Derivatives of indole for the treatment of cancer, viral infections and lung diseases

Patent metadata

Field	Value
Publication number	US-10189782-B2
Application number	US-201715586343-A
Country	US
Kind code	B2
Filing date	May 4, 2017
Priority date	Dec 7, 2012
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to a new class of indole derivatives, having a particular MKlp2 inhibition profile and useful as a therapeutic agent, in particular for the treatment of cancer, viral infections and lung diseases.

First claim

We claim:

1. A compound of formula (I):

wherein:
X represents a nitrogen atom, or a N+-O— unit;
R 1 and R 1 ′ are such that one is H and the other represents a halogen or one —NR 11 R 12 unit wherein R 11 and R 12 represent H or a (C 1 -C 6 )alkyl group;
R 2 represents:
a radical (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, aryloxy, (C 1 -C 6 )alkyl-aryloxy, said radical being optionally substituted with halogen, or a radical thio-(C 1 -C 6 )alkyl, thio-aryl, or thio-(C 1 -C 6 )alkyl-aryl, said radical being optionally substituted with halogen or a (C 1 -C 6 )alkoxy group;
a —NR 4 R 5 unit, a O—(C 1 -C 6 )alkyl-NR 4 R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit wherein R 4 and R 5 represent II or a (C 1 -C 6 )alkyl group, with the proviso that at least one among R 4 and R 5 is not H;
a NHCOR 6 unit wherein R 6 represents (C 1 -C 6 )alkyl group;
an aryl group, optionally substituted with a halogen, a trifluoromethyl group, or a (C 1 -C 3 )alkoxy group; or
a halogen;

and
R 3 represents a hydrogen, a (C 1 -C 3 )alkyl group, a (C 1 -C 3 )alkoxy group or a halogen;
and the compounds of formula (I), in which the nitrogen atom of the indole core is substituted by a group selected from the group consisting of a COR 7 and a CO 2 R 7 group, wherein R 7 represents:
a (C 1 -C 6 )alkyl group, optionally substituted by at least a hydroxy group, a (C 1 -C 6 )alkyloxy group, a (C 1 -C 6 ) n polyalkyloxy group wherein n is 1<n<6, a phosphate or pyrophosphate group and a salt thereof or (C 1 -C 3 )alkyl ester thereof, a R 8 group, a —NHCO 2 R 8 unit, a COR 8 group, or a CO 2 R 8 group, wherein R 8 is:
a (C 1 -C 6 )alkyl group;
an aryl or a (C 1 -C 6 )alkylaryl;
a —NR 9 R 10 unit wherein R 9 and R 10 represent a hydrogen or a (C 1 -C 6 )alkyl group;
a NH—NR 9 R 10 unit wherein R 9 and R 10 are as defined above;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein the compound has the formula (Ia):

wherein X, R 1 , R 1′ , R 2 , and R 3 are such as defined in claim 1 .

3. The compound according to claim 1 , wherein the compound has the formula (Ib):

wherein X, R 1 , R 1′ , R 2 , and R 3 are such as defined in claim 1 .

4. The compound according to claim 1 , wherein R 1 ′ is H.

5. The compound according to claim 1 , wherein R 1 represents a halogen selected from the group consisting of a bromine and a chlorine.

6. The compound according to claim 1 , wherein R 1 is H.

7. The compound according to claim 1 , wherein R 1 ′ is a halogen selected from a bromine, a chlorine or a fluorine.

8. The compound according to claim 1 , wherein R 2 represents:
a radical (C 1 -C 6 )alkoxy, or phenoxy, said radical being optionally substituted with halogen;
a halogen;
a R 4 —N—R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit, wherein R 4 and R 5 represent H or a (C 1 -C 6 )alkyl group, with the proviso that at least one among R 4 and R 5 is not H;
a NHCOR 6 unit wherein R 6 represents (C 1 -C 6 )alkyl group;
a radical thio-(C 1 -C 6 )alkyl, thio-aryl, or thio-(C 1 -C 6 )alkyl-aryl, said radical being optionally substituted with halogen or a (C 1 -C 6 )alkoxy group; or
an aryl group optionally substituted with halogen, or a trifluoromethyl group.

9. The compound according to claim 1 , wherein R 2 represents:
a radical (C 1 -C 6 )alkoxy selected from the group consisting of a methoxy group, an ethoxy group, and an isopropoxy group, or a phenoxy group, optionally substituted with fluorine or trifluoromethyl;
a halogen selected from the group consisting of a fluorine and a chlorine;
a R 4 —N—R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit wherein R 4 and R 5 represent a methyl or an ethyl group;
a NHCOR 6 unit wherein R 6 represents a tert-butyl group;
a radical selected from the group consisting of a thio-methyl group, a thio-ethyl group, a thio-benzyl group and a thio-phenyl group, optionally substituted with fluorine or a trifluoromethyl group; or
a phenyl group optionally substituted with bromine or a trifluoromethyl group.

10. The compound according to claim 1 , wherein said compound is selected from the group consisting of:
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-chloropyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-chloropyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;
(E)-2-(5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-dimethylamino)pyridine-3-yl)-acrylonitrile, hydrochloride;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;
(E)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-ethoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-isopropoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(methylthio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(ethylthio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(3-bromophenyl)pyridin-3-yl)-acrylonitrile;
(Z)-3-(4-(3-bromophenyl)pyridin-3-yl)-2-(5-chloro-1H-indol-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(phenylthio)pyridin-3-yl)-acrylonitrile;
(Z)-3-(4-(benzylthio)pyridin-3-yl)-2-(5-bromo-1H-indol-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(3,4-dimethoxy)thio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(4-fluorophenoxy)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(4-fluorophenoxy)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(diethylamino)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(4-(trifluoromethyl))phenyl)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-((4-fluorophenyl)thio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-((4-fluorophenyl)thio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;
(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(2-(dimethylamino)ethylthio)pyridin-3-yl)-acrylonitrile;
(Z)-2-(6-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
(Z)-2-(6-fluoro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
(Z)-2-(6-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-methoxypyridine-1-oxide;
(Z)-2-(1-acetyl-5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
(Z)-2-(5-bromo-1-pivaloyl-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
(Z)-methyl
3-(5-bromo-3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1H-indol-1-yl)-3-oxopropanoate;
(Z)-2-(5-bromo-1-(2-(dimethylamino)acetyl)-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;
and their pharmaceutically acceptable salt.

11. The compound according to claim 1 , wherein said compound is selected from the grou

Assignees

• Biokinesis
• Centre Nat Rech Scient

Inventors

• Bougeret Cecile
• Guillou Catherine
• Rouleau Julien
• Rivollier Julie
• Carniato Denis

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title