WO1995012588A1 - Antineoplastic heteronaphthoquinones - Google Patents
Antineoplastic heteronaphthoquinones Download PDFInfo
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- WO1995012588A1 WO1995012588A1 PCT/CA1994/000210 CA9400210W WO9512588A1 WO 1995012588 A1 WO1995012588 A1 WO 1995012588A1 CA 9400210 W CA9400210 W CA 9400210W WO 9512588 A1 WO9512588 A1 WO 9512588A1
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- 0 *[C@](C(C(c1c(*)cccc11)=O)=C2C1=O)O[C@](C1)[C@@]2OC1=O Chemical compound *[C@](C(C(c1c(*)cccc11)=O)=C2C1=O)O[C@](C1)[C@@]2OC1=O 0.000 description 12
- NJHRUOKVTNTVMY-UHFFFAOYSA-N CCCC1OC(C(NCCc2ccc[n]2C)=O)=CC(C(c2ccccc22)=O)=C1C2=O Chemical compound CCCC1OC(C(NCCc2ccc[n]2C)=O)=CC(C(c2ccccc22)=O)=C1C2=O NJHRUOKVTNTVMY-UHFFFAOYSA-N 0.000 description 1
- CGAWCVWKGZNNQL-UHFFFAOYSA-N CCCC1OC(C(O)=O)=CC(C(c2c3cccc2)=O)=C1C3=O Chemical compound CCCC1OC(C(O)=O)=CC(C(c2c3cccc2)=O)=C1C3=O CGAWCVWKGZNNQL-UHFFFAOYSA-N 0.000 description 1
- OHBQPCCCRFSCAX-UHFFFAOYSA-N COc(cc1)ccc1OC Chemical compound COc(cc1)ccc1OC OHBQPCCCRFSCAX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- This invention relates to heterocyclic naphthoquinone derivatives, to processes, and to intermediates for
- Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B.,
- Tricyclic variants (3) of daunorubicin have been reported to possess antitumor activity (EPA 91202015.3)
- R is COCH 3 or C-CH or C-C-Si(CH 3 ) 3
- R 3 is H or COCF 3
- nanaomycin A (4) and kalafungin (5) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
- Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P.l and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently
- thiopyranoanthraquinone (7) and pyranoanthraquinone ( 8 ) were found to possess antitumor activity (PCT, CA9100208).
- antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycles 26 (4), 879-82, 1987).
- the present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
- the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused at carbon 1 to an alkyl, oxygen functionality, or alternatively to a sugar moiety.
- This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity.
- Some of the compounds are very active against certain doxorubicin-resistant tumor cells.
- X 1 and X 2 are independently selected from the group
- R 20 is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 1-16 acyl and C 1-16 alkylamine.
- X 3 is selected from the group consisting of O, S, SO, SO2, and
- R 21 is selected from the group consisting of hydroxyl, C 1-16 acyl, C 1-16 alkyl, C 1-16 aryl, C 1- 16 haloacyl, and hydrogen.
- X 4 is selected from the group consisting of C-Q, nitrogen, and NO.
- R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen; hydroxyl; C 1-16 alkyl; C 1-16 alkoxyl; C 3-8 cycloalkyl; tosyl; mesylate; triflate;
- aminoalkylaminoalkylhalide of formula NH(CH 2 ) n NH(CH 2 ) m X 10 wherein n and m are independently 1 to 4 and X 10 is halogen;
- alkenyl or C 2-8 alkynyl
- R 24 is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 2-12 alkoxyalkyl, C 7-18 aralkyl, C 7- 18 araloxyalkyl, C 7-18 aryloxyalkyl and C 6-18 aryl.
- Z is selected from the group consisting of hydrogen;
- Z may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, trifluoroacyl, cyano, C 7-18 aralkyl, C 6-18 aryl, a naturally occurring amino acid, a group of the formula -CHR 26 R 27 , wherein R 26 and R 27 are independently selected from the group consisting of C 1-8 alkyl, hydrogen, C 1-8 acyl, C6- 1 8 aryl, C 7-18 aralkyl, PO(OR 28 ) 2 wherein R 28 is hydrogen or C 1-8 alkyl.
- R 26 and R 27 may also be a group of the formula - (CH 2 ) n X 15 wherein n is 0 to 7 and X 15 is selected from the group consisting of hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
- R 29 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
- cycloalkyl C 1-8 acyl, trifluoroacyl, C 7- 18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
- R 25 may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, trifluoroacyl, cyano, C 7-18 aralkyl, C 6-18 aryl, or a naturally occurring amino acid.
- R 25 may also be an amino substituted with a group of the formula -CHR 26 R 27 , wherein R 26 and R 27 are independently selected from the group consisting of C 1-8 alkyl, hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, PO(OR 28 ) 2 wherein R 28 is hydrogen or C 1-8 alkyl,
- n 0 to 7 and X 15 is selected from the group consisting of hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
- R 29 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl. amino, which may be unsubstituted or mono- or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
- X 15 can also be a group of the formula - NR 30 R 31 or NOR 30 R 31 wherein R 30 , and R 31 , are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8
- alkoxyalkyl C 1-8 acyloxyalkyl, C 6-12 araloxyalkyl, a naturally occurring amino acid, and a group of formula
- n 1 to 6 and wherein R 34 is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkoxyalkyl, C 1-8 alkoxy, C 7- 18 aryloxyalkyl, C 7-18 araloxyalkyl, C 6-18 aryl, C 7-18 aralkyl,
- Z can also be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms
- R 35 is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C 1-4 alkyl and C 6-12 aryl,
- heterocycle being optionally substituted with one or more halogens, C 6-18 arylsulfone, hydroxy, C 1-16 alkoxy, nitro, C 1-16 alkyl, C 1-16 hydroxyalkyl, and amino which may be unsubstituted or mono- or
- C 1-8 alkyl C 3-8 cycloalkyl, acyl, trifluoroacyl, C 7-12 aralkyl, C 6-12 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy;
- halogen. and R 8 are independently selected from the group
- R 40 and R 41 are independently selected from a group consisting of C 1-8 alkyl, C 1-4 acyl, C 3-8 cycloalkyl, hydrogen, C 2-8 carboalkoxy, C 2-8 alkene, C 2-8 alkyne, C 6-12 aryl, and
- R 46 is selected from the group consisting of hydrogen, thiol, Ci-ig thioalkyl, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8
- R 47 is selected from the group consisting of hydrogen, C 1-16 alkyl and C 3-8 cycloalkyl,
- acosamine glucosamine
- N-chloroethyl- nitrosoureidoglucosamine 2,6-dideoxyrhamnose
- thioglucose thiodaunosamine
- thiol C 1-12 thioalkyl
- X 16 is selected from the group consisting of O, CH 2 , and
- R 50 is from the group consisting of
- R 48 and R 49 are independently selected from the group consisting of hydrogen, C 1-12 alkyl, C 6- 12 aryl, C 2-8 dihydroxyalkyl, C 2-8 alkene, C 2-8 alkyne, C 1-8 alkoxy, C 1-8 alkylamino, C 3-8
- R 48 and R 49 may also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
- heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
- R 5 and R 8 may also be mono or oligosaccharides of the
- Y is selected from the group consisting of
- R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C 1-16 alkoxy, C 1-16 alkyl, C 3-8 cycloalkyl, thiol, amino, trifluoroacetamido,
- R 11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, t-butylacyl, C 1-8 alkoxy, t- butyloxycarbonyl, trifluoroacyl, C 7-12 aralkyl, C 6-12 aryl, and a naturally occurring or
- n 0 to 5 and R 55 is selected from the group consisting of C 1-16 alkyl, C 1-16 acyl and C 7-18 aroyl,
- R 12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropyranyl ether (-OTHP), mesylate, tosylate, halogen, mono or
- oligosaccharides C 1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C 1-16 alkoxy, C 3-8 cycloalkyl, C 2-8 haloalkylacetate,
- R 5 and R 8 can also independently be a 5 or 6 membered
- aromatic or non-aromatic ring optionally containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO 2 , P, PO and NR 56 wherein R 56 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2- 8 alkenyl, C 2-8 alkynyl and hydroxy.
- R 8 and X 12 can further form a 5 or 6 membered aromatic or nonaromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
- R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
- Preferred compounds of formula (12) are those wherein: X 1 and X 2 are independently selected from the group
- X 3 is preferably selected from the group consisting of O; S;
- X 4 is preferably selected from the group consisting of CQ;
- R 1 , R 2 , R 3 , and Q are preferably independently selected from the group consisting of hydrogen; hydroxy; methoxy;
- n and m are independently 1 to 3;
- chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH 2 ) n CH 2 CI, wherein n is 0 to 4;
- R 24 is selected from the group consisting of hydrogen, C 1-6 alkyl, and
- Z is preferably selected from the group consisting of
- R 62 and R 63 are independently selected form the group consisting of C 1- 4 alkyl, hydrogen, C 1-4 acyl,
- X 21 is a hydrogen, C 1-4 acyl, hydroxyl
- heterocycle containing one or more heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C 1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C 1-4 alkyl, C 1-4 acyl, trifluoroacyl, and C 2-4 alkynyl.
- X 21 can also be a group of the formula NR 64 R 65 wherein R 64 and R 65 are independently selected from hydrogen, C 1-4 alkyl, C 1-4
- chloroalkyl C 1-4 hydroxyalkyl, and C 1-4 acyl.
- aminopropanol diacetoxy acetal aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl, C 2-4 alkenyl, C 2-4 acetylyl, C 1-4 alkoxy, hydroxy, C 1-4 aceto, amino which may be unsubstituted or
- heterocycle containing one or more heteroatoms selected from the group
- heterocycle consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C 1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C 1-4 alkyl, C 1-4 acyl,
- X 21 can also be a group of the
- C 1-4 alkyl independently selected from hydrogen, C 1-4 alkyl, C 1-4 chloroalkyl, C 1-4 hydroxyalkyl, and C 1-4 acyl.
- R 34 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 hydroxyalkyl, straight or branched C 1-8 alkyl, and
- amino which may be unsubstituted or mono- or di- substituted with C 1-8 alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, and
- heterocycle being optionally substituted with one or more halogen, hydroxy, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C 1-4 alkyl, C 3-5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy.
- R 8 are independently selected from the group
- n 1 to 4 and R 40 and R 41 are independently selected from the group consisting of hydrogen, C 1-5 alkyl, C 1-4 acyl.
- R 5 and R 8 also include acosamine; 2,6-dideoxyrhamnose; thiodaunosamine; C 1-5 thioalkyl; a naturally occurring amino acid or dipeptides thereof.
- Other preferred R 5 and R 8 are a group of the formula -X 16 - CHR 48 R 49 wherein X 16 is selected from the group
- R 50 is C 1-4 alkyl or C 2-4 acyl
- R 48 and R 49 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkene, C 1-5 alkylamino, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and
- heterocycle being optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di- substituted by C 1-4 alkyl, C 1-4 acyl and
- Y is preferably selected from the group
- R 9 and R 10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl.
- Preferred R 11 is selected from the group consisting of amino which may be unsubstituted or mono- or di- substituted with C 1-8 acetoxy alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl,
- R 12 is selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, halogen,
- amicetose aculose, rednose, rhodinose, 2- deoxyfucose, daunosamine, trifluoroacetyl- daunosamine,
- R 5 and R 8 can also preferably be independently selected from a 5 or 6 membered aromatic or non-aromatic ring
- heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
- R 56 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2- 8 alkenyl, C 2-8 alkynyl and hydroxy.
- R 8 and Z, or R 8 and X 21 can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and NR 57 wherein R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
- heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, and trifluoroacyl.
- More preferred compounds of formula (12) are those wherein:
- X 1 and X 2 are independently selected from the group
- X 3 is more preferably selected from the group consisting of
- X 4 is more preferably selected from the group consisting of
- R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen; hydroxy; methoxy; halogen; aminoethylaminoethanol;
- Z is selected from the group consisting of hydrogen; fluorine; methoxy; cyano; C 1-4 hydroxime; C 6-10 hydrazone; C 1-4 alkyl; C 1-4 hydroxyalkyl; phenyl; C 1-4 dihydroxyalkyl;
- X 15 can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C 1-3 alkoxy, and cyano.
- R 34 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, amino,
- R 5 and R 8 are independently selected from the group consisting of hydrogen; halogen; hydroxy; C 1-4 alkoxy; C 1-6 alkyl; C 2-4 alkene; methoxy; cyano; C 1-4 acetate; C 1-4 acetyl;
- Y is more preferably oxygen, sulfur, or CH 2 .
- R 9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, chlorine, amino, trifluoroacetamido, iodine, and hydroxyl.
- R 11 is selected from the group
- R 55 is selected from the group consisting of C 1-4 alkyl, C 1-4 acyl or C 7-8 aroyl and wherein n is
- R 12 is selected from the group
- R 5 and R 8 independently a 5 or 6
- R 56 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 acyl,
- cycle being optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, and
- R 8 and Z, or R 8 and X 21 can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
- R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl. said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, and trifluoroacyl.
- Still further preferred compounds of formula (12) are those wherein:
- X 1 and X 2 are both oxygen.
- X 3 is O; S; or SO.
- X 4 is CQ.
- R 1 , R 2 , R 3 and Q are each independently selected from the group consisting of hydrogen; fluorine; hydroxyl; and methoxy.
- n 0 to 2 and X 15 is a C 1-3 alkyl or a group of the formula - NR 30 R 31 wherein R 30 and R 31 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 acyl, and
- X 15 can also be a 5 or 6 membered aromatic or non- aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally
- Z can be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or two
- heteroatoms selected from the group consisting of O, S, N, and NH, said heterocycle being optionally substituted with one or more fluorine, hydroxy, methoxy, methyl, hydroxymethyl, cyano, amino and acylamino groups.
- R 5 and R 8 are independently selected from the group consisting of hydrogen; hydroxyl; methoxy; C 1-4 alkyl; bromine; chlorine; cyano; acetate; acetyl; and a saccharide of the formula
- Y is further preferably oxygen or CH 2 .
- R 9 and R 10 are independently
- R 11 is selected from the group
- n 3 to 5 and R 55 is selected from the group consisting of methyl, acyl or benzoyl,
- R 12 is hydroxyl, iodine, or bromine.
- R 5 and R 8 independently selected from 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, and N, and
- said cycle being optionally substituted by cyano, hydroxy, amino, or dimethylamino.
- X 1 and X 2 are both oxygen.
- X 3 is O or S.
- X 4 is CQ.
- R 2 and R 3 are both hydrogen.
- R 1 and Q are independently selected from the group
- Z is selected from the group consisting of ethyl
- acyl of the formula -C(R 25 ) O wherein R 25 is selected from the group consisting of methyl, fluoromethyl,
- R 5 is selected from the group consisting of hydrogen; hydroxyl; cyano; acetate; acetyl; methoxy;
- R 9 and R 10 are independently
- R 11 is preferably selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino.
- R 12 is preferably selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine.
- the invention also seeks to provide a process for the preparation of a compound of formula 12,
- X 3 is selected from the group consisting NR, O, or S; and R 1 , R 2 , R 3 , R 5 , R 8 , X 1 , X 2 , X 4 , and z are as defined above, selected from the group of processes consisting of:
- L is a leaving group selected from the group
- L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR* or -SR* wherein R* is a C 1-8 alkyl, and wherein R 1 , R 2 , R 3 and X 4 are as defined above, to yield only compounds of formula 21:
- the quinones at positions X 1 and X 2 of formula 21 may be converted to other moieties such as, for example, OH, S, NR 120 , where R 120 is hydrocarbon, and others.
- moieties such as, for example, OH, S, NR 120 , where R 120 is hydrocarbon, and others.
- the compound may further be optionally coupled with a saccharide of formula 50:
- alkyl as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, CI, Br, I or CF 3 , one or more alkoxy sustituent, one or more hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
- halo substituent such as
- cycloalkyl as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and
- aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C 1-4 alkyl, halogen, C 1-4 alkoxy, hydroxy or nitro.
- halogen as used herein means chlorine, bromine, fluorine or iodine.
- aralkyl refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and
- aroyl refers to a group of the formula -COAr wherein Ar denotes an "aryl” group as defined above.
- alkoxy or “aralkoxy” as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
- alkoxyalkyl as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
- aryloxyalkyl as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
- araloxyalkyl as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
- acyloxyalkyl as used herein means a C 1-8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
- hydroxyalkyl as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl.
- dimer as used herein means two compounds of formula 12 similar (homo-) or different (heterodimer) that are linked together by a common Z moiety, Z being as defined hereinabove. It will be appreciated by those skilled in the art that when reference is made to substituents, these substituents may be directly or indirectly linked to the tricyclic compound via a heteroatom or a carbon chain.
- R 5 and R 8 may independently be -X 101 -X 102 wherein X 101 may be O, OCH 2 , or CH 2 , and X 102 may be selected from the group consisting of a 5 or 6 membered aromatic or non-aromatic ring.
- This invention also includes all the possible dimers, epimers, salts, and isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at C 1 , C 2 and C 3 as well as in all the other chiral centers.
- This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (42) and (43).
- Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973) or “Protective Groups in Organic Synthesis” by Theodora W. Greene (John Wiley and Sons, 1981, 1991).
- suitable hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl,
- heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
- acyl e.g. acetyl or benzoyl
- silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
- alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic
- Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions.
- Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups.
- Heteronaphthoquinones of general formula (12) are prepared as illustrated in Scheme I.
- new or known isochromans of formula (14) are oxidatively demethylated with an oxidant such as eerie ammonium nitrate or silver oxide in an adequate solvent mixture such as acetonitrile-water, to give key
- heteronaphthoquinone of general formula (16) are air-oxidized in the presence of an inorganic base such as sodium hydroxide or an organic base such as triethylamine or 1,4-diaza-bicyclo-[2,2,2]-octane or a fluoride salt such as tetrabutylammonium fluoride to form a mixture of compounds of general formula 21 and 19.
- an inorganic base such as sodium hydroxide or an organic base such as triethylamine or 1,4-diaza-bicyclo-[2,2,2]-octane or a fluoride salt such as tetrabutylammonium fluoride
- compounds of general formula 19 can be deoxygenated to compounds of general formula 21 by using a reducing agent such as triphenylphosphine.
- An alternative method of preparing compounds of general formula 12 is by route B designated through the sequence consisting of steps B1-B3.
- the isochromans of formula 14 are first oxidized via an oxidative sequence consisting of an enolate addition to a selenylating agent such as
- organometallic reagents to the aldehydes 30 or addition of metalated 31 to epoxides 32 as shown in step A or B.
- step C position with a nucleophile such as an ester enolate 34, as seen in step C, can also lead to the formation of 35.
- the ring closure step C can be effected using an aldehyde or its acetal form under the influence of a Lewis acid such as borontrifluoride etherate.
- a Lewis acid such as borontrifluoride etherate.
- Compounds of general formula 14 may be prepared through the process described in Scheme 2. However, when Z is a group consisting of electron-withdrawing functional group such as methylester group, the ring closure step (step C, scheme 2) does not proceed with certain R 5 substituents. In this case, reduction of the carboxylate group is required. After the ring cyclization, the carboxylate functionality can be re-installed by an oxidative reactive step.
- compounds of formula 14 where R 5 is OCH 3 can serve as a precursor for other compounds of formula 14 where R 5 is not OCH 3 .
- a compound of formula 14 where R 5 is an alkyl can be obtained through the steps involving a Lewis acid treatment of the compound of formula 14 where R 5 is OCH 3 in the presence
- the diastereoisomers may be separated by conventional chromatography or fractional crystallization techniques.
- the racemic mixture whose enantiomic excess can be determined by the technique such as HPLC using a chiral column or NMR experiments using a chiral shifting agent known in the art. It is therefore appreciated that each enantiomer of the mixture is included within the scope of the invention.
- Resolution of the final product, or an intermediate or starting material therefor may be effected by any suitable method known in the art: see for example, “Stereochemistry of Carbon Compounds”, by E.L. Eliel (McGraw Hill, 1962), “Tables of Resolving Agents", by S.H. Wilen and
- the compounds of the formula (12) and (13) possess anti-cancer and anti-tumor activity. It is also believed that they are active against tumor cell lines for ex vivo treatments. While it is possible to administer one or more of the compounds of the invention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
- the invention therefore provides
- compositions primarily suitable for use as antitumor and anticancer agents comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in
- the compounds or pharmaceutical compositions of the invention may be formulated with the therapeutic agent to form a composition and administered to the patient or the compounds or compositions and the therapeutic agent may be administered separately, as appropriate for the medical condition being treated.
- composition of this invention can be used in association with one or more of the therapeutic agents belonging to any of the following groups:
- Hormones e.g. estrogens, androgens, tamoxifen,
- nafoxidine nafoxidine, progesterone, glucocorticoids, mitotane, prolactin);
- Cardioprotecting compounds such as ( ⁇ )-1,2- bis(3,5-dioxopiperazin-1-yl) propane, commonly
- Drug-resistance reversal compounds such as P- glycoprotein inhibitors, for example Verapamil, cyclosporin-c, fujimycin;
- Cytotoxic cells such as lymphokine activated killer - cells or T-cells
- Other Immunostimulants such as interleukin factors or antigens.
- Taxanes such as taxol and taxotere.
- compositions of the invention can be in forms suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intraarterial, intraperitoneal, intramuscular, subcutaneous and intravenous administration), by inhalation or by
- formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- the pharmaceutical composition forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the
- the carrier can be a solvent or
- dispersion medium containing, for example, water, ethanol.
- polyol for example, chremophor-EL, Tween 80 1 , glycerol, dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum drying and the freeze-drying
- compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, sachets or tablets each containing a predetermined
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
- the tablets may be coated according to methods well known in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
- the expression "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except isofar as any conventional media or agent is incompatible with the active ingredient, its use in the present compositions is contemplated.
- Supplementary active ingredients can be incorporated into the inventive compositions.
- Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
- the dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its severity; the particular form of the active ingredient, the potency of the active
- a daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient. The preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
- the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.
- a unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred.
- the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier.
- the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
- Antitumor treatment comprises the administration of any of the compounds of this invention in an acceptable
- compositions at the effective therapeutic dosage can require the use of any of the compounds of this invention bound to an agent which facilitates targeting the compound to the tumor cells.
- the agent may be chosen from, for example,
- monoclonal or polyclonal antibodies, proteins and liposomes could also be administered as monomeric, dimeric, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
- the compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian cancer, and melanoma. This list of conditions is however not exclusive, and it is believed that the compounds of the invention will exhibit activity against other tumors and cancers, such as for example pancreatic cancer, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxorubicin against P-170 mediated multidrug resistant cancers.
- Preferred compounds of this invention are as follows:
- BCH-2168 3-hydrochlorodimethylaminopropyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-)-carboxamide.
- BCH-2170 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
- BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide
- BCH-2166 1-methoxy-3-(3-N-pyrrolidinonylpropylcarboxamide)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2129 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H-naphtho [2,3-C] pyran.
- BCH-2157 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
- BCH-2160 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-methoxycarbonyl.
- BCH-2161 3-carboxyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2186 trans-1-methoxy-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-4a,10a-epoxy-naphtho-[2,3-c]-pyran.
- BCH-2824 1-methoxy-3-(3-bromopropylaminocarbonyl)5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2825 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2829 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-5a,10a-epoxy-naphtho-[2,3-c]-pyran.
- BCH-2830 3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2831 1-methoxy-3-(3-methylthiopropylamino)carbonyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
- BCH-2835 3-[2-(2-pyridinyl)ethlaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] hydrochloride.
- BCH-2836 3-[2-(N-morpholino)ethylaminocarbonyl]-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
- BCH-2837 3-(2-trimethylammoniumethylaminocarbonyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride.
- BCH-2840 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2841 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2861 1-Methoxy-3-[(2-(N-pyrrolidinylethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH-2877 3-N-oxo-dimethylaminopropyl-(1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide.
- BCH-2878 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]thiine-3-[N-(dimethylaminopropyl)carboxamide].
- BCH-2880 N-Methyl-N, N'-bis ⁇ 1-methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl ⁇ -propyldiamine.
- BCH2847 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methylamino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH2848 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH2849 1-methoxy-3-(3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- BCH2854 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran.
- microculture tetrazolium assay was used to test in vi tro cytotoxicity. This assay is described in Plumb, J.A. et al., 1989 Cancer Research 49, 4435-4440, which is herein incorporated by reference. The cytotoxicity of compounds towards tumor cells is measured in vi tro using the assay.
- This assay method is based upon the ability of live, but not dead cells to reduce the yellow water soluble dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to its water insoluble purple formazan product.
- MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- SKOV3 (Ovarian adenocarcinoma) - provided by Dr. V. Ling, Ontario Cancer Institute.
- T47D Ductal carcinoma of breast
- HTB-133 ATCC catalog # HTB-133.
- HT 29 Cold adenocarcinoma ATCC catalog # HTB- 38.
- the cells were maintained in exponential growth in culture in minimal essential media (MEM) supplemented with non-essential amino acids, and containing 15% (v/v) fetal bovine serum, 5mM L-glutamine, 1 mM sodium pyruvate, and 0.1 U/ml insulin. All cell lines were grown at 37°C in an atmosphere of 5% CO 2 in air.
- MEM minimal essential media
- Sorensen's buffer 0.1M glycine/NaOH, pH 10.5,
- Test compounds 20 mM in DMSO and diluted to a final concentration of 200 ⁇ M in culture medium before use.
- doxorubicin is included as an inter-assay standard. This allows us to monitor the behaviour of the assay in general, and in particular, to check that the SKVLB line has maintained its resistant phenotype.
- the plate layout is done in the following manner:
- the assays are carried out in 96-well (8 well ⁇ 12 well) microtiter plates. Serial dilutions of the compound are tested along the length of the plate. A 1:3 serial dilution of compound in culture medium covers a concentration range from 100 uM to 1.7nM. Each concentration of compound is tested in quadruplet, allowing two compounds to be tested per plate. Wells containing no cells (blank) and cells with no test compound (control) are included on each plate. Cells are plated out in 100 ⁇ l of culture medium in the microtiter plates at a density of around 1,500 - 4,000 cells per well.
- the plates are incubated overnight to allow the cells to become adherent after which the test compound is added (100 ⁇ l of appropriate dilution per well).
- the cells are incubated with test compound at 37°C for 48h after which the compound is replaced with fresh medium. After a further 48h incubation at 37°C, 50 ⁇ l of MTT solution (2mg/ml) is added to each well.
- the plates are incubated in the dark for 4h at 37°C after which the medium is removed.
- the MTT formazan product is extracted from the cells by the addition of 200 ⁇ l DMSO followed by 50 ⁇ l of Sorensen's buffer.
- the plates are shaken briefly and the absorbance at 570 nm is read using a Molecular Devices UV max plate reader. Curves are fit to the MTT assay data using a four parameter
- Table 1 shows the antitumor activity of some of synthetic tricyclic pyranylnaphthoquinones of this invention. A range of potency is observed in this set of compounds. Most notably BCH-2051, a "sugarless" tricyclic naphthoquinone, possesses intense in vitro antitumor potency while
- Methyl (5,8-dimethoxy-isochroman-3-yl) formate (15.00 g, 59.46 mmol) and DDQ (16.20 g, 71.35 mmol) were dissolved in dry dichloromethane (500 ml), and dry methanol (7.2 ml, 178.37 mmol) was added. The solution was stirred at ambient temperature overnight, then refluxed for 8 hours. Methanol (1.0 ml, 24.69 mmol) and DDQ (2.00 g, 8.81 mmol) was added and further refluxed for 8 hours. The reaction mixture was cooled down, filtered, and the filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml).
- Step 2 Methyl (1-Methoxy-5,8-dioxo-5,8-dihydro- isochroman-3-yl) formate
- CAN 83.24 g, 151.84 mmol
- sodium bicarbonate 8.50 g, 101.22 mmol
- water 500 ml
- methyl (1,5,8-trimethoxy-isochroman-3-yl) formate 14.34 g, 50.61 mmol
- Step 3 Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro- 1H-naphtho[2,3-c]pyran-3-yl) formate
- Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol)
- 1-acetoxybutadiene (30.00 g, 267.55 mmol)
- dry toluene 100 ml was stirred overnight at 50 C°.
- the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g).
- Step 4 Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl) formate
- Step 5 Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl)formate.
- Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1-acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in
- Step 8 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
- Example 3 1-methoxy-3-methoxy carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
- 1 H NMR (CDCI 3 , 300 MHz, Bruker), ⁇ : 3.69 (3H, s, COOCH 3 ),
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2947, 2938, 2855, 1734, 1678, 1659, 1595, 1562, 1444, 1384, 1327, 1294, 1275, 1234, 1133, 1069, 1001, 957, 863, 799, 770, 718.
- Step 1 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H- naphtho-(2,3-c)-pyran (BCH-2129) To a solution of 3-acetyl-5,10-dioxo-1-methoxy-3,4-5,10-tetrahydro-1H-naphtho (2, 3-c) pyran (50 mg, .175 mmole) in CH 3 CN (8 ml) and THF (4 ml) at 0°C was added 0.5N sodium hydroxide (1 equiv.). The mixture was stirred at 0°C for 15 minutes and it was allowed to come to room temperature.
- Example 5 Using the same carboxylic acid as described in Example 2, 1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran-3- carboxamides were prepared
- Step 1 1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2044)
- step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound
- IR (Nicolet , 205 FT, film on NaCl plate): cm -1 , 3322.9, 2929.3 2848.3, 1682.9, 1659.8, 1594.2, 1527.7, 1443.7,
- Step 2 1-methoxy-3-(3-N- pyrrolidinomylpropylaminocarbonyl)-5,10-dioxo- 5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2166)
- Step 4 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3- carboxamide (BCH-2157) 6 mg of product from step 3 herein was dissolved in 2 ml of ether. To this was added 6 ⁇ l of 1M HCl/ether solution (from Aldrich). The mixture was stirred, and then the solvent evaporated to give 6.7 mg of the HCl salt.
- Step 5 1-methoxy-3-[2-(N-morpholino) ethyl amino
- Step 6 1-methoxy-3-[2-(N-morpholine) ethyl amino
- step 8 The title compound was prepared using similar steps as detailed in example 2, step 8. During the process, compound I was present in the amountof 33 mg, 0.081 mmol, HCl (0.25 ⁇ l in ether) in the amount of 0.4 ml, 0.103 mmol, and 30 mg, 0.068 mmol of the title compound was produced.
- Step 7 1-methoxy-3-[2-(2-pyridinyl) ethyl amino
- step 7 The title compound was prepared using a similar method as detailed in example 2, step 7. During the process, compound I was present in the amount of 20 mg, 0.070 mmol, oxalyl chloride was present in the amount of 9.2 ⁇ l, 0.105 mmol, THF in the amount of 4 ml, DMF in the amount of 1 ⁇ l, and 1- (2-aminoethyl)-pyrrolidine in the amount of 8.28 ⁇ l, 0.070 mmol.
- Step 8 1-methoxy-3-[2-(2-pyridinyl) ethyl amino carbonyl]
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3324 (strong), 2926.1, 1677.6, 1651.0, 1522.6, 1274.3, 1083.6, 723.39.
- Step 9 1-methoxy-3-[(2-pyridinyl) methyl amino carbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3360.1, 2934.7, 1675.5, 1655.5, 1595.5, 1518.4, 1292.9, 1270.0, 1084.4, 950.23, 861.04, 719.77.
- Step 10 1-methoxy-3-[(2-pyridinyl) methyl amino
- Step 11 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: See example 2, step 7.
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3356.7, 2960.5, 2935.8, 2797.8, 1676.5, 1651.7, 1520.8, 1276.7, 1097.4, 1083.4, 953.25, 863.58, 794.8, 722.19.
- Step 12 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt
- Step 12 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt
- Step 13 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
- IR (Nicolet, 205FT, film on NaCl plate): cm -1 , 3337.8, 2967.7, 2932.3, 2877.2 ,1676.3, 1652.7, 1522.8, 1294.4, 1270.8, 1129.8, 1085.0, 952.02, 863.71, 798.63, 721.95.
- Step 14 1-methoxy-3- (3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: see example 12.
- IR (Nicolet, 205FT, film on NaCl plate): cm -1 , 3365.4, 2928.4, 1676.3, 1652.7, 1526.7, 1275.5, 1085.5, 950.95, 862.66, 795.81, 721.91.
- EXAMPLE 6 Preparation of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho- [2,3-c]-pyran.
- Step 1 (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8- dimethoxy-isochroman
- step 1 500 mg, 1.773 mmol
- allyl trimethyl silane 571 ⁇ l, 3.55 mmol
- boron trifluoride etherate 436.12 ⁇ l, 3.55 mmol
- the resulting liquid was stirred for 2 hours as it warmed to 20°C.
- the crude product was diluted with dichloroform, washed with sodium bicarbonate (10%), 0.01 N hydrogen chloride and brine. The organic layer was dried and
- step 1 The (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman described in step 1 (734 mg, 2.51 mmol) was dissolved in 40 ml of THF and subjected to hydrogenation conditions (1 at m, Pd/c-10%, 27 mg, 0.0251 mmol). After 2 hours at room temperature, the reaction mixture was
- step 2 The 1-propyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman isochroman described in step 2 (93 mg, 0.316 mmol) was dissolved in acetonitrile (8 ml) and then cooled to 0°C. A solution of ammonium cerium (IV) nitrate (519.7 mg, 0.948 mmol) in 2.0 ml of water buffered with sodium bicarbonate (53 mg, 0.632 mmol) was added dropwise. After 10 minutes the reaction mixture was poured to dichloromethane. The organic layer was washed with brine, dried and evaporated to give the titled compound (77 mg, 92%).
- IV ammonium cerium
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2958.4, 2932.9, 2873.2, 1745.3, 1657.2, 1489.6, 1461.2, 1444.1, 1304.9, 1262.3, 1219.7, 1097.5, 1040.7, 840.8.
- Step 4 1-propyl-3-methoxycarbonyl-3,4,5,10-tetrahydro- 5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2959.3, 2931.1, 2877.2, 1751.1, 1663.8, 1594.6, 1461.2, 1440.7, 1330.4, 1291.9, 1284.2, 1225.2, 1179.0, 1179.0, 1104.5, 872.11, 790.4, 717.4.
- Step 5 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran.
- Step 6 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H- naphtho-[2,3-c]-pyran.
- 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran 63 mg, 0.201 mmol was dissolved in tetrahydrofuran (4 ml) and cooled to 0°C. A solution of sodium hydroxide (2.41 ml, 0.1 N, 0.241 mmol) was added dropwise.
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3667-2500 (strong), 2864.6, 2927.4, 2869.6, 2634.0, 1732.9, 1712.3, 1670.9, 1654.4, 1592.4, 1567.6, 1394.0, 1332.0, 1298.9, 1265.9, 1227.6, 1071.1, 719.09.
- step 7 this compound was prepared. During the preparation, 29 mg of 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran, 21.2 ⁇ l, 0.243 mm of oloxalyl chloride, and 12.5 ⁇ l, 0.99 mmol of 3-dimethyl amino propyl amine was used to produce 33.6 mg, 90% of the title compound.
- This compound was prepared using similar steps as explained in example 2, step 8. During the process, 16 mg, 0.042 mmol of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran was used along with HCl in ether - 1 eq, to produce 15 mg of the title compound.
- IR (Nicolet, 205 FT, film on NaCl) : cm -1 , 2958.9, 2926.0, 2978.4, 1736.2 1699. 6, 1644 .7, 1589. 8, 1432.4 , 1297.0, 1267.7, 1238.4, 1120.1, 764.48 , 711.07 , 632.30.
- triphenylphosphine 308.4 mg, 1.176 mmol
- Tricyclic carboxylic acid 25 mg, 0.084 mmol
- CH 2 CI 2 2 ml
- oxalyl chloride 0.1 ml of 2 M solution in CH 2 CI 2
- Excess reagent was pumped off and the acid chloride in CH 2 CI 2 (2 ml) was treated with 1-(2-amino ethyl)-pyrrolidine (9 mg, 0.079 mmol) in CH 2 CI 2
- Example 12 1-methoxy-3-(2-trimethyl ammonium ethyl amino carbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran chloride salt
- Example 14 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran
- step 7 the titled compound was prepared.
- IR Nicolet 205 FT, film on NaCl plate
- Example 16 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2937.0, 2771.1, 1676.7, 1648.2, 1595.6, 1565.9, 1300.8, 1108.7, 1054.6, 949.16, 839.44, 801.92, 722.25.
- Example 17 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
- IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2942.4, 2768.2, 1677.5, 1643.2, 1597.5, 1571.8, 1297.7, 1109.3,
- Example 18 1-Methoxy-3 [2- (N-pyrrolidinylethoxylcarbonyl)]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
- step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound.
- IR Nicolet 205 FT, film on NaCl plate
- cm -1 2959, 2932, 2863, 1733, 1677, 1659, 1594, 1565, 1497, 1461, 1393, 1337, 1287, 1267, 1236, 1139, 1069, 990, 860, 798, 769, 743, 720.
- Step 1 Methyl-1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho [2,3-c] thiine-3- carboxylate Methyl-1-methoxy-5,8-dioxo-5,8-dihydro-3-isothiocromane
- Step 1 (1'S) Methyl (5,8-dimethoxy-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-1H-benzo[2,3-c]thiopyran-3- yl) ketone
- 3-acetyl-5,8-dimetoxythioisochromane (2.52 g, 10.00 mmol)
- 3,4-di-O-acetyl-2,6-dideoxy-L-lyxohexopyranose (sugar) (2.79 g, 12.00 mmol)
- Step 2 (1'S) Methyl (5,8-dioxo-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-5,8-dihydro-1H-benzo[2,3- c]thiopyran-3-yl) ketone
- Step 3 ( 1 ' S ) Methyl ( 5, 10-dioxo-1- (2 ' , 3 ' , 4 ' , 6 ' - tetradeoxy-3 ' , 4 ' -diacetoxy-L- lyxohexopyranose-5,10-dihydro-1H-naphtho[2,3- c]thiopyran-3-yl) ketone
- step 7 the carboxylic acid from step 6, example 2, was converted to the titled compound.
- the title compound is a mixture of three isomers.
- IR Nicolet 205 FT, film on NaCl plate
- cm -1 3339, 2935, 2843, 1679, 1655, 1592, 1517, 1404, 1381, 1334, 1278, 1202, 1093, 954, 865, 796, 721.
- step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound.
- the title compound is a mixture of four isomers.
- 1 HNMR 300MHz, Bruker, CDCI 3 ) ⁇ : 1.92 (2H, m, -CH 2 -), 3.15
- IR Nicolet 205 FT, film on NaCl plate
- cm -1 3341, 2936, 2833, 1675, 1656, 1597, 1570, 1520, 1450, 1411, 1383, 1330, 1276, 1199, 1121, 1083, 1057, 987, 946, 915, 863, 794, 722.
- N-Boc-propyldiamine was prepared according to a procedure described by W. S. Saari, J. E. Schwering, P. A. Lyle, S. J. Smith and E. L. Engelhardt, J. Med. Chem. 1990, 33, 97-101.
- IR Nicolet 205 FT, film on NaCl plate
- cm -1 3339, 2973, 2934, 1679, 1659, 1603, 1522, 1451, 1365, 1335, 1276, 1170, 1083, 950, 864, 796, 720.
Abstract
Tricyclic heteronaphthoquinone derivatives, that have antineoplastic activity, are disclosed, together with processes for their synthesis. Some of these antineoplastic compounds have a saccharide moiety. Some members of this structurally distinct group exhibit activity against multiple drug resistant cancer cells.
Description
ANTINEOPLASTIC HETERONAPHTHOQUINONES
This invention relates to heterocyclic naphthoquinone derivatives, to processes, and to intermediates for
preparing these derivatives, to pharmaceutical compositions containing them, and to the use of these derivatives as antitumor agents in mammals.
BACKGROUND OF THE INVENTION
Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions.While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B.,
Sarosy, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986;
Arcamone, F., Doxorubicin, Academic Press, New York, 1980).
The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as
myelosuppression (Crooke, S.K., Anthracyclines; Current
Status and New Developments, Academic Press, N.Y. 1980) and cardiotoxicity (Olson, R.D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E.G. et al, Cancer Research, 49, 8-15, 1989; McGrath, T. et al.
Biochemical Pharmacology, 38 497-501, 1989). In view of the
proven effectiveness of known anthracyclines in the
treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
Several thousand anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, N.Y. 1980; Thomson, R.H., Naturally Occurring Quinones III:
Recent Advances, Chapman and Hall, New York 1987;
Anthracyclines: Current Status and New Developments,
Academic Press, New York, 1980; Brown, J.R. and Iman, S.H., Recent Studies on Doxorubicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J.R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med. Chem., 15, 125-164, 1978). The majority of known anthracyclines show two types of structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides attached at C-7 or C-10
(doxorubicin numbering). Some examples of the structural diversity of anthracycline antibiotics are:
Tricyclic variants (3) of daunorubicin have been reported to possess antitumor activity (EPA 91202015.3)
Pyranonaphthoquinones such as nanaomycin A (4) and kalafungin (5) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P.l and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently
thiopyranoanthraquinone (7) and pyranoanthraquinone ( 8 ) were found to possess antitumor activity (PCT, CA9100208). In contrast antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycles 26 (4), 879-82, 1987).
DESCRIPTION OF THE INVENTION
The present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
More specifically, the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused at carbon 1 to an alkyl, oxygen functionality, or alternatively to a sugar moiety. This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity. Some of the compounds are very active against certain doxorubicin-resistant tumor cells.
In one aspect of the invention, there is provided a compound of the formula (12):
and all salts, mono-epimers, poly-epimers, and dimers thereof, wherein
X1 and X2 are independently selected from the group
consisting of O, S, and
NR20, wherein R20 is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-16 acyl and C1-16 alkylamine.
X3 is selected from the group consisting of O, S, SO, SO2, and
NR21 , wherein R21 is selected from the group consisting of hydroxyl, C1-16 acyl, C1-16 alkyl, C1-16 aryl, C1- 16 haloacyl, and hydrogen. X4 is selected from the group consisting of C-Q, nitrogen, and NO.
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen; hydroxyl; C1-16 alkyl; C1-16 alkoxyl; C3-8 cycloalkyl; tosyl; mesylate; triflate;
thiol;
acetate optionally substituted with C1-8 alkyl,
trifluoroacetate, halogen, nitro, cyano, C1-16 acyl, C1- 16 arylacyl, nitroso;
aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH
wherein n and m are independently 1 to 4;
aminoalkylaminoalkylhalide of formula NH(CH2)nNH(CH2)mX10 wherein n and m are independently 1 to 4 and X10 is halogen;
amino which may be unsubstituted or mono or disubstituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8
alkenyl, or C2-8 alkynyl;
haloalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2X11, wherein n is 0 to 4 and X11 is halogen;
NH(CH2)nNR22R23 wherein n is 1 to 6, and R22 and R23 are
independently selected from hydrogen, C1-8 alkyl, C6- 18 aryl, C7-18 aralkyl, C1-8 acyl, and trifluoroacyl; and,
a group of the formula -O-(CO)R24 wherein R24 is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-12 alkoxyalkyl, C7-18 aralkyl, C7- 18 araloxyalkyl, C7-18 aryloxyalkyl and C6-18 aryl. Z is selected from the group consisting of hydrogen;
hydroxy; halogen; thiol; C1-16 sulfide; C1-16 alkoxy; C1- 16 hydroxime; C6-18 hydrazone; C1-16 hydroxyalkyl; C6-18 aryl; C7-18 aryloxyalkyl; C7-18 araloxyalkyl; phenyl; C1- 16 alkyl; C2-16 acetoxy; C1-16 dihydroxyalkyl; C2-8 alkenyl; C2-8 alkynyl; C3-8 cycloalkyl; squaric acid; C1- 16 alkyl squarate; cyano; dimethylphosphonato; phenyl sulfone; C1-18 aryl sulfone; C1-8 acetyl.
Z may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, trifluoroacyl, cyano, C7-18 aralkyl, C6-18 aryl, a naturally occurring amino acid, a group of the formula -CHR26 R27, wherein R26 and R27 are independently selected from the group
consisting of C1-8 alkyl, hydrogen, C1-8 acyl, C6- 18 aryl, C7-18 aralkyl, PO(OR28)2 wherein R28 is hydrogen or C1-8 alkyl.
R26 and R27 may also be a group of the formula - (CH2)nX15 wherein n is 0 to 7 and X15 is selected from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR29 wherein R29 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8
cycloalkyl, C1-8 acyl, trifluoroacyl, C7- 18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy.
Z may also be a group of the formula -C(R25)=X12 wherein X12 is selected from the group consisting of two hydrogens, 0, or its dioxolane or dioxane or dialkoxy C1-8 ketal, one hydrogen and R25i , wherein R25i is selected from C1-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and wherein R25 is selected from the group consisting of hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8
cycloalkyl, C6-18 aryl, C7-18 aralkyl,
fluoromethyl, difluoromethyl, C1-8 hydroxyalkyl, C2-16 alkene, squaric acid or squarate, C2-16
alkyne, C1-8 thioalkyl, C6-18 thioaryl, C1-4 alkyl squarate, C2-8 alkoxyalkyl, C6-18 araloxyalkyl, C2- 18 acyloxyalkyl, C1-16 alkoxy, C6-12 aryloxyalkyl, hydroxy, acetoxymethyl, bromomethyl, C1-8 aceto. R25 may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, trifluoroacyl, cyano, C7-18 aralkyl, C6-18 aryl, or a naturally occurring amino acid.
R25 may also be an amino substituted with a group of the formula -CHR26 R27, wherein R26 and R27 are independently selected from the group consisting of C1-8 alkyl, hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, PO(OR28)2 wherein R28 is hydrogen or C1-8 alkyl,
a group of the formula -(CH2)nX15 wherein n is 0 to 7 and X15 is selected from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR29 wherein R29 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl.
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy.
X15 can also be a group of the formula - NR30 R31 or NOR30R31 wherein R30, and R31, are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C1-8
alkoxyalkyl, C1-8 acyloxyalkyl, C6-12 araloxyalkyl, a naturally occurring amino acid, and a group of formula
CO(CH2)nC(PO(OR32)2)2 wherein n is 1 to 4 and R32 is hydrogen or C1-8 alkyl.
Z can also be a group of the formula -C(OR33)=O, wherein R33 is selected from the group consisting of hydrogen, C1- 16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C7-18 aryloxyalkyl, C6-18 araloxyalkyl, C6- 18 aryl, C1-16 alkenyl, and C7-18 aralkyl;
a group of the formula -(CH2)nC(R34)=O, wherein n is 1 to 6 and wherein R34 is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C1-8 alkoxy, C7- 18 aryloxyalkyl, C7-18 araloxyalkyl, C6-18 aryl, C7-18 aralkyl,
amino which may be unsubstituted, mono- or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C7-12 aralkyl, or C6-12 aryl.
Z can also be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms
selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR35 wherein R35 is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, C6-18 arylsulfone, hydroxy, C1-16 alkoxy, nitro, C1-16 alkyl, C1-16 hydroxyalkyl, and amino which may be unsubstituted or mono- or
disubstituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C7-12 aralkyl, C6-12 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy;
and,
NH(CO)N(NO) (CH2)nCH2X**, wherein n is 0 to 4 and X**
halogen. and R8 are independently selected from the group
consisting of hydrogen; halogen; hydroxyl; C1-16 alkoxyl;
C1-16 alkyl; C2-16 acetylenyl; C3-8 cycloalkyl; C2-16 alkenyl; C1-16 alkoxyalkylamino; cyano;
a group of the formula - (CH2)n-NR40R41 wherein n is 1 to
6, and, R40 and R41 are independently selected from a group consisting of C1-8 alkyl, C1-4 acyl, C3-8 cycloalkyl, hydrogen, C2-8 carboalkoxy, C2-8 alkene, C2-8 alkyne, C6-12 aryl, and
(OCH2CH(PO(OR42)2)2 wherein n is 0 to 5 and R42 is a hydrogen or a C1-8 alkyl;
a group of the formula -O-C(R45)=O, wherein R45 is
selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-8 alkoxyalkyl, and C6-12 aryl;
an acyl of the formula -C(R46)=O, wherein R46 is selected from the group consisting of hydrogen, thiol, Ci-ig thioalkyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8
hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 araloxyalkyl, C2-8 acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid or a synthetic amino acid;
a group of the formula -C(OR47)=O, wherein R47 is selected from the group consisting of hydrogen, C1-16 alkyl and C3-8 cycloalkyl,
acosamine; glucosamine; N-chloroethyl- nitrosoureidoglucosamine; 2,6-dideoxyrhamnose;
thioglucose; thiodaunosamine; thiol; C1-12 thioalkyl; a naturally occuring amino acid or di- and tri-peptides thereof;
a group of the formula -X16-CHR48R49 wherein X16 is selected from the group consisting of O, CH2, and
NR50 wherein R50 is from the group consisting of
hydrogen, C1-8 alkyl, C2-8 acyl and C6-12 aryl, and wherein R48 and R49 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C6- 12 aryl, C2-8 dihydroxyalkyl, C2-8 alkene, C2-8 alkyne, C1-8 alkoxy, C1-8 alkylamino, C3-8
cycloalkyl, C2-8 carboalkoxy.
R48 and R49 may also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR51 wherein R51 is selected from the group
consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl
sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6- 18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy.
R5 and R8 may also be mono or oligosaccharides of the
formula:
oxygen, sulfur, sulfoxide, sulfone,
CR52R53, wherein R52 and R53 are independently
hydrogen, or C1-8 alkyl,
NR54 wherein R54 is selected from the group
consisting of hydrogen, C1-8 alkyl, and C1-8 acyl.
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol, amino, trifluoroacetamido,
chloroethylnitrosoureido, and chloroethylureido.
R11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, t- butyloxycarbonyl, trifluoroacyl, C7-12 aralkyl,
C6-12 aryl, and a naturally occurring or
synthetic amino acid;
mono or dibenzylated amino, azido, acylated amino, trifluoroacylated amino, morpholino, cyano, substituted morpholino, mono-, di-, tri- or tetra- methoxy substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, C1-16 alkoxyl, C3-8 cycloalkyl, thiol, C1-8 sulfide,
a group of the formula NH(CH2)nCH(OR55)2 wherein n is 0 to 5 and R55 is selected from the group consisting of C1-16 alkyl, C1-16 acyl and C7-18 aroyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and
NH(CH2)2 OCH2CH(OAc)2.
R12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropyranyl ether (-OTHP), mesylate, tosylate, halogen, mono or
oligosaccharides, C1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C1-16 alkoxy, C3-8 cycloalkyl, C2-8 haloalkylacetate,
benzoate which may be unsubstituted or substituted with nitro,
acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)nCH2Cl wherein n is
0 to 4, and NH(CH2)2 OCH2CH(OAC)2. R5 and R8 can also independently be a 5 or 6 membered
aromatic or non-aromatic ring optionally containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR56 wherein R56 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2- 8 alkenyl, C2-8 alkynyl and hydroxy. and Z, or R8 and X12, can further form a 5 or 6 membered aromatic or nonaromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8
alkenyl, C2-8 alkynyl and hydroxy.
Preferred compounds of formula (12) are those wherein: X1 and X2 are independently selected from the group
consisting of O; S; and NH. X3 is preferably selected from the group consisting of O; S;
SO; SO2; NH; and NOH.
X4 is preferably selected from the group consisting of CQ;
N; and NO.
R1, R2, R3, and Q are preferably independently selected from the group consisting of hydrogen; hydroxy; methoxy;
halogen; C1-4 alkoxyl; tosyl; triflate; fluorine;
chlorine; amino;
aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH
wherein n and m are independently 1 to 3;
aminoalkylaminoalkylchloride of formula
NH(CH2)nNH(CH2)mCl where n and m are independently 1 to 3;
chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)n CH2 CI, wherein n is 0 to 4; and
a group of the formula -O-(CO)R24, wherein R24 is selected from the group consisting of hydrogen, C1-6 alkyl, and
C6-18 aryl.
Z is preferably selected from the group consisting of
hydrogen; C1-8 hydroxyalkyl; fluorine; C1-4 alkoxy;
cyano; C1-8 dihydroxyalkyl; C1-4 hydroxime; C6-10
hydrazone; phenyl; squaric acid; C1-16 alkylsquarate; C1- 4 alkyl;
amino which may be unsubstituted or mono- or di- substituted with hydrogen, C1-8 alkyl, C3-8
cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, or a group of the formula CHR62R63 wherein R62 and R63 are
independently selected form the group consisting of C1- 4 alkyl, hydrogen, C 1-4 acyl,
a group of the formula (CH2)nX21 wherein n is 0 to 3
and X21 is a hydrogen, C1-4 acyl, hydroxyl,
a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or more heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C1-4 alkyl, C1-4 acyl, trifluoroacyl, and C2-4 alkynyl.
Preferably X21 can also be a group of the formula NR64 R65 wherein R64 and R65 are independently selected from hydrogen, C1-4 alkyl, C1-4
chloroalkyl, C1-4 hydroxyalkyl, and C1-4 acyl.
Z may also preferably be a group of the formula - C(R25)=X12, wherein X12 is two hydrogens, or oxygen, and wherein R25 is preferably selected from the group consisting of hydrogen, C1-8 alkyl, C1-8
hydroxylalkyl, cyano, squaric acid, C1-4 alkyl
squarate, alkoxyalkyl, aminoacetaldehyde diethyl acetal, aminoacetaldehyde diacetoxy acetal,
aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl, C2-4 alkenyl, C2-4 acetylyl, C 1-4 alkoxy, hydroxy, C1-4 aceto, amino which may be unsubstituted or
mono- or di-substituted with hydrogen, C1-8 alkyl,
C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, or a group of the formula CHR26R27 wherein R26 and R27 are independently selected from the group consisting of C1-4 alkyl, hydrogen, C 1-4 acyl, a group of the formula (CH2)nX15 wherein n is 0 to 3 and X15 is a hydrogen, C1-4 acyl, hydroxyl, a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or more
heteroatoms selected from the group
consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C1-4 alkyl, C1-4 acyl,
trifluoroacyl, and C2-4 alkynyl.
Preferably, X21 can also be a group of the
formula NR30 R31 wherein R30 and R31 are
independently selected from hydrogen, C1-4 alkyl, C1-4 chloroalkyl, C1-4 hydroxyalkyl, and C1-4 acyl.
Z may also preferably be a group of the formula - C(OR33)=O, wherein R33 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aralkyl; and a group of the formula -(CH2)nC(R34)=O, wherein n is 1 to
3 and R34 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 hydroxyalkyl, straight or branched C1-8 alkyl, and
amino which may be unsubstituted or mono- or di- substituted with C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, and
a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N,
NO, NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-8 alkoxy, C1-8 alkyl, C1-8 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, C3-5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy. and R8 are independently selected from the group
consisting of hydrogen; halogen; hydroxyl; C1-8 alkoxy;
C1-8 alkyl; C2-4 alkene; C2-8 acetylenyl; C2-8 alkenyl; C1- 4 acetate; C1-4 acetyl; cyano;
a group of the formula -(CH2)n NR40R41 wherein n is 1 to 4 and R40 and R41 are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-4 acyl.
Preferred R5 and R8 also include acosamine; 2,6-dideoxyrhamnose; thiodaunosamine; C1-5 thioalkyl; a naturally occurring amino acid or dipeptides thereof. Other preferred R5 and R8 are a group of the formula -X16- CHR48 R49 wherein X16 is selected from the group
consisting of O, CH2 and
NR50 wherein R50 is C1-4 alkyl or C2-4 acyl,
and wherein R48 and R49 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkene, C1-5 alkylamino, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and
NR51 wherein R51 is selected from the group
consisting of hydrogen, C1-4 alkyl, and C1-4 acyl,
said heterocycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di- substituted by C1-4 alkyl, C1-4 acyl and
trifluoroacyl.
Other preferred R5 and R8 are a group of the formula -O- C(R45)=O, wherein R45 is selected from the group consisting of hydrogen and C1-8 alkyl,
acyl of the formula -C(R46)=O, wherein R46 is selected
from the group consisting of hydrogen, thiol, C1-8 alkyl, hydroxyalkyl, amino;
a group of the formula -C(OR47)=O, wherein R47 is hydrogen or C1-8 alkyl;
glucosamine; and
a saccharide of formula:
consisting of oxygen, sulfur, and CHR53 wherein R53 is hydrogen or C1-4 alkyl Preferred R9 and R10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl.
Preferred R11 is selected from the group consisting of amino which may be unsubstituted or mono- or di- substituted with C1-8 acetoxy alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl,
C1-8 alkoxyl, morpholino, azido, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, hydroxyl, mono or
dialkylated amino with 1 to 16 carbons, fluorine, a group of the formula NH(CH2)nCH(OR55)2 wherein n is 1 to 5 and R55 is independently selected from a group consisting of C1-8 alkyl, C1-8 acyl and
C7-12 aroyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and
NH(CH2)2 OCH2CH(OAc)2.
Preferably R12 is selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, halogen,
mono or oligosaccharide selected from the group
consisting of rhodosamine, cinerulose-B, L- cinerulose, D-cinerulose, cinerulose A,
amicetose, aculose, rednose, rhodinose, 2- deoxyfucose, daunosamine, trifluoroacetyl- daunosamine,
amino, trifluoroacetamido, mono or dimethylated amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkyl-nitrosoureido, acetoxy and
trifluoroacetoxy. R5 and R8 can also preferably be independently selected from a 5 or 6 membered aromatic or non-aromatic ring
optionally containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2 , P, PO and
NR56 wherein R56 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2- 8 alkenyl, C2-8 alkynyl and hydroxy. R8 and Z, or R8 and X21, can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, and trifluoroacyl.
More preferred compounds of formula (12) are those wherein:
X1 and X2 are independently selected from the group
consisting of 0 and NH.
X3 is more preferably selected from the group consisting of
O; S; and SO.
X4 is more preferably selected from the group consisting of
CQ; and N.
More preferably R1, R2, R3, and Q are independently selected from the group consisting of hydrogen; hydroxy; methoxy; halogen; aminoethylaminoethanol;
aminoethylaminoethylchloride;
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 2;
amino; and fluorine.
More preferably Z is selected from the group consisting of hydrogen; fluorine; methoxy; cyano; C1-4 hydroxime; C6-10 hydrazone; C1-4 alkyl; C1-4 hydroxyalkyl; phenyl; C1-4 dihydroxyalkyl;
acyl of the formula -C(R25)=O, wherein R25 is selected
from the group consisting of hydrogen, C1-4 alkyl, hydroxymethyl, acyloxymethyl, cyano, and
amino which may be unsubstituted or mono-or di- substituted by hydrogen, C1-3 alkyl, C2-3 acyl, a group of the formula -CHR26R27 wherein R26 and R27 are independently selected from hydrogen, and C1-3 alkyl,
a group of the formula -(CH2)nX15 wherein n is 0 to 2 and X15 is C1-3 alkyl or a group of the formula -NR30R31 wherein R30 and R31 are
independently selected from hydrogen, C1-3 alkyl, C1-3 acyl, and C2-3 chloroalkyl, and,
X15 can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano.
Z can also more preferably be a group of the formula - C(OR33)=O, wherein R33 is selected from the group consisting of hydrogen, C1-4 alkyl, C 1-4 alkenyl, aryl;
a group of the formula - (CH2)nC(R34)= O, wherein n is 1 to
3 and R34 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, amino,
dimethylamino;
a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, NH; said heterocycle being optionally substituted with one or more
halogens, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, amino which may be unsubstituted or mono-or disubstituted by methyl, cyclopropyl, acyl, and hydroxy.
More preferably R5 and R8 are independently selected from the group consisting of hydrogen; halogen; hydroxy; C1-4 alkoxy; C1-6 alkyl; C2-4 alkene; methoxy; cyano; C1-4 acetate; C1-4 acetyl;
a group of the formula -O-C(R45)=O, wherein R45 is
hydrogen or C1-8 alkyl;
acyl of the formula -C(R46)=O, wherein R46 is selected
from the group consisting of hydrogen, thiol, C1-8 alkyl, hydroxyalkyl, amino,
a group of the formula -C(OR47)=O, wherein R47 is hydrogen or C1-8 alkyl;
glucosamine; and
a group of the formula
More preferably R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, chlorine, amino, trifluoroacetamido, iodine, and hydroxyl.
More preferably R11 is selected from the group
consisting of hydroxy, acetoxy, amino,
dimethylamino, trifluoroacetamido, morpholino, cyano substituted morpholino, mono-, di-, tri-, tetra-methoxy substituted morpholino,
a group of the formula NH(CH2)nCH(OR55)2 wherein R55 is selected from the group consisting of C1-4
alkyl, C1-4 acyl or C7-8 aroyl and wherein n is
2 to 5,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, NH(CH2)4CH(OAc)2, NH(CH2)2OCH2CH(OAc)2, and
NH(CH2)OCH2CH2CH(OAc)2.
More preferably R12 is selected from the group
consisting of hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, amino, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine.
Also more preferred are R5 and R8 independently a 5 or 6
membered aromatic or non-aromatic ring optionally
containing one or two heteroatoms selected from the group consisting of O, S, N, and
NR56 wherein R56 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 acyl,
said cycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and
amino, which may be unsubstituted or mono-or di- substituted by C1-4 alkyl, C1-4 acyl and
trifluoroacyl.
More preferred, R8 and Z, or R8 and X21, can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl.
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, and trifluoroacyl.
Still further preferred compounds of formula (12) are those wherein:
X1 and X2 are both oxygen.
Further preferred, X3 is O; S; or SO.
Further preferred, X4 is CQ.
Further preferred, R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen; fluorine; hydroxyl; and methoxy.
Further preferred, Z is selected from the group consisting of hydrogen, fluorine, cyano, C1-3 hydroxime, methyl, ethyl, C1-3 alkyl, hydroxymethyl, 1,2 dihydroxymethyl, a group of the formula -C(R25)= X, wherein X is selected from the group of two hydrogen and oxygen, and wherein R25 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, hydroxymethyl,
acetoxymethyl, bromomethyl and C1-4 alkoxy, C2-3 alkenyl, C1-3 aceto,
amino which may be unsubstituted or mono-or di- substituted by hydrogen, C1-3 alkyl, C2-3 acyl a group of the formula -CH2R27 wherein R27 is selected from hydrogen, C1-3 alkyl, and C2-3 chloroalkyl, and,
a group of the formula -(CH2)nX15 wherein n is 0 to 2 and X15 is a C1-3 alkyl or a group of the formula - NR30R31 wherein R30 and R31 are independently selected
from hydrogen, C1-3 alkyl, C1-3 acyl, and
chloroethyl.
X15 can also be a 5 or 6 membered aromatic or non- aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally
substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano.
More preferred, Z can be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or two
heteroatoms selected from the group consisting of O, S, N, and NH, said heterocycle being optionally substituted with one or more fluorine, hydroxy, methoxy, methyl, hydroxymethyl, cyano, amino and acylamino groups.
Further preferred, R5 and R8 are independently selected from the group consisting of hydrogen; hydroxyl; methoxy; C1-4 alkyl; bromine; chlorine; cyano; acetate; acetyl; and a saccharide of the formula
Further preferably, R9 and R10 are independently
selected from the group consisting of hydrogen, fluorine, and iodine.
Further preferably, R11 is selected from the group
consisting of amino, hydroxy, dimethylamino, acetoxy, trifluoroacetamido, morpholino, cyano substituted morpholino, methoxymorpholino and
a group of the formula NH(CH2)nCH(OR55)2 wherein n is 3 to 5 and R55 is selected from the group consisting of methyl, acyl or benzoyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and
NH(CH2)OCH2CH(OAC)2.
Further preferably, R12 is hydroxyl, iodine, or bromine.
Also further preferred are R5 and R8 independently selected from 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, and N, and
said cycle being optionally substituted by cyano, hydroxy, amino, or dimethylamino.
Much further preferred compounds of formula (12) are those wherein:
X1 and X2 are both oxygen.
X3 is O or S.
X4 is CQ.
R2 and R3 are both hydrogen.
R1 and Q are independently selected from the group
consisting of hydrogen; fluorine; and hydroxyl.
Z is selected from the group consisting of ethyl;
hydroxymethyl; 1,2-dihydroxyethyl; carbonyl;
acyl of the formula -C(R25)=O wherein R25 is selected from the group consisting of methyl, fluoromethyl,
difluoromethyl, hydroxymethyl, and
amino optionally substituted with a group of the
formula (CH2)nX15 wherein n is 2 or 3, and X15 is hydroxyl, or a group of the formula
NH(R31)2 wherein R31 is selected from the group consisting of hydrogen, C1-3 alkyl, chloroethane, and hydroxyethane. More preferably. R8 is hydrogen.
More preferably, R5 is selected from the group consisting of hydrogen; hydroxyl; cyano; acetate; acetyl; methoxy;
propyl; and a saccharide of the formula
selected from the group consisting of hydrogen, fluorine, and iodine.
R11 is preferably selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino.
R12 is preferably selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine.
The invention also seeks to provide a process for the preparation of a compound of formula 12,
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected from the group consisting NR, O, or S; and R1, R2, R3, R5, R8, X1, X2, X4, and z are as defined above, selected from the group of processes consisting of:
Process A la. selecting a precursor isochroman compound of formula 14:
wherein X3, Z, R5 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula 15
2a. cyclo-adding said quinone 15 with a diene of formula 20:
consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR* or -SR* wherein R* is C1-8 alkyl, and wherein R1, R2, R3 and X4 are as defined above; to yield a tricyclic
heteronaphthoquinone of formula 16:
3a. air-oxidizing said tricyclic heteronaphthoquinone 16 in the presence of an inorganic base, an organic base, or a flouride salt, to yield a mixture of compounds of formula 21 and 19:
or, if a hydrogen peroxide scavenger such as
trimethylphosphite, triphenylphosphine, or dialkylsulfide is added, to yield the compound of formula 21:
4a. and, optionally, if compound of formula 19 is present, converting this compound to compounds of formula 21 by deoxygenating compounds of formula 19 using a reducing agent;
Process B
1b. selecting a precursor isochroman compound of formula 14:
wherein Z, R5, X3, and R8 are defined as above, oxidizing said compound 14 using a selenylating agent and a subsequent
hydrogen peroxide assisted oxidative elimination to give isochromans of formula 17:
2b. oxidatively demethylating said compound 17 with an oxidant to give a quinone compound of formula 18:
3b. cyclo-adding said quinone with a diene of formula 20
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR* or -SR* wherein R* is a C1-8 alkyl, and wherein R1, R2, R3 and X4 are as defined above, to yield only compounds of formula 21:
The quinones at positions X1 and X2 of formula 21 may be converted to other moieties such as, for example, OH, S, NR120, where R120 is hydrocarbon, and others. Such
conversions are carried out using known methodology by chemists skilled in the art. For example, these conversions are taught in "The Chemistry of the Quinonoid Compounds" V 1 and 2. John Wiley and Sons, 1988, which is incorporated herein by reference.
The compound may further be optionally coupled with a saccharide of formula 50:
The term "alkyl" as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, CI, Br, I or CF3, one or more alkoxy sustituent, one or more hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
The term "cycloalkyl" as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and
cyclooctyl. The term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C1-4 alkyl, halogen, C1-4 alkoxy, hydroxy or nitro.
The term "halogen" as used herein means chlorine, bromine, fluorine or iodine.
The term "aralkyl" as used herein refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and
triphenylmethyl.
The term "aroyl" as used herein refers to a group of the formula -COAr wherein Ar denotes an "aryl" group as defined above. The term "alkoxy" or "aralkoxy" as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
The term "alkoxyalkyl" as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
The term "aryloxyalkyl" as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
The term "araloxyalkyl" as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
The term "acyloxyalkyl" as used herein means a C1-8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
The term "hydroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl. The term "dimer" as used herein means two compounds of formula 12 similar (homo-) or different (heterodimer) that are linked together by a common Z moiety, Z being as defined hereinabove. It will be appreciated by those skilled in the art that when reference is made to substituents, these substituents may be
directly or indirectly linked to the tricyclic compound via a heteroatom or a carbon chain. For example, R5 and R8 may independently be -X101-X102 wherein X101 may be O, OCH2, or CH2, and X102 may be selected from the group consisting of a 5 or 6 membered aromatic or non-aromatic ring.
It will be further appreciated by those skilled in the art that when R1 = hydroxyl, X4 = C-OH, and X1=X2=O that
compounds of formula (42) exist in equilibrium with
tautomers of formula ( 43 ). Therefore, compounds of formula (43) are included within the scope of the invention.
This invention also includes all the possible dimers, epimers, salts, and isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at C1, C2 and C3 as well as in all the other chiral centers.
This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (42) and (43).
It will also be appreciated that the following reactions may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and
deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl or aryl (e.g. 2,4-dinitrophenyl), subsequent removal of the protecting group being effected when desired by
hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981, 1991). Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl,
diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic
conditions. Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups.
Heteronaphthoquinones of general formula (12) are prepared as illustrated in Scheme I. With reference to Scheme I route A, new or known isochromans of formula (14), are oxidatively demethylated with an oxidant such as eerie ammonium nitrate or silver oxide in an adequate solvent mixture such as acetonitrile-water, to give key
isochromandiones of formula (15). Cycloaddition of this latter quinone with dienes of general formula (20) in a solvent such as toluene can give the tricyclic
heteronaphthoquinone of formula (16). Tricyclic
heteronaphthoquinone of general formula (16) are air-oxidized in the presence of an inorganic base such as sodium hydroxide or an organic base such as triethylamine or 1,4-diaza-bicyclo-[2,2,2]-octane or a fluoride salt such as tetrabutylammonium fluoride to form a mixture of compounds of general formula 21 and 19. This transformation of step A3 can be directed to the unique formation of compound 21 provided that a hydrogen peroxide scavenger such as
trimethylphosphite, triphenylphosphine or dialkylsulfide is added. Alternatively, compounds of general formula 19 can be deoxygenated to compounds of general formula 21 by using a reducing agent such as triphenylphosphine. An alternative method of preparing compounds of general formula 12 is by route B designated through the sequence consisting of steps B1-B3. The isochromans of formula 14 are first oxidized via an oxidative sequence consisting of an enolate addition to a selenylating agent such as
phenylselenyl chloride and a subsequent hydrogen peroxide-assisted oxidative elimination (B1) known in the art.
Compounds of general formula 17 are converted to compounds of formula 21 following a sequence of steps B2 and B3 corresponding to the steps of A1 and A2 respectively.
The said process of the sequence of steps B1-B3 using selenylating agents such as phenylselenyl chloride and hydrogen peroxide to introduce a degree of unsaturation as shown in formula 21 may cause complications to compounds of general formula 14 where X3 is S or SO. It is suggested that dichlorodicyanoquinone is used to introduce the unsaturation with concomitant introduction of a group consisting of alkoxy such as methoxy or a glycoside consisting of formula
wherein Y, R9, R10, R11, and R12 are as defined above.
Where compounds of formula 30 and 31 are converted to the alcohol of formulation 35 using the addition of
organometallic reagents to the aldehydes 30 or addition of metalated 31 to epoxides 32 as shown in step A or B.
Alternatively, nucleophilic substitution at benzylic
position with a nucleophile such as an ester enolate 34, as seen in step C, can also lead to the formation of 35.
The ring closure step C can be effected using an aldehyde or its acetal form under the influence of a Lewis acid such as borontrifluoride etherate.
Compounds of general formula 14 may be prepared through the process described in Scheme 2. However, when Z is a group consisting of electron-withdrawing functional group such as methylester group, the ring closure step (step C, scheme 2) does not proceed with certain R5 substituents. In this case, reduction of the carboxylate group is required. After the ring cyclization, the carboxylate functionality can be re-installed by an oxidative reactive step. Alternatively, compounds of formula 14 where R5 is OCH3 can serve as a precursor for other compounds of formula 14 where R5 is not OCH3. For example, a compound of formula 14 where R5 is an alkyl can be obtained through the steps involving a Lewis acid treatment of the compound of formula 14 where R5 is OCH3 in the presence of an allyltrimethylsilane.
In the above processes, the compounds of formula (42) and (43) are generally obtained as a racemic mixture or
diastereoisomers. The diastereoisomers may be separated by conventional chromatography or fractional crystallization techniques. The racemic mixture whose enantiomic excess can be determined by the technique such as HPLC using a chiral column or NMR experiments using a chiral shifting agent known in the art. It is therefore appreciated that each enantiomer of the mixture is included within the scope of the invention.
Where the compound of formula (42) or (43) is desired as a single isomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate.
Resolution of the final product, or an intermediate or starting material therefor, may be effected by any suitable method known in the art: see for example, "Stereochemistry
of Carbon Compounds", by E.L. Eliel (McGraw Hill, 1962), "Tables of Resolving Agents", by S.H. Wilen and
"Stereoselective Aldol Condensations" by D.A. Evans, J.V. Nelson, and T.R. Taber (Top. Stereochem. 1982, 13, 1-115)
The compounds of the formula (12) and (13) possess anti-cancer and anti-tumor activity. It is also believed that they are active against tumor cell lines for ex vivo treatments. While it is possible to administer one or more of the compounds of the invention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
In another aspect, the invention therefore provides
pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents, comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in
association with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or
prophylactic ingredients. All the pharmaceutically
acceptable salts for example the HCl and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
It will be appreciated by those familiar with the art of clinical oncology that the compound (s) of this invention can be used in combination with other therapeutic agents, including chemotherapeutic agents (Cancer: Principles and Practices of Oncology, 3rd Edition, V.T. DeVito Jr., S.
Hellman and S.A. Rosenberg; Antineoplastic Agents edited by W.A. Remers, John Wiley and Sons, N.Y., 1984). Thus, it will be understood that the compounds or pharmaceutical compositions of the invention may be formulated with the therapeutic agent to form a composition and administered to the patient or the compounds or compositions and the
therapeutic agent may be administered separately, as appropriate for the medical condition being treated.
Therefore, for therapeutic purposes, a compound or
composition of this invention can be used in association with one or more of the therapeutic agents belonging to any of the following groups:
1) Alkylating agents
2) Antimetabolites
3) Intercalators
4) Mitotic inhibitors
5) Hormones (e.g. estrogens, androgens, tamoxifen,
nafoxidine, progesterone, glucocorticoids, mitotane, prolactin);
6) Immunostimulants
(e.g. human interferons, levamisole and tilorane);
7) Monoclonal and polyclonal antibodies;
8) Radiosensitizing and radioprotecting compounds
(e.g. metronidazole and misonidazole);
9) Other miscellaneous cytotoxic agents such as:
camptothecins;
quinolinequinones
cisplatin, cisrhodium and related platinum series complexes;
tricothecenes;
cephalotoxines;
10) Cardioprotecting compounds, such as (±)-1,2- bis(3,5-dioxopiperazin-1-yl) propane, commonly
known as ICRF-187, and ICRF-198;
II) Drug-resistance reversal compounds such as P- glycoprotein inhibitors, for example Verapamil, cyclosporin-c, fujimycin;
12) Cytotoxic cells such as lymphokine activated killer - cells or T-cells,
13) Other Immunostimulants such as interleukin factors or antigens.
14) Polynucleotides of sence or antisensing nature.
15) Polynucleotides capable of forming triple helices with DNA or RNA.
16) Polyethers
17) Distamycin and analogs.
18) Taxanes such as taxol and taxotere. The above list of possible therapeutic agents is not
intended to limit this invention in any way.
The pharmaceutical compositions of the invention can be in forms suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intraarterial, intraperitoneal, intramuscular, subcutaneous and intravenous administration), by inhalation or by
insufflation. Where appropriate, the formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
For injectable use, the pharmaceutical composition forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the
conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol.
polyol for example, chremophor-EL, Tween 801 , glycerol, dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other
ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying
technique. These methods yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, sachets or tablets each containing a predetermined
1 denotes trademark
amount of the active ingredient; as a powder or granules; as a solution; as a suspension; or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
As used herein, the expression "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except isofar as any conventional media or agent is incompatible with the active ingredient, its use in the present compositions is contemplated.
Supplementary active ingredients can be incorporated into the inventive compositions.
It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms
of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its severity; the particular form of the active ingredient, the potency of the active
ingredient, and the route of administration. A daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient. The preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred. Expressed in
proportions, the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier. In the case of compositions containing supplementary active ingredients,
the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Antitumor treatment comprises the administration of any of the compounds of this invention in an acceptable
pharmaceutical formulation at the effective therapeutic dosage. It is understood that chemotherapy can require the use of any of the compounds of this invention bound to an agent which facilitates targeting the compound to the tumor cells. The agent may be chosen from, for example,
monoclonal or polyclonal antibodies, proteins and liposomes. The compounds of this invention could also be administered as monomeric, dimeric, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
The compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian cancer, and melanoma. This list of conditions is however not exclusive, and it is believed that the compounds of the invention will exhibit activity against other tumors and cancers, such as for example pancreatic cancer, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxorubicin against P-170 mediated multidrug resistant cancers.
Preferred compounds of this invention are as follows:
BCH-2051 3-dimethylaminopropyl(1-methoxy-5,10-dioxo-5,10-dihydro-1H-naptho-[2,3-c]-pyran-3-yl)-carboxamide
hydrochloride.
BCH-2167 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylaminopropyl)carboxamide].
BCH-2168 3-hydrochlorodimethylaminopropyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-)-carboxamide.
BCH-2170 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide
hydrochloride.
BCH-2166 1-methoxy-3-(3-N-pyrrolidinonylpropylcarboxamide)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2839 3-[2-(N-pyrrolydinyl)ethylcarboxamide]-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
hydrochloride.
BCH-2129 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H-naphtho [2,3-C] pyran.
BCH-2044 phenyl-(1,3-cis-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran)-3-carboxamide.
BCH-2140 1[(tetraethyl-3,3-bis phosphonic ester)
propriamido ethoxy]-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran.
BCH-2157 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide. BCH-2160 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-methoxycarbonyl.
BCH-2161 3-carboxyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2184 (+/-)-Methyl╌(1-[trifluoroacetamidomethyl]-5,10-dioxo-5,10-dihydronaphto-[2,3-c]-pyran-3-yl)ketone.
BCH-2186 trans-1-methoxy-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-4a,10a-epoxy-naphtho-[2,3-c]-pyran.
BCH-2824 1-methoxy-3-(3-bromopropylaminocarbonyl)5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2825 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2829 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-5a,10a-epoxy-naphtho-[2,3-c]-pyran.
BCH-2830 3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2831 1-methoxy-3-(3-methylthiopropylamino)carbonyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
BCH-2835 3-[2-(2-pyridinyl)ethlaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] hydrochloride.
BCH-2836 3-[2-(N-morpholino)ethylaminocarbonyl]-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
hydrochloride.
BCH-2837 3-(2-trimethylammoniumethylaminocarbonyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride.
BCH-2840 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2841 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2861 1-Methoxy-3-[(2-(N-pyrrolidinylethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2871 N,N'-bis {1-Methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine.
BCH-2875 2-hydrochloro-(N-pyrrolidinyl)-ethyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]pyran-3)
carboxamide.
BCH-2876 2-(2-N-Methyl pyrrolyl) ethyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide.
BCH-2877 3-N-oxo-dimethylaminopropyl-(1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide.
BCH-2878 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]thiine-3-[N-(dimethylaminopropyl)carboxamide].
BCH-2879 Methyl 5,10-dioxo-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L-lyxohexapyranose)-5,10-dihydronaphtho-[2,3-c]thiopyran-3-yl) ketone.
BCH-2880 N-Methyl-N, N'-bis {1-methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine.
BCH-2881 N-BOC-N-{1-mehtoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine.
BCH2847 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methylamino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH2848 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH2849 1-methoxy-3-(3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
BCH2854 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran.
In order that this invention may be more fully understood, the following examples are provided for the purpose of illustration only, and are not intended to be limiting in any way.
EXAMPLES
EXAMPLE 1 - In Vitro Cytotoxicity - Microculture Tetrazolium Assay
The microculture tetrazolium assay was used to test in vi tro cytotoxicity. This assay is described in Plumb, J.A. et al., 1989 Cancer Research 49, 4435-4440, which is herein incorporated by reference. The cytotoxicity of compounds towards tumor cells is measured in vi tro using the assay.
This assay method is based upon the ability of live, but not dead cells to reduce the yellow water soluble dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to its water insoluble purple formazan product.
The following reagents were used for :
tissue Culture, (Irvine Scientific Catalog)
-MEM containing nucleosides (Catalog # 9144)
Fetal Bovine Serum (Catalog # 3000)
Non-essential amino acids (Catalog # 9304)
Dulbecco's phosphate buffered saline (Catalog # 9240)
Sodium pyruvate (Catalog # 9334).
All other tissue culture and general reagents were from Sigma Chemical Company.
Human Tumor Cell lines, used were:
SKOV3 (Ovarian adenocarcinoma) - provided by Dr. V. Ling, Ontario Cancer Institute.
SKVLB (Ovarian; multidrug resistant) - Dr. V.
Ling, Ontario Cancer Institute.
T47D (Ductal carcinoma of breast) - ATCC catalog # HTB-133.
Lox (Melanoma) - Southern Research Institute.
HT 29 (Colon adenocarcinoma) ATCC catalog # HTB- 38.
The cells were maintained in exponential growth in culture in minimal essential media (MEM) supplemented with non-essential amino acids, and containing 15% (v/v) fetal bovine serum, 5mM L-glutamine, 1 mM sodium pyruvate, and 0.1 U/ml insulin. All cell lines were grown at 37°C in an atmosphere of 5% CO2 in air.
Stock solutions, used were the following;
MTT: 2 mg/ml in phosphate buffered saline
(stable at 4°C in dark for 1 week).
Sorensen's buffer: 0.1M glycine/NaOH, pH 10.5,
containing 0.1M NaCl.
Test compounds: 20 mM in DMSO and diluted to a final concentration of 200 μM in culture medium before use.
The following is the generic description of the assay method. It should be noted that although the conditions described work well with the cells listed above, the initial plating density and the MTT concentration used should be verified for each new cell line used to test compounds.
For each assay, doxorubicin is included as an inter-assay standard. This allows us to monitor the behaviour of the assay in general, and in particular, to check that the SKVLB line has maintained its resistant phenotype.
The plate layout is done in the following manner:
The assays are carried out in 96-well (8 well × 12 well) microtiter plates. Serial dilutions of the compound are tested along the length of the plate. A 1:3 serial dilution of compound in culture medium covers a concentration range from 100 uM to 1.7nM. Each concentration of compound is tested in quadruplet, allowing two compounds to be tested per plate. Wells containing no cells (blank) and cells with no test compound (control) are included on each plate.
Cells are plated out in 100 μl of culture medium in the microtiter plates at a density of around 1,500 - 4,000 cells per well. The plates are incubated overnight to allow the cells to become adherent after which the test compound is added (100 μl of appropriate dilution per well). The cells are incubated with test compound at 37°C for 48h after which the compound is replaced with fresh medium. After a further 48h incubation at 37°C, 50 μl of MTT solution (2mg/ml) is added to each well. The plates are incubated in the dark for 4h at 37°C after which the medium is removed. The MTT formazan product is extracted from the cells by the addition of 200 μl DMSO followed by 50 μl of Sorensen's buffer. The plates are shaken briefly and the absorbance at 570 nm is read using a Molecular Devices UV max plate reader. Curves are fit to the MTT assay data using a four parameter
logistic equation, and the data are normalized to fit a 0% to 100% survival scale. RESULTS
Table 1 shows the antitumor activity of some of synthetic tricyclic pyranylnaphthoquinones of this invention. A range of potency is observed in this set of compounds. Most notably BCH-2051, a "sugarless" tricyclic naphthoquinone, possesses intense in vitro antitumor potency while
significantly avoiding multidrug resistance as observed from the SKVLB cell line.
BIOLOGICAL RESULTS
TABLE 1
IC50 μM
COMPOUND SKOV3 SKVLB T47D LOX HT29 VLB/OV3
Adriamycin 0.012- 1.49- 0.07 0.034 0.090- 121.5
0.033 4.9 0.31
BCH2044 1.44 5.11 4.25 0.38 0.194 3.55
BCH2051 0.0073 0.0675 0.0419 0.0167 0.091 - 9.3 -
-0.029 -0.403 - 0.03 0.134 14.14
0.0685
BCH2129 0.3590 1.06 0.4520 0.2280 2.07 2.95
BCH2140 2.2 13 1.5 0.45 3.22 5.94
BCH2157 0.1870 3.39 0.2330 0.0155 1.23 18.13
BCH2160 4.93 9.12 9.59 7.43 15.70 1.85
BCH2161 0.6250 3.08 1.35 0.6510 4.14 4.93
BCH2166 0.14- 0.4950- 0.2370 0.4430- 2.73
0.1810 1.2 1.2
BCH2167 0.0384 0.1130 0.0520
BCH2168 0.18- 0.98 0.5730 0.3930- 0.2760 1.2
BCH2170 0.2590 0.3940 0.2440 1.52
BCH2171 0.088- 0.4220- 0.3980 0.2190 2.16
0.1950 0.44
BCH2184
BCH2186
BCH2824 1.06 2.76 2.76 2.60
BCH2825 12.50 27.10 25.50 2.17
BCH2829 55.10 >100 69.90
BCH2830 7.12 10.80 12.50 1.52
BCH2831
BCH2835
BCH2836
BCH2837
BCH2839 0.0365- 0.2240- 0.0581- 0.2620- 0.1740- 6.14-
0.0461 0.4600 0.2910 0.9750 -0.4900 9.98
BCH2840
BCH2841
BCH2847
BCH2848
BCH2849
BCH2854
BCH2861
BCH2871
BCH2875
BCH2876
BCH2877
BCH2878
BCH2879
BCH2880
BCH2881
BCH2881
Example 2: Preparation of naphthopyran derivatives
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate (BCH-2051)
Methyl (5,8-dimethoxy-isochroman-3-yl) formate (15.00 g, 59.46 mmol) and DDQ (16.20 g, 71.35 mmol) were dissolved in dry dichloromethane (500 ml), and dry methanol (7.2 ml, 178.37 mmol) was added. The solution was stirred at ambient temperature overnight, then refluxed for 8 hours. Methanol (1.0 ml, 24.69 mmol) and DDQ (2.00 g, 8.81 mmol) was added and further refluxed for 8 hours. The reaction mixture was cooled down, filtered, and the filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml). The organic phase was separated, washed with saturated sodium
bicarbonate solution (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title product (white crystals, 14.34 g, 85.1 %).
1H-NMR (250 MHz, Brucker, CDCI3), d: 2.70 (1H, dd, J=11.8 and 17.1 Hz, 4-Hax), 3.08 (1H, dd, J=4.2 and 17.1 Hz, 4- Heq), 3.57 (3H, s, 1-MeO), 3.77 (3H, s, Ar-OMe), 3.80 (3H, s, Ar-OMe), 3.83 (3H, s, COOMe), 4.79 (1H, dd, J=4.2 and 11.8 Hz, 3-Hax), 5.70 (1H, s, 1-H), 6.68 (1H, d, J=8 Hz, Ar-H), 6.74 (2H, d, J=8 Hz, Ar-H).
Step 2: Methyl (1-Methoxy-5,8-dioxo-5,8-dihydro- isochroman-3-yl) formate The solution of CAN (83.24 g, 151.84 mmol) and sodium bicarbonate (8.50 g, 101.22 mmol) in water (500 ml) was added to the solution of methyl (1,5,8-trimethoxy-isochroman-3-yl) formate (14.34 g, 50.61 mmol) in
acetonitrile (700 ml) at 0 - 5 C° over 20 minutes. The reaction mixture was stirred at 0 C° for 20 minutes, then extracted with dichloromethane (4x200 ml). The combined organic phases were washed with brine (200 ml), dried
(MgSO4) and evaporated under reduced pressure to give a light yellow solid (12.76 g, quantitative yield) which was used for the next step without further purification.
1H-NMR (250 MHz, Brucker, CDCI3), d: 2.52 (1H, dd, J=11.4 and 19.4 Hz, 4-Hax), 2.83 (1H, dd, J=4.2 and 19.4, 4-Heq),
3.56 (1H, s, 1-MeO), 3.82 (1H, s, COOMe), 4.66 (1H, dd, J=4.2 and 11.4 Hz, 3-Hax), 5.48 (1H, s, 1-H), 6.62 (1H, d, CHCO), 6.78 (1H, d, CHCO).
Step 3: Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro- 1H-naphtho[2,3-c]pyran-3-yl) formate
Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1-acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in toluene (200 ml), silica gel (20 g) was added and stirred over 24 hours in an open flask at ambient temperature. The silica was filtered, the filtrate was concentrated to dryness. The residue was recrystallized in methanol. The mother liquor was concentrated to dryness and the silica gel treatment was repeated as above. After recrystallization the mother liquor was concentrated to dryness and the residue was purified by flash chromatography on silica. Eluent:
toluene/ethyl acetate (4/1). All the crystals and the clean fraction from flash chromatography were combined to give 9.07 g, (59.6 %) title product.
1H-NMR (250 MHZ, Brucker, CDCI3), d: 2.68 (1H, dd, J=11.1 and 19.9 Hz, 4-Hax), 3.07 (1H, dd, J=4.4 and 19.9 Hz, 4-Heq), 3.62 (1H, s, 1-MeO), 3.83 (1H, s, COOMe), 4.72 (1H, dd, J=4.4 and 11.1 Hz, 3-Hax), 5.70 (1H, s, 1-H), 7.75 (2H, m, Ar-H), 8.08 (2H, m Ar-H).
Step 4: Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl) formate
Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-3-yl) formate (6.12 g, 20.25 mmol) was dissolved in dichloromethane (120 ml), triethylamine (5.64 ml, 40.49 mmol) was added and stirred at ambient temperature over 1 hour. The reaction mixture was poured onto water (100 ml) and ethyl acetate (400 ml), then neutralized with acetic acid. The organic layer was separated, the water layer was extracted with ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO4) and concentrated to dryness. To
the residue dichlorometane (60 ml) and saturated sodium bicarbonate solution (20 ml) was added, then stirred for 5 minutes. After separation the organic layer was dried
(MgSO4) and concentrated to 10 ml. This solution was
filtered through a short silica gel column. Eluent:
dichloromethane and 5% ethyl acetate in dichloro-methane. The clean fractions were combined and concentrated to dryness to give the title product (5.49g, 90.3 %).
1H-NMR (250 MHz, Brucker, CDCI3), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, s, COOMe), 6.38 (1H, s, 1-H), 7.33 (1-H, s, 4-H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 5: Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl)formate.
Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1-acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in
dichloromethane (200 ml), triethylamine (10.2 ml, 73.11 mmol) was added and stirred at ambient temperature over 1 hour. The reaction mixture was poured onto water (200 ml) and ethyl acetate (800 ml), then neutralized with acetic acid. The organic layer was separated, the water layer was extracted with ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO4) and concentrated to dryness. To the residue dichlorometane (120 ml) and saturated sodium bicarbonate solution (40 ml) was added, stirred for 5 minutes. After separation the organic layer was dried
(MgSO4) and concentrated to dryness to give the title product (8.98 g, 59.4 %).
1H-NMR (250 MHz, Brucker, CDCI3), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, S, COOMe), 6.38 (1H, s, 1-H), 7.33 (1-H, s, 4-H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H). Step 6: 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-carboxylic acid
Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl) formate (6.31 g, 21.01 mmol) was suspended in tetrahydrofuran (126 ml) and sodium hydroxide (0.92 g, 23.12 mmol) dissolved in water (63 ml) was added dropwise at 0 C° over 30 minutes. The reaction mixture was stirred at 0 C° over 1 hour, then it was acidified to pH = 3 with 5%
hydrochloric acid. Sodium chloride (2 g) was added. The water layer was separated and extracted with ethyl acetate (3x40 ml). The water layer was acidified to pH = 2. The crystals formed were filtered and washed with water. The filtrate was extracted with ethyl acetate (4x40 ml). All the organic fractions - including the previous extractions as well - were combined, dried (MgSO4) and concentrated to dryness. The residue was combined with the crystals filtered out of the water phase before, and stirred with methanol (50 ml). for 15 minutes. The yellow crystals were filtered, washed with methanol to give the title product (5.21 g, 86.6 %).
1H-NMR (250 MHz, Brucker, DMSO-d6), d: 3.50 (3H, s, 1-MeO),
6.37 (1H, s, 1-H), 7.02 (1H, s, 4-H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H). Step 7: 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide]
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid (4.6 g, 16.13 mmol) was suspended in
tetrahydrofuran (46 ml) and DMF (0.1 ml) was added. The
suspension was cooled to 0 C° and oxalyl chloride (3.24 ml, 37.09 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0 C° over 30 minutes, then evaporated to dryness at reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), cooled to 0 C° and N,N-dimethylaminopropylamine (2.23 ml, 17.74 mmol) was added dropwise over 10 minutes. The solution was stirred at 0 C° over 15 minutes, then it was poured onto a saturated
solution of potassium carbonate (20 ml). The organic layer was separated, the water layer was extracted with
dichloromethane (3x10 ml). The combined organic phases were dried (MgSO4) and concentrated to dryness. The residue was dissolved in methanol (50 ml) and stirred with charcoal at ambient temperature over 30 minutes. After filtration the filtrate was concentrated to dryness. The residue was dissolved in a minimal amount of methanol and ether (15 ml) was added. The crystals were filtered, washed with ether to give the title product (4.15 g, 69.6 %).
1H-NMR (250 MHz, Brucker, CDCI3), d: 1.74 (2H, quint., CH2), 2.29 (6H, s, NMe2), 2.47 (2H, m, CH2), 3.35 - 3.65 (2H, m,
CH2), 3.63 (3H, s, 1-MeO), 6.37 (1H, s, 1-H), 7.33 (1H, s,
4-H), 7.75 (2H, m, Ar-H), 8.15 (2H, m, Ar-H), 8.70 (1H, broad, NH). Step 8 : 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] (4.15 g, 11.23 mmol) was dissolved in anhydrous dichloromethane (10 ml) and 1 M hydrochloric acid solution in ether (11.3 ml, 11.23 mmol) was added dropwise at 0 C°. At the end more ether (20 ml) was added and the suspension was stirred at 0 C° over 30 minutes. The crystals were filtered under argon atmosphere,
washed with dry ether and hexane to give the title product (4.32 g, 90.5 % ) .
1H-NMR (250 MHz, Brucker, DMS0-d6), d: 1.90 (2H, m, 2'-CH2),
2.72 (6H, s, NMe2), 3.00 (2H, m, 3'-CH2), 3.30 (2H, m, 1'-CH2), 3.60 (3H, s,MeO), 6.35 (1H, s, 1-H), 7.00 (1H, s, 4- H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.92 (1H, t,
CONH), 10.53 (1H, broad, NH+).
13C-NMR (250 MHz, Brucker, DMSO-d6), d: 23.8, 36.1, 41.8,
54.0, 56.2, 94.9, 98.1, 124.5, 125.6, 126.1, 130.9, 131.5, 134.1, 134.5, 149.9, 159.6, 181.2, 181.4.
Example 3 1-methoxy-3-methoxy carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
Triethylamine (0.479, 4.6 mmol) was added to a solution of compound I (0.709, 2.32 mmol) and triphenylphosphine (1.82 g, 6.95 mmol) in THF (15 ml). The mixture was stirred at room temperature for 3 hours. Silica gel (10 g) was added. The residue from solvent evaporation was chromatographed on silica gel, eluting with ethyl acetate:hexane = 3:7. Evaporation of the fractions provided the titled compound (II) as a yellow solid (0.53 g, 76%). 1H NMR (CDCI3, 300 MHz, Bruker), δ: 3.69 (3H, s, COOCH3),
3.95 (3H, s, OCH3), 6.41 (1H, s, 1-H), 7.37 (1H, s, 4-H),
7.80 (2H, m, Ar-H), 8.17 (2H, m, Ar-H).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2947, 2938, 2855, 1734, 1678, 1659, 1595, 1562, 1444, 1384, 1327, 1294, 1275, 1234, 1133, 1069, 1001, 957, 863, 799, 770, 718.
Example 4: Preparation of 3-aceto-5,10-dioxo-1-methoxy- 5,10-dihydro-1H-naphtho [2,3-c] pyran (BCH- 2129)
Step 1: 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H- naphtho-(2,3-c)-pyran (BCH-2129) To a solution of 3-acetyl-5,10-dioxo-1-methoxy-3,4-5,10-tetrahydro-1H-naphtho (2, 3-c) pyran (50 mg, .175 mmole) in CH3CN (8 ml) and THF (4 ml) at 0°C was added 0.5N sodium hydroxide (1 equiv.). The mixture was stirred at 0°C for 15 minutes and it was allowed to come to room temperature.
After 1.5 hour at room temperature the mixture was acidified with dil. HCl to pH~6. Saturated NH4Cl (5 ml) was added and the mixture was extracted with CH2CI2 (3x50 ml), washed with water (10 ml), dried and evaporated. The crude titled product was subjected to preparative TLC (eluent:
toluene:EtOAc=96:4) and pure product was isolated as a light yellow solid, mp. 154-56°C (3mg; 6%).
NMR (acetone-d6, δ): 2.50 (3H, s, ketomethyl), 3.63 (3H,s,- OCH3), 6.42 (1H,s,H-1), 7.11 (1H,s;H-4), 7.92 (2H,m;Ar-H),
8.14 (2H,m;Ar-H).
Example 5: Using the same carboxylic acid as described in Example 2, 1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran-3- carboxamides were prepared
Using a similar procedure as described in step 7, example 2, the carboxylic acid from step 6, example 2, was converted to the titled compound,
dec. 140°C; m.p. 200°C.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 3.68 (3H, s, OCH3), 6.48 (1H, s, 1-CH), 7.18 (1H, tr, J = 7.6 Hz, p-Ani-H), 7.49 (2H, tr, J = 8.0 Hz, m-Ani-H), 7.50 (1H, s, 4-CH), 7.66 (2H, d, J = 7.8 Hz, O-Ani-H), 7.79 (2H, m, 7, 8-ArH), 8.15 (2H, m, 6, 9-ArH), 8.40 (1H, s, NHCO).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3322.9, 2929.3 2848.3, 1682.9, 1659.8, 1594.2, 1527.7, 1443.7,
1374.2, 1297.0, 1258.4, 1063.2, 947.6, 863.1, 719.7, 693.6.
Step 2: 1-methoxy-3-(3-N- pyrrolidinomylpropylaminocarbonyl)-5,10-dioxo- 5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2166)
60 mg of the acid from step 6, example 2, was dissolved in 6.8 ml of dry THF, cooled to 0°C and 63 μl of oxalyl
chloride was added. The mixture was allowed to stir at 0°C for 20 minutes, and then at room temperature for 20 minutes. The solvent was then evaporated, the residue was redissolved in dichloromethane and evaporated, and then the residue was again dissolved into dry THF. The solution was cooled to -10°C. 29.3 μl of triethylamine and 19.90 μl of 1-(3-aminopropyl)-2-pyrrolidinone was added and allowed to stir for 45 minutes at -10°C and then 2 hours at room
temperature. The solvent was then evaporated to half of its original volume, the remaining solution was poured onto sat. brine and extracted into dichloromethane. The organic layer was then washed with sat. sodium bicarbonate solution, dried
over sodium sulfate, and evaporated to dryness to give 24 mg of pure titled product.
NMR (CDCI3 250 MHz, Bruker): δ, 1.86 (2H, Quin, J = 6.6 Hz, C-CH2-C), 2.08. (2H, Quin, J = 7.5 Hz, 4 '-pyrr-CH2), 2.45 (2H, t, J = 7.5 Hz, 3'-pyrr-CH2), 3.15-3.34 (2H, m,
CONHCH2), 3.36-3.55 (4H, m, CH2-pyrr, 5'-pyrr-CH2), 3.74 (3H, s, -OCH3), 6.43 (s, 1H, 4-CH), 7.32 (s, 1H, 1-CH), 7.70-7.78 (2H, m, 6, 9-ArH), 8.08-8.16 (3H, m, 7, 8-ArH, NH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3320.9, 2936.7, 2871.3, 1679.9, 1658.1, 1597.0, 1527.2, 1335.2, 1291.5, 1278.4, 1082.1, 947.98, 857.41, 801.34, 723.70. Step 3: (3-N-imidazolylpropyl)-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran-3-carboxamide
To a stirred solution of acid from step 6, example 2, (0.185 mmol, 53 mg) and catalytic amounts of DMF in 6 ml of THF at 0°C was added oxalyl chloride (0.426 mmol). After stirring at 0°C for one hour, and at room temperature for a further 20 minutes, the solvent was evaporated to dryness. 6 ml of THF was then added, and the mixture divided into two. 3 ml of solution was then cooled to -10°C, and 1-(3-amminopropyl)-imidazole (8.39 μl, 0.20 mmol) dissolved in 1 ml of THF was added dropwise. The mixture was allowed to stir for one hour at which time it was poured onto sat.
sodium bicarbonate solution, extracted into methylene chloride, washed with brine, dried over sodium sulfate and the solvent evaporated. Purification on TLC using 8% methanol/chloroform system produced 6 mg of pure titled product.
1H NMR (acetone -d6, 250 MHz, Bruker), δ: 2.10 (m, 2H, CH2-imidazol), 3.42 (m, 2H, C-CH2-C), 3.60 (s, 3H, OCH3), 4.14
(t, 2H, CH2NCO, 6.34 (s, 1H, 4-CH), 6.96 (s, 1H, 4-CH
(imidazol)), 7.16 (s, 1H, 1-CH), 7.18 (s, 1H, 5-CH
(imidazol)), 7.70 (s, 1H, 2-CH (imidazol)), 7.90 (m, 2H, 6, 9-ArH), 8.12 (m, 2H, 7, 8-ArH), 8.29 (m, 1H, NH).
IR (Nicolet 205 FT, film on NaCl plate), cm-1: 3313.5, 2932.1, 2853.4, 1676.1, 1665.4, 1593.2, 1552.8, 1334.1, 1274.0, 1087.5, 950.72, 859.52, 718.64.
Step 4: (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3- carboxamide (BCH-2157) 6 mg of product from step 3 herein was dissolved in 2 ml of ether. To this was added 6 μl of 1M HCl/ether solution (from Aldrich). The mixture was stirred, and then the solvent evaporated to give 6.7 mg of the HCl salt.
1H NMR (acetone-d6, 250 MHz, Bruker) for salt, δ: 2.29 (m, 2H, CH2-imidazol), 3.53 (m, 2H, C-CH2-C), 3.62 (s, 3H,
OCH3), 4.50 (m, 2H, CH2NHCO) , 6.33 (s, 1H, 4-CH), 7.14 (s, 1H, 1-CH), 7.55 (s, 1H, 5-CH(imi)), 7.76 (s, 1H, 4-CH(imi)), 7.88 (m, 2H, 7, 8-ArH), 8.05 (m, 2H, 6, 9-ArH), 8.64 (m, 1H, NH), 9.285 (s, 1H, 2-CH(imi)).
IR (Nicolet 205 FT, film on NaCl plate) cm-1: 3345.8,
1676.5, 1652.2, 1527.0, 1280.4, 1090.9, 955.01.
Step 5: 1-methoxy-3-[2-(N-morpholino) ethyl amino
carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3- c]-pyran
The title compound was prepared using a similar method as detailed in example 2, step 7. During the process, compound I was present in the amount of 20 mg, oxalyl chloride in the amount of 9.2 μl, 0.105 mmol, 4-(2-aminoethyl) morpholine in the amount of 9.3 μl, 0.07 mmol, to produce 33 mg of the title compound 1H NMR (CDCI3, 250 MHz, Bruker), δ: 2.50 (4H, tr, J = 6.1 Hz, morph-H), 2.58 (2H, tr, J = 5.8 Hz, CON-C-CH2), 3.50 (2H, m, CON-CH2), 3.63 (3H, s, OCH3), 3.71 (4H, tr, J = 6.1 Hz, morph-H), 6.37 (1H, s, 1-H), 7.30 (1H, br s, NH), 7.33 (1H, s, 4-H), 7.75 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
Step 6: 1-methoxy-3-[2-(N-morpholine) ethyl amino
carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3- c]-pyran
The title compound was prepared using similar steps as detailed in example 2, step 8. During the process, compound I was present in the amountof 33 mg, 0.081 mmol, HCl (0.25 μl in ether) in the amount of 0.4 ml, 0.103 mmol, and 30 mg, 0.068 mmol of the title compound was produced.
dec. 130°C, m.p. 187°C. 1H NMR (Acetone-d6, 250 MHz, Bruker), δ: 3.22 (2H, br tr, J
= 10 Hz, morph-CH2), 3.40 (2H, m, CONHCH2CH2), 3.62 (2H, br d, J = 11.0 Hz, morph-CH2), 3.74 (3H, s, OCH3), 3.88 (2H, m,
CONHCH2-CH2), 4.00 (2H, br d, J = 11 Hz, morph-CH2), 4.22
(2H, br tr, J = 10 Hz, morph-CH2), 6.35 (1H, s, 1-H), 7.15 (1H, s, 4-H), 7.93 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 9.46 (1H, br s, NH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3765.4 (strong), 2936.3, 2581.9, 1679.2, 1650.4, 1527.3, 1274.5, 1102.4, 948.4, 857.87, 720.70.
Step 7: 1-methoxy-3-[2-(2-pyridinyl) ethyl amino
carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3- c]-pyran
The title compound was prepared using a similar method as detailed in example 2, step 7. During the process, compound I was present in the amount of 20 mg, 0.070 mmol, oxalyl chloride was present in the amount of 9.2 μl, 0.105 mmol, THF in the amount of 4 ml, DMF in the amount of 1 μl, and 1- (2-aminoethyl)-pyrrolidine in the amount of 8.28 μl, 0.070 mmol. 1H NMR (CDCI3, 250 MHz, Bruker), δ: 3.07 (2H, tr, J = 6 Hz, CH2-py), 3.56 (3H, s, OCH3), 3.83 (2H, m, NCH2), 6.35 (1H, s, 1-CH), 7.18 (2H, m, py-H), 7.31 (1H, s, 4-CH), 7.63 (1H, tr d, J = 8.3 H, 2 Hz, py-H), 7.73 (2H, m, 7, 8-ArH), 8.00 (1H, tr, J = 6 Hz, NH), 8.11 (2H, m, 6, 9-ArH), 8.53 (1H, d, J = 4.8 Hz, py-H).
Step 8: 1-methoxy-3-[2-(2-pyridinyl) ethyl amino carbonyl]
Preparative details: See example 2, step 8.
I: 23 mg, 0.059 mmol
HCl (0.25 M in ether): 0.26 ml, 0.065 mmol
II: 20 mg, 0.047 mmol
m.p. 135°C (dec. 113°C). 1H NMR (Acetone-d6, 250 MHz, Bruker), δ: 3.60 (3H, s, OCH3), 3.60 (2H, m, CH2py), 3.94 (2H, m, NHCH2), 6.81 (1H,
s, 1-H), 7.08 (1H, s, 4-H), 7.91 (2H, m, 7, 8-ArH), 8.0 (2H, m, py-H), 8.12 (2H, m, 6, 9-ArH), 8.53 (1H, tr, J = 6Hz, py- H), 8.71 (1H, d, J = 6Hz, py-H), 8.71 (1H, br s, NH) .
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3324 (strong), 2926.1, 1677.6, 1651.0, 1522.6, 1274.3, 1083.6, 723.39.
Step 9: 1-methoxy-3-[(2-pyridinyl) methyl amino carbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
Preparative details: See example 2, step 7.
I: 20 mg, 0.07 mmol
Oxalyl chloride: 9.2 μl, 0.10 mmol
II: 23 mg 1H NMR (CDCI3, 250 MHz, Bruker), δ: 3.65 (3H, s, OCH3),
4.72 (2H, d, J = 5.4 Hz, NHCH2), 6.43 (1H, s, 1-H), 7.23 (1H, m, py-H), 7.30 (1H, d, J = 7.9 Hz, py-H), 7.38 (1H, s, 4-H), 7.69 (1H, tr d, J = 8.9 Hz, 1.2 Hz, py-H), 7.75 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH), 8.12 (1H, overlapped, NHCO), 8.56 (1H, d, J = 4.2 Hz, py-H).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3360.1, 2934.7, 1675.5, 1655.5, 1595.5, 1518.4, 1292.9, 1270.0, 1084.4, 950.23, 861.04, 719.77.
Step 10: 1-methoxy-3-[(2-pyridinyl) methyl amino
carbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt
Preparative details: See example 2, step 8.
I: 12 mg
HCl in ether: 1 eq
II: 11 mg
1H NMR (DMSO-d6, 250 MHz, Bruker), δ: 3.61 (3H, s, OCH3), 4.64 (2H, tr, J = 4.8 Hz, CONHCH2), 6.40 (1H, s, 1-H), 7.03 (1H, s, 4-H), 7.50 (2H, m, py-H), 7.92 (2H, m, 7, 8-ArH), 8.06 (2H, m, 6, 9-ArH), 8.05 (2H, m, py-H), 8.63 (1H, br d, J = 4.23 Hz, py-H), 9.36 (1H, tr, J = 4.9 Hz, NHCO).
Step 11: 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: See example 2, step 7.
I: 20 mg, 0.07 mmol
Oxalyl chloride: 9.2 μl, 0.105 mmol
1-(2-aminoethyl)-pyrrolidine: 9.1 μl, 0.07 mmol
II: 24.9 mg
1H NMR (CDCI3, 250 MHz, Bruker), δ: 1.81 (4H, br s, pyrr- H), 2.60 (4H, br s pyrr-H), 2.72 (2H, m, CH2-pyrr), 3.52
(2H, qua, J = 5.4 Hz, NHCH2), 3.62 (3H, s, OCH3), 6.38 (1H, s, 1-H), 7.33 (1H, s, 4-H), 7.47 (1H, br s, NHCO), 7.75 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3356.7, 2960.5, 2935.8, 2797.8, 1676.5, 1651.7, 1520.8, 1276.7, 1097.4, 1083.4, 953.25, 863.58, 794.8, 722.19.
Step 12 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt Preparative details: See example 2, step 8.
I: 24.9 mg, 0.068 mmol
HCl in ether: 1 eq
II: 23 mg
1H NMR (DMSO-d6 , 250 MHz , Bruker ) , δ : 1 . 85 ( 2H, m, pyrr-H) ,
2.01 (2H, m, pyrr-H, other pyrrolidine signals were covered by solvents), 3.05 (2H, m, CH2pyrr), 3.59 (3H, s, OCH3),
3.59 (2H, m, CONHCH2), 6.37 (1H, s, 1-H), 7.02 (1H, s, 4-H), 7.93 (2H, m, 7, 8-ArH), 8.07 (2H, m, 6, 9-ArH), 8.96 (1H, tr
J = 5.7 Hz, NHCO), 9.32 (1H, br s, NH+).
Step 13: 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
Preparative details: see example 12.
I: 20 mg, 0.07 mmol
Oxalyl chloride: 9.2 μl, 0.105 mmol
4-aminobutynaldehyde diethylacetyl : 13.6 μl, 0.077 mmol II: 29 mg 1H NMR (CDCI3, 250 MHz, Bruker), δ: 1.20 (6H, tr, J = 7.9
Hz, 2xCH3), 1.69 (4H, m, -CH2CH2-), 3.54-3.41 (4H, m,
2xOCH2), 3.61 (3H, s, OCH3), 3.64 (2H, m, CONHCH2), 4.50 (1H, br s, CH(OEt)2), 6.36 (1H, s, 1-H), 6.93 (1H, tr, J =
5.4 Hz, NHCO), 7.34 (1H, s, 4-H), 7.74 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH).
IR (Nicolet, 205FT, film on NaCl plate): cm-1, 3337.8, 2967.7, 2932.3, 2877.2 ,1676.3, 1652.7, 1522.8, 1294.4, 1270.8, 1129.8, 1085.0, 952.02, 863.71, 798.63, 721.95.
Step 14: 1-methoxy-3- (3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: see example 12.
I: 20 mg, 0.07 mmol
Oxalyl chloride: 9.2 μl, 0.105 mmol
diisopropyl ethyl amine: 14.75 μl, 0.077 mmol
3-amino-1-propanol: 5.35 μl, 0.07 mmol
II: 26.3 mg
1H NMR (CDCI3, 250 MHz, Bruker), δ: 1.81 (2H, quin, J = 6.1
Hz, C-CH2-C), 2.26 (1H, br, OH), 3.57 (2H, m, CONHCH2), 3.61
(3H, s, OCH3), 3.72 (2H, tr, J = 5.4 Hz, CH2OH), 6.36 (1H, s, 1-H), 7.24 (1H, br s, NHCO), 7.34 (1H, s, 4-H), 7.75 (2H, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet, 205FT, film on NaCl plate): cm-1, 3365.4, 2928.4, 1676.3, 1652.7, 1526.7, 1275.5, 1085.5, 950.95, 862.66, 795.81, 721.91.
EXAMPLE 6: Preparation of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho- [2,3-c]-pyran.
Step 1: (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8- dimethoxy-isochroman
At -10°C, to a solution of isochroman as described in example 2, step 1 (500 mg, 1.773 mmol) and allyl trimethyl silane (571 μl, 3.55 mmol) in 20 ml of dichloromethane was
added boron trifluoride etherate (436.12 μl, 3.55 mmol).
The resulting liquid was stirred for 2 hours as it warmed to 20°C. The crude product was diluted with dichloroform, washed with sodium bicarbonate (10%), 0.01 N hydrogen chloride and brine. The organic layer was dried and
evaporated to give desired product (525.0 mg, 90%).
m.p. 67.7-68.5°C.
!H NMR (CDCI3, 250 MHz, Bruker), δ: 2.52 (1H, m, CH2- CH=CH2), 2.69 (1H, m, CH2-CH=CH2), 2.77 (1H, dd, J = 18.2
Hz, 10.9 Hz, 4-Ha), 3.02 (1H, dd, J = 18.2 Hz, 5.4 Hz, 4- He), 3.75 (3H, s, OCH3), 3.77 (6H, s, 2xOCH3), 4.58 (1H, dd,
J = 10.9 Hz, 5.4 Hz, 3-H), 5.13-5.03 (2H, m, CH=CH2), 5.15 (1H, dd, J = 9.6 Hz, 3.6 Hz, 1-H), 5.96 (1H, m, CH=CH2), 6.65 (2H, m ,ArH).
Step 2: 1-propyl-3-methoxy carbonyl-5, 8-dimethoxyisochroman
The (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman described in step 1 (734 mg, 2.51 mmol) was dissolved in 40 ml of THF and subjected to hydrogenation conditions (1 at m, Pd/c-10%, 27 mg, 0.0251 mmol). After 2 hours at room temperature, the reaction mixture was
filtered. The filtrate was evaporated to give desired product (772 mg, 95%). 1H NMR (CDCI3, 250 MHz, Bruker), δ: 0.95 (3H, tr, J = 6.6 Hz, CH3), 1.45-1.90 (4H, m, CH2CH2), 2.74 (1H, dd, J = 18.1 Hz, 11.0 Hz, 4-Ha), 3.01 (1H, dd, J = 18.1 Hz, 4.2 Hz, 4-He), 3.74 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.52 (1H, dd, J = 11.0 Hz, 4.2 Hz, 3-H), 5.06 (1H, dd, J = 10.9 Hz, 1-H), 6.63 (2H, br s, ArH).
Step 3: 1-propyl-3-methoxycarbonyl-3,4,5,8-tetrahydro- 5,8-dioxo-1H-benzo-[2,3-c]-pyran.
The 1-propyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman isochroman described in step 2 (93 mg, 0.316 mmol) was dissolved in acetonitrile (8 ml) and then cooled to 0°C. A solution of ammonium cerium (IV) nitrate (519.7 mg, 0.948 mmol) in 2.0 ml of water buffered with sodium bicarbonate (53 mg, 0.632 mmol) was added dropwise. After 10 minutes the reaction mixture was poured to dichloromethane. The organic layer was washed with brine, dried and evaporated to give the titled compound (77 mg, 92%). 1H NMR (CDCI3, 250 MHz, Bruker), δ: 0.94 (3H, tr, J = 6.6 Hz, CH3), 1.45-1.75 (4H, m, CH2CH2), 2.62 (1H, ddd, J = 18.9 Hz, 9.7 Hz, 1.8 Hz, 4-Ha), 2.80 (1H, ddd, J = 18.9 Hz, 5.4 Hz, 0.8 Hz, 4-He), 3.76 (3H, s, OCH3), 4.44 (1H, dd, J = 9.7 Hz, 5.4 Hz, 3-H), 4.84 (1H, br d, J = 9.6 Hz, 1-H), 6.67 (1H, d, J = 10.3 Hz, ArH), 6.73 (1H, d, J = 10.3 Hz, ArH). IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2958.4, 2932.9, 2873.2, 1745.3, 1657.2, 1489.6, 1461.2, 1444.1, 1304.9, 1262.3, 1219.7, 1097.5, 1040.7, 840.8.
Step 4: 1-propyl-3-methoxycarbonyl-3,4,5,10-tetrahydro- 5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
The 1-propyl-3-methoxycarbonyl-3,4,5,8-tetrahydro-5,8-dioxo-1H-benzo-[2,3-c]-pyran described in step 3 (76 mg, 0.288 mmol) was stirred with 1-acetoxyl-1,3-butadiene (136 μl,
1.152 mmol) at 45°C for 20 hours. Solvent was evaporated and the crude product was chromatographed (toluene/ethyl acetate ~100/15, v/v) to give the titled compound (65 mg, 71.9%).
m.p. 111.5-113.6°C.
1H NMR (CDCI3, 250 MHz, Bruker), δ: 0.97 (3H, tr, J = 6.7 Hz, CH3), 1.45-1.85 (4H, m, CH2CH2) 2.78 (1H, ddd, J = 19.9 Hz, 10.4 Hz, 1.2 Hz, 4-Ha), 2.97 (1H, dd, J = 19.9 Hz, 5.4 Hz, 7-He), 3.80 (3H, s, OCH3), 4.51 (1H, dd, J = 10.4 Hz, 5.4 Hz, 3-H), 5.04 (1H, br d, J = 8.5 Hz, 1-H), 7.72 (2H, m, 7, 8-ArH), 8.07 (2H, m 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2959.3, 2931.1, 2877.2, 1751.1, 1663.8, 1594.6, 1461.2, 1440.7, 1330.4, 1291.9, 1284.2, 1225.2, 1179.0, 1179.0, 1104.5, 872.11, 790.4, 717.4.
Step 5: 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran.
The 1-propyl-3-methoxycarbonyl-3,4,5,10-tetrahydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran described in step 4 (50 mg, 0.159 mmol) was stirred with triphenylphosphine (166.6 mg, 0.636 mmol) and 1,4-diaza bicyclo-[2,2.2]-octane (19.6 mg, 0.175 mmol) in presence of air for a few hours at room temperature until the starting material was entirely
consumed. The reaction mixture was evaporated to dryness. The crude product obtained was chromatographed
(toluene/ethyl acetate = 10/1, v/v) to give the titled compound (35 mg, 70%).
1H NMR (CDCI3, 250 MHz, Bruker), δ: 0.93 (3H, tr, J = 6.9 Hz, CH3), 1.35-1.60 (4H, m, CH2CH2), 3.87 (3H, s, OCH3), 5.69 (1H, dd, J = 4.3 Hz, 10.9 Hz, 1-H), 7.07 (1H, s, 4-H), 7.74 (2H, m, 7, 8-ArH), 8.07 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2959.8,
2876.4, 1737.3, 1669.0, 1652.3, 1596.2, 1564.3, 1438.4,
1397.5, 1268.0, 1233.7, 1133.6, 1133.6, 1074.4, 716.45.
Step 6: 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H- naphtho-[2,3-c]-pyran. 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran (63 mg, 0.201 mmol) was dissolved in tetrahydrofuran (4 ml) and cooled to 0°C. A solution of sodium hydroxide (2.41 ml, 0.1 N, 0.241 mmol) was added dropwise. The resulting reaction mixture was stirred for 1 hour at room temperature. It was then acidified with 0.1 N HCl and extracted with ethyl acetate. After evaporation of the solvent, the titled compound was obtained (58 mg, 96%). 1H NMR (Acetone-d6, 250 MHz, Bruker), δ: 0.96 (3H, tr, J = 6.4 Hz, CH3), 1.40-1.68 (4H, m, CH2CH2), 5.64 (1H, dd, J = 9.7 Hz, 3.1 Hz, 1-H), 7.03 (1H, s, 4-H), 7.87 (2H, m, 7, 8-ArH), 8.07 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3667-2500 (strong), 2864.6, 2927.4, 2869.6, 2634.0, 1732.9, 1712.3, 1670.9, 1654.4, 1592.4, 1567.6, 1394.0, 1332.0, 1298.9, 1265.9, 1227.6, 1071.1, 719.09.
Step 7: 1-propyl-3-(3-dimethyl amino propyl amino
carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho- [2,3-c]-pyran.
Using similar steps as explained in example 2, step 7, this compound was prepared. During the preparation, 29 mg of 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran, 21.2 μl, 0.243 mm of oloxalyl chloride, and 12.5 μl, 0.99 mmol of 3-dimethyl amino propyl amine was used to produce 33.6 mg, 90% of the title compound.
Step 8: 1-propyl-3-(3-dimethyl amino propyl amino
carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho- [2,3-c]-pyran.
This compound was prepared using similar steps as explained in example 2, step 8. During the process, 16 mg, 0.042 mmol of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran was used along with HCl in ether - 1 eq, to produce 15 mg of the title compound.
Dec. 175°C: m.p. 185-188°C.
EXAMPLE 7:
1: (1,10a-trans)-1-methoxy-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-4a,10a,epoxy-naphtho-[2,3-c]-pyran
Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl)formate (15.5 mg, 0.052 mmol) was dissolved in
2.2 ml of tetrahydrofuran, then cooled to 0°C. Sodium bicarbonate (74 mg, 0.886 mmol) was added and this was followed by addition of hydrogen peroxide (30%, 42.3 μl,
0.373 mmol). The reaction proceeded as the yellow solution turned colorless. After two hours, the crude product was poured to NH4CI (sat) and extracted with dichloromethane. The organic layer was dried over sodium sulfate and then evaporated to give the titled product (15.4 mg, 95%). 1H NMR (CDCI3, 250 MHz, Bruker), δ: 3.60 (3H, s, OCH3), 3.84 (3H, s, OCH3), 5.90 (1H, s, 1-H), 7.20 (1H, s, 4-H),
7.78 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH).
2: (1,10a-trans)-1-propyl-3-methoxycarbonyl-5,10-dihydro- 5,10-dioxo-4a,10a-epoxy-naphtho-[2,3-c]-pyran 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran (17 mg, 0.254 mmol) was dissolved in ice-cold THF-H2O (3 ml-1 ml) medium. Sodium bicarbonate (77.8 mg, 0.926 mmol) was added. Then hydrogen peroxide (30%, 47.3 μl, 0.463 mmol) was added. After 45 minutes, the reaction mixture was poured to water and extracted with ethyl acetate. The titled compound was obtained in good purity (16.3 mg, 91.1%). 1H NMR (CDCI3, 250 MHz, Bruker), δ: 0.96 (3H, tr, J = 7.3 Hz, CH3) , 1.50-1.77 (4H, m, CH2CH2 ) , 3.84 ( 3H, s, OCH3) ,
5.12 (1H, dd, J = 7.9 Hz, 1.8 Hz, 1-H) , 7.10 ( 1H, s, 4-H) ,
7.79 (2H, m, 7, 8-ArH) , 8 .05 (2H, m, 6, 9-ArH) .
IR (Nicolet, 205 FT, film on NaCl) : cm-1, 2958.9, 2926.0, 2978.4, 1736.2 1699. 6, 1644 .7, 1589. 8, 1432.4 , 1297.0, 1267.7, 1238.4, 1120.1, 764.48 , 711.07 , 632.30.
Preparative details: See example 3.
I: 80 mg, 0.294 mmol
Triethyl amine: 59.4 μl, 0.588 mmol
triphenylphosphine: 308.4 mg, 1.176 mmol
II: 12 mg 1H NMR (CDCI3, 250 MHz, Bruker), δ: 3.90 (3H, s, OCH3), 5.30 (2H, s, OCH2), 7.13 (1H, s, 4-H), 7.75 (2H, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet, 205FT, film on NaCl plate) cm 2962.7,
2924.6, 2851.5, 1736.0, 1669.3, 1653.4, 1589.8, 1437.3, 1395.9, 1338.7, 1287.9, 1268.8, 1237.0, 1125.8, 718.81.
EXAMPLE 9: 2-hydrochloro-(N-pyrrolidinyl)ethyl-(1- propyl-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran-3)-carboxamide (BCH2875)
Step 1:2-(N-pyrrolidinyl) ethyl-(1-propyl-5,10-dioxo-5,10-dihydro
Tricyclic carboxylic acid (25 mg, 0.084 mmol) in CH2CI2 (2 ml) was converted into acid chloride by oxalyl chloride (0.1 ml of 2 M solution in CH2CI2). Excess reagent was pumped off and the acid chloride in CH2CI2 (2 ml) was treated with 1-(2-amino ethyl)-pyrrolidine (9 mg, 0.079 mmol) in CH2CI2
(0.75 ml) at -10°C. Reaction was almost complete in 5 minutes. 1-(2-amino ethyl)-pyrrolidine (1.2 mg) in CH2CI2
(0.1 ml) was further added and the reaction was stirred for
10 minutes at -10°C. The mixture was poured into .05 N HCl (10 ml), extracted with CH2CI2 (50 ml). The aqueous part was basified with NaHCO3 (2.5%), extracted with ethyl acetate (3x25 ml), washed with water (2x10 ml), dried and evaporated. Pure product was obtained by column chromatography over silica gel eluted with 5% and 10% MeOH in CH2Cl2 in 52% yield (17 mg).
NMR (CDCI3, δ): 0.98 (3H, t, J = 6.6 Hz, CH3 of the propyl), 1.43-1.58 (4H, m, CH2 of propyl group), 1.84 (4H,
br signal, CH2 of pyrrolidine), 2.63 (4H, br signal, CH2 of pyrrolidine, next to nitrogen), 2.69-2.77 (2H, m, CH2 of the side-chain next to pyrrolidine), 3.52 (2H, q, J = 5.7 Hz, CH2NHCO), 5.71 (1H, dd, J = 1.8, 9.6 Hz, H-1), 7.13 (1H, s, olefinic proton), 7.39 (1H, br signal, -NHCO-), 7.73-7.78 (2H, m, Ar-H), 8.06-8.15 (2H, m, Ar-H).
Step 2:
2-hydrochloro-(N-pyrrolidinyl) ethyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide
Amine (17 mg) was dissolved in CH2CI2 (3 ml) and filtered. It was diluted with ether (10 ml). Hydrochloric acid in ether (1 M) (1 equivalent) was added. The mixture was evaporated, and redissolved in CH2CI2 (2 ml). Hydrochloride salt was precipitated from the solution by adding ether, separated, washed with ether and dried (8 mg) (yield = 43%). Mother liquor contained some hydrochloride salt. 1H NMR (acetone-d6, δ): 0.96 (3H, t, J = 6.4 Hz, CH3 of the propyl) 1.47-1.63 (4H, m, CH2 of the propyl side-chain), 3.07 (2H, m, ), 3.33-3.40 (2H, m), 3.68-3.82 (4H, m), 5.69 (1H, br d, J = 10.7 Hz, H-l), 6.93 (1H, s, olefinic proton), 7.89 (2H, m, Ar-H), 8.05-8.09 (2H, m, Ar-H), 8.83-8.92 (1H,m,) .
EXAMPLE 10: 3-N-oxo-dimethylaminopropyl-(1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran- 3)-carboxamide (BCH2877)
To a solution of tricyclic amide (17 mg, 0.046 mmol) in CH2CI2 (5 ml) at 0°C was added a solution of m-chloroperbenzoic acid (8 mg, 0.046 mmol) in CH2CI2 (1.1 ml) slowly. The mixture was stirred for 0.5 hour at 0°C; 2.5% sodium bicarbonate (3 ml) was added. It was extracted with CH2CI2 (3x50 ml), washed with water (10 ml), and with saturated NaCl (10 ml), dried and evaporated. NMR revealed that it contained some starting material (~33%). It was dissolved in CH2CI2 (5 ml), cooled to 0°C; m-choloperbenzoic acid (5 mg, 0.029 mmol) in CH2CI2 (1 ml) was added and the mixture was stirred at 0°C for 45 minutes. It was worked up in the same way as described before. NMR showed disappearance of starting material. Pure N-oxide was obtained by column chromatography over a small column of silica gel eluted with 20% methanol in CH2CI2 (yield = 5 mg, 28%).
NMR (CDCI3, δ): 2.19-2.29 (2H, m, CH2 of the side-chain), 3.26 (6H, s, -N(O) (CH3)2), 3.46-3.50 (2H, m, CH2 of the side-chain), 3.59-3.67 (2H, m, CH2 of the side-chain), 3.69 (3H, s, OCH3), 6.42 (1H, s, H-l), 7.32 (1H, s, olefinic proton), 7.71-7.79 (2H, m, Ar-H), 8.10-8.16 (2H, m, Ar-H), 9.47 (1H, br signal, -NHCO-).
EXAMPLE 11 2-(2-N-methyl pyrrolyl)-ethyl-(1-propyl- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran-3)-carboxamide (BCH2876)
To a cold solution of tricyclic carboxylic acid (25 mg,
0.084 mmol) in dry THF (1 ml) at-15°C was added N-methyl morpholine (9.2 μl, 0.084 mmol) in THF (0.1 ml) followed by addition of isobutyl chloroformate (10.9 μl, 0.084 mmol) in
THF (0.1 ml). The mixture was stirred at -15°C for 15 minutes. 2-(2-Amino ethyl)-1-methyl pyrrole (10.41 mg, 0.084 mmol) in THF (0.6 ml) was added. After 10 minutes the mixture was diluted with ethyl acetate (50 ml), acidified with 0.1 N HCl. Water was added and the organic layer was separated, washed with 2.5% NaHCO3 (5 ml), water and saturated NaCl solution, dried and evaporated. Pure product was obtained by passing through a column of silica gel eluted with 2% and 5% methanol in CH2CI2 (yield = 29 mg, 85%).
NMR (CDCI3, δ) : 0.97 (3H, t, J = 6.8 Hz, CH3 of the propyl side-chain), 1.41-1.52 (4H, m, CH2 of the propyl side-chain), 2.87 (2H, t, J = 6.7 Hz, CH2 of the side-chain), 3.57-3.67 (5H, a sharp singlet in the middle of a multiplet, N-CH3 and CH2 of the side-chain), 5.67 (1H, dd, J = 2.6, 10.3 Hz, H-l), 5.96 (1H, br singlet, pyrrole-H), 6.08 (1H, t, J = 2.9 Hz, pyrrole-H), 6.60 (1H, br singlet, pyrrole-H), 6.87 (1H, ill-resolved triplet, -NHCO-), 7.14 (1H, s,
olefinic proton), 7.73-7.78 (2H, m, Ar-H), 8.06-8.15 (2H, m, Ar-H).
Example 12 1-methoxy-3-(2-trimethyl ammonium ethyl amino carbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran chloride salt
The acid I (20 mg, 0.07 mmol) in 2 ml of dichloromethane was treated with oxalyl chloride (9.2 μl, 0.105 mmol) and trace of DMF. After stirred at room temperature for 1 hour, all the solid was dissolved to give a yellow solution. The crude liquid was evaporated and the solid residue was subjected to vacuum until oxalyl chloride was entirely pumped out. The acid chloride thus obtained was redissolved in THF. After chilled to -10°C, (2-aminoethyl)-trimethyl ammonium chloride hydrochloride (12.3 mg, 0.07 mmol) was added. This was followed by addition of diisopropyl ethyl amine (24.4 μl, 0.14 mmol). After 20 minutes, the solvent was evaporated. The crude product wetted with dichloromethane was filtered. The filtrate was concentrated to give a product which can be further purified on RP-8 silica gel. Yield 70%.
1H NMR (CDCI3, 250 MHz, Bruker), δ: 1.39 (9H, br s, 3xCH3),
3.14 [2H, m, CH2N(CH3)3], 3.62 (3H, s, OCH3), 3.74 (2H, m,
NHCH2), 6.40 (1H, s, 1-H), 7.20 (1H, s, 4-H), 7.71 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm -1 3415.5,
2991.0, 2929.3, 2832.8, 2693.9, 2508.7, 1671.7, 1655.9,
1598.0, 1563.3, 1339.6, 1324.1, 1300.9, 1067.0, 989.6, 954.5, 864.4, 722.9.
Example 13 1-methoxy-3-(3-S-methyl mercapto propyl
amino carbonyl)-5,10-dihydro-5,10-dioxo-1H- naphtho-[2,3-c]-pyran
The compounds were prepared using a similar process as described in Example 12.
I: 40 mg, 0.140 mmol
Oxalyl chloride: 18.4 μl, 0.205 mmol
Diisopropyl ethylamine: 24.4 μl
3-methyl mercapto propyl amine trifluoroacetate: 25.75 mg,
0.140 mmol
II: 34 mg, 65% 1H NMR (CDCI3, 250 MHz, Bruker), δ: 1.93 (2H, quin, J = 6.7 Hz, CH2-C-N), 2.11 (3H, s, SCH3), 2.57 (2H, tr, J = 6.1 Hz, CH2S), 3.54 (2H, m, CONHCH2), 3.62 (3H, s, OCH3), 6.37 (1H, s, 1-H), 7.03 (1H, tr, J = 6.1 Hz, 4-H), 7.75 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
Example 14: 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran
Using a similar procedure as described in example 2, step 7, the titled compound was prepared.
1H NMR (CDCI3, 300 MHz, Bruker), δ: 1.87 (4H, broad, pyrr-CH2), 2.73 (4H, broad, pyrr-NCH2), 2.95 (3H, t, J = 5.9 Hz, CH2N), 3.66 (3H, s, OCH3), 4.52 (2H, t, J = 5.9 Hz, OCH2), 6.40 (1H, s, 1-H), 7.28 (1H, s, 4-H), 7.79 (2H, m, Ar-H), 8.15 (2H, m, Ar-H).
Example 15: 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran hydrochloride
Preparative details: See example 2, step 8.
1H NMR (DMSO-d6, 300 MHz, Bruker), δ: 2.11 (2H, broad, pyrr-CH2), 2.84 (2H, broad, pyrr-CH2), 3.19 (2H, broad, pyrr-NCH2), 3.61 (3H, s, OCH3), 3.66 (2H, broad, CH2N), 3.75
(2H, broad, pyrr-NCH2), 4.87 (2H, broad, OCH2), 6.40 (1H, s,
1-H), 7.28 (1H, s, 4-H), 7.94 (2H, m, Ar-H), 8.12 (2H, m, Ar-H), 10.45 (1H, broad, NH+).
IR (Nicolet 205 FT, film on NaCl plate) cm-1: 2951, 2930, 2845, 2361, 2345, 1234, 1665, 1660, 1585, 1564, 1453, 1384, 1330, 1299, 1267, 1240, 1144, 1075, 953, 862.
Example 16: 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
Preparative details : See example 2 , step 7 .
I : 20 mg, 0 . 070 mmol
Oxalyl chloride: 9.2 μl, 0.105 mmol
N,N,N'-trimethyl ethylene diamine: 10.1 μl, 0.077 mmol
II: 27 mg 1H NMR (CDCI3, 250 MHz, Bruker), δ: 2.25 (6H, br s N(CH3)2), 2.52 [2H, br tr, J = 5.9 Hz, CH2N(Me)2]/ 3.09 (3H, br s, CONCH3), 3.54 (2H, br m, CONCH2) , 3.64 (3H, s, OCH3), 6.36 (1H, s, 1-H), 6.67 (1H, s, 4-H), 7.74 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm -1, 2937.0, 2771.1, 1676.7, 1648.2, 1595.6, 1565.9, 1300.8, 1108.7, 1054.6, 949.16, 839.44, 801.92, 722.25.
Example 17: 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
Preparative details: See example 2, step 8
I: 22.9 mg, 0.062 mmol
HCl in ether: 1 eq.
II: 22.9 mg
1H NMR (Acetone-d6, 300 MHz, Bruker), δ: 2.23 (6H, br s, N(CH3)2), 2.56 (2H, tr, J = 5.4 Hz, CH2N(CH3)2), 3.07 (3H, br, CONCH3), 3.58 (2H, m, CONCH3CH2), 3.65 (3H, s, OCH3),
6.40 (1H, s, 1-H), 6.54 (1H, s, 4-H), 7.91 (2H, m, 7, 8- ArH), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2942.4, 2768.2, 1677.5, 1643.2, 1597.5, 1571.8, 1297.7, 1109.3,
1057.9, 1080.7, 946.5, 861.9, 721.99.
Example 18 : 1-Methoxy-3 [2- (N-pyrrolidinylethoxylcarbonyl)]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
Using a similar procedure as described in step 7, example 2, the carboxylic acid from step 6, example 2, was converted to the titled compound.
1HNMR (300MHz, Bruker, CDCI3) δ: 2.08 (2H, m, pyrr-CH2), 2.42 (2H, t, J = 8.09 Hz, pyrr-COCH2), 3.56 (2H, t, J = 7.05Hz, pyrr-NCH2), 3.66 (3H, s, OCH3), 3.68 (2H, m, CH2N), 4.47 (2H, m, OCH2), 6.40 (1H, s, 1-H), 7.34 (1H, s, 4-H), 7.79 (2H, m, Ar-H), 8.15 (2H, m, Ar-H).
IR ( Nicolet 205 FT, film on NaCl plate) cm-1: 2959, 2932, 2863, 1733, 1677, 1659, 1594, 1565, 1497, 1461, 1393, 1337, 1287, 1267, 1236, 1139, 1069, 990, 860, 798, 769, 743, 720.
Example 19:
Step 1: Methyl-1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho [2,3-c] thiine-3- carboxylate Methyl-1-methoxy-5,8-dioxo-5,8-dihydro-3-isothiocromane
(1.14 g, 4.25 mmol), 1-acetoxybutadiene (1g, 8.92 mmol) and dry toluene (10 ml) was stirred for 14 hours at room
temperature. The solvent was removed under reduced
pressure, the residue was dissolved in CH2CI2 (20 ml) and thiethylamine (1 ml, 7.22 mmol). The reaction mixture was stirred for 3 hours at room temperature. The solvents were removed under reduced pressure, the residue was dissolved in CH2CI2 (20 ml), triphenylphosphine (1.1 g, 4.2 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The product was isolated by flash
chromatography (toluene:ethylacetate, 50:1), 0.77 g (56.6% of the product was obtained).
1H NMR (300 MHz, Bruker, CDCI3), δ: 3.40 (3H, s, 1-MeO), 3.95 (3H, s, COOMe), 6.12 (1H, s, 1-H), 7.28 (2H, m, Ar-H), 8.16 (2H, m, Ar-H), 8.27 (1H, s, 4H).
Step 2: 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho [2,3-c] thiine-3-carboxylic acid
Methyl 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho [2,3-c] thiine-3-carboxylate (106 mg, 0.33 mmol) was dissolved in THF (2 ml). 1.75 M solution of sodium hydroxide (0.32 mg, 0.55 mmol) was added dropwise at 0°C followed by water (0.5 ml). The reaction mixture was stirred at 0°C for 3 hours, then water (10 ml) was added, and the reaction mixture was acidified to pH=3 with 5% hydrochloric acid. After that, the reaction mixture was extracted with dichloromethane (5x5 ml). Organic fractions were evaporated to dryness. The residue 98 mg (crude) was used in the next step. Step 3: 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho
[2,3-c] thiine-3-[N-(3-dimethylaminopropyl) carboxamide] 1-methoxy-5,6-dioxo-5,10-dihydro-1H-naphtho [2,3-c] thiine-3-carboxylic acid (55 mg, 0.18 mmol) was dissolved in THF (2 ml). DMF (1 drop) was added. The reaction mixture was cooled to 0°C and 2 M solution of oxalyl chloride in
dichloromethane (0.18 ml, 0.36 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 0.5 hour, then evaporated to dryness at reduced pressure. The residue was dissolved in THF (2 ml), cooled to 0°C and N,N-dimethylaminopropylamine (20 μl, 0.2 mmol) was added
dropwise. The reaction mixture was stirred for 0.5 hour, then saturated solution of sodium carbonate (3 ml) was added, and organics were extracted by dichloromethane (3x5 ml). Dichloromethane solution was dried over MgSO4, evaporated to dryness and the title product (25 mg, 35%) was isolated by thin layer chromatography (MeOH). 1H NMR (300 MHz, Brucker, CD2Cl2), δ: 1.74 (2H, quint,
CH2), 2.36 (6H, s, NMe2), 2.54 (2H, t, CH2), 3.39 (s, 3H,
OMe), 3.54 (2H, quint, CH2), 6.14 (1H, s, 1-H), 7.75 (2H, m, Ar-H), 7.91 (1H, s, 4H), 8.14 (2H, m, Ar-H), 9.42 (1H, broad, NH).
Example 20:
Step 1: (1'S) Methyl (5,8-dimethoxy-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-1H-benzo[2,3-c]thiopyran-3- yl) ketone A mixture of 3-acetyl-5,8-dimetoxythioisochromane (2.52 g, 10.00 mmol), 3,4-di-O-acetyl-2,6-dideoxy-L-lyxohexopyranose (sugar) (2.79 g, 12.00 mmol) and diciano dichloro
benzoquinone (DDQ) (2.72 g, 12.00 mmol) in dichloromethane (30 ml) was stirred for 4 hours at ambient temperature, then more sugar (1.00 g, 4.31 mmol) and DDQ (1.00 g, 4.41 mmol) were added. The reaction mixture was stirred overnight, then saturated NaHCO3 solution (10 ml) was added. The
solids were filtered, the organic phase of the filtrate was washed with NaHCO3 solution (10 ml), dried (MgSO4) and evaporated to dryness. The residue was flash
chromatographed on silica (hexane/CH2Cl2/EtOAc, 5/9/1) to give the title product (1.16 g, 21.1%).
1H NMR (CDCI3), δ: 1.20 (d, 3H, 6.5 Hz), 1.58 (dd, 1H, 4.9 Hz, 29.2 Hz), 1.91 (s, 3H), 2.03 (td, 1H, 3.3 Hz, 29.2 Hz), 2.16 (s, 3H), 2.59 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 4.17 (q, 1H, 6.5 Hz), 4.98 (m, 1H), 5.11 (s, 1H, broad), 5.60 (d, 1H, 2.0 Hz), 6.55 (s, 1H), 6.92 (d, 1H, 8.8 Hz), 7.04 (d, 1H, 8.8 Hz), 8.29 (s, 1H).
Step 2: (1'S) Methyl (5,8-dioxo-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-5,8-dihydro-1H-benzo[2,3- c]thiopyran-3-yl) ketone
To a stirred solution of the thioisochromane glycoside from Step 1 (0.50 g, 1.04 mmol) was added a solution of CAN (1.71 g, 3.12 mmol) and NaHCO3 (0.17 g, 2.08 mmol) in water, dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then it was extracted with dichloromethane (4x5 ml). The combined organic layers were washed with saturated NaHCO3 solution, dried (MgSO4) and concentrated to dryness. The crude product (0.50 g, 100%) was used for the next step without purification. 1H NMR (CDCI3), δ: 1.27 (d, 3 H, 6.4 Hz), 1.59 (dd, 1H, 5.1 Hz, 12.8 Hz), 1.94 (s, 3H), 2.05 (td, 1H, 4.1 Hz, 12.8 Hz), 2.16 (s, 3H), 2.62 (s, 3H), 3.92 (q, 1H, 6.4 Hz), 4.98 (m, 1H), 5.10 (s, 1H, broad), 5.54 (d, 1H, 3.3 Hz), 6.41 (s, 1H), 6.98 (s, 2H). Step 3 : ( 1 ' S ) Methyl ( 5, 10-dioxo-1- (2 ' , 3 ' , 4 ' , 6 ' - tetradeoxy-3 ' , 4 ' -diacetoxy-L-
lyxohexopyranose-5,10-dihydro-1H-naphtho[2,3- c]thiopyran-3-yl) ketone
The solution of benzo [2,3-c] thiopyrane glycoside from Step 2 (0.10 g, 0.22 mmol) and 1-acetoxy-l, 3-butadiene (0.05 g, 0.44 mmol) in toluene (1 ml) was left to stand over 3 days at ambient temperature, then it was flash chromatographed on silica (hexane/EtOAc, 7/3) to give the title compound (0.073 g, 66.3%). 1H NMR (CDCI3), δ: 1.29 (d, 3H, 6.4 Hz), 1.61 (dd, 1H, 3.3 Hz, 12.8 Hz), 1.92 (s, 3H), 2.06 (td, 1H, 3.6 Hz, 12.8 Hz), 2.17 (s, 3H), 2.66 (s, 3H), 4.02 (q, 1H, 6.4 Hz), 5.00 (m, 1H), 5.09 (s, 1H, broad), 5.58 (d, 1H, 3.3 Hz), 6.65 (s, 1H), 7.81-7.88 (m, 2H), 8.20 (s, 1H), 8.20-8.27 (m, 2H).
Example 21: N, N'-bis{l-Methoxy-5,10-dihydro-5,10-dioxo- 1H-naphtho-[2,3-c]-pyran-3-carbonyl)-propyldiamine
Using a similar procedure as described in example 2, step 7, the carboxylic acid from step 6, example 2, was converted to the titled compound. The title compound is a mixture of three isomers.
1HNMR (300MHz, Bruker, CDCI3) δ: 1.85 (2H, m, -CH2), 3.55 (4H, m, -NCH2 and CH2N), 3.69 (3H, s, OCH3), 3.71 (3H, s, OCH3), 6-42 (1H, s, 1-H), 6.44 (1H, s, 1-H), 7.36 (1H, s, 4- H),7.38 (1H, s, 4-H),7.48 (2H, m, NH), 7.72 (4H, m, Ar-H and Ar-H'), 8.14 (4H, m, Ar-H and Ar-H').
IR ( Nicolet 205 FT, film on NaCl plate) cm-1: 3339, 2935, 2843, 1679, 1655, 1592, 1517, 1404, 1381, 1334, 1278, 1202, 1093, 954, 865, 796, 721.
Example 22: N-Methyl-N, N'-bis{1-Methoxy-5,10-dihydro- 5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine
Using a similar procedure as described in step 7, example 2, the carboxylic acid from step 6, example 2, was converted to
the titled compound. The title compound is a mixture of four isomers. 1HNMR (300MHz, Bruker, CDCI3) δ: 1.92 (2H, m, -CH2-), 3.15
(3H, s, -NCH3), 3.5 (4H, m, NCH2 and CH2N), 3.61 (3H, s,
OCH3), 3.72 (3H, s, OCH3), 6.39 (1H, s, 1-H), 6.44 (1H, s,
1-H'), 6.71 (1H, s, 4-H), 7.36 (1H, s, 4-H'), 7.75 (4H, m, Ar-H and Ar-H'), 8.0 (1H, broad, NH), 8.25 (4H, m, Ar-H and Ar-H').
IR ( Nicolet 205 FT, film on NaCl plate) cm-1: 3341, 2936, 2833, 1675, 1656, 1597, 1570, 1520, 1450, 1411, 1383, 1330, 1276, 1199, 1121, 1083, 1057, 987, 946, 915, 863, 794, 722.
Example 23: N-Boc-N-{1-methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine
N-Boc-propyldiamine was prepared according to a procedure described by W. S. Saari, J. E. Schwering, P. A. Lyle, S. J. Smith and E. L. Engelhardt, J. Med. Chem. 1990, 33, 97-101.
Preparation of N-Boc-N-{1-methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine
Using a similar procedure as described in step 7, example 2, the carboxylic acid from step 6, example 2, was converted to the titled compound.
1HNMR (300MHz, Bruker, CDCI3) δ: 1.46 (9H, s, -Boc), 1.72
(2H, m, Hb), 3.28 (2H, m, Hc), 3.42 (1H, m, Ha), 3.52 (1H, m, Ha,), 3.69 (3H, s, OCH3), 4.88 (1H, broad, NHBoc), 6.42 (1H, s, 1-H), 7.34 (1H, s, 4-H), 7.75 (2H, m, Ar-H), 7.84 (1H, broad, NH), 8.14 (2H, m, Ar-H).
IR ( Nicolet 205 FT, film on NaCl plate) cm-1: 3339, 2973, 2934, 1679, 1659, 1603, 1522, 1451, 1365, 1335, 1276, 1170, 1083, 950, 864, 796, 720.
Carbon tetrabromide (0.47g, 1.25mmol) and triphenylphosphine (0.47g, 1.25mmol) were added to a solution of 2,5-dimethoxylbenzylalcohol (0.2g, 1.19mmol) in THF (10ml) at room temperature. The mixture was stirred for two hours to form a precipitate which the preciptate was filtered off. The filtrate was evaprated and the crude product was chromatographed (ethyl acetate and hexane 7:3). The desired compound was isolated as a white solid (0.25g, 93%).
1HNMR (300MHz, Bruker, CDCI3) δ: 3.79 (3H, s, OCH3), 3.87
(3H, s, OCH3), 4.55 (2H, s, CH2), 6.83 (2H, q, Ar-H), 6.90 (1H, s, Ar-H).
Example 25: Methyl 3-(2' 5'-dimethoxy)phenyl-2-hydroxypropionate
BuLi (1.96mmol) was adde to a solution of diisopropylamine
(1.96mmol) in dry THF (15ml) at -78°C. The mixture was then warmed to 0°C and stirred for 30 minutes. Then the mixturw was recooled to -78°C, and methyl-2-methoxyisopropyloxy-acetate (0.3g, 1.96mmol) in THF (2ml) was added. After 15minutes, 2,5-dimethoxybenzylbromide (0.19g, 0.83mmol) was added dropwise, this was followed by addtion of HMPA (0.2ml). The reaction mixture was stirred for another hour, then warmed to room temperature. Saturated NH4CI (5ml) was added, PH was adjusted to 2 using cone. HCl. After 1hr, the mixture was extracted with ethyl acetate, the solvent was dried and evaporated. The pure titled compound was obtained as an oil (purification by chromatography with ethyl acetate and hexane 3:7).
1HNMR (300MHz, Bruker, CDCI3) δ: 3.0 (2H, m, CH2), 3.73 (6H, s, AX-OCH3), 3.77 (3H, s, OCH3), 4.46 (1H, m, CH2), 6.76
(3H, m, Ar-H).
To a freshly prepared lithium diisopropylamide
(diisopropylamine, 123.2 μl, 0.873 mmol, n-butyllithium, 2.5 M in hexane, 0.35 ml, 0.873 mmol) at -78°C, was added a solution of isochroman I (198 mg, 0.794 mmol). The mixture was stirred for 30 minutes. Hexamethyl phosphoramide (151.9 μl, 0.873 mmol) was added. It was followed by the addition of phenyl selenyl chloride in THF (167.2 mg, 0.873 mmol). The reaction mixture was stirred for 1 hour at -78°C. The reaction was quenched with NH4CI (sat). The organic layer was evaporated to give the selenyl product which was redissolved in dichloromethane. Following this, pyridine
(148 μl) and 30% hydrogen peroxide (207.8 μl, 1.83 ml) was added in sequence. The mixture was vigorously stirred for
30 minutes at room temperature then washed with NaHSO3 and extracted with dichloromethane. After evaporation of the solvent, the crude product was chromatographed to give desired product (impured with little amount of I) in 50% yield (97 mg).
1H NMR (300 MHz, Bruker, CDCI3), δ: 3.78 (3H, s, OCH3),
3.81 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.24 (2H, s, 1-H),
6.71 (1H, d, J = 6.9 Hz), 6.78 (1H, d, J = 6.9 Hz), 7.22 (1H, s, 4-H).
At room temperature, a mixture of isochroman I (48 mg, 0.192 mmol), as described in example 35, dichlorodicyanoquinone (56.7 mg, 0.249 mmol) and methanol (0.3 ml) was stirred in dichloromethane (5 ml) for 10 mintues. It was then poured to NaHCO3 (sat.) and extracted with dichloromethane. The desired product was obtained in 68% yield (37 mg). 1H NMR (300 MHz, Bruker, CDCI3), δ: 3.59 (3H, s, 1-OCH3), 3.83 (6H, s, 2xOCH3), 3.89 (3H, s, OCH3), 6.31 (1H, s, 1-H), 6.85 (2H, m, 6, 7-ArH), 7.45 (1H, s, 4-H).
Example 28: 1-methoxy-3-methoxycarbonyl-5,8-dioxo-1H-benzo-[2,3-c]-pyran
At room temperature, compound I (17 mg, 0.061 mmol) in acetonitrile (4 ml) as described in example 36, was oxidized by ammonium cerium nitrate (100 mg, 0.182 mmol) dissolved in 1 ml of water. After dichloromethane extraction and
evaporation of the solvent, the desired compound was
obtained (12 mg, 79%).
1H NMR (300 MHz, Bruker, CDCI3), δ: 3.62 (3H, s, OCH3), 3.93 (3H, s, OCH3), 6.21 (1H, s, 1-H), 6.85 (2H, br, s, 6, 7-ArH), 7.15 (1H, s, 4-H). Example 29: 1-methoxy-3-methoxycarbonyl-5,8-dihydro-5,10-dioxo-naphtho-1H-[2,3-c]-pyran
A sample of I (12 mg, 0.048 mmol) as described in example 37, dissolved in toluene (4 ml), was heated to 50°C with 1-acetoxy-1,3-butadiene (34 μl, 0.288 mmol) for 18 hours. Solvent was evaporated and the crude product was chromatographed (v/v, Tol/EtOAc, 100/15) to give desired product (4 mg, 28%).
1H NMR (300 MHz, Bruker, CDCI3), δ: 3.67 (3H, s, OCH3),
3.95 (3H, s, OCH3), 6.41 (1H, s, 1-H), 7.37 (1H, s, 4-H),
7.81 (2H, m, 7, 8-ArH), 8.16 (2H, m, 6, 9-ArH).
Example 30 : 1-hydroxy-3-methoxycarbonyl-3, 4-didehydro-5, 8-dimethoxy isochroman
Compound I (8 mg, 0.028 mmol), as described in example 36, was stirred with para-toluene sulfonic acid (catalytic amount) in the solvent of water and acetone (1 ml/3 ml) for 17 hours at room temperature. After work-up (H2θ-EtOAc), the desired product was obtained (5 mg, 65%).
1H NMR (300 MHz, Bruker, CDCI3), δ: 3.40 (1H, bs, OH), 3.86 (6H, s, 2xOCH3), 3.90 (3H, s, OCH3), 6.79 (1H, s, 1-H), 6.87 (2H, m, ArH), 7.46 (1H, s, 4-H).
Claims
We claim: 1. A compound of general formula 12:
and salts, mono-epimers, poly-epimers, dimers,
isomers and mixtures thereof, including diastereomer and racemic mixtures, thereof wherein
X1 and X2 are independently selected from the group
consisting of O, S, and
NR20, wherein R20 is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-16 acyl and C1-16 alkylamine;
X3 is selected from the group consisting of O, S, SO, SO2, and
NR21 , wherein R21 is selected from the group consisting of hydroxyl, C1-16 acyl, C1-16 alkyl, C1-16 aryl, C1- 16 haloacyl, and hydrogen;
X4 is selected from the group consisting of C-Q, nitrogen, and NO;
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-16 alkoxyl, C3-8 cycloalkyl, tosyl, mesylate, triflate, thiol. acetate optionally substituted with C1-8 alkyl,
trifluoroacetate, halogen, nitro, cyano, C1-16 acyl, C1- 16 arylacyl, nitroso,
aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH
wherein n and m are independently 1 to 4,
aminoalkylaminoalkylhalide of formula NH(CH2)nNH(CH2)mX10 wherein n and m are independently 1 to 4 and X10 is halogen,
amino which may be unsubstituted or mono or disubstituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8
alkenyl, or C2-8 alkynyl,
haloalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2X11, wherein n is 0 to 4 and X11 is halogen,
NH(CH2)nNR22R23 wherein n is 1 to 6, and R22 and R23 are
independently selected from hydrogen, C1-8 alkyl, C6- 18 aryl, C7-18 aralkyl, C1-8 acyl, and trifluoroacyl, and,
a group of the formula -O-(CO)R24 wherein R24 is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-12 alkoxyalkyl, C7-18 aralkyl, C7- 18 araloxyalkyl, C7-18 aryloxyalkyl and C6-18 aryl; Z is selected from the group consisting of hydrogen,
hydroxy, halogen, thiol, C1-16 sulfide, C1-16 alkoxy, C1- 16 hydroxime, C6-18 hydrazone, C1-16 hydroxyalkyl, C6-18 aryl, C7-18 aryloxyalkyl, C7-18 araloxyalkyl, phenyl, C1- 16 alkyl, C2-16 acetoxy, C1-16 dihydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, squaric acid, C1- 16 alkyl squarate, cyano, dimethylphosphonato, phenyl sulfone, C1-18 aryl sulfone, C1-8 acetyl. amino which may be unsubstituted or mono- or disubstituted by hydrogen, C1 - 8 alkyl, C3-8 cycloalkyl, C2-8 acyl, trifluoroacyl, cyano, C7-18 aralkyl, C6-18 aryl, a naturally occurring amino acid,
a group of the formula -CHR26 R27, wherein R26 and R27 are independently selected from the group
consisting of C1-8 alkyl, hydrogen, C1-8 acyl, C6- 18 aryl, C7-18 aralkyl, PO(OR28)2 wherein R28 is hydrogen or C1-8 alkyl,
a group of the formula -(CH2)nX15 wherein n is O to
7 and X15 is selected from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, a
5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR29 wherein R29 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8
cycloalkyl, C1-8 acyl, trifluoroacyl, C7- 18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy. a group of the formula -C(R25)=X12 wherein X12 is selected from the group consisting of two hydrogens, 0, or its dioxolane or dioxane or dialkoxy C1-8 ketal, one hydrogen and R25i , wherein R25i is selected from C1-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and
wherein R25 is selected from the group consisting of hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8
cycloalkyl, C6-18 aryl, C7-18 aralkyl,
fluoromethyl, difluoromethyl, C1-8 hydroxyalkyl, C2-16 alkene, squaric acid or squarate, C2-16 alkyne, C1-8 thioalkyl, C6-18 thioaryl, C1-4 alkyl squarate, C2-8 alkoxyalkyl, C6-18 araloxyalkyl, C2- 18 acyloxyalkyl, C1-16 alkoxy, C6-12 aryloxyalkyl, hydroxy, acetoxymethyl, bromomethyl, C1-8 aceto, amino which may be unsubstituted or mono- or di- substituted by hydrogen, C1-8 alkyl, 03-8 cycloalkyl, C2-8 acyl, trifluoroacyl, cyano, C7- 18 aralkyl, C6-18 aryl, a naturally occurring amino acid,
a group of the formula -CHR26 R27, wherein R26 and R27 are independently selected from the group consisting of C1-8 alkyl, hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, PO(OR28)2 wherein R28 is hydrogen or C1-8 alkyl, a group of the formula -(CH2)nX15 wherein n is 0 to 7 and X15 is selected from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, a
5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR29 wherein R29 is selected from the group consisting of hydrogen. hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy,
and,
X15 can also be a group of the formula - NR30 R31 or NOR30 R31 wherein R30 and R31 are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C1-8
alkoxyalkyl, C1-8 acyloxyalkyl, C6-12 araloxyalkyl, a naturally occurring amino acid, and a group of formula
CO(CH2)nC(PO(OR32)2)2 wherein n is 1 to 4 and R32 is hydrogen or C1-8 alkyl,
and,
Z can also be a group of the formula -C(OR33)=O, wherein
R33 is selected from the group consisting of hydrogen, C1- 16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C7-18 aryloxyalkyl, C6-18 araloxyalkyl, C6- 18 aryl, C1-16 alkenyl, C7-18 aralkyl,
a group of the formula - (CH2)nC(R34)=O, wherein n is 1 to
6 and wherein R34 is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C1-8 alkoxy, C7- 18 aryloxyalkyl, C7-18 araloxyalkyl, C6-18 aryl, C7-18 aralkyl,
amino which may be unsubstituted, mono- or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C7-12 aralkyl, or C6-12 aryl, a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR35 wherein R35 is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl and
C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, C6-18 arylsulfone, hydroxy, C1-16 alkoxy, nitro, C1-16 alkyl, C1-16 hydroxyalkyl, and amino which may be unsubstituted or mono- or
disubstituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C7-12 aralkyl, C6-12 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy;
and,
NH(CO)N(NO) (CH2)nCH2X17 wherein n is 0 to 4 and X17 is
halogen; and R8 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, C1-16 alkoxyl, C1-16 alkyl, C2-16 acetylenyl, C3-8 cycloalkyl, C2-16 alkenyl, C1-16 alkoxyalkylamino, cyano,
a group of the formula - (CH2)n-NR40R41 wherein n is 1 to 6, and, R40 and R41 are independently selected from a group consisting of C1-8 alkyl, C1-4 acyl, C3-8 cycloalkyl, hydrogen, C2-8 carboalkoxy, C2-8 alkene, C2-8 alkyne, C6-12 aryl, and (OCH2CH(PO(OR42)2)2 wherein n is 0 to 5 and R42 is a hydrogen or a C1-8 alkyl;
a group of the formula -O-C(R45)=O, wherein R45 is
selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-8 alkoxyalkyl, and C6-12 aryl,
an acyl of the formula -C(R46)=O, wherein R46 is selected from the group consisting of hydrogen, thiol, C1-16 thioalkyl, C1-16 alkyl,C3-8 cycloalkyl, C1-8
hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 araloxyalkyl, C2-8 acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid or a synthetic amino acid,
a group of the formula -C(OR47)=O, wherein R47 is selected from the group consisting of hydrogen, C1-16 alkyl and C3-8 cycloalkyl,
acosamine, glucosamine, N-chloroethylnitrosoureidoglucosamine, 2,6-dideoxyrhamnose,
thioglucose, thiodaunosamine, thiol, C1-12 thioalkyl, a naturally occuring amino acid or di- and tri-peptides thereof,
a group of the formula -X16-CHR48R49 wherein X16 is selected from the group consisting of O, CH2, and
NR50 wherein R50 is from the group consisting of
hydrogen, C1-8 alkyl, C2-8 acyl and C6-12 aryl, and wherein R48 and R49 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C6- 12 aryl, C2-8 dihydroxyalkyl, C2-8 alkene, C2-8 alkyne, C1-8 alkoxy, C1-8 alkylamino, C3-8
cycloalkyl, C2-8 carboalkoxy,
a 5 or 6 membered aromatic or non-aromatic
heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N,
SO, SO2, P, PO, and
NR51 wherein R51 is selected from the group
consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6- 18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy,
mono or oligosaccharides of the formula
CR52R53, wherein R52 and R53 are independently
hydrogen, or C1-8 alkyl,
NR54 wherein R54 is selected from the group
consisting of hydrogen, C1-8 alkyl, and C1-8 acyl;
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol, amino, trifluoroacetamido,
chloroethylnitrosoureido, and chloroethylureido; R11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, t- butyloxycarbonyl, trifluoroacyl, C7-12 aralkyl, C6-12 aryl, and a naturally occurring or
synthetic amino acid;
mono or dibenzylated amino, azido, acylated amino, trifluoroacylated amino, morpholino, cyano,
substituted morpholino, mono-, di-, tri- or tetra- methoxy substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, C1-16 alkoxyl,C3-8 cycloalkyl, thiol, C1-8 sulfide,
a group of the formula NH (CH2)nCH(OR55)2 wherein n is 0 to 5 and R55 is selected from the group consisting of C1-16 alkyl, C1-16 acyl and C7-16 aroyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and,
NH(CH2)2 OCH2CH(OAc)2; R12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropyranyl ether (-OTHP), mesylate, tosylate, halogen, mono or
oligosaccharides, C1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C1-16 alkoxy,
C3-8 cycloalkyl, C2-8 haloalkylacetate,
benzoate which may be unsubstituted or substituted with nitro. acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)nCH2Cl wherein n is
0 to 4, and NH(CH2)2 OCH2CH(OAC)2;
and,
R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic ring optionally
containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR56 wherein R56 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2- 8 alkenyl, C2-8 alkynyl and hydroxy,
and,
R8 and Z, or R8 and X12, can further form a 5 or 6 membered aromatic or nonaromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8
alkenyl, C2-8 alkynyl and hydroxy.
2. A compound according to claim 1, wherein
X1 and X2 are independently selected from the group
consisting of O, S, and NH;
X3 is selected from the group consisting of O, S, SO, SO2, NH, and NOH;
X4 is selected from the group consisting of CQ, N, and NO;
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxy, methoxy, halogen, C1-4 alkoxyl, tosyl, triflate, fluorine, chlorine, amino, aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH
wherein n and m are independently 1 to 3,
aminoalkylaminoalkylchloride of formula
NH(CH2)nNH(CH2)mCl where n and m are independently 1 to 3,
chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)n CH2 CI, wherein n is 0 to 4,
and,
a group of the formula -O-C(R24)=O, wherein R24 is
selected from the group consisting of hydrogen, C1-6 alkyl, and aryl;
Z is selected from the group consisting of hydrogen, C1-8 hydroxyalkyl, fluorine, C1-4 alkoxy, cyano, C1-8
dihydroxyalkyl, C1-4 hydroxime, C6-10 hydrazone, phenyl, squaric acid, C1-16 alkylsquarate, C1-4 alkyl,
amino which may be unsubstituted or mono- or di- substituted with hydrogen, C1-8 alkyl, C3-8
cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, or a group of the formula CHR62R63 wherein R62 and R63 are independently selected form the group consisting of C1- 4 alkyl, hydrogen, C 1-4 acyl,
a group of the formula (CH2)nX40 wherein n is 0 to 3
and X40 is a hydrogen, C1-4 acyl, hydroxyl,
a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or more heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C1-4 alkyl, C1-4 acyl, trifluoroacyl, and C2-4 alkynyl,
X40 can also be a group of the formula NR64 R65 wherein R64 and R65 are independently selected from hydrogen, C1-4 alkyl, C1-4 chloroalkyl, C1- 4 hydroxyalkyl, and C1-4 acyl,
roup of the formula -C(R25)=X12, wherein X12 is two hydrogens, or oxygen, and wherein R61 is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 hydroxylalkyl, cyano, squaric acid, C1-4 alkyl
squarate, alkoxyalkyl, aminoacetaldehyde diethyl acetal, aminoacetaldehyde diacetoxy acetal,
aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl, C2-4 alkenyl, C2-4 actylyl, C 1-4 alkoxy, hydroxy, C1-4 aceto,
amino which may be unsubstituted or mono- or di- substituted with hydrogen, C1-8 alkyl, C3-8
cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, or a group of the formula CHR26R27 wherein R26 and R27 are independently selected form the group
consisting of C1-4 alkyl, hydrogen, C 1-4 acyl, a group of the formula (CH2)nX15 wherein n is 0 to 3 and X15 is a hydrogen, C1-4 acyl, hydroxyl, a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or more heteroatoms selected from the group
consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C1-4 alkyl, C1-4 acyl,
trifluoroacyl, and C2-4 alkynyl,
X15 can also be a group of the formula NR30 R31 wherein R30 and R31 are independently selected from hydrogen, C1-4 alkyl, C1-4 chloroalkyl, C1- 4 hydroxyalkyl, and C1-4 acyl,
a group of the formula -C(OR33)=O, wherein R33 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aralkyl,
and,
a group of the formula - (CH2)nC(R34)=O, wherein n is 1 to
3 and R34 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 hydroxyalkyl, straight or branched C1-8 alkyl, and
amino which may be unsubstituted or mono- or di- substituted with C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, and
a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N,
NO, NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-8 alkoxy, C1-8 alkyl, C1-8 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, C3-5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy; R5 and R8 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, C1-8 alkoxy. C1-8 alkyl, C2-4 alkene, C2-8 acetylenyl, C2-8 alkenyl, C1- 4 acetate, C1-4 acetyl, cyano,
a group of the formula -(CH2)n NR40R41 wherein n is 1 to 4 and R40 and R41 are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-4 acyl, acosamine, 2, 6-dideoxyrhamnose, thiodaunosamine, C1-5 thioalkyl, a naturally occurring amino acid, or
dipeptides thereof,
a group of the formula -X16-CHR48 R49 wherein X16 is
selected from the group consisting of O, CH2 and
NR50 wherein R50 is C1-4 alkyl or C2-4 acyl,
and wherein R48 and R49 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkene, C1-5 alkylamino, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and
NR51 wherein R51 is selected from the group
consisting of hydrogen, C1-4 alkyl, and C1-4 acyl,
said heterocycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di- substituted by C1-4 alkyl, C1-4 acyl and
trifluoroacyl,
a group of the formula -O-C(R45)=O, wherein R45 is
selected from the group consisting of hydrogen and C1- 8 alkyl,
acyl of the formula -C(R46)=O, wherein R46 is selected
from the group consisting of hydrogen, thiol, C1-8 alkyl, hydroxyalkyl, amino,
a group of the formula -C(OR47)=O, wherein R47 is hydrogen or C1-8 alkyl,
glucosamine, and accharide of formula
wherein Y is selected from the group consisting of oxygen, sulfur, and CHR53 wherein R53 is hydrogen or C1-4 alkyl
R9 and R10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl;
R11 is selected from the group consisting of
amino which may be unsubstituted or mono- or di- substituted with C1-8 acetoxy alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl,
C1-8 alkoxy, morpholino, azido, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, hydroxyl, mono or
dialkylated amino with 1 to 16 carbons, fluorine a group of the formula NH(CH2)nCH(OR55)2 wherein n is 1 to 5 and R55 is independently selected from a group consisting of C1-8 alkyl, C1-8 acyl and C7-12 aroyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)2 OCH2CH(OAc)2; R12 is selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, halogen, mono or oligosaccharide selected from the group consisting of rhodosamine, cinerulose-B, L- cinerulose, D-cinerulose, cinerulose A,
amicetose, aculose, rednose, rhodinose, 2- deoxyfucose, daunosamine, trifluoroacetyl- daunosamine,
amino, trifluoroacetamido, mono or dimethylated amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkyl-nitrosoureido, acetoxy and
trifluoroacetoxy;
R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic ring optionally
containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR56 wherein R56 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2- 8 alkenyl, C2-8 alkynyl and hydroxy;
and,
R8 and Z, or R8 and X12, can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl. said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, and trifluoroacyl.
3. A compound according to claim 2, wherein
X1 and X2 are independently selected from the group
consisting of O and NH;
X3 is selected from the group consisting of O, S and SO;
X4 is selected from the group consisting of CQ and N;
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxy, methoxy, halogen, aminoethylaminoethanol, aminoethylaminoethylchloride, chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 2,
amino, and fluorine; Z is selected from the group consisting of hydrogen,
fluorine, methoxy, cyano, C1-4 hydroxime, C6-10
hydrazone, C1-4 alkyl, C1-4 hydroxyalkyl, phenyl, C1-4 dihydroxyalkyl,
acyl of the formula -C(R25)=O, wherein R25 is selected
from the group consisting of hydrogen, C1-4 alkyl, hydroxymethyl, acyloxymethyl, cyano, and
amino which may be unsubstituted or mono-or di- substituted by hydrogen, C1-3 alkyl, C2-3 acyl, a group of the formula -CHR26R27 wherein R26 and R27 are independently selected from hydrogen, and C1-3 alkyl,
a group of the formula -(CH2)nX15 wherein n is 0 to 2 and X15 is C1-3 alkyl or a group of the formula -NR30R31 wherein R30 and R31 are
independently selected from hydrogen, C1-3 alkyl, C1-3 acyl, and C2-3 chloroalkyl, and,
X15 can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano,
and,
a group of the formula -C(OR33)=O, wherein R33 is selected from the group consisting of hydrogen, C1-4 alkyl, C 1- 4 alkenyl, aryl,
a group of the formula - (CH2)nC(R34) = O, wherein n is 1 to
3 and R34 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, amino,
dimethylamino,
a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, NH; said heterocycle being optionally substituted with one or more
halogens, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, amino which may be unsubstituted or mono-or disubstituted by methyl, cyclopropyl, acyl, and hydroxy; R5 and R8 are independently selected from the group
consisting of hydrogen, halogen, hydroxy, C1-4 alkoxy, C1-6 alkyl, C2-4 alkene, methoxy, cyano, C1-4 acetate, C1-4 acetyl,
a group of the formula -O-C(R45)=O, wherein R45 is
hydrogen or C1-8 alkyl. acyl of the formula -C(R46)=O, wherein R46 is selected from the group consisting of hydrogen, thiol, C1-8 alkyl, hydroxyalkyl, amino,
a group of the formula -C(OR47)=O, wherein R47 is hydrogen or C1-8 alkyl,
glucosamine, and
a group of the formula
R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, chlorine, amino, trifluoroacetamido, iodine, and hydroxyl;
Rll is selected from the group consisting of hydroxy, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano substituted morpholino, mono-, di-, tri-, tetra-methoxy substituted morpholino, a group of the formula NH(CH2)nCH(OR55)2 wherein R55 is selected from the group consisting of C1-4 alkyl, C1-4 acyl or C7-8 aroyl and wherein n is
2 to 5,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4,
NH(CH2)4CH(OAc)2, NH(CH2)2OCH2CH(OAc)2, and
NH (CH2) OCH2CH2CH (OAc)2; R12 is selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, amino, trifluoroacetamido,
chloroethylnitrosoureido, fluorine, and iodine; and,
R5 and R8 can also be independently selected from 5 or 6
membered aromatic or non-aromatic ring optionally
containing one or two heteroatoms selected from the group consisting of O, S, N, and
NR56 wherein R56 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 acyl,
said cycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and
amino, which may be unsubstituted or mono-or di- substituted by C1-4 alkyl, C1-4 acyl and
trifluoroacyl,
and
R8 and Z, or R8 and X21, can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and
NR57 wherein R57 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl,
said cycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, and trifluoroacyl.
4. A compound according to claim 3, wherein
X1 and X2 are both oxygen;
X3 is O, S or SO;
X4 is CQ; R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, and methoxy;
Z is selected from the group consisting of hydrogen,
fluorine, cyano, C1-3 hydroxime, methyl, ethyl, C1-3 alkyl, hydroxymethyl, 1,2 dihydroxymethyl,
a group of the formula -C(R25)= X, wherein X is selected from the group of two hydrogen and oxygen, and wherein R25 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, hydroxymethyl,
acetoxymethyl, bromomethyl and C1-4 alkoxy, C2-3 alkenyl, C1-3 aceto,
amino which may be unsubstituted or mono-or di- substituted by hydrogen, C1-3 alkyl, C2-3 acyl, a group of the formula -CH2R27 wherein R27 is selected from hydrogen, C1-3 alkyl, and C2-3 chloroalkyl, and,
a group of the formula -(CH2)nX15 wherein n is 0 to 2 and X15 is a C1-3 alkyl or a group of the formula - NR30R31 wherein R30 and R31 are independently selected from hydrogen, C1-3 alkyl, C1-3 acyl, and chloromethyl,
X15 can also be a 5 or 6 membered aromatic or non- aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano,
a 5 or 6 membered aromatic or non aromatic
heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and NH, said heterocycle being optionally substituted with one or more fluorine, hydroxy, methoxy, methyl, hydroxymethyl, cyano, amino and acylamino groups; R5 and R8 are independently selected from the group
consisting of hydrogen, hydroxyl, methoxy, C1-4 alkyl, bromine, chlorine, cyano, acetate, acetyl, and a
saccharide of the formula
R9 and R10 are independently selected from the group
consisting of hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of amino,
hydroxy, dimethylamino, acetoxy, trifluoroacetamido, morpholino, cyano substituted morpholino,
methoxymorpholino, and
a group of the formula NH(CH2)nCH(OR55)2 wherein n is 3 to 5 and R55 is selected from the group consisting of methyl, acyl or benzoyl,
chloroalkylnitrosoureido of the formula
NH(CO)N(NO) (CH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)OCH2CH(OAc)2;
R12 is hydroxyl, iodine, or bromine;
and,
R5 and R8 can also be independently selected from 5 or 6
membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, and N,
said heterocycle being optionally substituted by cyano, hydroxy, amino, or dimethylamino.
5. A compound according to claim 1, 2, or 3, wherein X1 and X2 are both oxygen.
6. The compound according to claim 4 or 5, wherein X3 is O, or S.
7. The compound according to claim 6, wherein X4 is CQ.
8. The compound according to claim 5 or 7, wherein R2 and R3 are both hydrogen.
9. The compound according to claim 8, wherein R1 and Q are independently selected from the group consisting of hydrogen, fluorine, and hydroxyl.
10. The compound according to claim 1, 2, 3, or 4, wherein Z is selected from the group consisting of hydrogen, methyl, ethyl, fluorine, hydroxymethyl, 1,2- dihydroxyethyl, and
acyl of the formula -C(R)=O, wherein R is selected from the group consisting of methyl, fluoromethyl,
difluoromethyl, and hydroxymethyl.
11. The compound according to claim 1, 2, 3, or 4, wherein R5 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and
a saccharide of the formula
wherein
R9 and R10 are independently selected from the group
consisting of hydrogen, fluorine, and iodine; R11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano substituted morpholino,
methoxymorpholino,
R12 is selected from the group consisting of acetoxy,
hydroxyl, hydrogen, and iodine.
12. A compound according to claim 9, wherein
Z is selected from the group consisting of ethyl,
hydroxymethyl, 1,2-dihydroxyethyl, carbonyl,
acyl of the formula -C(R25)=O wherein R25 is selected from the group consisting of methyl, fluoromethyl,
difluoromethyl, hydroxymethyl, and
amino optionally substituted with a group of the
formula (CH2)nX15 wherein n is 2 or 3, and X15 is hydroxyl, or
a group of the formula NHR31 2 wherein R31 is selected from the group consisting of hydrogen, C1-3 alkane, chloroethane, and hydroxyethane .
13. The compound according to claim 12, wherein R8 is hydrogen.
14. The compound according to claim 13, wherein R5 is
selected from the group consisting of hydrogen, hydroxyl, cyano, acetate, acetyl, methoxy, propyl, and a saccharide of the formula
wherein R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, and iodine; R11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino,
methoxymorpholino;
R12 is selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine.
15. A compound according to claim 1, wherein :
X1 and X2 are both oxygen;
X3 is O, or S;
X4 is CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group
consisting of hydrogen, fluorine, and hydroxyl;
Z is selected from the group consisting of hydrogen, ethyl, hydroxymethyl, 1,2-dihydroxyethyl,
acyl of the formula -C(R)=O, wherein R is selected from the group consisting of methyl, fluoromethyl,
difluoromethyl, hydroxymethyl;
R5 and R8 are independently selected from the group
consisting of hydrogen, hydroxyl and acetyl.
16. A compound according to claim 1, 2, 3, or 4, wherein at least one of R5 and R8 is independently a saccharide of the formula:
wherein
R9 and R10 are independently selected from hydrogen,
fluorine, and iodine; R11 is selected from hydroxyl, amino, dimethylamino,
ammonium chloride, trifluoroacetamido, morpholino, cyano substituted morpholino, methoxy morpholino;
R12 is selected from the group consisting of hydrogen, hydroxyl, iodine, and acetoxy.
17. A compound according to claim 8 wherein Rn is selected from the group consisting of hydroxyl, amino, and
trifluoroacetamido.
18. A compound according to claim 1, 2, 3, or 4, wherein X3 is oxygen.
19. A compound according to claim 1, 2, 3, or 4, wherein X3 is sulfur.
20. A compound according to claim 18, wherein R8 is
hydrogen.
21. The compound according to claim 11, wherein R8 is hydrogen.
22. A compound according to claim 17 wherein R8 is
hydrogen.
23. A compound according to claim 5 wherein R8 is hydrogen.
24. A compound according to claim 18, where R5 is methoxy or C1-5 alkyl.
25. A compound according to claim 19, where R5 is methoxy or C1-5 alkyl.
26. A compound according to claim 24 or 25, wherein X1 and X2 both are O, and Z is
a group of the formula -C(R25)=O wherein R25 is selected from the group consisting of hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8 cycloalkyl, C6-18 aryl, C7-18 aralkyl, fluoromethyl, difluoromethyl, C1-8
hydroxyalkyl, C2-16 alkene, C2-16 alkyne, C1-8 thioalkyl, C6-18 thioaryl, C2-8 alkoxyalkyl, C6-18 araloxyalkyl, C2-18 acyloxyalkyl, C1-16 alkoxy, C6-12 aryloxyalkyl, hydroxy, acetoxymethyl, bromomethyl, C1- 8 aceto,
amino which may be unsubstituted or mono- or di- substituted by hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, trifluoroacyl, cyano, C7- 18 aralkyl, C6-18 aryl, a naturally occurring amino acid,
a group of the formula -CHR26 R27, wherein R26 and
R27 are independently selected from the group consisting of C1-8 alkyl, hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, PO(OR28)2 wherein R28 is hydrogen or Cι_8 alkyl, a group of the formula -(CH2)nX15 wherein n is
0 to 7 and X15 is selected from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, a
5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and
NR29 wherein R29 is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and
C6-12 aryl,
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl. amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy,
and,
X15 can also be a group of the formula - NR30 R31 or NOR30R31 wherein R30 and R31 are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C1-8
alkoxyalkyl, C1-8 acyloxyalkyl, C6-12 araloxyalkyl, a naturally occurring amino acid, and a group of formula
CO(CH2)nC(PO(OR32)2)2 wherein n is 1 to 4 and R32 is hydrogen or C1-8 alkyl.
27. A compound according to claim 26, wherein Z is an
acyl of the formula -C(R25)=O, wherein R25 is selected
from the group consisting of hydrogen, C1-4 alkyl, hydroxymethyl, acyloxymethyl, cyano, and
amino which may be unsubstituted or mono-or di- substituted by hydrogen, C1-3 alkyl, C2-3 acyl, a group of the formula -CHR26R27 wherein R26 and R27 are independently selected from hydrogen, and C1-3 alkyl,
a group of the formula -(CH2)nX15 wherein n is 0 to 2 and X15 is C1-3 alkyl or a group of the formula -NR30R31 wherein R30 and R31 are
independently selected from hydrogen, C1-3 alkyl, C1-3 acyl, and C2-3 chloroalkyl, and, X15 can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano.
28. A compound according to claim 27, wherein Z is selected from the group consisting of ethyl, hydroxymethyl, 1,2- dihydroxyethyl, carbonyl, squarate,
acyl of the formula -C(R25)=O wherein R25 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, hydroxymethyl, and
amino optionally substituted with a group of the formula (CH2)n X15 wherein n is 2 or 3, and X15 is hydroxyl, or
a group of the formula NHR* wherein R* is
selected from the group consisting of
hydrogen, C1-3 alkane, chloroethane, and hydroxyethane,
and,
X15 can also be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or two heteroatoms selected from O or N, said heterocycle being optionally substituted with methoxy or cyano.
29. A compound according to claim 1, 2, 3, or 4 wherein R5 is selected from a group of the formula -X101-X102 wherein X101 is O, OCH2, or CH2 and wherein X102 is a 5 or 6 membered aromatic or non-aromatic heterocycle
incorporating one or two heteroatoms selected from the group consisting of O, S, and N,
said cycle being optionally substituted by hydroxyl, methoxy, amino or cyano.
30. A compound according to claim 1 selected from the group consisting of:
BCH-2051 3-dimethylaminopropyla(1-methoxy-5,10- dihydro-1H-naptho-[2,3-c]-pyran)-3-carboxamide
BCH-2167 1-Methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-[N-(3- dimethylaminopropyl)carboxamide] BCH-2168 3-hydrochlorodimethylaminopropyl-(1-propyl- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-)- carboxamide
BCH-2170 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide
BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide hydrochloride
BCH-2166 1-methoxy-3-(3-Npyrrolidinonylpropylaminocarbonyl)-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran BCH-2839 3-[2-(N-pyrrolydinyl)ethylaminocarbonyl]-1- methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran hydrochloride
BCH-2129 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H- naphtho [2,3-C] pyran
BCH-2044 phenyl-(1,3-cis-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran)-3-carboxamide BCH-2140 1[(tetraethyl-3,3-bis phosphonic ester) propriamido ethoxy]-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran BCH-2157 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide
BCH-2160 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyranyl-3-methoxycarbonyl
BCH-2161 3-carboxyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran BCH-2184 (+/-)-Methyl╌(1-[trifluoroacetamidomethyl]-5,10-dioxo-5,10-dihydronaphto-[2,3-c]-pyran-3-yl)ketone
BCH-2186 trans-1-methoxy-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-4a,10a-epoxy-naphtho-[2,3-c]-pyran
BCH-2824 1-methoxy-3-(3-bromopropylaminocarbonyl)5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH-2825 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH-2829 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-5a,10a-epoxy-naphtho-[2,3-c]-pyran BCH-2830 3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH-2831 1-methoxy-3-(3-methylthiopropylamino)carbonyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran BCH-2835 3-[2-(2-pyridinyl)ethlaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]hydrochloride BCH-2836 3-[2-(N-morpholino)ethylaminocarbonyl]-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride
BCH-2837 3-(2-trimethylammoniumethylaminocarbonyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride
BCH-2840 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH-2841 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH-2861 1-Methoxy-3-[(2-(N-pyrrolidinylethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran BCH-2871 N,N'-bis {1-Methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine
BCH-2875 2-hydrochloro-(N-pyrrolidinyl)-ethyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]pyran-3) carboxamide
BCH-2876 2-(2-N-Methyl pyrrolyl) ethyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide BCH-2877 3-N-oxo-dimethylaminopropyl-(1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)- carboxamide BCH-2878 1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]thiine-3-[N- (dimethylaminopropyl)carboxamide]
BCH-2879 Methyl 5,10-dioxo-1-(2',3',4',6'-tetradeoxy- 3',4'-diacetoxy-L-lyxohexapyranose)-5,10- dihydronaphtho-[2,3-c]thiopyran-3-yl) ketone
BCH-2880 N-Methyl-N, N'-bis {1-methoxy-5,10-dihydro- 5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl}- propyldiamine
BCH-2881 N-BOC-N-{1-mehtoxy-5,10-dihydro-5,10-dioxo- 1H-naphtho-[2,3-c]-pyran-3-carbonyl}-propyldiamine BCH2847 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N- methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H- naphtho-[2,3-c]-pyran
BCH2848 1-methoxy-3-[(4-diethoxy) butyl amino
carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran
BCH2849 1-methoxy-3-(3-hydroxy) propyl amino carbonyl- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
BCH2854 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran.
31. A compound according to claim 1 selected from the group consisting of: BCH-2051 3-dimethylaminopropyla(1-methoxy-5,10- dihydro-1H-naptho-[2 ,3-c]-pyran)-3-carboxamide.
BCH-2166 1-methoxy-3-(3-N- pyrrolidinonylpropylaminocarbonyl)-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran.
BCH-2167 1-Methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-[N-(3- dimethylaminopropyl)carboxamide].
BCH-2168 3-hydrochlorodimethylaminopropyl-(1-propyl- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-)- carboxamide.
BCH-2170 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide hydrochloride.
BCH-2839 3-[2-(N-pyrrolydinyl)ethylaminocarbonyl]-1- methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran hydrochloride.
BCH-2129 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H- naphtho [2, 3-C] pyran.
32. A compound according to claim 1 selected from the group consisting of:
BCH-2051 3-dimethylaminopropyla(1-methoxy-5,10- dihydro-1H-naptho-[2,3-c]-pyran)-3-carboxamide. BCH-2166 1-methoxy-3-(3-N- pyrrolidinonylpropylaminocarbonyl)-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran. BCH-2167 1-Methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-[N-(3- dimethylaminopropyl)carboxamide].
BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide hydrochloride.
BCH-2839 3-[2-(N-pyrrolydinyl)ethylaminocarbonyl]-1- methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran hydrochloride.
33. A compound according to claim 1, wherein the compound is BCH-2051 - 3-dimethylaminopropyla(1-methoxy-5,10-dioxo-5,10- dihydro-1H-naptho-[2,3-c]-pyran-3-yl)-carboxamide hydrochloride.
34. A compound according to claim 1, wherein said compound is BCH 2839
3-[2-(N-pyrrolydinyl)ethylcarboxamide]-1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
hydrochloride.
35. A compound according to claim 1, wherein said compound is BCH 2166
1-methoxy-3-(3-N-pyrrolidinonylpropylcarboxamide)-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
36. A compound according to claim 1, wherein said compound is BCH 2167
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylaminopropyl)carboxamide].
37. A process for the preparation of a compound of
formula 12:
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected from the group consisting NR, O, or
S; X1 and X2 are O, and R1, R2, R3, R5, R8, X4, and Z are as defined in claim 1, comprising the step of:
c) air-oxidizing a tricyclic heteronaphthoquinone of formula
16:
in the presence of an inorganic base or an organic base or a fluoride salt to yield a mixture of compounds of formula 21 and 19:
and.
d) optionally, if compounds of formula 19 are present, converting said compounds 19 to compounds of formula 21 by deoxygenation using a reducing agent.
38. The process according to claim 37, wherein said
tricyclic heteronaphtoquinone 16 is obtained by the step of: b) cyclo-adding a quinone of formula 15:
with a diene of formula 20
wherein L is a leaving group selected from the group
consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and - OR* or -SR*, wherein R* is a C1-8 alkyl, and wherein R1, R2, R3 and X4 are as defined above.
39. The process according to claim 38, wherein said quinone of formula 15 is obtained by the step of:
a) selecting a precursor isochroman compound of formula 14:
wherein X3, Z, R5 and R8 are defined as above, and
oxidatively demethylating said compound with selenylating agent.
40. The process according to claim 37, 38, or 39, wherein in step c), an hydrogen peroxide scavenger is added, to yield the compound of formula 21:
41. A process for the preparation of a compound of formula 12 wherein 0 in formula 21 at the X1 and X2 position of formula 12:
are replaced with other substituents as defined for X1 and X2 in claim 1 to obtain a compound of formula 12.
42. A process for the preparation of a compound of
formula 12:
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected from the group consisting NR, O, or S; X1 and X2 are O, and R1, R2, R3, R5, R8 , X4, and Z are as defined in claim 1, comprising the step of:
c) cyclo-adding a quinone of formula 18:
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR* or -SR* where R* is a C1-8 alkyl, and wherein R1, R2, R3 and X4 are as defined above, to yield compounds of formula 21:
43. The process according to claim 42, wherein said quinone of formula 15 is obtained by the step of:
b) oxidatively demethylating isochromans of formula 17:
with a selenylating agent
44. The process according to claim 42, wherein said
isochromans of formula 17 is obtained by the step of:
a) selecting a precursor isochroman compound of formula 14
45. The process according anyone of claim 37 to 40, wherein said inorganic base in step c) is sodium hydroxide.
46. The process according anyone of claim 37 to 40, wherein said organic base in step c) is triethylamine, or 1,4-diazabicyclo-[2,2,2]-octane.
47. The process according to claim 40, wherein said
hydrogen peroxide scavenger is trimethylphosphite,
triphenylphosphine, or diaklylsulfide.
48. The process according to claim 39, wherein in step a), said oxidant is an oxidative sequence consisting of enolate addition to a selenylating agent.
49. The process according to claim 48 wherein said
selenylating agent is phenylselenylchloride.
50. The process according to claim 37, wherein X3 is O or S.
51. The process accoridng to claim 37, wherein X3 is O.
52. A process according to claim 37 further comprising the steps of:
- attaching a protecting group to at least one of the moieties at positions R1, R2, R3, R6, R7 and R8 and
positions R9, R10, R11, and R12 of the saccharide prior to glycosylation and then removing said protecting group or groups.
53. A process according to claim 52 wherein said protected positions are at R1, R2 and R3.
54. A process according to claim 39 or 45 wherein compound 14:
is produced by:
a) reacting:
wherein X is halogen, L is a leaving group, Z and R8 is as defined in claim 36,
to yield product:
and
c) further reacting said product with: ~
or
wherein L and R5 are as defined in claim 36,
with the proviso that where R5 is a C1-16 alkenyl and Z is an electron-withdrawing functional group, then compounds of formula 14 must be further treated with a Lewis acid in the presence of propenyl delivering agents.
55. An intermediate of formula 14
56. An intermediate of formula 15:
57. An intermediate of formula 18:
58. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 1, 2, 3, 4, or 31 in admixture with a pharmaceutical acceptable carrier.
59. A use of a compound according to claim 1, 2, 3, 4, or 31, and pharmaceutically acceptable derivatives thereof, for the treatment of tumors or cancer.
60. The use of a pharmaceutical composition according to claims 58, for the treatment of tumors or cancer.
61. The use of compounds according to claim 1, 2, 3, 4, or 31, for the manufacture of a medicament for the treatment of tumors or cancer.
62. The use of compositions according to claim 58, for the manufacture of a medicament for the treatment of tumors or cancer.
63. The use according to claim 61, wherein said medicament is administered orally, parenterally, rectally, nasally, vaginally, or topically.
64. The use according to claim 62, wherein said medicament is administered orally, parenterally, rectally, nasally, vaginally, or topically.
65. The use according to claim 63 or 64 wherein said medicament is administered at a dose of about 0.001 to at least 100 mg/kg of bodyweight per day.
66. The use according to claim 65 wherein said medicament is administered at a dose of about 0.1 to about 50 mg/kg up to 5 times per day.
67. The use according to claim 66 wherein said medicament is administered at a dose of about 0.2 to about 30 mg/kg up to 5 times per day.
68. The use according to claim 63 or 64 wherein said compound is present in dosage unit form in the medicament.
69. The use according to claim 68 wherein said compound is present in dosage unit form in the medicament at about 0.1 to 1000 mg.
70. The use according to claim 69 wherein said compound is present in dosage unit form in the medicament at about 1.0 to about 500 mg.
71. A method for the treatment of tumors or cancer
comprising the step of administering to an animal, a therapeutically effective amount of at least one compound according to claim 1, 2, 3, 4, or 31.
72. A method for the treatment of tumors or cancer
comprising the step of administering to an animal, a therapeutically effective amount of at least one
pharmaceutical composition according to claim 58.
73. A method according to claim 71, wherein said animal is a mammal.
74. A method according to claim 72, wherein said animal is a mammal.
75. The method according to claim 73, or 74, wherein said medicament is administered orally, parenterally, rectally, nasally, vaginally, or topically.
76. The method according to claim 75 wherein said
medicament is administered at a dose of about 0.001 to at least 100 mg/kg of bodyweight per day.
77. The method according to claim 76 wherein said
medicament is administered at a dose of about 0.1 to about 50 mg/kg up to 5 times per day.
78. The method according to claim 77 wherein said
medicament is administered at a dose of about 0.2 to about 30 mg/kg up to 5 times per day.
79. The method according to claim 75 wherein said compound is present in dosage unit form in the medicament.
80. The method according to claim 79 wherein said compound is present in dosage unit form in the medicament at about 0.1 to 1000 mg.
81. The method according to claim 80 wherein said compound is present in dosage unit form in the medicament at about 1.0 to about 500 mg.
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AU66727/94A AU6672794A (en) | 1993-11-05 | 1994-05-06 | Antineoplastic heteronaphthoquinones |
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US14825193A | 1993-11-05 | 1993-11-05 | |
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PCT/CA1994/000210 WO1995012588A1 (en) | 1993-11-05 | 1994-05-06 | Antineoplastic heteronaphthoquinones |
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WO (1) | WO1995012588A1 (en) |
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