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):	Bos; Michael (Montreal, CA), Branca; Quirico (Binningen, CH), Galley; Guido (Rheinfelden, DE), Godel; Thierry (Basel, CH), Hoffmann; Torsten (Birsfelden, CH), Hunkeler; Walter (Magden, CH), Schnider; Patrick (Oberwil, CH), Stadler; Heinz (Rheinfelden, CH)
Assignee:	Hoffmann-La Roche Inc. (Nutley, NJ)
Application Number:	09/507,456
Patent Claims:	1. A compound of the formula ##STR107## wherein R is lower alkyl, lower alkoxy, halogen or trifluoromethyl; R.sup.1 is halogen or hydrogen; and when p is 1, R.sup.1 may in addition to the above substituents be taken together with R to form --CH.dbd.CH--CH.dbd.CH-- R.sup.2 and R.sup.2' are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; and when n is 1, R.sup.2 and R.sup.2' may in addition to the above substituents form --CH.dbd.CH--CH.dbd.CH--, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy; R.sup.3 and R.sup.3' are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; R.sup.4 is hydrogen, --N(R.sup.5).sub.2, --N(R.sup.5)(CH.sub.2).sub.n OH, --N(R.sup.5)S(O).sub.2 -lower alkyl, --N(R.sup.5)S(O).sub.2 -phenyl, --N.dbd.CH--N(R.sup.5).sub.2, ##STR108## R.sup.5 is hydrogen, C.sub.3-6 -cycloalkyl, benzyl or lower alkyl; R.sup.6 is hydrogen, hydroxy, lower alkyl, --(CH.sub.2).sub.n COO--(R.sup.5), --N(R.sup.5)CO-lower alkyl, hydroxy-lower alkyl, --(CH.sub.2).sub.n CN, --(CH.sub.2).sub.n O(CH.sub.2),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; ##STR109## 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 --(CH.sub.2).sub.n N(R.sup.5)--; X is, --(CH.sub.2).sub.m O--, --(CH.sub.2).sub.n N(R.sup.5)--, --N(R.sup.5)C(O)--, or --N(R.sup.5)(CH.sub.2).sub.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 R.sup.1 is halogen or hydrogen. 3. The compound of claim 1 wherein R.sup.2 and R.sup.2' are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano. 4. The compound of claim 2 wherein R.sup.2 and R.sup.2' are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano. 5. A compound of claim 4 wherein X is --N(R.sup.5)C(O)--. 6. A compound of claim 5 wherein R.sup.4 is hydrogen. 7. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chlorophenyl)-pyridin-3-yl]-N-m ethyl-isobutyramide. 8. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-iso butyramide. 9. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-o-tolyl-pyridin-3-yl)-isobutyramid e. 10. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-ace tamide. 11. A compound of claim 6 which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-pro pionamide. 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 R.sup.4 is ##STR110## 14. A compound of claim 13 wherein R.sup.4 is a six-membered ring. 15. A compound of claim 14 wherein R.sup.4 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-piper azin-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-me thyl-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-piperaz in-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 R.sup.4 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-tol yl-pyridin-3-yl)-acetamide. 29. A compound of claim 14 wherein R.sup.4 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-tetrahyd ro-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-tetrahy dro-2H-[1,2'] bipyridinyl-5'-yl)-N-methyl-isobutyramide. 32. A compound of claim 13 wherein R.sup.4 is a five-membered ring. 33. A compound of claim 32 wherein R.sup.4 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 R.sup.4 is attached through the linker --(CH.sub.2).sub.n N(R.sub.5)--. 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 R.sup.4 is --N(R.sup.5).sub.2, --N(R.sup.5)(CH.sub.2).sub.n OH, --N(R.sup.5)S(O).sub.2 -lower alkyl, N(R.sup.5)S(O).sub.2 -phenyl, --N.dbd.CH--N(R.sup.5).sub.2, --N(R.sup.5)C(O)R.sup.5. 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-p yridin-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-me thyl-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-pyr idin-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-trifluorometh yl-phenyl)-N-methyl-isobutyramide. 46. A compound of claim 4 wherein X is --(CH.sub.2).sub.m O--. 47. A compound of claim 46 wherein R.sup.4 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 --(CH.sub.2).sub.m N(R.sup.5)--. 50. A compound of claim 49 wherein R.sup.4 is hydrogen. 51. A compounds of claim 50 which is (3,5-bis-trifluoromethyl-benzyl)-methyl-(4-o-tolyl-pyridin-3-ylmethyl)-ami ne. 52. A compound of claim 49 wherein R.sup.4 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-et hyl)-amino]-4-o-tolyl-nicotinamide. 54. A compound of claim 2 wherein R.sup.2 and R.sup.2' together form --CH.dbd.CH--CH.dbd.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(R.sup.5)--. 56. A compound of claim 55 wherein R is lower alkyl; R.sup.1 is hydrogen, R.sup.3 and R.sup.3' are hydrogen, and R.sup.4 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-nic otinamide. 58. A compound of claim 56 which is N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nic otinamide. 59. A compound of claim 56 which is N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-ni cotinamide. 60. A compound of claim 56 which is N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-ni cotinamide. 61. A compound of claim 56 which is N-(1,4-dimethoxy-naphthalen-2-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-toly l-nicotinamide. 62. A compound of claim 3 wherein Rand R.sup.1 together form --CH.dbd.CH--CH.dbd.CH--. 63. A compound of claim 62 wherein Xis --C(O)N(R.sup.5)--. 64. A compound of claim 63 wherein R.sup.2 and R.sup.2' are trifluoromethyl; R.sup.3 and R.sup.3 are hydrogen, and R.sup.4 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.