5,6-disubstituted oxindole-derivatives and use thereof for treating vasopressin-dependent diseases
View Patent ↗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.
1. A compound of the formula I.A
in which
R 1 and R 2 are independently of one another hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -fluoroalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -fluoroalkoxy, halogen or CN;
R 3 is hydrogen or C 1 -C 4 -alkyl;
R 4 is ethoxy, fluorinated ethoxy or isopropoxy;
R 5 is hydrogen or methyl;
R 6 is Br, Cl, F or CN;
R 7 is Cl, F or CN;
X 1 is O, NH or CH 2 ;
X 2 and X 3 are N or CH, with the proviso that X 2 and X 3 are not simultaneously N; and
X 4 is N or CH;
and their pharmaceutically acceptable salts and prodrugs thereof.
2. A compound of claim 1 , in which R 1 is hydrogen, methoxy, ethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy.
3. A compound of claim 1 , in which R 2 is hydrogen or methoxy.
4. A compound of claim 1 , in which R 1 and R 2 are methoxy.
5. A compound of claim 1 , in which R 3 is hydrogen, methyl or ethyl.
6. A compound of claim 1 , in which R 4 is ethoxy and R 5 is H.
7. A compound of claim 1 , in which R 4 is 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy and R 5 is H.
8. A compound of claim 1 , in which R 6 and R 7 are not simultaneously CN.
9. A compound of claim 1 , in which at least one of the radicals R 6 and R 7 is F.
10. A compound of claim 9 , in which R 7 is F and R 6 is F, Cl, Br or CN.
11. A compound of claim 1 , in which X 2 is N and X 3 is CH.
12. A compound of claim 1 , in which X 2 is CH and X 3 is N.
13. A compound of claim 1 , in which X 2 is CH and X 3 is CH.
14. A compound of claim 1 , in which X 1 is O.
15. A compound of claim 1 , in which X 1 is NH.
16. A compound of claim 1 , in which X 4 is N.
17. A compound of claim 1 in which
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is NH;
X 2 is N;
X 3 is CH; and
X 4 is N.
18. A compound of claim 1 in which
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is NH;
X 2 is CH;
X 3 is N; and
X 4 is N.
19. A compound of claim 1 in which
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is CH 2 ;
X 2 is N;
X 3 is CH; and
X 4 is N.
20. A compound of claim 1 in which
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is CH 2 ;
X 2 is CH;
X 3 is N; and
X 4 is N.
21. A compound of claim 1 in which
R 1 is methoxy or H;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is O;
X 2 is N;
X 3 is CH; and
X 4 is N.
22. A compound of claim 1 in which
R 1 is methoxy or H;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is O;
X 2 is CH;
X 3 is N; and
X 4 is N.
23. A compound of claim 1 in which
R 1 is methoxy;
R 2 is methoxy;
R 3 is methyl or ethyl;
R 4 is ethoxy;
R 5 is H;
R 6 is Cl or CN;
R 7 is F;
X 1 is NH;
X 2 is N;
X 3 is CH; and
X 4 is CH.
24. 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-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]carboxamide;
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]carboxamide;
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-ethoxy-pyridin-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-ethoxy-pyridin-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-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
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-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
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-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
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-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;
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-trifluoromethoxyphenyl-sulfonyl)-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-trifluoromethoxyphenyl-sulfonyl)-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.
25. 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.