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Details for Patent: 6,479,483

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Details for Patent: 6,479,483

Title: 4-phenyl-pyridine derivatives
Abstract:Compounds of the present invention are 4-phenyl-pyridine derivatives with activity as NK-1 receptor antagonists.
Inventor(s): Bos; Michael (Montreal, CA), Branca; Quirico (Binningen, CH), Galley; Guido (Rheinfelden, DE), Godel; Thierry (Basle, CH), Hoffmann; Torsten (Birsfelden, CH), Hunkeler; Walter (Magden, CH), Schnider; Patrick (Oberwil, CH), Stadler; Heinz (Rheinfelden, CH)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)
Filing Date:Jul 10, 2001
Application Number:09/901,982
Claims:1. A compound of the formula ##STR110##

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 --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, ##STR111## 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).sub.n 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; ##STR112## 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 --C(O)--N(R.sup.5)--; n, p and q are 1 to 4; and m is 1 or 2;

or pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein X is --C(O)N(R.sup.5)--.

3. A compound of claim 1 wherein R.sup.4 is ##STR113##

4. A compound of claim 3 wherein R.sup.4 is a six-membered ring.

5. A compound of claim 4 wherein R.sup.4 is unsubstituted or substituted piperazinyl.

6. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4- o-tolyl-nicotinamide.

7. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-4-(2-chloro-phenyl)-N-methyl-6-(4-methy l-piperazin-1-yl)-nicotinamide.

8. A compound of claim 5 which is 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin -2-yl}-piperazine-1-carboxylic acid.

9. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4- o-tolyl-nicotinamide.

10. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nic otinamide.

11. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- N-methyl-4-o-tolyl-nicotinamide.

12. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-meth yl-4-o-tolyl-nicotinamide.

13. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piper azin-1-yl}-N-methyl-4-o-tolyl-nicotinamide.

14. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmeth yl-piperazin-1-yl)-4-o-tolyl-nicotinamide.

15. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4- o-tolyl-nicotinamide.

16. A compound of claim 5 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(1H-tetrazol-5-ylmethyl)- piperazin-1-yl]-4-o-tolyl-nicotinamide.

17. A compound of claim 4 wherein R.sup.4 is morpholino or substituted morpholino.

18. A compound of claim 17 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nic otinamide.

19. A compound of claim 17 which is N-(2-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide.

20. A compound of claim 17 which is N-(5-chloro-2-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotina mide.

21. A compound of claim 17 which is N-(2-chloro-5-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotina mide.

22. A compound of claim 17 which is N-(2-chloro-5-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotina mide.

23. A compound of claim 17 which is N-[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-N-methyl-6-morpho lin-4-yl-4-o-tolyl-nicotinamide.

24. A compound of claim 4 wherein R.sup.4 is thiomorpholino or oxidized thiomorpholino.

25. A compound of claim 24 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl -nicotinamide.

26. A compound of claim 24 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(1-oxo-1.lambda..sup.4 -thiomorpholin-4-yl)-4-o-tolyl-nicotinamide.

27. A compound of claim 24 which is N-(3,5-bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-1.lambda..sup.6 -thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide.

28. A compound of claim 4 wherein R.sup.4 is unsubstituted or substituted piperidinyl.

29. A compound of claim 28 which is 5'-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4'-o-tolyl-3,4,5,6- tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid.

30. A compound of claim 3 wherein R.sup.4 is a five-membered ring.

31. A compound of claim 30 wherein R.sup.4 is unsubstituted or substituted pyrrolidinyl.

32. A compound of claim 30 which (RS)-6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-N-(3,5-bis-trifluoromethy l-benzyl)-N-methyl-4-o-tolyl-nicotinamide.

33. A compound of claim 3 wherein R.sup.4 is attached through the linker --(CH.sub.2).sub.n N(R.sub.5)--.

34. A compound of claim 33 which is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-et hyl)-amino]-4-o-tolyl-nicotinamide.
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