5-halogen-substituted oxindole derivatives and use thereof for treating vasopressin-dependent diseases

1. A compound of the formula I

in which

R 1 is hydrogen, methoxy or ethoxy;

R 2 is hydrogen or methoxy;

R 3 is hydrogen, methyl, ethyl, n-propyl or isopropyl;

R 4 is ethoxy or isopropoxy;

R 5 is H or methyl;

R 6 is Cl or F;

X 1 is O, NH or CH 2 ; and

X 2 and X 3 are N or CH, with the proviso that X 2 and X 3 are not simultaneously N; a racemate thereof, an enantiomeric, or a pharmaceutically acceptable salt of thereof.

2. A compound of claim 1 , in which R 1 is hydrogen or methoxy.

3. A compound of claim 1 , in which R 1 and R 2 are methoxy.

4. A compound claim 1 , in which R 3 is hydrogen, methyl or ethyl.

5. A compound of claim 1 , in which R 4 is ethoxy and R 5 is H.

6. A compound of claim 1 , in which R 4 is ethoxy and R 5 is methyl.

7. A compound of claim 1 , in which R 4 is isopropoxy and R 5 is H.

8. A compound of claim 1 , in which R 6 is Cl.

9. A compound of claim 1 , in which R 6 is F.

10. A compound of claim 1 , in which X 2 is N and X 3 is CH.

11. A compound of claim 1 , in which X 2 is CH and X 3 is N.

12. A compound of claim 1 , in which X 1 is O.

13. A compound of claim 1 , in which X 1 is NH.

14. A compound of claim 1 , in which X 1 is CH 2 .

15. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

R 4 is ethoxy;

R 5 is H;

R 6 is Cl;

X 1 is NH;

X 2 is N; and

X 3 is CH.

16. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

R 4 is ethoxy;

R 5 is methyl;

R 6 is Cl;

X 1 is NH;

X 2 is N; and

X 3 is CH.

17. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is ethyl;

R 4 is ethoxy;

R 5 is H;

R 6 is Cl;

X 1 is NH;

X 2 is N; and

X 3 is CH.

18. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

R 4 is ethoxy;

R 5 is H;

R 6 is Cl;

X 1 is NH;

X 2 is CH; and

X 3 is N.

19. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

(±)-4-(1-Methylpiperidin-4-yl)piperazin-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-[4,4′]Bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-y1)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-1′-Ethyl-[4,4″]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-1′-Methyl-[4,41]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(±)-4-(1-Ethylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(1-Methylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(1-Ethylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(1-methylpiperidin-4-Apiperazine-1-carboxylate;

5-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(1-methylpiperidin-4-Apiperazine-1-carboxylate;

1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;

5-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;

1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;

(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;

(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpip eridin-4-yl)piperazin-1 -yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;

(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl) piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one;

(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;

(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1 -yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;

(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl) -3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;

(−)4 (1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;

(+)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide; and

(+)4 (4 Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.

20. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

21. A method for the treatment of a disease selected from the group consisting of arterial hypertension and congestive heart failure (CHF), the method comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

22. A method for the treatment of major depression, the method comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

23. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (+)-4-(1-Methylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.

24. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.

25. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.

26. The pharmaceutical composition of claim 20 , wherein the compound is (+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition of claim 20 , wherein the compound is (+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition of claim 20 , wherein the compound is (+)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

29. The method of claim 21 , wherein the compound is (+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

30. The method of claim 21 , wherein the compound is (+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

31. The method of claim 21 , wherein the compound is (+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

32. The method of claim 22 , wherein the compound is (+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

33. The method of claim 22 , wherein the compound is (+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.

34. The method of claim 22 , wherein the compound is (+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide, or a pharmaceutically acceptable salt thereof.