Hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-10711010-B2
Application number	US-201916247614-A
Country	US
Kind code	B2
Filing date	Jan 15, 2019
Priority date	Jun 23, 2015
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

Medicinal products containing the same which are useful in treating conditions requiring a pro-apoptotic agent.

First claim

The invention claimed is:

1. A method of treating multiple myeloma in a subject in need thereof, comprising administration of a compound of formula (I):

alone or in combination with one or more pharmaceutically excipients, wherein:
A represents the group

wherein 1 is linked to the oxygen atom and 2 is linked to the phenyl ring,
R 1 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 linear or branched (C 1 -C 6 )alkoxy group, a —S—(C 1 -C 6 )alkyl group, a linear or branched (C 1 -C 6 )polyhaloalkyl, a hydroxy group, a hydroxy(C 1 -C 6 )alkyl group, a cyano group, —NR 11 R 11 ′, -Cy 6 , or a halogen atom,
R 2 , R 3 , R 4 and R 5 independently of one another represent a hydrogen atom, a halogen 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, a linear or branched (C 1 -C 6 )polyhaloalkyl, a hydroxy group, a hydroxy(C 1 -C 6 )alkyl group, a linear or branched (C 1 -C 6 )alkoxy group, a —S—(C 1 -C 6 )alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )—NR 9 R 9 ′, —O-alkyl(C 1 -C 6 )—NR 9 R 9 ′, —O-alkyl(C 1 -C 6 )—R 10 , —C(O)—OR 9 , —O—C(O)—R 9 , —C(O)—NR 9 R 9 ′, —NR 9 —C(O)—R 9 ′, —NR 9 —C(O)—OR 9 ′, -alkyl(C 1 -C 6 )—NR 9 —C(O)—R 9 ′, —SO 2 —NR 9 R 9 ′, —SO 2 -alkyl(C 1 -C 6 ),
or the substituents of one of the pairs (R 2 , R 3 ), (R 3 , R 4 ), (R 4 , R 5 ), when grafted onto two adjacent carbon atoms, together with the carbon atoms carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by a group selected from the group consisting of a linear or branched (C 1 -C 6 )alkyl group, —NR 11 R 11 ′, -alkyl(C 0 -C 6 )-Cy 1 , and oxo,
R 6 and R 7 independently of one another represent a hydrogen atom, a halogen 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, a linear or branched (C 1 -C 6 )polyhaloalkyl, a hydroxy group, a linear or branched (C 1 -C 6 )alkoxy group, a —S—(C 1 -C 6 )alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 9 )—NR 9 R 9 ′, —O-alkyl(C 1 -C 6 )—NR 9 R 9 ′, —O-Cy 1 , -alkyl(C 0 -C 6 )-Cy 1 , -alkenyl(C 2 -C 6 )-Cy 1 , -alkynyl(C 2 -C 6 )-Cy 1 , —O-alkyl(C 1 -C 6 )—R 10 , —C(O)—OR 9 , —O—C(O)—R 9 , —C(O)—NR 9 R 9 ′, —NR 9 —C(O)—R 9 ′, —NR 9 —C(O)—OR 9 ′, -alkyl(C 1 -C 6 )—NR 9 —C(O)—R 9 ′, —SO 2 —NR 9 R 9 ′, —SO 2 -alkyl(C 1 -C 6 ),
or the substituents of the pair (R 6 , R 7 ), when grafted onto two adjacent carbon atoms, together with the carbon atoms carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by a group selected from the group consisting of a linear or branched (C 1 -C 6 )alkyl group, —NR 11 R 11 ′, -alkyl(C 0 -C 6 )-Cy 1 , and oxo,
R 8 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, -Cy 3 , -alkyl(C 1 -C 6 )-Cy 3 , -alkenyl(C 2 -C 6 )-Cy 3 , -alkynyl(C 2 -C 6 )-Cy 3 , -Cy 3 -Cy 4 , -alkynyl(C 2 -C 6 )—O-Cy 3 , -Cy 3 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 4 , a halogen atom, a cyano group, —C(O)R 12 , or —C(O)—NR 12 R 12 ′,
R 9 and R 9 ′ independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, -alkyl(C 0 -C 6 )-Cy 1 ,
or the substituents of the pair (R 9 , R 9 ′), together with the nitrogen atom carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the nitrogen may be substituted by a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group and wherein one or more of the carbon atoms of the possible substituents, may be deuterated,
R 10 represents -Cy 1 , -Cy 1 -alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -alkyl(C 0 -C 6 )—NR 9 -alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -Cy 2 -O-alkyl(C 0 -C 6 )-Cy 5 , —C(O)—NR 9 R 9 ′, —NR 9 R 9 ′, —OR 9 , —NR 9 —C(O)—R 9 —O-alkyl(C 1 -C 6 )—OR 9 , —SO 2 —R 9 , —C(O)—OR 9 , or —NH—C(O)—NH—R 7 ,
R 11 , R 11 ′, R 12 and R 12 ′, independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C 1 -C 6 )alkyl group,
R 13 represents a hydrogen atom, a hydroxy group, or a hydroxy(C 1 -C 6 )alkyl group,
R a represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
R b represents a —O—C(O)—O—R c group, a —O—C(O)—NR c R c ′ group, or a —O—P(O)(OR c ) 2 group,
R c and R c ′ independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 8 )alkyl group, a cycloalkyl group, a (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group, or a (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl group,
or the substituents of the pair (R c , R c ′), together with the nitrogen atom carrying them, form a non-aromatic ring having from 5 to 7 ring members, which ring may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, wherein the nitrogen may be substituted by a linear or branched (C 1 -C 6 )alkyl group,
Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 and Cy 6 , independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
n is an integer equal to 0 or 1,

wherein:
“aryl” means a phenyl, naphthyl, biphenyl, indanyl 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 containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
“heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems,

wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (C 1 -C 6 )alkyl, optionally substituted linear or branched (C 2 -C 6 )alkenyl group, optionally substituted linear or branched (C 2 -C 6 )alkynyl group, optionally substituted linear or branched (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkyl-S—, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″, —NR′R′, —(C═NR′)—OR″, linear or branched (C 1 -C 6 )polyhaloalkyl, trifluoromethoxy, or halogen, wherein R′ and R″, independently of one another, represent a hydrogen atom or an optionally substituted linear or branched (C 1 -C 6 )alkyl group, and wherein one or more of the carbon atoms of the preceding possible substituents, may be deuterated,
its enantiomers, diastereoisomers and atropisomers, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein at least one of th

Assignees

• Servier Lab
• Vernalis R&D Ltd
• Les Laboratories Servier
• Vernalis R&D Ltd

Inventors

• Szlávik Zoltán
• Kotschy András
• Chanrion Maïa
• Demarles Didier
• Geneste Olivier
• Davidson James Edward Paul
• Murray James Brooke
• Sipos Szabolcs
• Paczal Attila
• Bálint Balázs

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title