Phenyl- and pyridylpiperidines with TNF activity

1. A compound of formula (I):

in which

X represents N or CH;

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

R 2 and R 3 independently represent a hydrogen atom or a methyl group;

n is 0 or 1;

A represents a condensed heterocyclic group of formula (w)

where W completes

either an aromatic or saturated 6-membered ring system comprising one or two nitrogen atoms, it being possible for the ring system to be substituted by one or two halogen atoms or one or two (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or CF 3 groups;

or an aromatic or saturated 5-membered ring system comprising a nitrogen, oxygen or sulfur atom, it being possible for the ring system to be substituted by one or two (C 1 -C 4 ) alkyl groups;

or an N-oxide, salt or solvate thereof.

2. A compound according to claim 1 , where A represents a group of formula (a) or (b)

where

R 4 represents a hydrogen or halogen atom, a (C 1 -C 4 ) alkyl group, a CF 3 group or an amino, mono(C 1 -C 4 )alkylamino or di(C 1 -C 4 )alkylamino group;

R 5 represents a hydrogen or halogen atom, a (C 1 -C 4 ) alkoxy group, a (C 1 -C 4 ) alkyl group or a CF 3 group; and

R 6 represents a hydrogen atom, a (C 1 -C 4 ) alkyl group or a (C 1 -C 4 ) alkoxy group.

3. A compound according to claim 1 , where A is chosen from benzofuran, benzothiophene, indole, quinoxaline, cinnoline and phthalazine, optionally substituted by one or two (C 1 -C 4 ) alkyl groups.

4. A compound according to claim 1 where n is zero.

5. A compound according to claim 1 where X is CH and R 1 is in the 2- or 3-position of the benzene.

6. A compound according to claim 4 where X is a nitrogen atom and the pyridine is substituted in the 2,6-positions.

7. A compound according to claim 2 , where R 4 , R 5 and R 6 are hydrogen atoms.

8. A compound selected from the group consisting of 7-(2-(4-(3-(Trifluoromethyl)phenyl)piperidino)ethyl)isoquinoline, its mono-N-oxide, its bis-N-oxide, its salts and its solvates.

9. A process for the preparation of a compound of formula (I) according to claim 1 which comprises carrying out a reductive alkylation of a compound of formula (II):

with an aldehyde of formula (III):

wherein R 1 , X, R 2 , R 3 , n and A are as defined in claim 1 , isolating the compound of formula (I) and optionally converting it to one of its salts or solvates or to its N-oxide derivatives.

10. A pharmaceutical composition, comprising, as active principle, a compound according to claim 1 together with a pharmaceutically acceptable carrier.

11. A composition according to claim 10 , which comprises from 0.001 to 100 mg of active principle.

12. A compound according to claim 2 where n is zero.

13. A compound according to claim 3 where n is zero.

14. A compound according to claim 12 where R 2 and R 3 are each H.

15. A compound according to claim 13 where R 2 and R 3 are each H.

16. A compound according to claim 14 where R 1 is a CF 3 group.

17. A compound according to claim 15 where R 1 is a CF 3 group.

18. A compound according to claim 14 where R 1 is a fluorine atom.

19. A compound according to claim 15 where R 1 is a fluorine atom.

20. A compound according to claim 16 wherein X is CH and R 1 is in the 2- or 3 -position of the benzene.

21. A compound according to claim 17 wherein X is CH and R 1 is in the 2- or 3-position of the benzene.

22. A compound according to claim 20 wherein R 1 is in the 3-position of the benzene.

23. A compound according to claim 21 wherein R 1 is in the 3-position of the benzene.

24. A compound according to claim 12 where X is a nitrogen atom and the pyridine is substituted in the 2,6-positions.

25. A compound according to claim 12 where R 4 , R 5 and R 6 are hydrogen atoms.

26. A compound according to claim 20 where R 4 , R 5 and R 6 are hydrogen atoms.

27. A compound according to claim 1 selected from the group consisting of:

7-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)isoquinoline;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)-1,2,3,4-tetrahydroisoquinoline;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)-1,2,3,4-tetrahydroquinoxaline;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)benzofuran;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)quinoline;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)benzothiophene;

6-(2-(4-phenylpiperidino)ethyl)isoquinoline;

6-(2-(4-(3-(trifluoromethyl)phenyl)piperidino)ethyl)isoquinoline;

6-(2-(4-(6-(trifluoromethyl)pyrid-2-yl)piperidino)ethyl)isoquinoline; and

the acid-addition salts and solvates thereof.

28. A pharmaceutical composition, comprising, as active principle, a compound according to claim 12 together with a pharmaceutically acceptable carrier.

29. A pharmaceutical composition, comprising, as active principle, a compound according to claim 20 together with a pharmaceutically acceptable carrier.

30. A pharmaceutical composition, comprising, as active principle, a compound according to claim 27 together with a pharmaceutically acceptable carrier.

31. A pharmaceutical composition, comprising, as active principle, a compound according to claim 8 together with a pharmaceutically acceptable carrier.

32. A method of producing analgesia in a patient in need thereof which comprises administering to said patient an analgesically effective amount of a compound according to claim 1 .

33. A method of producing analgesia in a patient in need thereof which comprises administering to said patient an analgesically effective amount of a compound according to claim 12 .

34. A method of producing analgesia in a patient in need thereof which comprises administering to said patient an analgesically effective amount of a compound according to claim 20 .

35. A method of producing analgesia in a patient in need thereof which comprises administering to said patient an analgesically effective amount of a compound according to claim 27 .

36. A method of producing analgesia in a patient in need thereof which comprises administering to said patient an analgesically effective amount of a compound according to claim 8 .