Amidomethyl-substituted oxindole derivatives and the use thereof for the treatment of vasopressin-dependent illnesses

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;

X 1 and X 2 are N or CH, with the proviso that X 1 and X 2 are not simultaneously N;

a racemate, or an enantiomer, or a pharmaceutically acceptable salt thereof.

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

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

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

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

6. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

X 1 is CH; and

X 2 is N.

7. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

X 1 is N; and

X 2 is CH.

8. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is methyl;

X 1 is CH; and

X 2 is CH.

9. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is ethyl;

X 1 is CH; and

X 2 is N.

10. A compound of claim 1 , in which

R 1 is methoxy;

R 2 is methoxy;

R 3 is ethyl;

X 1 is N; and

X 2 is CH.

11. A compound of claim 1 , where the (−) enantiomer has an enantiomeric purity of at least 90% enantiomeric excess (ee).

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

(±)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-1-(4-methoxyphenylsulfonyl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(−)-3-(2-Ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(±)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-[2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;

(+)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-[2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile; and

(−)-1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-[2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile.

13. 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.

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.