Patent EA-004103-B1 (EA)
Title: QUINOLINE AND QUINOXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56lck TYROSINE KINASES
Inventor: SPADA ALFRED P
IPC: A61K/
Filed: 1998-05-28
Abstract: 1. A compound of formula 1 wherein X is L1OH or L2Z2; L1 is -Z3-(CR3`aR3`b)3; L2 is -Z4-(CR3`aR3`b)q; Z1 is CH or N; Z2 is C5-7 hydroxycycloalkyl, optionally substituted hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide; C5-7 hydroxycycloalkenyl, optionally substituted with hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide; or 5- or 6-membered hydroxyheterocyclyl, optionally substituted with hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide; Z3 is O, NH; Z4 is O, NH; q = 0 or 1; R1a and R1b are independently (C1-C6)alkoxy, cyclohexyloxy, 2-morpholinylethoxy, carboxymethoxy, carbamoylmethoxy or one of R1a and R1b is halogen and the other is (C1-C6)alkoxy. R1c is H; R3`a and R3`b are independently H or (C1-C6)alkyl; or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.] 2. The compound of formula 1 of claim 1 wherein Z2 is C5-7 hydroxycycloalkyl, optionally substituted with hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide, or 5- or 6-membered hydroxyheterocyclyl, optionally substituted with hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide; 3. The compound of formula 1 of claim 1 wherein X is L2Z2; L2 is -Z4-(CR3`aR3`b)q; Z2 is C5-7 hydroxycycloalkyl, optionally substituted hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide; Z4 is O and NR; q is 0 or 1; R1a and R1b are independently (C1-C6)alkoxy, cyclohexyloxy, 2-morpholinylethoxy, carboxymethoxy, carbamoylmethoxy or one of R1a and R1b is halogen and the other is (C1-C6)alkoxy; R1c is H; R3`a and R3`b are independently H; or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 4. The compound of claim 1 wherein Z1 is CH. 5. The compound of claim 1 wherein Z1 is N. 6. The compound of claim 1 wherein Z2 is C5-7 hydroxycycloalkyl, optionally substituted with hydroxy, C1-6alkyl, C1-6alkoxy, dimethylcarbamide, acetyl or ethylamide. 7. The compound of claim 1 wherein q is 0. 8. The compound of claim 1 wherein q is 1. 9. The compound of claim 1 wherein Z4 is O. 10. The compound of claim 1 wherein Z4 is O, and q is 0. 11. The compound of claim 1 wherein Z4 is O, and q is 1. 12. The compound of claim 1 wherein Z4 is NR. 13. The compound of claim 1 wherein Z4 is NR, and q is 0. 14. The compound of claim 1 wherein Z4 is NR and q is 1. 15. The compound of claim 1 wherein R1a and R1b are independently (C1-C6)alkoxy, cyclohexyloxy, 2-morpholinylethoxy, or one of R1a and R1b is halogen and the other is (C1-C6)alkoxy. 16. The compound of claim 1 wherein R1a and R1b are independently (C1-C6)alkoxy, or morpholinylethoxy. 17. The compound of claim 16 wherein (C1-C6)alkoxy is methoxy or ethoxy. 18. The compound of claim 1 wherein one of R1a and R1b is halogen and the other is (C1-C6)alkoxy. 19. The compound of claim 18 wherein (C1-C6)alkoxy is methoxy or ethoxy and the halo is chloro or bromo. 20. The compound of claim 1 wherein one of R1a and R1b is (C1-C6)alkoxy, and the other is cyclohexyloxy. 21. The compound of claim 20 wherein (C1-C6)alkoxy is methoxy or ethoxy. 22. The compound of claim 1 wherein Z2 is C5-7 hydroxycycloalkyl optionally substituted with hydroxy or (C1-C6)alkyl. 23. The compound of claim 22 wherein Z2 is C5-7 hydroxycycloalkyl optionally substituted with (C1-C6)alkyl. 24. The compound of claim 1 wherein one of R1a and R1b is methoxy, and the other is 2-(4-morpholinyl)ethoxy, carboxymethoxy or N,N-dimethylaminocarbonylmethoxy. 25. The compound according to claim 1 which is trans-4-(7-Chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol; trans-4-(6-Chloro-7-methoxyquinoxalin-2-ylamino)-cyclohexanol; trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol; cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol; (2endo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol; (2exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1)heptan-2-ol; (2endo,3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane- 2,3-diol; cis-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol; trans-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol; trans-4-(6-Methoxyquinoxalin-2-ylamino)-cyclohexanol; [3aR,4S,6R,6aS]-6-(6,7-Dimethoxyquinoxalin-2-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1.3]dioxole-4-carboxylic ethylamide: 2-(1,4-Dioxaspiro[4,5]dec-8-yloxy)-6,7-dimethoxyquinoxaline; 4-(6,7-Dimethoxyquinoxalin-2-yloxymethyl)-cyclohexanol; 3-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol; 4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol; 5-(6,7-Dimethoxyquinoxalin-2-yloxy)-bicyclo[2.2.1]heptane-2,3-diol; (2exo,3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane-2,3-diol; Acetic acid cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester: cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol; Dimethyl-carbamic acid 4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester; trans-4-(6,7-Dimethoxy-4-oxyquinoxalin-2-ylamino)-cyclohexanol; Acetic acid trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexyl ester: (2exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]-heptan-2-ol; (2endo,5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino)-bicyclo[2.2.1] heptan-2-ol; (2exo,6exo)-6-(6,7-Dimethoxyquinolin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol; 4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (+)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (-)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (2trans,4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (2cis,4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; (2cis,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol; and 4-(6,7-Dimethylquinoxalin-2-ylamino)cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 26. The compound according to claim 1 which is trans-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 27. The compound according to claim i which is cis-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 28. The compound according to claim 1 which is 4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 29. The compound according to claim 1 which is (2exo, 5exo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol, or an N-oxide thereof, hydrate thereof. solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 30. The compound according to claim 1 which is traps-4-(7-chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 31. The compound according to claim 1 which is 4-(6,7-dimethoxyquinolin-3-ylamino)-cyclohexanol or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 32. The compound according to claim 1 which is (-)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol or an N-oxide thereof; hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 33. The compound according to claim 1 which is (1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]-heptan-2-ol or an N-oxide thereof, hydrate thereof. solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 35. A method of inhibiting PDGF tyrosine kinase activity comprising contacting a compound according to claim 1 with a composition containing a PDGF tyrosine kinase. 36. A method of inhibiting Lck tyrosine kinase activity comprising contacting a compound according to claim 1 with a composition containing a Lck tyrosine kinase. 37. 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 a patient a pharmaceutically effective amount of the compound according to claim 1. 38. A method for treating a pathology linked to a hyperproliferative disorder, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of the compound according to claim 1. 39. The method according to claim 38, wherein said pathology is restenosis. 40. A method of treating restenosis comprising administering to a patient in need of such treatment a pharmaceutically effective amount of the compound according to claim 1, that is capable of inhibiting vascular smooth muscle cell proliferation and migration at a predetermined site. 41. The method according to claim 40, wherein said site is a site of mechanical injury to an arterial wall produced by treatment of an atherosclerotic lesion by angioplasty. 42. The method according to claim 40, wherein the compound according to claim 1 is administered by means of an angioplasty balloon coated with a hydrophilic film saturated with the compound according to claim 1. 43. A method according to claim 40, wherein the compound according to claim 1 is administered by means of a catheter comprising an infusion chamber containing a solution of the compound according to claim 1. 44. A method for treating inflammation in a patient suffering from such disorder comprising administering to said patient an effective amount of a com