Claims for Patent: 6,297,375

Summary for Patent: 6,297,375

Title:	4-phenyl-pyridine derivatives
Abstract:	The compounds of the related invention are related to 4-phenyl-pyridine derivatives connected by a bridge containing oxygen or nitrogen to a phenyl derivative.
Inventor(s):	Michael Bös, Quirico Branca, Guido Galley, Thierry Godel, Torsten Hoffmann, Walter Hunkeler, Patrick Schnider, Heinz Stadler
Assignee:	Hoffmann La Roche Inc
Application Number:	US09/507,456
Patent Claims:	1. A compound of the formula wherein R is lower alkyl, lower alkoxy, halogen or trifluoromethyl; R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH— R2 and R2′ are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; and when n is 1, R2 and R2′ may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy; R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; R4 is hydrogen, —N(R5)2, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, R5 is hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl; R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2),OH, —CHO or a 5- or 6 membered heterocyclic ring containing from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH2)nN(R5)—; X is, —(CH2)mO—, —(CH2)nN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—; n, p and q are 1 to 4; and m is 1 or 2; or pharmaceutically acceptable acid addition salts thereof. 2. The compound of claim 1 wherein R is lower alkyl, lower alkoxy, halogen or trifluoromethyl and R1 is halogen or hydrogen. 3. The compound of claim 1 wherein R2 and R2′ are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano. 4. The compound of claim 2 wherein R2 and R2′ are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano. 5. A compound of claim 4 wherein X is —N(R5)C(O)—. 6. A compound of claim 5 wherein R4 is hydrogen. 7. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chlorophenyl)-pyridin-3-yl]-N-methyl-isobutyramide. 8. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide. 9. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide. 10. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-acetamide. 11. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-propionamide. 12. A compound of claim 6 which is 1-(3,5-bis-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amide. 13. A compound of claim 5 wherein R4 is 14. A compound of claim 13 wherein R4 is a six-membered ring. 15. A compound of claim 14 wherein R4 is unsubstituted or substituted piperazinyl. 16. A compound of claim 15 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide. 17. A compound of claim 15 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chlorophenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide. 18. A compound of claim 15 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide. 19. A compound of claim 15 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide. 20. A compound of claim 15 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. 21. A compound of claim 15 which is [2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine. 22. A compound of claim 14 wherein R4 is morpholino. 23. A compound of claim 22 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. 24. A compound of claim 22 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chlorophenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide. 25. A compound of claim 22 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. 26. A compound of claim 22 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide. 27. A compound of claim 22 which is 2-(3,5-dimethoxy-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide. 28. A compound of claim 22 which is 2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide. 29. A compound of claim 14 wherein R4 is unsubstituted or substituted piperidinyl. 30. A compound of claim 29 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chlorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′] bipyridinyl-5′-yl]-N-methyl-isobutyramide. 31. A compound of claim 29 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′] bipyridinyl-5′-yl)-N-methyl-isobutyramide. 32. A compound of claim 13 wherein R4 is a five-membered ring. 33. A compound of claim 32 wherein R4 is unsubstituted or substituted pyrrolidinyl. 34. A compound of claim 33 which is (R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide. 35. A compound of claim 13 wherein R4 is attached through the linker —(CH2)nN(R5)—. 36. A compound of claim 35 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide. 37. A compound of claim 5 wherein R4 is —N(R5)2, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5. 38. A compound of claim 37 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-dimethylamino-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide. 39. A compound of claim 37 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chlorophenyl)-6-dimethylamino-pyridin-3-yl]-isobutyramide. 40. A compound of claim 37 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide. 41. A compound of claim 37 which is N-(6-benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. 42. A compound of claim 37 which is N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. 43. A compound of claim 37 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(dimethylamino-methyleneamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide. 44. A compound of claim 37 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-methanesulfonylamino-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide. 45. A compound of claim 37 which is N-(6-benzenesulfonylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. 46. A compound of claim 4 wherein X is —(CH2)mO—. 47. A compound of claim 46 wherein R4 is hydrogen. 48. A compound of claim 47 which is 3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-o-tolyl-pyridine. 49. A compound of claim 4 wherein X is —(CH2)mN(R5)—. 50. A compound of claim 49 wherein R4 is hydrogen. 51. A compounds of claim 50 which is (3,5-bis-trifluoromethyl-benzyl)-methyl-(4-o-tolyl-pyridin-3-ylmethyl)-amine. 52. A compound of claim 49 wherein R4 is substituted morpholino. 53. A compound of claim 52 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide. 54. A compound of claim 2 wherein R2 and R2′ together form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy. 55. A compound of claim 54 wherein X is —C(O)N(R5)—. 56. A compound of claim 55 wherein R is lower alkyl; R1 is hydrogen, R3 and R3′ are hydrogen, and R4 is morpholino. 57. A compound of claim 56 which is N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 58. A compound of claim 56 which is N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 59. A compound of claim 56 which is N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 60. A compound of claim 56 which is N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 61. A compound of claim 56 which is N-(1,4-dimethoxy-naphthalen-2-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 62. A compound of claim 3 wherein Rand R1 together form —CH═CH—CH═CH—. 63. A compound of claim 62 wherein Xis —C(O)N(R5)—. 64. A compound of claim 63 wherein R2 and R2′ are trifluoromethyl; R3 and R3 are hydrogen, and R4 is piperazinyl substituted with lower alkyl. 65. A compound of claim 64 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide.