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

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.

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-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide,   N-(4-hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{[(phenoxyacetyl)amino]methyl}phenyl)-1H-pyrrole-3-carboxamide,   N-(4-hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{[(phenoxyacetyl)amino]methyl}phenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide,   5-(5-[2-({[2-(4-fluorophenyl)ethyl]sulphonyl}amino)ethyl]-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-{2-[(benzylcarbamoyl)amino]ethyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide,   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,   N-(4-hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{2-[(phenylcarbamoyl)amino]ethyl}phenyl)-1H-pyrrole-3-carboxamide,   5-(4-[({[2-(4-fluorophenyl)ethyl]sulphonyl}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,   4-methylphenyl (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,   
       or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. 
     
     
         12 . A method of treating a condition selected from cancer, auto-immune diseases, and diseases of the immune system in a subject in need thereof, comprising administration of the pharmaceutical composition according to  claim 1 . 
     
     
         13 . The method according to  claim 12 , wherein the cancer is selected from the group consisting of cancers of the bladder, brain, breast and uterus, chrome lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, and small-cell lung cancer. 
     
     
         14 . The method according to  claim 12 , wherein the pharmaceutical composition is administered in combination with an anti-cancer agent selected from gentoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. 
     
     
         15 . The method according to  claim 12 , wherein the pharmaceuticalcomposition is administered in combination with radiotherapy.