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

Patent metadata

Field	Value
Publication number	US-2019192528-A1
Application number	US-201916271171-A
Country	US
Kind code	A1
Filing date	Feb 8, 2019
Priority date	Jul 23, 2013
Publication date	Jun 27, 2019
Grant date	—

Abstract

wherein A1, A2, Ra, Rb, Rc, Rd, R3, R4, R5 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 process for the preparation of 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 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 , R c and R d , each independently of the others, represent 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, a heteroaryl group, a halogen atom, a linear or branched (C 1 -C 6 )alkoxy group, a hydroxy group, a linear or branched (C 1 -C 6 )polyhaloalkyl group, a trifluoromethoxy group, —NR 7 R 7 ′, nitro, R 7 -CO—(C 0 -C 6 )alkyl-, R 7 —CO—NH—(C 0 -C 6 )alkyl-, NR 7 R 7 ′—CO—(C 0 -C 6 )alkyl-, NR 7 R 7 ′—, CO—(C 0 -C 6 )alkyl-O—, R 7 —SO 2 —NH—(C 0 -C 6 )alkyl-, R 7 —NH—CO—NH—(C 0 -C 6 )alkyl-, R 7 —O—CO—NH—(C 0 -C 6 )alkyl-, a heterocycloalkyl group, or the substituents of one of the pairs (R a ,R b ), (R b ,R c ), or R c ,R d ) form together with the carbon atoms carrying them a ring composed of from 5 to 7 ring members, which ring may have from one to 2 hetero atoms selected from oxygen and sulphur, wherein one or more carbon atoms of the ring defined hereinbefore may be deuterated or substituted by from one to 3 groups selected from halogen and linear or branched (C 1 -C 6 )alkyl;
R 7 and R 7 ′, each independently of the other, represent 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, or R 7 and R 7 ′, together with the nitrogen atom carrying them, form a heterocycle composed of from 5 to 7 ring members;

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 bi-cyclic, 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 and 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-5-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, —COOR′, —OCOR′, NR′R″, linear or branched (C 1 -C 6 )polyhalo alkyl, 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 diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base,
which process comprises subjecting a compound of formula (II)

to a Heck reaction in an aqueous or organic medium, in the presence of a palladium catalyst, a base, a phosphine and a compound of formula (III):

wherein Alk represents a linear or branched (C 1 -C 6 )alkyl, to obtain the compound of formula (IV):

the aldehyde function of which compound of formula (IV) is oxidized to a carboxylic acid to form a compound of formula (V):

which compound of formula (V) is then subjected to peptide coupling with a compound of formula (VI):

to yield a compound of formula (VII):

the ester function of which compound of formula (VII) is hydrolyzed to yield the corresponding carboxylic acid or carboxylate, which may be converted into an acid derivative, including an acyl chloride or anhydride, which compound is then coupled with an amine NHR 3 R 4 , to yield the compound of formula (I),
which compound of formula (I) may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique,
wherein, at any time considered appropriate in the course of the above-described process, certain groups of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.

2 . The process according to claim 1 , wherein one of the groups R 3 or R 4 of the amine NHR 3 R 4 is substituted by a hydroxy function, which hydroxyl function is subjected to a protection reaction prior to any coupling with the carboxylic acid formed from the compound of formula (VII), or with a corresponding acid derivative thereof, and wherein the resulting protected compound of formula (I) undergoes a deprotection reaction and is then optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base.

3 . The process according to claim 1 , wherein A 1 represents a hydrogen atom or a methyl group.

4 . The process 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.

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

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title