, 6.24 mmol), and stirred for 16 hours. The reaction was adsorbed onto silica gel, purified by flash silica gel
chromatography and then reverse phase HPLC. Fractions from the reverse phase HPLC were treated with saturated aqueous NaHC03, and extracted with DCM. The organic phases were concentrated, dried (MgS04), redissolved in minimal DCM, and then treated with excess 1M HC1 in ethanol to precipitate a white solid. The mixture was concentrated, dissolved in
minimal DCM, treated with ethanol to cause precipitation. The solid obtained was filtered to provide 3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine, HC1 (55 mg, 0.14 mmol, 22 % yield). 1H NMR (400 MHz, chloroform-d) δ ppm 1.64 (m, 3 H), 6.70 (m, 1 H), 7.27 (m, 1 H), 7.46 (m, 4 H), 7.55 (m, 3 H), 7.77 (m, 4 H), 8.62 (dt J=6.8, 1.2 Hz, 1 H); LC/MS: Method 1 , retention time 4.697 minutes; HRMS (m/z) calculated for C20Hi8N2PS+ (M+H)+ 349.0923, found 349.0927.
EXAMPLE 1 1
[0122] The synthesis of imidazo[l ,2-a]pyridin-3-yldiphenylmethanol is described below.
[0123] 3-Bromoimidazo[l ,2-a]pyridine (172 mg, 0.873 mmol) was dissolved in THF (5 ml), cooled to -15 °C under nitrogen. Isopropylmagnesiumchloride-lithium chloride (1.5 ml, 1.5 mmol) was added and the reaction gradually warmed to 10 °C. A solution of
benzophenone (175 mg, 0.960 mmol) in THF (1 ml) was added via syringe, and the reaction warmed to room temperature. The reaction was quenched by addition of saturated aqueous NH4C1, and then extracted with EtOAc. The organic layer was separated, concentrated, and purified by reverse phase HPLC which provided the TFA salt. This was converted to its free base by dissolution in EtOAc, and then treatment with saturated aqueous NaHC03. The organic phase was dried (MgS04), filtered, and concentrated. The oily residue was dissolved in minimal DCM, treated with ethanol, and sonicated to cause precipitation of a solid which was filtered and air dried to provide imidazo[l ,2-a]pyridin-3-yldiphenylmethanol (80 mg, 0.266 mmol, 17.76 % yield). 1 H NMR (400 MHz, Chloroform- ) δ ppm 3.05 (s, 1 H), 6.63 (m, 1 H), 7.01 (s, 1 H), 7.18 (m, 1 H), 7.35 (m, 8 H), 7.61 (m, 1 H), 8.06 (m, 1 H); LC/MS: Method 1 , retention time 4.143 minutes; HRMS (m/z) calculated for C2oH] 7N20+ (M+H)+ 301.1335, found 301.1337.
EXAMPLE 12
[0124] The synthesis of 3-(diphenylphosphoryl)-2-methylimidazo[l ,2-a]pyridine, HCl is described below.
[0125] 3-Bromo-2-methylimidazo[l ,2-a]pyridine (290 mg, 1.37 mmol, not completely pure) was dissolved in THF (5 ml), cooled to -15 °C under nitrogen.
Isopropylmagnesiumchloride-lithium chloride (2 ml, 2 mmol) was added and the reaction allowed to warm to 10 °C, at which point it was determined by thin layer chromatography (TLC) (1 : 1 DCM:EtOAc) that the halogen-metal exchange was complete. A solution of chlorodiphenylphosphine (300 mg, 1.36 mmol) in THF (1 ml) was added via syringe and the reaction was allowed to gradually warm to room temperature. The reaction was quenched by addition of saturated aqueous NH4C1, extracted with EtOAc. The organic layer was separated, purified by silica gel chromatography (0 to 100% EtOAc/DCM). The product, which was not completely pure by 1 H NMR, was taken in THF and treated with excess 30%o hydrogen peroxide, and stirred overnight. Water was added, extracted with EtOAc, then concentrated, and the residue purified by reverse phase HPLC. The fractions were treated with saturated aqueous NaHC03, extracted with EtOAc, dried (MgS04), filtered, and concentrated, redissolved in DCM, and converted to HCl salt by treatment with excess 1 M HCl in Et20 and then further concentrated.
[0126] The residue was then redissolved in DCM and treated with ethanol to cause precipitation. The solid obtained was filtered and washed with ethanol, to obtain 3- (diphenylphosphoryl)-2-methylimidazo[l ,2-a]pyridine, HCl (30 mg, 0.08 mmol, 5.9 % yield). 1 H NMR (400 MHz, DMSO- 6) δ ppm 1.82 (d, J=1.2 Hz, 3 H), 7.24 (m, 1 H), 7.68 (m, 1 1 H), 7.85 (d, J=8.6 Hz, 1 H), 8.84 (d, J=6.7 Hz, 1 H); LC/MS: Method 1 , retention time 3.734 minutes; HRMS (m/z) calculated for C20H18N2OP+ (M+H)+ 333.1 151 , found
333.1 157.
EXAMPLE 13
[0127] The synthesis of (2-methylimidazo[l ,2-a]pyridin-3-yl)diphenylmethanol is described below.
[0128] 3-Bromo-2-methylimidazo[l,2-a]pyridine (220 mg, 1.042 mmol, not completely pure) was dissolved in THF (5 ml), and cooled to -15 °C under nitrogen.
Isopropylmagnesiumchloride-lithium chloride (2.7 ml, 2.70 mmol) was added and the reaction was allowed to warm to 10 °C. A solution of benzophenone (208 mg, 1.141 mmol) in THF (1 ml) was added via syringe and the reaction warmed to room temperature. The reaction was quenched by addition of saturated aqueous NH4C1 and then extracted with EtOAc. The organic layer was separated and then purified by silica gel chromatography (0 to 100% EtOAc in DCM) to provide (2-methylimidazo[l ,2-a]pyridin-3-yl)diphenylmethanol
(100 mg, 0.318 mmol, 30.5 % yield). 1H NMR (400 MHz, DMSO-i 6) δ ppm 1.38 (s, 3 H), 6.65 (m, 1 H), 6.93 (s, 1 H), 7.14 (ddd, J=9.0, 6.7, 1.4 Hz, 1 H), 7.23 (m, 4 H), 7.33 (m, 6 H), 7.43 (dt, J=9.0, 1.2 Hz, 1 H), 8.1 1 (dt, J=7.0, 1.3 Hz, 1H); LC/MS: Method 1, retention time 4.290 minutes; HRMS (m/z) calculated for C2iH19N20+ (M+H)+ 315.1492, found 315.1495.
EXAMPLE 14
[0129] The synthesis of 3-(hydroxydiphenylmethyl)-l ,2-dimethylimidazo[l,2-a]pyridin- 1-ium, TFA" is described below.
[0130] General Procedure C: (2-Methylimidazo[l ,2-a]pyridin-3-yl)diphenylmethanol (32 mg, 0.102 mmol) and dimethyl acetate (15 μΐ, 0.157 mmol) were heated in a sealed tube overnight. An oily residue was observed suspended in dioxane. The reaction was concentrated, purified with reverse phase HPLC (25 to 70% AcCN in Water, 0.1% TFA) to
provide 3-(hydroxydiphenylmethyl)-l ,2-dimethylimidazo[l ,2-a]pyridin-l -ium, TFA" (25 mg, 0.057 mmol, 55.5 % yield). The counter anion (MeS04 ") was assumed to be exchanged out with TFA". 1H NMR (400 MHz, DMSO- ) δ ppm 1.49 (s, 3 H), 3.88 (s, 3 H), 7.37 (m, 1 1 H), 7.60 (m, 1 H), 7.99 (m, 1 H), 8.25 (d, J=9.2 Hz, 1 H), 8.58 (d, J=7.0 Hz, 1 H); LC/MS: Method 1 , retention time 4.321 minutes; HRMS (m/z) calculated for C22H2iN20+ (M)+ 329.1648, found 329.1656.
EXAMPLE 15
[0131] The synthesis of 3-(hydroxydiphenylmethyl)-l-methylimidazo[l ,2-a]pyridin-l- ium, TFA" is described below.
[0132] Imidazo[l ,2-a]pyridin-3-yldiphenylmethanol (48 mg, 0.16 mmol) and dimethyl sulfate (25 μΐ, 0.26 mmol) were reacted according to General Procedure C, to obtain 3- (hydroxydiphenylmethyl)-l -methylimidazo[l ,2-a]pyridin-l -ium, TFA" (35 mg, 0.082 mmol, 51.1 % yield). 1H NMR (400 MHz, DMSO--4) δ ppm 7.41 (m, 1 1 H), 7.56 (s, 1 H), 8.05 (ddd, J=9.1 , 7.1 , 1.2 Hz, 1 H), 8.24 (dt, J=9.2, 1.1 Hz, 1 H), 8.39 (m, 1H); LC/MS: Method 1 , retention time 4.074 minutes; HRMS (m/z) calculated for C21H19N20+ (M)+ 315.1492, found 315.1497.
EXAMPLE 16
[0133] The synthesis of 3-(diphenylphosphorothioyl)-l ,2-dimethyl-l H-indole is described below.
General Procedure D: A solution of chlorodiphenylphosphine (1310 mg, 5.94 mmol) in toluene (5 ml) was treated with iodotrimethylsilane (1000 mg, 5.00 mmol) and stirred for lhour. This was added to a stirring solution of 1 ,2-dimethyl-lH-indole (650 mg, 4.48 mmol) and triethylamine (2.5 ml, 17.94 mmol) in pyridine (8 ml). A portion (approximately a fifth) of the reaction was removed and treated with excess sulfur (300 mg, 9.36 mmol), and stirred overnight. The reaction was concentrated, redissolved in DCM, and subjected to purification by silica gel chromatography (0 to 100 % EtOAc/DCM). The crude residue (white powder) obtained was suspended in diethyl ether, filtered, and air dried to obtain 3- (diphenylphosphorothioyl)-l ,2-dimethyl-lH-indole (130 mg, 0.360 mmol, 40.1 % yield). 1 H NMR (400 MHz, DMSO-< ) 5 ppm 2.17 (d, J=1.4 Hz, 3 H), 3.72 (s, 3 H), 6.36 (dt, J=8.0, 1.0 Hz, 1 H), 6.78 (ddd, J=8.2, 7.1 , 1.2 Hz, 1 H), 7.10 (ddd, J=8.2, 7.0, 1.2 Hz, 1 H), 7.53 (m, 5 H), 7.59 (m, 2 H), 7.82 (m, 4 H); LC/MS: Method 1 , retention time 6.915 minutes; HRMS (m/z) calculated for C22H2iNPS+ (M+H)+ 362.1 127, found 362.1 134.
EXAMPLE 17
[0134] The synthesis of 3 -(diphenylphosphorothioyl)-l -methyl- lH-indole (SPA02-002) is described below.
[0135] Chlorodiphenylphosphine (1310 mg, 5.94 mmol), iodotrimethylsilane (1000 mg, 5.00 mmol), 1 -methyl- lH-indole (640 mg, 4.88 mmol), and triethylamine (2.5 ml, 17.94 mmol) were reacted according to General Procedure D. A portion of the reaction
(approximately a fifth) was treated with excess sulfur to produce 3- (diphenylphosphorothioyl)-l -methyl- l H-indole (130 mg, 0.374 mmol, 38.9 % yield). 1 H NMR (400 MHz, OMSO-d6) δ ppm 3.85 (s, 3 H), 7.05 (ddd, J=8.1 , 7.0, 1 .1 Hz, 1 H), 7.25 (ddd, J=8.3, 7.1 , 1.3 Hz, 1 H), 7.30 (dt, J=8.0, 1.0 Hz, 1 H), 7.44 (d, J=4.5 Hz, 1 H), 7.56 (m, 7 H), 7.74 (m, 4 H); LC/MS: Method 1 , retention time 6.793 minutes; HRMS (m/z) calculated for C2iH19NPS+ (M+H)+ 348.0970, found 348.0974.
EXAMPLE 18
The synthesis of 3-(diphenylphosphoryl)-l ,2-dimethyl-lH-indole is described
[0137] Chlorodiphenylphosphine, iodotrimethylsilane, 1 ,2-dimethyl-l H-indole, and triethylamine were reacted according to General Procedure D, and then a fifth of the reaction was treated with excess 30% hydrogen peroxide, to produce 3-(diphenylphosphoryl)-l ,2- dimethyl-lH-indole. 1H NMR (400 MHz, DMSO-rf6) δ ppm 2.46 (m, 3 H), 3.73 (s, 3 H), 6.58 (d, J=8.0 Hz, 1 H), 6.84 (m, 1 H), 7.1 1 (m, 1 H), 7.51 (m, 5 H), 7.61 (m, 6 H); LC/MS: Method 1 , retention time 5.696 minutes; HRMS (m/z) calculated for C22H2iNOP+ (M+H)+ 346.1355, found 346.1356.
EXAMPLE 19
[01 -(diphenylphosphoryl)-l -methyl-1 H-indole is described below.
[0139] Chlorodiphenylphosphine, iodotrimethylsilane, 1 -methyl- 1 H-indole, and triethylamine were reacted according to General Procedure D, and then a fifth of the reaction was treated with excess 30% hydrogen peroxide, to produce 3-(diphenylphosphorothioyl)- l - methyl-1 H-indole. 1 H NMR (400 MHz, DMSO-d6) 5 ppm 3.84 (s, 3 H), 7.04 (m, 1 H), 7.24 (m, 2 H), 7.44 (d, J=3.9 Hz, 1 H), 7.55 (m, 7 H), 7.68 (m, 4 H); LC/MS: Method 1 , retention time 5.469 minutes; HRMS (m/z) calculated for C2iH,9NOP+ (M+H)+ 332.1 199, found
332.1202.
EXAMPLE 20
[0140] The synthesis of 3-(diphenylphosphorothioyl)-l -methyl-2-phenyl-lH-indole is described below.
[0141] l -Methyl-2-phenyl-lH-indole was treated according to General Procedure A, to yield 3-(diphenylphosphorothioyl)-l -methyl-2-phenyl-l H-indole. 1H NMR (400 MHz, DMSO-i/6) δ ppm 3.53 (s, 3 H), 6.95 (m, 2 H), 7.09 (m, 2 H), 7.15 (m, 1 H), 7.25 (m, 7 H), 7.35 (m, 2 H), 7.62 (m, 1 H), 7.73 (m, 4 H); LC/MS: Method 1 , retention time 7.299 minutes; HRMS (m/z) calculated for C27H23NPS+ (M+H)+ 424.1283, found 410.1287.
EXAMPLE 21
[0142] The synthesis of 3 -(diphenylphosphorothioyl)-l H-indole is described below.
[0143] Chlorodiphenylphosphine (1.88 g, 8.54 mmol) and iodotrimethylsilane (1.16 ml,
8.54 mmol) were dissolved in toluene (5 ml), stirred for 2 hours and then transferred to a premixed solution of triethylamine (2.59 g, 25.6 mmol), IH-indole (1.00 g, 8.54 mmol), and pyridine (5 ml). The reaction was stirred overnight, concentrated, and then purified by flash silica gel chromatography, to provide 3-(diphenylphosphorothioyl)-lH-indole (0.60 g, 1.8 mmol, 21 % yield). 1 H NMR (400 MHz, DMSO- 6) 6 ppm 7.00 (ddd, J=8.1 , 7.0, 1.1 Hz, 1 H), 7.18 (ddd, J=8.3, 7.0, 1.4 Hz, 1 H), 7.31 (dt, J=8.0, 1.1 Hz, 1 H), 7.35 (d, J=4.5 Hz, 1 H),
7.55 (m, 7 H), 7.74 (m, 4 H), 1 1 .94 (br. s., 1 H); LC/MS: Method 1 , retention time 6.353 minutes; HRMS (m/z) calculated for C2iHi9NPS+ (M+H)+ 348.0970, found 348.0973.
[0144] The major reaction product, l ,3-bis(diphenylphosphorothioyl)-l H-indole could also be refluxed with aqueous KOH in ethanol, to provide the title compound.
EXAMPLE 22
[0145] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l H-indole is described below.
[0146] General Procedure E: Chlorodiphenylphosphine (3.36 g, 15.3 mmol) and iodotrimethylsilane (2.075 ml, 15.25 mmol) were dissolved in toluene (5 ml), stirred for 2 hours, and then transferred to a premixed solution of triethylamine (6.34 ml, 45.7 mmol), 2- methyl-lH-indole (2.00 g, 15.3 mmol), and pyridine (5 ml). After stirring overnight, excess sulfur (2.444 g, 76 mmol) was added. The reaction was stirred for another 6 hours, then concentrated, diluted with ethanol, aqueous 2.5 M KOH (-10 eq) was added, refluxed for 2 hours, cooled, and concentrated.
[0147] The reaction mixture was then diluted with toluene, and the precipitated solids (presumed to be Et3N and pyridium salts) were filtered off. The filtrate was concentrated and taken up in DCM. Hexanes were also added to cause further precipitation. The resulting solids were then filtered off. The mixture was adsorbed on silica gel and subjected purification by flash column chromatography (0 to 100% EtOAc/hexanes), to obtain a mixture of the required product and an unidentified impurity. On addition of DCM and letting stand, a white solid precipitate formed, which was filtered and identified as pure 3- (diphenylphosphorothioyl)-2-methyl-lH-indole (0.8 g, 2.3 mmol, 15 % yield). 1H NMR
(400 MHz, DMSO- ) δ ppm 2.05 (s, 3 H), 6.52 (d, J=8.0 Hz, 1 H), 6.76 (ddd, J=8.2, 7.1 , 1.0 Hz, 1 H), 7.03 (m, 1 H), 7.37 (dt, J=8.1 , 1.0 Hz, 1 H), 7.55 (m, 6 H), 7.81 (m, 4 H), 1 1.87 (br. s., 1 H); LC/MS: Method 1 , retention time 6.466 minutes; HRMS (m/z) calculated for C2iH19NPS+ (M+H)+ 348.0970, found 348.0973.
EXAMPLE 23
The synthesis of 3-(diphenylphosphorothioyl)-2-phenyl-l H-indole is described
[0149] 2-Phenyl-lH-indole was treated according to General Procedure E, to produce 3- (diphenylphosphorothioyl)-2-phenyl-lH-indole. 1H NMR (400 MHz, DMSO-cfe) δ ppm 6.65 (m, 1 H), 6.84 (ddd, J=8.3, 7.1 , 1.1 Hz, 1 H), 7.1 1 (m, 4 H), 7.26 (m, 4 H), 7.34 (m, 2 H), 7.43 (m, 2 H), 7.48 (dt, J=8.0, 1.0 Hz, 1 H), 7.84 (m, 4 H), 12.21 (m, 1 H); LC/MS: Method 1 , retention time 6.929 minutes; HRMS (m/z) calculated for C26H2iNPS+ (M+H)+ 410.1 127, found 410.1 135.
EXAMPLE 24
[0150] The synthesis of N-benzyl-3-(diphenylphosphorothioyl)-l H-indole-l- carboxamide is described below.
[0151] General Procedure F: Benzylamine (50 mg, 0.47 mmol) in THF (2 ml) was treated with triphosgene (58 mg, 0.20 mmol). A solid was observed to precipitate out of the solution. This solution was stirred for 30 minutes. A solution of 3-
(diphenylphosphorothioyl)-lH-indole (50 mg, 0.150 mmol), Et3N (200 μί, 1.435 mmol) in THF was then added to the reaction mixture, along with a small crystal of 4- dimethylaminopyridine (DMAP) (5 mg, 0.041 mmol). The reaction stirred for 2 hours and
worked up with water/EtOAc. The reaction contained unreacted 3-
(diphenylphosphorothioyl)-lH-indole and product, and was purified by HPLC to provide N- benzyl-3-(diphenylphosphorothioyl)-lH-indole-l -carboxamide. 1H NMR (400 MHz, DMSO- 6) δ ppm 4.46 (d, J=5.9 Hz, 2 H), 7.13 (ddd, J=8.1 , 7.0, 1.1 Hz, 1 H), 7.29 (m, 3 H), 7.35 (m, 4 H), 7.55 (m, 4 H), 7.61 (m, 2 H), 7.81 (m, 4 H), 7.96 (d, J=5.5 Hz, 1 H), 8.25 (dt, J=8.3, 0.8 Hz, 1 H), 9.1 1 (t, J=5.9 Hz, 1 H); LC/MS: Method 1 , retention time 7.169 minutes; HRMS (m/z) calculated for C28H24N2OPS+ (M+H)+ 467.1341 , found 467.1341.
EXAMPLE 25
[0152] The synthesis of 3-(diphenylphosphorothioyl)-N-(4-fluorobenzyl)-lH-indole- l - carboxamide is described below.
[0153] 4-Fluorobenzylamine was reacted with 3-(diphenylphosphorothioyl)-lH-indole according to General Procedure F, to produce 3-(diphenylphosphorothioyl)-N-(4- fluorobenzyl)-lH-indole-l -carboxamide. 1 H NMR (400 MHz, DMSO- ) δ ppm 4.45 (d, J=5.7 Hz, 2 H), 7.15 (m, 3 H), 7.31 (m, 2 H), 7.40 (m, 2 H), 7.55 (m, 4 H), 7.62 (m, 2 H), 7.81 (m, 4 H), 7.96 (d, J=5.5 Hz, 1 H), 8.25 (m, 1 H), 9.1 1 (t, J=5.8 Hz, 1 H); LC/MS:
Method 1 , retention time 7.188 minutes; HRMS (m/z) calculated for C28H23FN2OPS+ (M+H)+ 485.1247, found 485.1237.
EXAMPLE 26
[0154] The synthesis of N-benzyl-3-(diphenylphosphorothioyl)-2-methyl- lH-indole- l - carboxamide is described below.
[0155] Benzylamine was reacted with 3-(diphenylphosphorothioyl)-2-methyl-lH-indole according to General Procedure F, to produce N-benzyl-3-(diphenylphosphorothioyl)-2- methyl-1 H-indole- 1 -carboxamide. 1H NMR (400 MHz, DMSO- 6) δ ppm 2.1 1 (d, J=1.6 Hz,
3 H), 4.52 (d, J=5.9 Hz, 2 H), 6.51 (dt, J=8.1, 1.0 Hz, 1 H), 6.87 (ddd, J=8.2, 7.1 , 1.1 Hz, 1 H), 7.15 (ddd, J=8.4, 7.2, 1.3 Hz, 1 H), 7.29 (m, 1 H), 7.38 (m, 4 H), 7.49 (m, 1 H), 7.55 (m,
4 H), 7.62 (m, 2 H), 7.85 (m, 4 H), 9.37 (t, J=5.9 Hz, 1 H); LC/MS: Method 1 , retention time 7.090 minutes; HRMS (m/z) calculated for C29H26N2OPS+ (M+H)+ 481.1498, found
481.1499.
EXAMPLE 27
[0156] The synthesis of 3-(diphenylphosphorothioyl)-N-(4-fluorobenzyl)-2-methyl-lH- indole-1 -carboxamide is described below.
[0157] 4-Fluorobenzylamine was reacted with 3-(diphenylphosphorothioyl)-2-methyl- 1 H-indole according to General Procedure F, to produce 3-(diphenylphosphorothioyl)-N-(4- fluorobenzyl)-2-methyl- 1 H-indole- 1 -carboxamide. 1 H NMR (400 MHz, DMSO-i^) δ ppm 2.1 1 (s, 3 H), 4.51 (d, J=5.9 Hz, 2 H), 6.52 (d, J=8.0 Hz, 1 H), 6.88 (m, 1 H), 7.18 (m, 3 H),
7.46 (m, 3 H), 7.59 (m, 6 H), 7.85 (m, 4 H), 9.36 (t, J=5.9 Hz, 1 H); LC/MS: Method 1 , retention time 7.107 minutes; HRMS (m/z) calculated for C29H25FN2OPS+ (M+H)+ 499.1404.
EXAMPLE 28
[0158] The synthesis of 3-(diphenylphosphorothioyl)-N-(4-fluorobenzyl)-2-phenyl-l H- indole-l -carboxamide is described below.
[0159] 4-Fluorobenzylamine was reacted with 3-(diphenylphosphorothioyl)-2-phenyl- lH-indole according to General Procedure F, to produce 3-(diphenylphosphorothioyl)-N-(4- fluorobenzyl)-2-phenyl-l H-indole-l-carboxamide. 1H NMR (400 MHz, DMSO-^) δ ppm 4.25 (d, J=6.1 Hz, 2 H), 6.98 (m, 8 H), 7.10 (m, 1 H), 7.19 (m, 2 H), 7.27 (m, 5 H), 7.37 (m, 2 H), 7.55 (dt, J=8.3, 0.7 Hz, 1 H), 7.73 (m, 4 H), 9.13 (t, J=6.0 Hz, 1 H); LC/MS: Method 1 , retention time 7.345 minutes; HRMS (m/z) calculated for C34H27FN2OPS+ (M+H)+ 561.1560, found 561.1559.
EXAMPLE 29
[0160] The synthesis of 3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine is described below.
[0161] 3-(Diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine (62 mg, 0.178 mmol) and 2-bromo-l -phenyl ethanone (75 mg, 0.377 mmol) were reacted according to General Procedure B, to produce 3-(diphenylphosphorothioyl)-2-methyl-l-(2-oxo-2- phenylethyl)imidazo[l ,2-a]pyridin-l-ium, Br" (85 mg, 0.155 mmol, 87 % yield). 1H NMR (400 MHz, DMSO- ) δ ppm 1.62 (s, 3 H), 6.37 (s, 2 H), 7.66 (m, 7 H), 7.79 (m, 3 H), 7.91 (m, 4 H), 8.11 (dd, J=8.4, 1.4 Hz, 2 H), 8.18 (m, 1 H), 8.44 (m, 1 H), 8.76 (d, J=6.8 Hz, 1 H); LC/MS: Method 1 , retention time 5.391 minutes; HRMS (m/z) calculated for C28H24N2OPS+ (M)+ 467.1341, found 467.1346.
EXAMPLE 30
[0162] The synthesis of l-cinnamyl-3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2- a]pyridin-l-ium Br" is described below.
[0163] 3-(Diphenylphosphorothioyl)-2-methylimidazo[l,2-a]pyridine) and (E)-(3- bromoprop-l-enyl)benzene were reacted according to General Procedure B, to produce 1- cinnamyl-3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridin-l-ium, Br". 1H NMR (400 MHz, DMSO-< ) 6 ppm 1.75 (d, J=1.4 Hz, 3 H), 5.28 (m, 2 H), 6.43 (m, 1 H), 6.86 (d, J=16.0 Hz, 1 H), 7.32 (m, 3 H), 7.44 (m, 2H), 7.59 (td, J=7.1, 1.3 Hz, 1 H), 7.68 (m, 4 H), 7.78 (m, 2 H), 7.91 (m, 4 H), 8.20 (ddd, J=9.2, 7.2, 1.2 Hz, 1 H), 8.48 (m, 1 H), 8.70 (m, 1 H) ); LC/MS: Method 1, retention time 5.744 minutes; HRMS (m/z) calculated for C29H26N2PS+ (M)+ 465.1549, found 453.1553.
EXAMPLE 31
[0164] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l-phenethylimidazo[l ,2- a]pyridin-l-ium, Br" is described below.
[0165] 3-(Diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine and (2- bromoethyl)benzene were reacted according to General Procedure B, to produce 3- (diphenylphosphorothioyl)-2-methyl-l-phenethylimidazo[l,2-a]pyridin-l-ium Br". 1H NMR (400 MHz, DMSO- ) δ ppm 1.41 (d, J=1.4 Hz, 3 H), 3.07 (t, J=6.6 Hz, 2 H), 4.66 (t, J=6.8 Hz, 2 H), 7.1 1 (m, 2 H), 7.23 (m, 3 H), 7.49 (td, J=7.1, 1.3 Hz, 1 H), 7.66 (m, 4 H), 7.78 (m, 6 H), 8.04 (m, 1 H), 8.22 (m, 1 H), 8.65 (m, 1 H); LC/MS: Method 1, retention time: 5.180 minutes; HRMS (m/z) calculated for C28H26N2PS+ (M)+ 453.1549, found 453.1555.
EXAMPLE 32
[0166] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -(3- phenylpropyl)imidazo[l,2-a]pyridin-l-ium, TFA is described below.
[0167] 3-(Diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridine and (3- bromopropyl)benzene were reacted according to General Procedure B, to produce and purified by reverse phase HPLC, 3-(diphenylphosphorothioyl)-2-methyl-l-(3- phenylpropyl)imidazo[l ,2-a]pyridin-l-ium, TFA". 1H NMR (400 MHz, DMSO-</6) δ ppm 1.65 (m, 3 H), 2.05 (qd, J=8.0, 7.7 Hz, 2 H), 2.71 (m, 2 H), 4.42 (t, J=7.7 Hz, 2 H), 7.17 (m, 5 H), 7.52 (tt, J=7.0, 0.6 Hz, 1 H), 7.64 (m, 4 H), 7.74 (m, 2 H), 7.83 (m, 4 H), 8.13 (m, 1 H), 8.41 (m, 1 H), 8.62 (d, J=7.0 Hz, 1 H); LC/MS: Method 1 , retention time: 5.407 minutes; HRMS (m/z) calculated for C29H28N2PS+ (M)+ 467.1705, found 467.1709.
EXAMPLE 33
[0168] The synthesis of l -benzyl-3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2- a]pyridin-l -ium, TFA is described below.
3-Diphenylphosphorothioyl)-2-methylimidazo[ 1 ,2-a]pyridine and (bromomethyl)benzene were reacted according to General Procedure B, to provide l -Benzyl-3- (diphenylphosphorothioyl)-2-methyliniidazo[l ,2-a]pyridin-l -ium, TFA". 1H NMR (400 MHz, DMSO- e) 6 ppm 1.64 (m, 3 H), 5.76 (m, 2 H), 7.30 (m, 2 H), 7.39 (m, 3 H), 7.60 (m, 1 H), 7.68 (m, 4 H), 7.77 (m, 2 H), 7.91 (m, 4 H), 8.19 (m, 1 H), 8.44 (m, 1 H), 8.70 (d, J=6.8 Hz, 1 H); LC/MS: Method 1 , retention time: 5.160 minutes; HRMS (m/z) calculated for C27H24N2PS+ (M)+ 439.1392, found 439.1398.
EXAMPLE 34
[0169] The synthesis of l -benzyl-3-(diphenylphosphorothioyl)-2-methyl-lH-indole is described below.
[0170] General Procedure G: 3-(Diphenylphosphorothioyl)-2-methyl-l H-indole (40 mg, 0.1 15 mmol) and benzyl bromide (39.4 mg, 0.230 mmol) in DMF (2 ml) were treated with 95% sodium hydride (7.27 mg, 0.288 mmol) and stirred overnight. The reaction was quenched with careful addition of 1 ml of water, dried under a stream of nitrogen, and the residue was dissolved in DMSO, with slight amounts of MeOH, and then purified by reverse phase HPLC, to provide l -benzyl-3-(diphenylphosphorothioyl)-2-methyl-l H-indole. 1 H
NMR (400 MHz, DMSO- 6) δ ppm 2.13 (m, 3 H), 5.53 (s, 2 H), 6.37 (d, J=8.0 Hz, 1 H), 6.80 (m, 1 H), 7.02 (m, 2 H), 7.07 (m, 1 H), 7.26 (m, 1 H), 7.34 (m, 2 H), 7.57 (m, 7 H), 7.84 (m, 4 H); LC/MS: Method 1 , retention time: 7.308 minutes; HRMS (m/z) calculated for
C28H25NPS+ (M+H)+ 438.1440, found 439.1445.
EXAMPLE 35
[0171] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -phenethyl- lH-indole is described below.
[0172] 3-(Diphenylphosphorothioyl)-2-methyl-l -phenethyl-lH-indole was synthesized according to General Procedure G, from 3-(diphenylphosphorothioyl)-2-methyl-l H-indole and 2-bromoethylbenzene. 1H NMR (400 MHz, DMSO- ) δ ppm 1.74 (m, 3 H), 3.03 (m, 2 H), 4.43 (t, J=6.8 Hz, 2 H), 6.39 (d, J=8.0 Hz, 1 H), 6.81 (td, J=7.6, 1.0 Hz, 1 H), 7.05 (m, 2 H), 7.13 (m, 1 H), 7.26 (m, 3 H), 7.56 (m, 7 H), 7.76 (m, 4 H).; LC/MS: Method 1 , retention time: 7.393 minutes; HRMS (m/z) calculated for C29H27NPS+ (M+H)+ 452.1596, found 452.1604.
EXAMPLE 36
[0173] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -(3-phenylpropyl)-lH- indole is described below.
[0174] 3-(Diphenylphosphorothioyl)-2-methyl-l -(3-phenylpropyl)-l H-indole, was snthesized according to General Procedure G, from 3-(diphenylphosphorothioyl)-2-methyl- l H-indole and 3-bromopropylbenzene: 1H NMR (400 MHz, DMSO-i 6) δ ppm 1.99 (qd, J=7.7, 7.5 Hz, 2 H), 2.13 (m, 3 H), 2.67 (m, 2 H), 4.21 (m, 2 H), 6.34 (d, J=8.0 Hz, 1 H), 6.77 (m, 1 H), 7.08 (m, 1 H), 7.24 (m, 5 H), 7.47 (dd, J=8.3, 1.1 Hz, 1 H), 7.56 (m, 6 H), 7.82 (m, 4 H); LC/MS: Method 1 , retention time: 7.579 minutes; HRMS (m/z) calculated for
C30H29NPS+ (M+H)+ 466.1753, found 466.1752.
EXAMPLE 37
[0175] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -(3-phenylpropyl)-lH- indole is described below.
[0176] l -Cinnamyl-3-(diphenylphosphorothioyl)-2-methyl-lH-indole was synthesized according to General Procedure G, from 3-(diphenylphosphorothioyl)-2-methyl-lH-indole and 2-cinnamyl bromide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (d, 3 H), 5.04 (d, J=4.9 Hz, 2 H), 6.37 (m, 2 H), 6.44 (m, 1 H), 6.80 (m, 1 H), 7.10 (m, 1 H), 7.23 (m, 1 H), 7.31 (m, 2 H), 7.40 (m, 2 H), 7.57 (m, 7 H), 7.86 (m, 4 H); LC/MS: Method 1 , retention time: 7.578 minutes.
EXAMPLE 38
[0177] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -(4- phenylbutyl)imidazo[ l ,2-a]pyridin-l -ium, Br" is described below.
[0178] 1H NMR (400 MHz, DMSO-i/6) δ ppm 1.73 (m, 7 H), 2.62 (m, 2 H), 4.43 (m, 2 H), 7.18 (m, 3 H), 7.28 (m, 2 H), 7.55 (td, J=7.0, 1.4 Hz, 1 H), 7.68 (m, 4 H), 7.78 (m, 2 H), 7.89 (m, 4 H), 8.15 (ddd, J=9.1, 7.1, 1.2 Hz, 1 H), 8.42 (dd, J=9.1, 1.1 Hz, 1 H), 8.64 (m, 1 H); LC/MS: Method 1, retention time 5.638 minutes; HRMS (m/z) calculated for
C30H3oN2PS+ (M)+ 481.1868, found 481.1871.
EXAMPLE 39
[0179] The synthesis of 3-(diphenylphosphorothioyl)-2-methyl-l -(5- phenylpentyl)imidazo l ,2-a]pyridin-l-ium, TFA" is set forth below.
[0180] 1H NMR (400 MHz, DMSO-i 6) δ ppm 1.39 (m, 2 H), 1.61 (m, 2 H), 1.70 (s, 3 H), 1.76 (m, 2 H), 2.57 (t, J=7.4 Hz, 2 H), 4.39 (t, J=7.7 Hz, 2 H), 7.16 (m, 3 H), 7.26 (m, 2 H), 7.55 (m, 1 H), 7.68 (td, J=7.6, 3.5 Hz, 4 H), 7.78 (m, 2 H), 7.89 (ddd, J=14.7, 8.3, 1.3 Hz, 4 H), 8.15 (m, 1 H), 8.43 (m, 1 H), 8.65 (d, J=7.0 Hz, 1 H); LC/MS: Method 1, retention time 5.738 min; HRMS (m/z) calculated for C3iH32N2PS+ (M)+ 495.2030, found 495.2033.
EXAMPLE 40
[0181] The synthesis of l-cinnamyl-3-(diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l ,2-a]pyridin-l-ium, Br- is set forth below.
[0182] Step 1 : Preparation of 2-(4-fluorophenyl)imidazo[l,2-a]pyridine. 2-Bromo-l-(4- fluorophenyl)ethanone (1.15 g, 5.31 mmol) and pyridin-2-amine (500 mg, 5.31 mmol) in ethanol (10 ml) were heated in a microwave vessel at 150 °C for 30 minutes. The reaction was cooled, concentrated, diluted with dichloromethane, and washed with saturated aqueous NaHC03. The organic layer was separated, dried (MgS04) and purified via flash silica gel column chromatography (0 to 100% EtOAc/DCM) to provide 2-(4- fluorophenyl)imidazo[l,2-a]pyridine (0.67 g, 3.2 mmol, 59 % yield). 1H NMR (400 MHz, DMSO-c 6) δ ppm 1H NMR (400 MHz, DMSO-J6) δ ppm 6.90 (td, J=6.7, 1.4 Hz, 1 H), 7.26 (m, 3 H), 7.57 (m, 1 H), 8.00 (m, 2 H), 8.38 (d, J=0.8 Hz, 1 H), 8.52 (dt, J=6.8, 1.2 Hz, 1 H); LC/MS: Method 2, retention time 2.624 minutes.
[0183] Step 2: Preparation of 3-(Diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l ,2-a]pyridine. Chlorodiphenylphosphine (2.22 g, 10.1 mmol) was dissolved in toluene (2.5 ml) and treated with iodotrimethylsilane (1.37 ml, 10.1 mmol) under nitrogen at room temperature for 45 minutes. A solution of 2-(4-fluorophenyl)imidazo[l ,2- ajpyridine (0.61 g, 2.9 mmol), triethylamine (2.40 ml, 17.3 mmol)in pyridine (2.5 ml) was added to this mixture at rt under nitrogen. The mixture was stirred for 7 hours and then treated with sulfur (0.369 g, 11.5 mmol) and stirred for another 16 hours. The reaction was
concentrated, diluted with toluene and then concentrated again in vacuo (X2). The residue was adsorbed onto silica gel and then purified by flash silica gel column chromatography (5 to 100% EtOAc/DCM) to provide 3-(diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l ,2-a]pyridine (891 mg, 2.080 mmol, 72.3 % yield). 1H NMR (400 MHz, chloroform-;/) δ ppm 6.62 (m, 2 H), 6.75 (m, 1 H), 7.16 (m, 2 H), 7.24 (m, 4 H), 7.37 (ddd, J=7.8, 6.8, 1.2 Hz, 3 H), 7.71 (m, 5 H), 8.43 (d, J=7.0 Hz, 1 H); LC/MS: Method 2, retention time 3.544 minutes.
[0184] Final synthesis of l-cinnamyl-3-(diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l ,2-a]pyridin-l -ium, Br-. 3-(Diphenylphosphorothioyl)-2-(4- fluorophenyl)imidazo[l,2-a]pyridine and (E)-(3-bromoprop-l-enyl)benzene were reacted according to general procedure B to provide title compound. 1H NMR (400 MHz, chloroform- ) δ pp m 5.18 (m, 1 H), 6.09 (dt, J=15.8, 6.4 Hz, 1 H), 6.44 (d, J=15.8 Hz, 1 H), 6.79 (t, J=8.7 Hz, 2 H), 7.25 (m, 1 H), 7.34 (m, 9 H), 7.45 (m, 2 H), 7.55 (m, 2 H), 7.99 (m, 5 H), 8.16 (m, 1 H), 8.16 (dd, J=9.1, 1.1 Hz, 1 H), 5.18 (m, 1 H); LC/MS: Method 1 , retention time 5.732 minutes; HRMS (m/z) calculated for C34H27FN2PS+ (M)+ 545.1615, found 545.1617.
EXAMPLE 41
[0185] The following compounds were prepared by General procedure B and then purified by flash silica gel chromatography or reverse phase HPLC. The synthesis of (E)-l- (3-(4-chlorophenyl)allyl)-3-(diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridin-l - ium, TFA" is set forth below.
[0186] 1H NMR (400 MHz, DMSO- ) δ ppm 1.75 (d, 3 H), 5.28 (m, 2 H), 6.47 (m, 1 H), 6.84 (d, J=16.0 Hz, 1 H), 7.41 (m, 2 H), 7.47 (m, 2 H), 7.59 (td, J=7.1 , 1.2 Hz, 1 H), 7.69 (m, 4 H), 7.78 (m, 2 H), 7.91 (m, 4 H), 8.20 (ddd, J=9.2, 7.2, 1.2 Hz, 1 H), 8.47 (m, 1 H), 8.70 (m, 1 H); LC/MS: Method 1 , retention time 5.503 minutes; HRMS (m/z) calculated for C29H25C1N2PS+ (M)+ 499.1 168, found 499.1 166.
EXAMPLE 42
[0187] The synthesis of (E)-3-(diphenylphosphorothioyl)- 1 -(3-(4-fluorophenyl)allyl)-2- methylimidazo[l,2-a]pyridin-l -ium, TFA" is provided below.
[0188] LC/MS: Method 1 , retention time 5.313 minutes; HRMS (m/z) calculated for C29H25FN2PS+ (M)+ 483.1466, found 483.1465.
EXAMPLE 43
[0189] The synthesis of (E)-3-(diphenylphosphorothioyl)-l -(3-(4-fluorophenyl)allyl)-2- methylimidazo[l ,2-a]pyridin-l -ium, TFA" is provided below.
[0190] 1H NMR (400 MHz, DMSCW6) δ ppm 1.75 (d, J=1.4 Hz, 3 H), 3.75 (s, 3 H), 5.27 (m, 2 H), 5.75 (s, 1 H), 6.86 (m, 2 H), 7.01 (m, 2 H), 7.26 (m, 1 H), 7.59 (m, 1 H), 7.69 (m, 4 H), 7.78 (td, J=7.6, 1.6 Hz, 2 H), 7.91 (ddd, J=14.7, 8.4, 1.4 Hz, 4 H), 8.20 (m, 1 H), 8.48 (d, J=9.2 Hz, 1 H), 8.70 (m, 1 H); LC/MS: Method 1 , retention time 5.305 minutes; HRMS (m/z) calculated for C3oH28N2OPS+ (M)+ 495.1661 , found 495.1661.
EXAMPLE 44
[0191] The synthesis of (E)-l -(3-(2-chlorophenyl)allyl)-3-(diphenylphosphorothioyl)-2- methylimidazo[l ,2-a]pyridin-l -ium, TFA" is provided below.
[0192] 1 H NMR (400 MHz, DMSO- 6) δ ppm 1.76 (d, J=1.4 Hz, 3 H), 5.39 (m, 2 H), 6.46 (dt, J=15.8, 6.2 Hz, 1 H), 7.10 (d, J=16.0 Hz, 1 H), 7.33 (m, 2 H), 7.46 (m, 1 H), 7.65 (m, 6 H), 7.78 (m, 2 H), 7.91 (m, 4 H), 8.21 (ddd, J=8.9, 7.3, 1.2 Hz, 1 H), 8.50 (dd, J=9.2, 1.2 Hz, 1 H), 8.70 (m, 1 H); LC/MS: Method 1 , retention time 5.440 minutes; HRMS (m/z) calculated for C29H25C1N2PS+ (M)+ 499.1 168, found 499.1 170.
EXAMPLE 45
[0193] The synthesis of (E)-l -(3-(4-bromophenyl)allyl)-3-(diphenylphosphorothioyl)-2- methylimidazo[ l ,2-a]pyridin-l -ium, TFA" is set forth below.
[0194] 1H NMR (400 MHz, DMSCW6) δ ppm 1.74 (d, J=1.4 Hz, 3 H), 5.26 (dd, J=6.1 , 1.2 Hz, 2 H), 6.47 (m, 1 H), 6.81 (d, J=16.2 Hz, 1 H), 7.40 (d, J=8.6 Hz, 2 H), 7.57 (m, 3 H), 7.68 (m, 4 H), 7.78 (m, 2 H), 7.90 (m, 4 H), 8.19 (m, 1 H), 8.46 (dd, J=9.2, 1.2 Hz, 1 H), 8.70 (dd, J=6.9, 1.1 Hz, 1 H); LC/MS: Method 1 , retention time 5.555 minutes; HRMS (m/z) calculated for C29H25BrN2PS+ (M)+ 543.0660, found 543.0657.
EXAMPLE 46
[0195] The synthesis of (E)-l -(3-(3-chlorophenyl)allyl)-3-(diphenylphosphorothioyl)-2- methylimidazo l ,2-a]pyridin-l -ium, TFA" is provided below.
[0196] 1H NMR (400 MHz, DMSO-i¾) δ ppm 1.75 (m, 3 H), 5.29 (m, 2 H), 6.53 (dt, J=15.9, 6.1 Hz, 1 H), 6.82 (d, J=15.8 Hz, 1 H), 7.36 (m, 3 H), 7.54 (m, 1 H), 7.60 (m, 1 H), 7.69 (m, 4 H), 7.78 (m, 2 H), 7.90 (m, 4 H), 8.20 (m, 1 H), 8.46 (m, 1 H), 8.71 (d, J=7.0 Hz, 1 H); LC/MS: Method 1 , retention time 5.520 minutes; HRMS (m/z) calculated for
C29H25C1N2PS+ (M)+ 499.1 168, found 499.1 163.
EXAMPLE 47
[0197] The synthesis of (E)-3-(diphenylphosphorothioyl)-2-methyl-l -(3-(4
CF3CF(trifluoromethyl)phenyl)allyl)imidazo[l ,2-a]pyridin-l -ium, TFA" is set forth below.
[0198] 1H NMR (400 MHz, DMSO- 6) δ ppm 1.75 (d, J=l .4 Hz, 3 H), 5.32 (dd, J=6.7, 0.9 Hz, 2 H), 6.62 (dt, J=16.1 , 6.0 Hz, 1 H), 6.92 (d, J=16.0 Hz, 1 H), 7.59 (td, J=7.0, 1.2 Hz, 1 H), 7.68 (m, 8 H), 7.78 (m, 2 H), 7.91 (m, 4 H), 8.20 (ddd, J=8.9, 7.3, 1.2 Hz, 1 H), 8.47 (dd, J=9.2, 1.0 Hz, 1 H), 8.71 (m, 1 H); LC/MS: Method 1 , retention time 5.592 minutes; HRMS (m/z) calculated for C3oH25F3N2PS+ (M)+ 533.1427, found 533.1426.
EXAMPLE 48
[0199] The synthesis of (E)-l -(3-(3-bromophenyl)allyl)-3-(diphenylphosphorothioyl)-2- methylimidazo[l ,2-a]pyridin-l -ium, TFA" is provided below.
[0200] 1H NMR (400 MHz, chloroform-d) δ ppm 1.79 (d, J=0.4 Hz, 3 H), 5.35 (m, 2 H), 6.20 (m, 1 H), 6.57 (d, J=15.1 Hz, 1 H), 7.18 (t, J=7.7 Hz, 1 H), 7.26 (m, 2 H), 7.40 (m, 1 H), 7.47 (t, J=1.7 Hz, 1 H), 7.63 (m, 6 H), 7.96 (m, 5 H), 8.13 (m, 1 H), 8.81 (d, J=6.8 Hz, 1 H); LC/MS: Method 1 , retention time 5.552 minutes; HRMS (m/z) calculated for C29H25BrN2PS+ (M)+ 543.0660, found 543.0662.
EXAMPLE 49
[0201] The synthesis of (E)-l -(3-(3-bromo-4-fluorophenyl)allyl)-3- (diphenylphosphorothioyl)-2-methylimidazo[l ,2-a]pyridin-l -ium, TFA" is set forth below.
[0202] 1H NMR (400 MHz, chloroform-^ δ ppm 1.79 (d, J=1.4 Hz, 3 H), 5.35 (m, 2 H), 6.14 (m, 1 H), 6.58 (d, J=15.8 Hz, 1 H), 7.07 (t, J=8.3 Hz, 1 H), 7.27 (m, 2 H), 7.53 (dd, J=6.6, 2.2 Hz, 1 H), 7.59 (m, 4 H), 7.67 (m, 2 H), 7.96 (m, 5 H), 8.13 (d, J=9.2 Hz, 1 H), 8.80 (d, J=6.7 Hz, 1 H); LC/MS: Method 1 , retention time 5.566 minutes; HRMS (m/z) calculated for C29H24BrFN2PS+ (M)+ 561.0564, found 561.0565.
EXAMPLE 50
[0203] The synthesis of (E)-3-(diphenylphosphorothioyl)-2-methyl-l -(3-(naphthalen-2- yl)allyl)imidazo[l ,2-a]pyridin-l-ium, Br- is provided below.
[0204] LC/MS: Method 1 , retention time 5.633 minutes; HRMS (m/z) calculated for C33H28N2PS+ (M)+, 515.1712 found 515.1706.
EXAMPLE 51
[0205] In the following example, measurement of the inhibition of intracellular calcium stimulation of cells in vitro, after treating with one or more NPSAs of the present invention, using an intracellular calcium assay, is disclosed.
[0206] Intracellular calcium was measured using a BD PBX NW calcium assay kit (BD Bioscience, Rockville, MD). A Chinese hamster ovary cell line (CHO) stably expressing the NPSR (CHO-NPSR) was generated using standard tissue culture methods for CHO cells known in the art. The cells were maintained in F12 medium containing 10 % FBS, 100 units/ml Penicillin, 100 aglm\ Streptomycin, and 200 μg ml Geneticin (Invitrogen, Carlsbad, CA) at 37 °C, 5% C02. Cells were seeded at 3 μΐ/well with 1500 cells in black, tissue culture treated, clear bottom 1536-well plates (Greiner Bio-One, Monroe, NC). After overnight incubation at 37 °C 5% C02, cells were loaded with 3 μΐ of the calcium dye prepared as manufacture's instruction and incubated for another 1 hour. 23 nl of test compounds prepared in DMSO were then added using a pintool station (Kalypsys, San Diego, CA). Fluorescence was monitored over time as cells were challenged with EC80 of agonists (80 nM NPS for NPSR or 1 nM vasopressin for Vasopressin Vlb receptor) in a FDSS-7000 detector (Hamamatsu, Bridgewater, NJ). The basal fluorescence signal was first recorded for 10 seconds at 1 Hz, followed by addition of 2 μΐ agonist prepared in HBSS buffer supplemented with 0.1% BSA, and the antagonist response of compounds was recorded for another 170 seconds. The CCD binning was set to 2x2. The time-course fluorescence responses were expressed in terms of fluorescent change over background. The maximal fluorescent response was exported into a text file using the instrument's software data export utility. Concentration-response curves were fitted and EC50/IC50S were calculated with the GraphPad Prism® software (GraphPad, San Diego, CA), and are shown in Figure 1.
EXAMPLE 52
[0207] In the following example, measurement of the inhibition of cyclic AMP release in CHO-NPSR cells in vitro, after treating with one or more NPSAs of the present invention, using a cAMP assay, is disclosed.
[0208] Intracellular cAMP level was measured using LANCE cAMP detection kit (Perkin Elmer, Waltham, MA). After overnight incubation at 37 °C 5% C02, CHO-NPSR cells were
seeded at 4 μΐ/well with 2000 cells in white, tissue culture treated 1536-well plates. The cells were then treated with the addition of Ι μΐ of stimulation buffer (IX PBS buffer, 0.1 % BSA, 0.05% Tween-20, 500 μΜ Ro 20-1724 (Sigma-Aldrich), EC80 of NPS) to each well, and then the cells were incubated at 37 °C, 5 % C02 for 30 minutes. 1.25 μΐ of D2 conjugated cAMP, and 1 μΐ of cryptate conjugated anti-cAMP antibody were then added to the wells. D2 conjugated cAMP and cryptate conjugated anti-cAMP antibody were both prepared in cell lysis buffer according to the manufacturer's instructions. After 30 minutes, plates were then read in View Lux plate reader (Perkin Elmer, Waltham, MA) using the TRF detection mode optimized for HTRF.
[0209] About 23 nl of each of the NPSAs of the present invention, were added to each well by a pintool station, followed by addition of 1 μΐ stimulation buffer (IX HBSS buffer, 0.1% BSA, 5 mM HEPES, 500 μΜ RO-201724, 1.5% Alexa-647 conjugated anti-cAMP antibody stock, 100 nM NPS) by a BioRAPTR flying reagent dispenser (Beckman Coulter, Fullerton, CA). Cells were then incubated at 37 °C for 1 hour and 1 μΐ of detection reagent (IX detection buffer provided by the manufacturer, 1% TritionX-100, biotin labeled cAMP 1 :250 dilution, Eu-W8044 1 :750 dilution) were added. After 1 hour incubation at room temperature, plates were measured using the ViewLux ultraHTS microplate imager (Perkin Elmer) under LANCE setting (Figure 2).
EXAMPLE 53
[0210] In the following example, a competition binding assay for measurement of the inhibition of binding of radiolabeled NPS to NPS receptors after treatment with one or more NPSAs of the present invention, is disclosed.
[0211] Y10-NPS labeled with 125I was obtained from NEN Perkin Elmer (Boston, MA). In the competition binding assay, increasing concentrations of unlabeled human NPS or NPSAs were used to compete with 0.15nM [125I]Y10-NPS. Non-specific binding was determined in the presence of 1 μΜ unlabeled NPS. CHO-NPSR cells were first seeded into 24-well plates and cultured until reaching about 95% confluence. Cells were then washed once with 1 ml PBS and incubated with radioligand with, or without compounds, in DMEM medium containing 0.1% bovine serine albumin, at room temperature for about 90 minutes. Cells were washed twice with ice-cold PBS and lysed with 0.5ml IN NaOH. Bound
radioactivity was counted in a gamma counter. Data from duplicate were analyzed using GraphPad Prism (GraphPad, San Diego, CA), and the results are shown in Figure 3.
[0212] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[0213] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[0214] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Claims
1. A compound of General Formula I:
or a salt, solvate, or stereoisomer thereof;
wherein Ri and R2 are the same or different moieties and each are selected from the group consisting of: H, C]-C6 alkyl, C6-Ci4 aryl Cj-C6 alkyl, heterocyclyl Ci-C6 alkyl, Ci-C6 alkylamino Q-C6 alkyl, C C6 dialkylamino Ci-C6 alkyl, C6-C]4 aryl Q-Q alkylamino Ci-C6 alkyl, Q- , alkylthio Ci-C6 alkyl, C6-Ci4 arylthio, C6-Ci4 aryl Ci-C6 alkylthio d-C6 alkyl, C C6 alkylsulfonyl Ci-C6 alkyl, C6-C14 arylsulfonyl Ci-C6 alkyl, C6-Ci4 arylsulfinyl C C6 alkyl, hydroxy C\-C alkyl, Ci-C6 alkoxy, Ci-C alkoxy Cj-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, C6-Ci4 aryl, C6-Ci4 aryl CrC6 alkyl, Ci-C6 alkylamino, di Ci-C6 alkylamino, di Ci-C6 alkylamino Ci-C6 alkyl, thio Ci-C6 alkyl, thio C2-C6 alkenyl, thio C2-C6 alkynyl, C6- Ci4 aryloxy, C2-C6 acyloxy, thio C2-C6 acyl, amido, sulphonamido, Ci-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono Ci-C6 alkyl, carboxy Ci-C6 alkyl, dicarboxy Ci-C6 alkyl, dicarboxy halo Ci-C6 alkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, alkylamino, dialkylamino, trialkylamino, guanidine, aldehydo, ureido, and aminocarbonyl; wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl; wherein X is selected from the group consisting of a phosphorous atom and a carbon atom; wherein when X=C, R3=hydroxyl; when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom; and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
2. The compound, salt, solvate, or stereoisomer of claim 1, wherein Ri is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, C6-Ci4 aryl Ci-C6 alkyl, aryl Ci-C6 alkyamino, C6-Ci4 aryl Ci-C6 alkenyl, C -Ci4 aryl Ci-C6 alkylamino alkoxy, and C -C]4 aryl Ci-C6 alkoxy; wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy; wherein R2 is selected from the group consisting of H, Ci-C6 alkyl, C6-C]4 aryl, and C6- C14 aryl Ci-C6 alkyl; wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, and carboxy; wherein R3 is selected from the group consisting of thio, oxy, and hydroxyl; wherein X is selected from the group consisting of a phosphorous atom and a carbon atom; wherein when X=C, R3=OH; wherein when X=P, R3 is selected from the group consisting of a sulfur atom and an oxygen atom; and wherein Y is selected from the group consisting of a nitrogen atom and a carbon atom.
3. The compound, salt, solvate, or stereoisomer of either of claims 1 or 2, wherein Ri is selected from the group consisting of: H, Ci-C6 alkyl, C6-C]4 aryl, C6-C]4 aryl CrC6 alkyl, C6-Ci4 aryl Ci-C6 alkyamino, C6-Ci4 aryl Ci-C6 alkenyl, C6-Ci4 aryl Cj-C6 alkylamino alkoxy, and C6-Ci4 aryl Cj-C alkoxy; wherein the aryl, or heterocyclyl moiety is substituted with one or more halo groups.
4. The compound, salt, solvate, or stereoisomer of any one of claims 1-3, wherein the aryl, or heterocyclyl moiety is substituted with one or more fluoro groups.
5. A compound having the following General Formula I:
wherein R\ and R2 are the same or different moieties and each comprise a
hydrocarbon group which can be optionally substituted, R3 is either S, O, or OH, and X is either a phosphate atom or a carbon atom, wherein when X=C, R3=OH; and when X=P, R3=S, or O, and wherein Y is either N or C, and pharmaceutically acceptable salts, solvates or stereoisomers thereof.
6. The compound, salt, solvate, or stereoisomer of any one of claims 1-5, wherein R] is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, C6-Ci4 aryl Ci-C6 alkyl and C6-Ci4 aryl Ci-C6 alkenyl; wherein the aryl moiety is substituted with one or more halo groups; wherein R2 is selected from the group consisting of: H, Ci-C6 alkyl and C6-Ci4 aryl; wherein R3=S; wherein X=P; and wherein Y=N.
7. The compound, salt, solvate, or stereoisomer of any one of claims 1-6, wherein Ri is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, and C6-Ci4 aryl C C6 alkyl; wherein R2 is selected from the group consisting of: H, Ci-C6 alkyl and C6-C]4 aryl; wherein R3=S; wherein X=P; and wherein Y=N.
8. The compound, salt, solvate, or stereoisomer of any one of claims 1-7, wherein R1 is selected from the group consisting of: H, Ci-C6 alkyl, C6-Ci4 aryl, and C6-Ci4 aryl Ci-C6 alkyl; wherein R2 is selected from the group consisting of: H, and C]-C6 alkyl; wherein R3=S; wherein X=P; and wherein Y=N.
9. The compound, salt, solvate, or stereoisomer of any one of claims 1-8, wherein the compound is one of the following:
Example 27
10. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of any one of claims 1 -9, and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of any one of claims 1 -9, and at least one other compound, salt, solvate, or stereoisomer thereof, suitable for use in treating a neuropsychiatric disorder.
12. The pharmaceutical composition of claim 11, wherein the compound, salt, solvate, or stereoisomer suitable for use in treating a neuropsychiatric disorder is selected from the group consisting of the following drug classes: antipsychotics, antidepressants and anxiolytics.
13. A method of treating a neuropsychiatric disorder in a subject comprising administering a therapeutically effective amount of a compound, salt, solvate, or stereoisomer of any one of claims 1-9.
14. The method of treating a neuropsychiatric disorder of claim 13, wherein the neuropsychiatric disorder being treated comprises pain, sleep, mood, anxiety, eating and addictive disorders.
15. The method of claim 14, wherein the anxiety disorder being treated is selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder.
16. The method of claim 14, wherein the eating disorders being treated are selected from the group consisting of: anorexia nervosa and bulimia.
17. The method of claim 14, wherein the addictive disorders being treated are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction.
18. A method of treatment of a Neuropeptide S receptor related disorder in a subject comprising administering a therapeutically effective amount of a compound, salt, solvate, or stereoisomer of any one of claims 1-9.
19. A method of binding a Neuropeptide S receptor in a host cell comprising contacting the Neuropeptide S receptor with an effective amount of a compound, salt, solvate, or stereoisomer of any one of claims 1-9.
20. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of any one of claims 1-9, wherein the composition includes a pharmaceutically and physiologically acceptable carrier, in an amount effective for use in a medicament, preferably for use as a medicament for treating a neuropsychiatric disorder in a subject, preferably wherein the neuropsychiatric disorder comprises pain, sleep, mood, anxiety, eating and addictive disorders, or for use as a medicament for treating an anxiety disorder, preferably wherein the anxiety disorders are selected from the group consisting of: panic disorder, social phobia and obsessive-compulsive disorder, or for use as a medicament for treating an eating disorder, preferably wherein the eating disorders are selected from the group consisting of: anorexia nervosa and bulimia, or for use as a medicament for treating an addictive disorder, preferably wherein the addictive disorders are selected from the group consisting of: alcohol addiction, tobacco addiction, nicotine addiction, and intoxication and inhalation disorders associated with alcohol, tobacco and nicotine addiction, when
administered to the subject in an effective amount.
21. The pharmaceutical composition of claim 20, wherein the therapeutically effective amount of the compound, salt, solvate, or stereoisomer of any one of claims 1-6 administered to the subject is in a range of between about 0.001 mg kg/day to about 1000 mg/kg/day, preferably, at least about 0.01 mg/kg/day to about 100 mg/kg/day, more preferably, at least about 0.1 mg/kg/day to about 10 mg/kg/day.
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