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

Patent metadata

Field	Value
Publication number	US-10322131-B2
Application number	US-201615738601-A
Country	US
Kind code	B2
Filing date	Jun 22, 2016
Priority date	Jun 23, 2015
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Compounds of formula (I):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 14 , A and n are as defined in the description.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
A represents the group

 in which 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 12 R 12 ′, -Cy 5 , 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, —S—(C 1 -C 6 )alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )—NR 10 R 10 ′, —O-alkyl(C 1 -C 6 )—NR 10 R 10 ′, —O-alkyl(C 1 -C 6 )—R 11 , —C(O)—OR 10 , —O—C(O)—R 10 , —C(O)—NR 10 R 10 ′, —NR 10 —C(O)—R 10 ′, —NR 10 —C(O)—OR 10 ′, -alkyl(C 1 -C 6 )—NR 10 —C(O)—R 10 ′, —SO 2 —NR 10 R 10 ′, —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 the group consisting of oxygen, sulphur and nitrogen, wherein the resulting ring may be an substituted by a group selected from the group consisting of a linear or branched (C 1 -C 6 )alkyl group, —NR 12 R 12 ′, -alkyl(C 0 -C 6 )-Cy 1 , and oxo,
R 6 represents —O-alkyl(C 1 -C 6 )—R 11 ,
R 7 represents 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 brandied (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 6 )—NR 10 R 10 ′, —O-alkyl(C 1 -C 6 )—NR 10 R 10 ′, —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 11 , —C(O)—OR 10 , —O—C(O)—R 10 , —C(O)—NR 10 R 10 ′, —R 10 —C(O)—R 10 ′, —NR 10 —C(O)—OR 10 ′, -alkyl(C 1 -C 6 )—NR 10 —C(O)—R 10 ′, —SO 2 —NR 10 R 10 ′, —SO 2 -alkyl(C 1 -C 6 ),
R 8 represents a hydrogen atom, a linear or branched (C 1 -C 8 )alkyl group, a —CHR a R b group, an aryl group, a heteroaryl group, an arylalkyl(C 1 -C 6 ) group, or a heteroarylalkyl(C 1 -C 6 ) group,
R 9 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 13 , or —C(O)—NR 13 R 13 ′,
R 10 and R 10 ′, 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 10 , R 10 ′), together with the nitrogen atom carrying them, from 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 the group consisting of oxygen, sulphur and nitrogen, wherein the nitrogen may be substituted by from 1 to 2 groups selected from the group consisting of a hydrogen atom and 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 11 represents -Cy 5 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 6 , -Cy 5 -alkyl(C 0 -C 6 )-Cy 6 , -Cy 5 -alkyl(C 0 -C 6 )—NR 12 -alkyl(C 0 -C 6 )-Cy 6 ,
R 12 , R 12 ′, R 13 and R 13 ′, independently of one another, represent a hydrogen atom or an optionally substituted linear or branched (C 1 -C 6 )alkyl group,
R 14 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, 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, format 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 the group consisting of 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 and Cy 5 , independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
Cy 6 represents

 or Cy 6 represents a heteroaryl group which is substituted by a group selected from the group consisting of —O—P(O)(OR 20 ) 2 ; —O—P(O)(O − ) 2 ; —(CH 2 ) p —O—(CHR 18 —CHR 19 —O) q —R 20 ; hydroxy; hydroxy(C 1 -C 6 )alkyl; —(CH 2 ) r —(CH 2 ) s -heterocycloalkyl; and —Y—(CH 2 ) q —NR 21 R 21 ′,
R 15 represents a hydrogen atom; a —(CH 2 ) p —O—(CHR 18 —CHR 19 —O) q —R 20 group; a linear or branched (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group; a —Y—(CH 2 ) q —NR 21 R 21 ′ group; or a —(CH 2 ) r —Y—(CH 2 ) s -heterocycloalkyl group,
R 16 represents a hydrogen atom; a hydroxy group; a hydroxy(C 1 -C 6 )alkyl group; a —(CH 2 ) r —Y—(CH 2 ) s -heterocycloalkyl group; a (CH 2 ) r —Y—X—O—(O)(OR 20 ) 2 group; a —O—P(O)(O − ) 2 group; a —(CH 2 ) p —O—(CHR 18 —CHR 19 —O) q —R 20 group; a —(CH 2 ) p —O—C(O)—NR 22 R 23 group; or a —Y—(CH 2 ) q —NR 21 R 21 ′ group,
R 17 represents a hydrogen atom; a —(CH 2 ) p —O—(CHR 18 —CHR 19 —O) q —R 20 group; a —O—P(O)(OR 20 ) 2 group; a —O—P(O)(O − ) 2 group; a hydroxy group; a hydroxy(C 1 -C 6 )alkyl group; a —(CH 2 ) r —Y—(CH 2 ) s -heterocycloalkyl group; a —Y—(CH 2 ) q —NR 21 R 21 ′ group; or an aldonic acid,
X represents a —(CH 2 ) s — group or a —C(O)— group,
Y represents a bond or an oxygen atom,
R 18 represents a hydrogen atom or a (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group,
R 19 represents a hydrogen atom or a hydroxy(C 1 -C 6 )alkyl group,
R 20 represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
R 21 and R 21 ′, independently of one another, represent a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, or a hydroxy(C 1 -C 6 )alkyl group,
 or the substituents of the pair (R 21 , R 21 ′), 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 the group consisting of oxygen, sulphur and nitrogen wherein the resulting ring may be substituted by a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
R 22 represents a (C 1 -C 6 )

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Szlavik Zoltan
• Paczal Attila
• Balint Balazs
• Kotschy András
• Chanrion Maïa
• Geneste Olivier
• Davidson James Edward Paul
• Murray James Brooke
• Sipos Szabolcs
• Proszenyák Ágnes

Classifications

• A61K31/381

  having five-membered rings · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519 Primary

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

• A61K31/215

  of carboxylic acids · CPC title