Phenylsulfonyl-1,3-dihydro-2h-indole-2-one derivatives, their preparation and their therapeutic use

1. A compound of formula (I):

in which:

n is 1 or 2;

X represents —CH 2 —; —O—; —NH—; —O—CH 2 —; —NH—CH 2 —; or —NH—CH 2 —CH 2 —;

R 1 represents halogen; a (C 1 –C 4 )alkyl; or (C 1 –C 4 )alkoxy;

R 2 represents hydrogen; halogen; (C 1 –C 4 )alkyl; (C 1 –C 4 )alkoxy; trifluoromethyl;

R 3 represents halogen; (C 1 –C 3 )alkyl; (C 1 –C 3 )alkoxy; trifluoromethyl; or trifluoromethoxy;

R 4 represents hydrogen; halogen; (C 1 –C 3 )alkyl; or (C 1 –C 3 )alkoxy;

R 5 is chosen from:

R 6 represents (C 1 –C 4 )alkoxy; and

R 7 represents (C 1 –C 4 )alkoxy;

or a salt or hydrate thereof.

2. A compound according to claim 1 , in which:

R 1 represents chlorine or methyl;

R 2 represents hydrogen or is in position −6 of the indol-2-one and represents chlorine, methyl, methoxy or trifluoromethyl;

R 3 represents chlorine, fluorine, methoxy, ethoxy, isopropoxy, trifluoromethyl or trifluoromethoxy;

R 4 represents hydrogen or a methoxy;

R 5 represents 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 1,3-thiazol-2-yl;

R 6 is in position −2 of the phenyl and represents methoxy; and

R 7 represents methoxy.

3. A compound chosen from:

5-chloro-3-(2-ethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-3-(2-isopropoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(2-pyridyl)-1-piperazinecarboxylate;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate;

N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)homopiperazine-1-carboxamide;

N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(3-pyridyl)piperazine-1-carboxamide;

N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-3-[[3-oxo-3-[4-(2-pyridyl)-1-piperazinyl]propyl]amino]-1,3-dihydro-2H-indol-2-one;

5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate;

N-[5-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(2-pyridyl)piperazine-1-carboxamide;

N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide;

N-[6-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-3-(2,3-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-3-[2-oxo-2-[4-(3-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(3-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-homopiperazine]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(1,3-thiazol-2-yl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(3-pyridyl)-1-piperazinecarboxylate; and

5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate or a salt or hydrate thereof.

4. A process for preparing a compound according to claim 1 , wherein:

a compound of formula:

in which R 1 , R 2 , R 3 , R 4 and X are as defined in claim 1 , and:

Y represents hydroxyl or chlorine when X represents —CH 2 —; —OCH 2 —; —NH—CH 2 —; or —NH—CH 2 —CH 2 —;

or Y represents phenoxy when X represents —O—; or —NH—;

W represents hydrogen when X represents —CH 2 —; or —OCH 2 —;

or W represents

in which

R 6 and R 7 are as defined in claim 1 when X represents —O—;—NH—; —NH—CH 2 —; or —NH—CH 2 —CH 2 —;

is reacted with a compound of formula (III):

in which n and R 5 are as defined in claim 1 ;

when W represents

the corresponding compound of formula (I) is produced;

or, when W represents hydrogen, the compound thus obtained of formula (IV):

is reacted, in the presence of a base, with a sulphonyl halide of formula (V):

in which R 6 and R 7 are as defined in claim 1 and Hal represents a halogen atom to give the corresponding compound of formula (I).

5. A compound of formula (IV):

in which:

n is 1 or 2;

X represents —CH 2 —; or —O—CH 2 —;

R 1 represents halogen; (C 1 –C 4 )alkyl; or (C 1 –C 4 )alkoxy;

R 2 represents hydrogen; halogen; (C 1 –C 4 )alkyl; (C 1 –C 4 )alkoxy; or trifluoromethyl;

R 3 represents halogen; (C 1 –C 3 )alkyl; (C 1 –C 3 )alkoxy; trifluoromethyl; or trifluoromethoxy;

R 4 represents hydrogen; halogen; (C 1 –C 3 )alkyl; (C 1 –C 3 )alkoxy;

R 5 is chosen from:

or a salt thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

7. A compound according to claim 1 wherein:

R 1 is chlorine or methyl;

R 2 is hydrogen or is in position −4 or −6 of the indol-2-one and is chlorine, methyl, methoxy or trifluoromethyl;

R 3 is chlorine, fluorine, methoxy, ethoxy, isopropoxy, trifluoromethyl or trifluoromethoxy;

R 4 is hydrogen or methoxy;

R 5 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 1,3-thiazol-2-yl;

R 6 is in position −2 of the phenyl and is methoxy; and

R 7 is methoxy.

8. A compound according to claim 1 wherein:

is 1 or 2;

X is —CH 2 —, —O— or —NH—;

R 1 is chlorine;

R 2 is hydrogen;

R 3 is methoxy, ethoxy or isopropoxy;

R 4 is hydrogen;

R 5 is:

R 6 is in position −2 of the phenyl and is methoxy;

R 7 is methoxy.

9. A compound according to claim 1 wherein:

n is 1;

X is —CH 2 —, —O— or —NH—;

R 1 is chlorine or methyl;

R 2 is hydrogen or is in position −4 or −6 of the indol-2-one and is chlorine, methyl or methoxy;

R 3 is chlorine, fluorine or methoxy;

R 4 is hydrogen;

R 5 is

R 6 is in position −2 of the phenyl and is methoxy; and

R 7 is methoxy.

10. A compound according to claim 1 wherein:

n is 1;

X is —O—, —NH— or —NH—CH 2 —CH 2 —;

R 1 is chlorine;

R 2 is hydrogen;

R 3 is chlorine or methoxy;

R 4 is hydrogen;

R 5 is

R 6 is in position −2 of the phenyl and is methoxy; and

R 7 is methoxy.

11. A pharmaceutical composition comprising a compound according to claim 2 and one or more pharmaceutically acceptable excipients.

12. A pharmaceutical composition comprising a compound according to claim 3 and one or more pharmaceutically acceptable excipients.

13. A pharmaceutical composition comprising a compound according to claim 7 and one or more pharmaceutically acceptable excipients.

14. A pharmaceutical composition comprising a compound according to claim 8 and one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition comprising a compound according to claim 8 and one or more pharmaceutically acceptable excipients.

16. A pharmaceutical composition comprising a compound according to claim 10 and one or more pharmaceutically acceptable excipients.

17. A method for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, stress, anxiety, depression, obsessive-compulsive disorder, panic attacks, atherosclerosis, dysmenorrhoea, or premature labor, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .

18. A method for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, stress, anxiety, depression, obsessive-compulsive disorder, panic attacks, atherosclerosis, dysmenorrhoea, or premature labor, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 2 .

19. A method for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, stress, anxiety, depression, obsessive-compulsive disorder, panic attacks, atherosclerosis, dysmenorrhoea, or premature labor, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 3 .

20. A method according to claim 17 for the treatment of anxiety or depression.

21. A method according to claim 18 for the treatment of anxiety or depression.

22. A method according to claim 19 for the treatment of anxiety or depression.

23. A method for the treatment of anxiety or depression which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 7 .

24. A method for the treatment of anxiety or depression which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 8 .

25. A method for the treatment of anxiety or depression which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 9 .

26. A method for the treatment of anxiety or depression which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 10 .