Patent EA-002600-B1 (EA)
Title: QUINOLINE AND QUINPXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56<lck>
Inventor: MYERS MICHAEL
IPC: A61K/
Filed: 1998-05-28
Abstract: 1. A compound of formula I   wherein R1a is optionally substituted C1-C10alkyl, hydroxy, optionally substituted C1-C10alkoxy, optionally substituted C3-C7cycloalkyloxy, optionally substituted 4-7 membered oxaheterocyclyloxy or halo; R1b is hydrogen, optionally substituted C1-C10alkyl, hydroxy, optionally substituted C1-C10alkoxy, optionally substituted C3-C7cycloalkyloxy, optionally substituted 4-7 membered oxaheterocyclyloxy or halo; R1c is hydrogen, optionally substituted C1-C10alkyl or optionally substituted C1-C10alkoxy, R2 is   R3 is hydrogen, or ortho- or parafluoro, or meta-C1-C3 lower alkyl, C1-C3lower alkoxy, halo or carbamoyl; Zd is N or CH; and Zb is NH or O, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or salt thereof, provided that R1a and R1b are not both optionally substituted C1-C10alkyl. 2. The compound of formula 1 of Claim 1 wherein R1a is optionally substituted C1-C3lower alkoxy, optionally substituted monocyclic C1-C7cycloalkyloxy, optionally substituted 4-7 membered monocyclic oxaheterocyclyloxy. 3. The compound of Claim 2 wherein R1a is optionally substituted C1-C3lower alkoxy or optionally substituted 4-7 membered monocyclic oxaheterocyclyloxy. 4. The compound of Claim 3 wherein R1a is methoxy, ethoxy, 2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy or furanyloxy. 5. The compound of Claim 1 wherein R1b, is hydrogen, optionally substituted C1-C3lower alkoxy, optionally substituted monocyclic C3-C7cycloalkyloxy or optionally substituted 4-7 membered monocyclic oxaheterocyclyloxy. 6. The compound of Claim 5 wherein R1b is hydrogen or optionally substituted C1-C3lower alkoxy. 7. The compound of Claim 6 wherein R1b is methoxy or ethoxy. 8. The compound of Claim 1 wherein R1a and R1b are C1-C3lower alkoxy. 9. The compound of Claim 8 wherein R1a and R1b are methoxy or ethoxy. 10. The compound of Claim 1 wherein R1c is hydrogen. 11. The compound of Claim 1 wherein R3 is hydrogen, ortho- or parafluoro, or metamethyl, trifluoromethyl, methoxy, fluoro, chloro, bromo or carbamoyl. 12. The compound of Claim 1 wherein Za is N. 13. The compound of Claim 1 wherein Za is CH. 14. The compound of Claim 1 wherein Zb is NH. 15. The compound of Claim 1 wherein Zb is O. 16. A compound of Claim 1 which is selected from the following species: 2-anilino-6-quinoxalinol; 2-anilino-6-isopropoxyquinoxaline; 2-phenoxy-6-metoxyquinoxaline; 2-(3-carbamoylphenylamino)-6-methoxyquinoxaline; 2-(2-flurophenylamino)-6,7-diethoxyquinoxaline; 2-(3-trifluoromethylphenylamino)-6,7-diethoxyquinoxaline; phenyl-[6-(tetrahydrofuran-3(R)-yloxy)quinoxalin-2-yl]amine; (6-methoxyquinoxalin-2-yl)-(3-methylphenyl) amine; 6-methoxy-2-phenylaminoquinoxaline; 2-anilino-6-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; 2-(4-fluorophenylamino)-67-diethoxyquinoxaline; 6,7-diethoxy-2-phenoxyquinoxaline; 2-phenylamino-6,7-diethoxyquinoxaline; (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl) amine; 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl) amine; (6,7-dimethoxyquinoxalin-2-yl) phenylamine; and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl) amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 17. A compound of Claim 1 which is selected from the species: phenyl-[6-(tetrahydrofuran-3(R)-yloxy)quinoxalin-2-yl]amine; (6-methoxyquinoxalin-2-yl)-(3-methylphenyl) amine; 6-methoxy-2-phenylaminoquinoxaline; 2-anilino-6-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; 2-(4-fluorophenylamino)-6,7-diethoxyquinoxaline; 6,7-diethoxy-2-phenoxyquinoxaline; 2-phenylamino-6,7-diethoxyquinoxaline; (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl) amine; 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl) amine; (6,7-dimethoxyquinoxalin-2-yl) phenylamine; and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl) amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 18. The compound according to Claim 1 which is phenyl-[6-(tetrahydrofuran-3(R)-yloxy) quinoxalin-2-yl]amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 19. The compound according to Claim 1 which is (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl) amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 20. The compound according to Claim 1 which is (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl) amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 21. The compound according to Claim 1 which is (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2yl)-amine or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier. 23. A method of inhibiting PDGF tyrosine kinase activity comprising contacting a compound according to Claim 1 to a composition containing a PDGF tyrosine kinase. 24. A method of inhibiting Lck tyrosine kinase activity comprising contacting a compound according to Claim 1 to a composition containing a Lck tyrosine kinase. 25. A method of inhibiting cell proliferation, differentiation, or mediator release in a patient suffering from a disorder characterized by such proliferation and/or differentiation and/or mediator release comprising administering to said patient a pharmaceutically effective amount of the compound according to Claim 1, or a pharmaceutically acceptable salt thereof. 26. The method according to Claim 25 wherein the disorder is leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, arthritis, fibrosis of the lung, fibrosis of the kidney, fibrosis of the liver, atherosclerosis; or restenosis occurring subsequent to angioplasty of the coronary, femoral or kidney arteries. 27. A method for treating a patient subject to a pathology linked to a hyperproliferative disorder, said method comprising administrating to said patient a pharmaceutically effective amount of the compound according to Claim 1, or a pharmaceutically acceptable salt thereof. 28. A method according to Claim 27 wherein the pathology linked to a hyperproliferative disorder is a cancer susceptible to treatment by inhibition of PDGF tyrosine kinase. 29. A method according to Claim 28 wherein the cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma or malignant melanoma. 30. The method according to Claim 27, wherein said pathology is restenosis. 31. The method according to Claim 30 wherein the compound according to Claim 1 is administered by coating on a stent device, wherein the coating comprises the compound according to Claim 1. 32. A method for treating inflammation in a patient suffering from such comprising administering to said patient a pharmaceutically effective amount of a compound according to Claim 1, or a pharmaceutically acceptable salt thereof. 33. A method for treating of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, graft vs. host disease, asthma, inflammatory bowel disease or pancreatitis comprising administering to a patient suffering from such a Lck tyrosine kinase inhibitory amount of the compound according to Claim 1.