Pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-2021290631-A1
Application number	US-202117341751-A
Country	US
Kind code	A1
Filing date	Jun 8, 2021
Priority date	Jul 23, 2013
Publication date	Sep 23, 2021
Grant date	—

Abstract

wherein A 1 , A 2 , R 3 , R b , R c , R d , R 3 , R 4 , R 5 and T are as defined in the description. Medicinal products containing the same which are useful in treating pathologies involving a deficit in apoptosis, such as cancer, auto-immune diseases, and diseases of the immune system.

First claim

1 . A pharmaceutical composition comprising a compound of formula (I):

wherein:
A 1 and A 2 , each independently of the other, represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 )polyhaloalkyl group, a linear or branched (C 1 -C 6 )alkyl group or a cycloalkyl group:
T represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group optionally to substituted by from one to three halogen atoms, a (C 1 -C 4 )alkyl-NR 1 R 2 group, or a (C 1 -C 4 )alkyl-OR 6 group,
R 1 and R 2 , each independently of the other, represent a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
or R 1 and R 2 form with the nitrogen atom carrying them a heterocycloalkyl;

R 3 represents a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, a cycloalkyl group, a (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl group wherein the alkyl moiety is linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated;
R 4 represents an aryl group, a heteroaryl group, a cycloalkyl group or a linear or branched (C 1 -C 6 )alkyl group, wherein one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated;
R 5 represents a hydrogen or halogen atom, a linear or branched (C 1 -C 6 )alkyl group, or a linear or branched (C 1 -C 6 )alkoxy group;
R 6 represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group;
R a , R b and R d each represent a hydrogen atom and R c represents a group selected from R 7 —CO—NH—(C 1 -C 6 )alkyl-, R 7 —SO 2 —NH—(C 0 -C 6 )alkyl, R 7 —NH—CO—NH—(C 0 -C 6 )alkyl- and R 7 —O—CO—NH—(C 0 -C 6 )alkyl-;
R 7 represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, an aryl group or a heteroaryl group;

it being understood that:
“aryl” means a phenyl, naphthyl, biphenyl or indenyl group,
“heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and having from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens),
“cycloalkyl” means any mono- or bi-cyclic, non-aromatic, carbocyclic group having from 3 to 10 ring members,
“heterocycloalkyl” means any mono- or bicyclic, non-aromatic, condensed or spiro group composed of from 3 to 10 ring members and having from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO 2 and nitrogen,

wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl anti alkoxy groups may be optionally substituted by from 1 to 3 groups selected from optionally substituted, linear or branched (C 1 -C 6 )alkyl, (C 3 -C 6 )spiro, optionally substituted, linear or branched (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, —COOR′, —OCOR′, NR′R″, linear or branched (C 1 -C 6 )polyhaloalkyl, trifluoromethoxy, (C 1 -C 6 )alkylsulphonyl, halogen, optionally substituted aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, wherein R′ and R″, each independently of the other, represent a hydrogen atom or an optionally substituted, linear or branched (C 1 -C 6 )alkyl group,
or an enantiomer, a diastercoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base,
in combination with one or more pharmaceutical excipients.

2 . The pharmaceutical composition according to claim 1 , wherein A 1 represents a hydrogen atom or a methyl group.

3 . The pharmaceutical composition according to claim 1 , wherein A 2 represents a linear or branched (C 1 -C 6 )alkyl group optionally substituted by a group selected from halogen, hydroxy, linear or branched (C 1 -C 6 )alkoxy, NR′R″ and morpholine.

4 . The pharmaceutical composition according to claim 1 , wherein A 2 represents a linear or branched (C 1 -C 6 )polyhaloalkyl group or a cyclopropyl group.

5 . The pharmaceutical composition according to claim 1 , wherein A 1 and A 2 both represent a methyl group.

6 . The pharmaceutical composition according to claim 1 , wherein T represents methyl, aminomethyl, (morpholin-4-yl)methyl, (4-methylpipérazin-1-yl)methyl, 2-(morpholin-4-yl)ethyl, [2-(morpholin-4-yl)ethoxy]methyl, hydroxymethyl, [2-(dimethylamino)ethoxy]methyl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl, 1-oxa-6-azaspiro[3.3]hept-6-ylmethyl, 3-(morpholin-4-yl)propyl or trifluoromethyl.

7 . The pharmaceutical composition according to claim 1 , wherein R 4 represents phenyl, 4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 2-hydroxypyrimidine or 3-hydroxypyridine.

8 . The pharmaceutical composition according to claim 1 , wherein R 3 represents an aryl or heteroaryl group.

9 . The pharmaceutical composition according to claim 1 , wherein R 3 represents a group selected from methyl, phenyl, 1H-pyrazole, 1H-indole, 1H-indazole, pyridine, pyrimidine, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1H-benzimidazole, 1H-pyrrole, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 5H-pyrrolo[3,2-d]pyrimidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole, and 1H-pyrazolo[1,5-a]pyrimidine, which groups may be optionally substituted by one or more substituents selected from halogen, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, —CO—O—CH 3 , trideuteriomethyl, 2-(morpholin-4-yl)ethyl and 2-(morpholin-4-yl)ethoxy.

10 . The pharmaceutical composition according to claim 1 , wherein R 1 represents a linear or branched (C 1 -C 6 )alkyl or a heteroaryl optionally substituted by a linear or branched (C 1 -C 6 )alkyl, and R 4 represents a 4-hydroxyphenyl group.

11 . The pharmaceutical composition according to claim 1 , wherein the compound of formula (I) is selected from:
phenyl (4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)-carbamate, N-(4-hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-4-[(phenoxyacetyl)amino]methyl)phenyl)-1H-pyrrole-3-carboxamide, 5-(4-{[(ethylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide, 5-(4-{[(benzylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin -2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide, phenyl (3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)-carbamate, phenyl [2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-phenyl)ethyl]carbamate, N-(4-hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{2-[(phenoxyacetyl)amino]ethyl}phenyl)-1H-pyrrole-3-carboxamide, 5-(5-{[(benzylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide, 5-(5-{[(ethylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydr

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Le Tiran Arnaud
• Le Diguarher Thierry
• Starck Jérôme-Benoît
• Henlin Jean-Michel
• Guillouzic Anne-Françoise
• De Nanteuil Guillaume
• Geneste Olivier
• Fejes Imre
• Tatai János
• Nyerges Miklós
• Davidson James Edward Paul
• Murray James Brooke
• Chen I-Jen
• Durand Didier

Classifications

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title