Nitrogenous tetrahydropyridyl-alkyl-heterocycles with TNF activity

1. A compound of formula (1):

in which

X is N or CH;

R 1 is a hydrogen or halogen atom or a CF 3 group;

R 2 and R 3 independently are a hydrogen atom or a (C 1 –C 4 )alkyl group;

R 4 is a hydrogen atom or a (C 1 –C 4 )alkyl group;

n is 0 or 1; and

A is a nitrogenous hetereocycle of formula (a)–(d):

where R 5 and R 6 each independtly are a hydrogen atom or a (C 1 –C 4 )alkyl or (C 1 –C 4 )alkoxy group;

or an N-oxide, salt or solvate ihereof.

2. The compound as claimed in claim 1 , where n is zero.

3. The compound as claimed in claim 1 , where R 2 and R 3 are each hydrogen.

4. The compound as claimed in claim 1 , where R 1 is a CF 3 group.

5. The compound as claimed in claim 1 , where X is CH and R 1 is in the 3-position of the benzene.

6. The compound as claimed in claim 1 , where X is N and the pyridine thus formed is substituted in the 2,6-positions.

7. The compound as claimed in claim 1 , where the phenyl ring is substituted by the notrogenous heterocycle A in the 3-position.

8. The compound as claimed in claim 1 in the form of an N-oxide thereof.

9. A compound selected from the group consisting of:

1-[2-(4-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-(2-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-(6-Methylpyrid-3-yl)phenyl)ethyl]-4-(3-(triflouronmethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-(5-Pyrimidinyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(6-(trifluoromethyl)pyrid-2-yl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(3-flourophenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(2-Pyrazinyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(6-Methyl-3-pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(2-Pyrimidiyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(3-Pyridaziyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(3-Pyridyl)-4-methylphenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 1-oxide; and

1-[2-(3-(4-Pyridyl 1-oxide)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine; or salt or solvent thereof.

10. A process for the preparation of the compound of formula (I) comprising reacting a compound of formula (II)

in which X and R 1 are as defined in claim 1 , with a compound of formala (III):

in which R 2 , R 3 , R 4 , n and A are as defined in claim 1 and L is a leaving group, isolating the compound of formula (I), and optionally converting the compound of formula (I) to a salt, solvate or N-oxide thereof.

11. A pharmaceutical composition, comprising the comnound of formula (I) as claimed in claim 1 or a solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. The composition as claimed in claim 11 comprising 0.001 to 100 mg of the compound of formula (I).

13. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 1 or salt or solvate thereof.

14. The compound as claimed in claim 2 in the form of an N-oxide thereof.

15. The compound as claimed in claim 3 in the form of an N-oxide thereof.

16. The compound as claimed in claim 4 in the form of an N-oxide thereof.

17. The compound as claimed in claim 5 in the form of an N-oxide thereof.

18. The compound as claimed in claim 6 in the form of an N-oxide thereof.

19. The compound as claimed in claim 7 in the form of an N-oxide thereof.

20. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 2 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition, comprising the compound or formula (I) as claimed in claim 3 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 4 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 5 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 6 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 7 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

26. A pharmaceutical composititon, comprising the compound of formula (I) as claimed in claim 8 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 9 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 14 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 15 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 16 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 17 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 18 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition, comprising the compound of formula (I) as claimed in claim 19 or solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

34. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 2 or salt or solvate thereof.

35. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 3 or salt or solvate thereof.

36. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 4 or salt or solvate thereof.

37. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 5 or salt or solvate thereof.

38. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 6 or salt or solvate thereof.

39. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 7 or salt or solvate thereof.

40. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 8 or salt or solvate thereof.

41. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 9 or salt or solvate thereof.

42. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 14 or salt or solvate thereof.

43. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 15 or salt or solvate thereof.

44. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 16 or salt or solvate thereof.

45. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 17 or salt or solvate thereof.

46. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 18 or salt or solvate thereof.

47. A method for the treatment of pain comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 19 or salt or solvate thereof.