US 9,434,713 B2Granted

5,6-disubstituted oxindole-derivatives and use thereof for treating vasopressin-dependent diseases

AssigneeAbbVie Deutschland GmbH & Co. KG

InventorsWilfried Braje, Thorsten Oost, Astrid Netz, Wolfgang Wernet, Liliane Unger, Wilfried Hornberger, Wilfried Lubisch

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Abstract

The present invention relates to novel 5,6-disubstituted oxindole derivatives and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such derivatives, and to the use of such derivatives for the manufacture of a medicament, and methods of treating disorders in a subject in need thereof, such as vasopressin-dependent disorders, using 5,6-disubstituted oxindole derivatives.

Claims28

Dependent claims

A method for the treatment of vasopressin-dependent diseases selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, Schwartz-Bartter syndrome, hepatocirrhosis, diabetes insipidus, depression, anxiety, and hyperthermia, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof;

in which
R1 and R2 are independently of one another hydrogen, C1-C3-alkyl, C1-C3-fluoroalkyl, C1-C3-alkoxy, C1-C3-fluoroalkoxy, halogen or CN;
R3 is hydrogen or C1-C4-alkyl;
R4 is ethoxy, fluorinated ethoxy or isopropoxy;
R5 is hydrogen or methyl;
R6 is Br, Cl, F or CN;
R7 is Cl, F or CN;
R8 and R9 are independently of one another C1-C3-alkyl or C1-C3-fluoroalkyl;
X1 is O, NH or CH2;
X2 and X3 are N or CH, with the proviso that X2 and X3 are not simultaneously N;
X4 is N or CH;
a and b are independently of one another 0, 1 or 2;
and
m, n, o and p are independently of one another 1, 2 or 3.

11 more elements

the method comprising administering a compound, or a pharmaceutically acceptable salt thereof to a subject in need thereof, the compound selected from the group consisting of:
4-(1-Methylpiperidin-4-yl)piperazin-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
(−)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-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)-6-fluoro-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)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-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)-6-fluoro-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)-6-fluoro-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)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
1′-Methyl [4,4′]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-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)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
1′-Methyl[4,4′]bipiperidinyl-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carb oxamide;
5-Cyano-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
5-Cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
1-Phenylsulfonyl-5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-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)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxy-2-trifluoromethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
6-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxy-2-trifluoromethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
1-Phenylsulfonyl-6-chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxy-2-trifluoromethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;
and
(+)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-one.

57 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/040,412Filed 27 Sep 2013 · division
Priority: 7 Dec 2007
Published: US 2014/0194440 A110 Jul 2014
Granted: 6 Sep 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics

Family

Application61/012,265Us provisional application · filed 7 Dec 2007
PCT/EP2008/066935Parent of this division · filed 5 Dec 2008
US 2014/0194440 A1Pre-grant publication · published 10 Jul 2014
Application12/746,715Parent of this division
US 8,546,401 B2Parent of this division
US 2011/0092513 A1Published application
US 9,434,713 B2This patent

From the US filing history. Foreign family members aren’t listed.

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