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

Patent metadata

Field	Value
Publication number	US-9403796-B2
Application number	US-201414251384-A
Country	US
Kind code	B2
Filing date	Apr 11, 2014
Priority date	Dec 7, 2007
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The present invention relates to novel amidomethyl-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

First claim

The invention claimed is:

1. A method for the treatment of a disease selected from the group consisting of depressive disorders, childhood onset mood disorders, anxiety disorders, and stress-dependent anxiety disorders, the method comprising administering to a subject in need thereof a compound of 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. The method of claim 1 , wherein R 1 is hydrogen or methoxy.

3. The method of claim 1 , wherein R 3 is hydrogen, methyl or ethyl.

4. The method of claim 1 , wherein X 1 is N and X 2 is CH.

5. The method of claim 1 , wherein X 1 is CH and X 2 is N.

6. The method of claim 1 , wherein
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl;
X 1 is CH; and
X 2 is N.

7. The method of claim 1 , wherein
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl;
X 1 is N; and
X 2 is CH.

8. The method of claim 1 , wherein
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl;
X 1 is CH; and
X 2 is CH.

9. The method of claim 1 , wherein
R 1 is methoxy;
R 2 is methoxy;
R 3 is ethyl;
X 1 is CH; and
X 2 is N.

10. The method of claim 1 , wherein
R 1 is methoxy;
R 2 is methoxy;
R 3 is ethyl;
X 1 is N; and
X 2 is CH.

11. The method of claim 1 , wherein the (−) enantiomer has an enantiomeric purity of at least 90% enantiomeric excess (ee).

12. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, is 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-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;
(−)-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-

Assignees

• Abbvie Deutschland

Inventors

• Oost Thorsten
• Netz Astrid
• Geneste Hervé
• Braje Wilfried
• Wernet Wolfgang
• Unger Liliane
• Hornberger Wilfried
• Lubisch Wilfried

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title