IP Library › Granted Patent US 10,624,876

Granted Patent B2

US 10,624,876 · App. 16/344,390 · Granted Apr 21, 2020

Derivatives of indole for the treatment of endometriosis

Inventor: Philippe Pouletty (Paris, FR)

Assignee: BIOKINESIS

A61K31/404 A61K45/06 A61P15/00 C07D209/18 C07D401/06 C07D401/14 C07D405/14

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Quick Facts

Patent No.: US 10,624,876
App. No.: 16/344,390
Granted: Apr 21, 2020
Kind: B2

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Abstract

The present invention relates to compounds of formula (I) and pharmaceutical compositions comprising such compounds, for use for treating and/or preventing endometriosis.

Claims (164)

1. A method for treating endometriosis in a subject in need thereof, comprising administering an effective amount of a compound of formula (I):

wherein:

X represents a nitrogen atom, a C—CN unit or a N+—O— unit;

R 1 and R 1 ′ represent independently H, a halogen, a hydroxy, an amino, or a (C 1 -C 6 )alkoxy group, optionally substituted by a carboxylic group or one —NR 11 R 12 unit wherein R 11 and R 12 represent H, a (C 1 -C 6 )alkyl group, or R 11 and R 12 taken together form a 3- to 7-membered ring, optionally interrupted by one or several heteroatoms;

R 2 represents:

a radical (C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, aryloxy, heteroaryloxy, (C 1 -C 6 )alkyl-aryloxy, (C 1 -C 6 )alkyl-heteroaryloxy, said radicals being optionally substituted by at least one halogen, or a radical thio-(C 1 -C 6 )alkyl, thio-aryl, thio-heteroaryl, thio-(C 1 -C 6 )alkyl-aryl or thio-(C 1 -C 6 )-alkyl-heteroaryl, said radicals being optionally substituted by at least one halogen or by 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 H, a (C 1 -C 6 )alkyl group, or R 4 and R 5 taken together form a 3- to 7-membered ring, optionally interrupted by one or several heteroatoms, 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 or heteroaryl group optionally substituted by at least one halogen, a trifluoromethyl group, or a (C 1 -C 3 )alkoxy group,

a halogen, or

a hydroxy; 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) as above defined, 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 salts 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, a (C 1 -C 6 )alkylaryl, or a heteroaryl;

a —NR 9 R 10 unit wherein R 9 and R 10 represent a hydrogen, a (C 1 -C 6 )alkyl group, or R 9 and R 10 taken together form a 3- to 7-membered ring, optionally interrupted by one or several heteroatoms, and optionally the ring being substituted by at least one (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 saturated heterocycle or a heteroaryl;

or one of its pharmaceutically acceptable salts.

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

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

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

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

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

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

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

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

8. The method according to claim 1 , wherein R 2 represents:

a radical (C 1 -C 6 )alkoxy, or phenoxy, said radicals being optionally substituted by at least one 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, thio-heteroaryl, thio-(C 1 -C 6 )alkyl-aryl, said radicals being optionally substituted by at least one halogen or by a (C 1 -C 6 )alkoxy group;

an aryl group optionally substituted by at least one halogen, or a trifluoromethyl group; or

a heteroaryl group.

9. The method 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 by a fluorine;

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 in the group consisting of a thio-methyl group, a thio-ethyl group, a thio-benzyl group, a thio-pyridinyl group and a thio-phenyl group, optionally substituted by at least one fluorine or a trifluoromethyl group;

a phenyl group optionally substituted by at least one bromine or a trifluoromethyl group; or

a heteroaryl group selected from the group consisting of a furan or a triazol.

10. The method according to claim 1 , wherein said compound is selected from the group consisting of:

(Z)-3-(4-ethoxypyridin-3-yl)-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile;

(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)-acrylonitile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-dimethylamino)pyridine-3-yl)-acrylonitile hydrochloride;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitile;

(E)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitile;

(Z)-2-(5-methoxy-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-ethoxypyridin-3-yl)-acrylonitile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-isopropoxypyridin-3-yl)-acrylonitile;

(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)-acrylonitile;

(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)-acrylonitile;

(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)-acrylonitile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(4-fluorophenoxy)pyridin-3-yl)-acrylonitile;

(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-(furan-3-yl)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(pyridine-2-ylthio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(pyridine-2-ylthio)pyridin-3-yl)-acrylonitrile;

(Z)-3-(4-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-bromo-1H-indol-3-yl)-acrylonitile;

(Z)-3-(4-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-chloro-1H-indol-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(furan-3-yl)pyridin-3-yl)-acrylonitrile;

(E)-2-(5-bromo-1H-indol-3-yl)-3-(4-(furan-3-yl)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)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-(4-fluorophenoxy)benzonitrile;

(Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(E)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-(dimethylamino)benzonitrile;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-(dimethylamino)benzonitrile;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-(ethylthio)benzonitrile;

(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-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-(furan-3-yl)pyridine-1-oxide;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-methoxypyridine-1-oxide;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-(trifluoromethoxy)benzonitrile;

(Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-(trifluoromethoxy)benzonitrile;

(Z)-3-(2-cyano-2-(6-methoxy-1H-indol-3-yl)vinyl)-4-methoxybenzonitrile;

(Z)-2-(1-acetyl-5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-3-(2-(1-acetyl-5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(Z)-2-(5-bromo-1-pivaloyl-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-3-(2-(5-bromo-1-pivaloyl-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(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;

(Z)-2-(4-methylpiperazin-1-yl)ethyl 5-bromo-3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1H-indole-1-carboxylate;

((Z)-3-(2-(5-bromo-1-(2-(dimethylamino)acetyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(Z)-tert-butyl 5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indole-1-carboxylate;

(R,Z)-benzyl-4-(5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indol-1-yl)-2-(tert-butoxycarbonylamino)-4-oxobutanoate;

(R,Z)-tert-butyl-5-(5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indol-1-yl)-2-(tert-butoxycarbonylamino)-5-oxopentanoate;

(R,Z)-benzyl-2-amino-4-(5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indol-1-yl)-4-oxobutanoate;

(Z)-3-(2-(5-bromo-1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(Z)-3-(2-(5-bromo-1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile hydrochloride;

(S,Z)-3-(2-(1-(3-aminobutanoyl)-5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile hydrochloride;

(Z)-3-(2-(1-(2-aminoacetyl)-5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile hydrochloride;

(Z)-3-(2-(5-bromo-1-(2-(piperazin-1-yl)acetyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile hydrochloride;

(Z)-3-(2-(5-bromo-1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(S,Z)-3-(2-(1-(2-amino-3-hydroxypropanoyl)-5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile hydrochloride;

(Z)-3-(2-(5-bromo-1-(5-oxopyrrolidine-2-carbonyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

(R,Z)-3-(2-(5-bromo-1-(2,6-diaminohexanoyl)-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile dihydrochloride;

(Z)-3-(5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indol-1-yl)-3-oxopropyl dihydrogen phosphate;

(Z)-2-(1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-methoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-ethoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-isopropoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-fluoro-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(6-methoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-3-(6-fluoropyridin-3-yl)-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile;

(Z)-2-(5-hydroxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-3-[2-cyano-2-(5-methoxy-1H-indol-3-yl)-vinyl]-benzonitrile;

(Z)-2-(5-methoxy-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-2-(5-amino-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile;

(Z)-3-(4-chloro-pyridin-3-yl)-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile;

(Z)-3-(6-chloro-pyridin-3-yl)-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile;

(Z)-3-(6-methoxy-pyridin-3-yl)-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile;

(Z)-2-(5-methoxy-1H-indol-3-yl)-3-(6-methyl-pyridin-3-yl)-acrylonitrile; and

(Z)-3-[2-cyano-2-(5-hydroxy-1H-indol-3-yl)-vinyl]-benzonitrile;

and their pharmaceutically acceptable salts.

11. The method according to claim 1 , wherein said compound is selected from the group consisting of:

(Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile; and

(E)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile;

and their pharmaceutically acceptable salts.

12. A method for treating endometriosis in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising a compound of formula (I):

wherein:

X represents a nitrogen atom, a C—CN unit or a N+—O— unit;

R 2 represents:

a NHCOR 6 unit wherein R 6 represents (C 1 -C 6 )alkyl group,

an aryl or heteroaryl group optionally substituted by at least one halogen, a trifluoromethyl group, or a (C 1 -C 3 )alkoxy group,

a halogen, or

a hydroxy; 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) as above defined, 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 )polyalkyloxy group wherein n is 1<n<6, a phosphate or pyrophosphate group and salts 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, a (C 1 -C 6 )alkylaryl, or a heteroaryl;

a NH—NR 9 R 10 unit wherein R 9 and R 10 are as defined above; or

a saturated heterocycle or a heteroaryl;

or one of its pharmaceutically acceptable salts.

13. The method according to claim 12 , wherein said pharmaceutical composition further comprises an additional anti-endometriosis drug.

14. The method according to claim 12 , wherein said pharmaceutical composition further comprises an additional anti-endometriosis drug selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, hormonal contraceptives drugs, growth factor inhibitors, endogenous angiogenesis inhibitors, fumagillin analogues, statins, cyclo-oxygenase-2 inhibitors, phytochemical compounds, immunomodulators, dopamine agonists, peroxisome proliferator-activated receptor agonists, progestins, danazol, and gonadotropin-releasing hormone agonists.

Assignments (2)

MERGER Recorded Apr 27, 2022

From: BIOKINESIS

To: DIACCURATE

Reel/Frame 059728/0700 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 19, 2019

From: POULETTY, PHILIPPE

To: BIOKINESIS

Reel/Frame 049509/0951 →

Priority Claims (1)

EP 16306389 · Oct 24, 2016 · regional

Continuity (1)

Related Publication 20190275000A1 · Sep 12, 2019