Claims
- 1. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I:
- 2. The method of claim 1, wherein Z is O, S, NR8 or COR8.
- 3. The method of claim 1, wherein said compound has the formula:
- 4. The method of claim 1, wherein A is optionally substituted and selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, thienyl, furyl, pyrrolyl, 2-phenylethyl and cyclohexyl.
- 5. The method of claim 3, wherein said compound has one of the Formulae III-VI:
- 6. The method of claim 5, wherein A is optionally substituted and selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, thienyl, furyl, pyrrolyl, 2-phenylethyl and cyclohexyl.
- 7. The method of claim 5, wherein R1 and R2, or R2 and R3, or R3 and R4, are taken together to form a structure selected from the group consisting of —OCH2O—, —(CH2)3—, —(CH2)4—, —OCH2CH2O—, —CH2CR2O—, —CH2N(V)CH2—, —CH2CH2N(V)CH2—, —CH2N(V)CH2CH2—, —N(V)—CH═CH—, —CH═CH—N(V)—, —N(V)—CH═N—, —N═CH—O—, —N(V)—CH═N—, —O—CH═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—, —O—CH═CH—, —CH═CH—O—, —S—CH═CH—, —CH═CH—S, —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—CH═N—, —NH—CH2—NH—, —NH—CO—NH—, —N—CO—CO—N—, —N—CH2—CH2—N—, and —N═N—NH—, wherein V is hydrogen, C1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl.
- 8. The method of claim 5, wherein R1 and R2, or R2 and R3, or R3 and R4, are taken together to form a structure selected from the group consisting of —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH— and —CH═CH—CH═N—.
- 9. The method of claim 1, wherein X is O and Y is CN.
- 10. The method of claim 5, wherein R1-R4 are independently hydrogen, halogen, hydroxy, C1-10 alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, amino, acylamido, acyloxy, alkoxy, methylenedioxy or alkylthiol.
- 11. The method of claim 1, wherein A is
- 12. The method of claim 11, wherein R10 and R11, or R11 and R12, are taken together to form a structure selected from the group consisting of —OCH2O—, —(CH2)3—, —(CH2)4—, —OCH2CH2O—, —CH2N(V)CH2—, —CH2CH2N(V)CH2—, —CH2N(V)CH2CH2—, —CH═CH—CH═CH—, —N(V)—CH═CH—, —CH═CH—N(V)—, —O—CH═CH—, —CH═CH—O—, —S—CH═CH—, —CH═CH—S—, —N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N— and —N═CH—CH═N—, wherein V is hydrogen, C1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl.
- 13. The method of claim 3, wherein R3 and R4 together form an optionally substituted ring, wherein said ring is selected from the group consisting of benzo, pyrido, furo, dihydrofuro, thieno, pyrrolo, imidazolo, imidazol-2-one, pyrazo, thiazolo, oxazolo, oxazol-2-one, 2-oxadihydroimidazolo, 1,4-dihydropyrazine-2,3-dione, imidazolino, triazolo, and piperazo rings.
- 14. The method of claim 3, wherein said compound has the formula:
- 15. The method of claim 1, wherein said compound is selected from the group consisting of:
3-Cyano-7-methoxy-4-(3 -bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-phenyl-quinolin-1H-2-one; 3-Cyano-7-methoxy-4-(3 -methoxy-phenyl)quinolin-1H-2-one; 7-Chloro-3-cyano-4-(3 -methoxyphenyl)-quinolin-1H-2-one; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methoxy-quinolin-1H-2-one; 3-Cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3,5-Dimethoxyphenyl)-3-cyano-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-phenyl)-7-methoxy-2-oxo-2H-chromene; 7-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-2-oxo-2H-chromene; 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-5,6-dihydro-benzo[h]quinoline; 4-(3-Bromo-4,5-dimethoxyphenyl)-3-cyano-7,8-dihydro-8,8-dimethyl-2-oxo-2H-furo[3,2-h]chromene; 3-Cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene; 7-Amino-3-cyano-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-7-dimethylamino-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-4-(2,5-dimethoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methylamino-2-oxo-2H-chromene; 7-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene; 7-Bromo-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-oxo-2H-chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-imino-2H-chromene; 2-Imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene; 2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxy-phenyl)-2H-chromene; 3-Cyano-2-imino-7-methyl-4-(3-nitro-phenyl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-methoxy-phenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-bromophenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-7-methyl-4-(3-nitro-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-bromo-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; and 3-Cyano-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.
- 16. The method of claim 1, wherein said disorder is cancer.
- 17. The method of claim 16, wherein said cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute and chronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer and prostatic carcinoma.
- 18. The method of claim 16, wherein said cancer is a drug resistant cancer.
- 19. The method of claim 16, additionally comprising administering at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.
- 20. The method of claim 19, wherein said known cancer therapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5 -fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.
- 21. The method of claim 16, additionally comprising treating with radiation-therapy.
- 22. The method of claim 16, wherein said compound is administered after surgical treatment for cancer.
- 23. The method of claim 1, wherein said disorder is an autoimmune disease.
- 24. The method of claim 1, wherein said disorder is rheumatoid arthritis.
- 25. The method of claim 1, wherein said disorder is inflammation or inflammatory bowel disease.
- 26. The method of claim 1, wherein said disorder is psoriasis.
- 27. The method of claim 1, wherein said disorder is a skin disease.
- 28. A compound of Formula IIA:
- 29. The compound of claim 28, wherein X is O.
- 30. The compound of claim 28, wherein Z is O, S, NR8 or NCOR8.
- 31. The compound of claim 28, wherein A is optionally substituted and selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, thienyl, furyl, pyrrolyl, 2-phenylethyl and cyclohexyl.
- 32. A compound of claim 28, wherein said compound has one of the Formulae III-VI:
- 33. A compound of claim 28, wherein said compound is of Formula VII:
- 34. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of claim 28.
- 35. The pharmaceutical composition of claim 34, further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.
- 36. The pharmaceutical composition of claim 35, wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.
- 37. The pharmaceutical composition of claim 34, wherein said excipient or carrier is selected from the group consisting of saccharides, starch pastes, gelatin, tragacanth, cellulose preparations, calcium phosphates and polyvinyl pyrrolidone.
- 38. The pharmaceutical composition of claim 34, wherein said excipient or carrier is a saccharide selected from the group consisting of lactose, sucrose, mannitol and sorbitol.
- 39. The pharmaceutical composition of claim 34, wherein said excipient or carrier is a lipophilic solvent.
- 40. The pharmaceutical composition of claim 39, wherein said lipophilic solvent is selected from the group consisting of fatty oils, fatty acid esters, polyethylene glycols and paraffin hydrocarbons.
- 41. The pharmaceutical composition of claim 39, wherein said lipophilic solvent is selected from the group consisting of sesame oil, ethyl oleate, triglycerides, polyethylene glycol-400, cremophor and cyclodextrins.
- 42. The pharmaceutical composition of claim 34, wherein said excipient or carrier is selected from the group consisting of vegetable oils, mineral oils, white petrolatum, branched chain fats, branched chain oils, animal fats and high molecular weight alcohol (greater than C12).
- 43. The pharmaceutical composition of claim 34, wherein said excipient or carrier is a saline solution.
- 44. A compound selected from the group consisting of:
3-Cyano-7-methoxy-4-(3-bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-phenyl-quinolin-1H-2-one; 3-Cyano-7-methoxy-4-(3-methoxy-phenyl)quinolin-1H-2-one; 7-Chloro-3-cyano-4-(3-methoxyphenyl)-quinolin-1H-2-one; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methoxy-quinolin-1H-2-one; 3-Cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3,5-Dimethoxyphenyl)-3-cyano-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-phenyl)-7-methoxy-2-oxo-2H-chromene; 7-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-2-oxo-2H-chromene; 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-5,6-dihydro-benzo[h]quinoline; 4-(3-Bromo-4,5-dimethoxyphenyl)-3-cyano-7,8-dihydro-8,8-dimethyl-2-oxo-2H-furo[3,2-h]chromene; 3-Cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene; 7-Amino-3-cyano-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-7-dimethylamino-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene; 3-Cyano-4-(2,5-dimethoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methylamino-2-oxo-2H-chromene; 7-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene; 7-Bromo-4-(3 -bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-oxo-2H-chromene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-imino-2H-chromene; 2-Imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene; 2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxy-phenyl)-2H-chromene; 3-Cyano-2-imino-7-methyl-4-(3-nitro-phenyl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-methoxy-phenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-bromophenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-7-methyl-4-(3-nitro-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-methoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-bromo-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; and 3-Cyano-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.
- 45. A pharmaceutical composition comprising a compound of claim 44 and a pharmaceutically acceptable excipient or carrier.
- 46. A process for the preparation of a compound having Formula III:
- 47. The process of claim 46, wherein said organic solvent is dichloromethane, chloroform, toluene or xylene.
- 48. The process of claim 46, wherein said aqueous acid is aqueous sulfuric, hydrochloric, nitric and hydrobromic acid.
- 49. The process of claim 46, wherein said oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,3,5,6-tetrachloro-1,4-benzoquinone (chlorinal), bromine, palladium dichloride or ferric chloride.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This Application claims priority benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/290,978, filed May 16, 2001, the contents of which are entirely incorporated by reference herein.
Provisional Applications (1)
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Number |
Date |
Country |
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60290978 |
May 2001 |
US |