Piperazinylacylpiperidine derivatives, their preparation and therapeutic use thereof

1. A compound of formula (I):

in which:

n is 1 or 2;

p is 1 or 2;

R 1 represents a halogen atom; a trifluoromethyl radical; a (C 1 -C 4 )alkyl; a (C 1 -C 4 )alkoxy; or a trifluoromethoxy radical;

R 2 represents a hydrogen atom or a halogen atom;

R 3 represents a hydrogen atom; a group —OR 5 ; a group —CH 2 OR 5 ; a group —NR 6 R 7 ; a group —NR 8 COR 9 ; a group —NR 8 CONR 10 R 11 ; a group —CH 2 NR 12 R 13 ; a group —CH 2 NR 8 CONR 14 R 15 ; a (C 1 -C 4 )alkoxycarbonyl; or a group —CONR 16 R 17 ;

or else R 3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring;

R 4 represents a pyrazinyl

 which is being unsubstituted or being mono- or disubstituted by a substituent selected independently from a halogen atom; a (C 1 -C 4 )alkyl; a (C 1 -C 4 )alkoxy; and a trifluoromethyl radical;

R 5 represents a hydrogen atom; a (C 1 -C 4 )alkyl; or a (C 1 -C 4 )alkylcarbonyl;

R 6 and R 7 represent each independently a hydrogen atom or a (C 1 -C 4 )alkyl;

R 8 represents a hydrogen atom or a (C 1 -C 4 )alkyl;

R 9 represents a (C 1 -C 4 )alkyl or a group —(CH 2 ) m —NR 6 R 7 ;

m is 1, 2 or 3;

R 10 and R 11 represent each independently a hydrogen atom or a (C 1 -C 4 )alkyl;

R 12 represents a hydrogen atom or a (C 1 -C 5 )alkyl;

R 13 represents a hydrogen atom, a (C 1 -C 5 ) alkyl, a group —(CH 2 ) q —OH or a group —(CH 2 ) q —S—CH 3 ;

or else R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocycle selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine;

q is 2 or 3;

R 14 and R 15 represent each independently a hydrogen atom or a (C 1 -C 4 )alkyl;

R 16 represents a hydrogen atom or a (C 1 -C 4 )alkyl;

R 17 represents a hydrogen atom, a (C 1 -C 5 ) alkyl, or a group —(CH 2 ) q —NR 6 R 7 ;

or else R 16 and R 17 , together with the nitrogen atom to which they are attached, constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine and piperazine which is unsubstituted or substituted in position 4 by a (C 1 -C 4 )alkyl;

or an acid addition salt thereof.

2. A compound according to claim 1 wherein:

R 1 is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R 2 represents a hydrogen atom; or else R 1 is in position 3 of the phenyl and represents a trifluoromethyl radical and R 2 is in position 4 of the phenyl and represents a chlorine atom.

3. A compound according to claim 1 wherein:

R 3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an acetylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an (isobutylamino)methyl; an (N-methylisobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, or an azetidin-1-ylcarbonyl; or else R 3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring.

4. A compound according to claim 1 wherein:

R 4 represents a 2-pyrazinyl, a 5-chloro-2-pyrazinyl, or a 6-chloro-2-pyrazinyl.

5. A compound according to claim 1 wherein:

n is 1 or 2;

p is 1 or 2;

R 1 is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R 2 represents a hydrogen atom; or else R 1 is in position 3 of the phenyl and represents a trifluoromethyl radical and R 2 is in position 4 of the phenyl and represents a chlorine atom;

R 3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an acetylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (N-methylisopropylamino)methyl; an (isobutylamino)methyl; an (N-methylisobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, or an azetidin-1-ylcarbonyl; or else R 3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring;

R 4 represents a 2-pyrazinyl, a 5-chloro-2-pyrazinyl, or a 6-chloro-2-pyrazinyl.

6. A compound according to claim 1 wherein:

n is 1;

p is 1;

R 1 is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methoxy or a trifluoromethoxy radical and R 2 represents a hydrogen atom; or else R 1 is in position 3 of the phenyl and represents a trifluoromethyl radical and R 2 is in position 4 of the phenyl and represents a chlorine atom;

R 3 represents a hydroxyl, a dimethylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (isobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl or an aminocarbonyl; or else R 3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; and

—R 4 represents a 2-pyrazinyl.

7. A process for preparing a compound according to claim 1 in which n=1

wherein a compound of formula (IIA)

 in which R 1 , R 2 and R 3 are as defined in claim 1 and Hal represents a halogen atom, with the proviso that when R 3 contains a hydroxyl or amine function these functions may be protected, is reacted with a compound of formula (III)

 in which p and R 4 are as defined in claim 1 ;

and deprotection of the hydroxyl or amine functions present in R 3 where appropriate.

8. A process for preparing a compound according to claim 1 in which n=2

wherein a compound of formula IIb

 in which R 1 , R 2 and R 3 are as defined in claim 1 , with the proviso that when R 3 contains a hydroxyl or amine function these functions may be protected, is reacted with a compound of formula (III)

 in which p and R 4 are as defined in claim 1 ;

and deprotection of the hydroxyl or amine functions present in R 3 where appropriate.

9. A process for preparing a compound according to claim 1 in which R 3 represents a group —CH 2 NR 12 R 13 in which R 12 and R 13 each represent hydrogen

wherein a compound of formula (IIc) or (IId)

 in which R 1 and R 2 are as defined in claim 1 and Hal represents a halogen atom, is reacted with a compound of formula (III)

 in which p and R 4 are as defined in claim 1 to give a compound of formula (Ia)

 and the cyano group of the compound of formula (Ia) is reduced.

10. A compound of formula (Ia)

in which:

n is 1 or 2;

p is 1 or 2;

R 1 represents a halogen atom; a trifluoromethyl radical; a (C 1 -C 4 )alkyl; a (C 1 -C 4 )alkoxy; or a trifluoromethoxy radical;

R 2 represents a hydrogen atom or a halogen atom;

R 4 represents a pyrazinyl:

 which is being unsubstituted or mono- or disubstituted by a substituent selected independently from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethoxy radical;

or an acid addition salt thereof.

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

1-[4-(aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-hydroxy-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

2-[4-(2-pyrazinyl)-1-piperazinyl]-1-[4-[2-(trifluoromethyl)phenyl]-3,6-dihydro-1 (2H)-pyridyl]-1-ethanone;

1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide;

1-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(dimethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-(4-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(diethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(isobutylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(isopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

1-[4-[(N-methylisopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone; and

1-[4-hydroxy-4-[3-(trifluoromethoxy)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;

or an acid addition salt thereof.

12. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising a compound according to claim 2 together with a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising a compound according to claim 3 together with a pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising a compound according to claim 4 together with a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising a compound according to claim 5 together with a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound according to claim 6 together with a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound according to claim 11 together with a pharmaceutically acceptable excipient.

19. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .

20. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 2 .

21. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 3 .

22. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 4 .

23. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 5 .

24. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 6 .

25. A method for the treatment of pain, Parkinson's disease, prostate cancer, and atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 11 .