Isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-2020262816-A1
Application number	US-202016865799-A
Country	US
Kind code	A1
Filing date	May 4, 2020
Priority date	Jul 23, 2013
Publication date	Aug 20, 2020
Grant date	—

Abstract

Compound of formula (I):

wherein Het, R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , t, p, p′, q, and q′ are as defined in the description.
Medicinal products containing the same which are useful in treating conditions requiring pro-apoptotic agent.

First claim

1 . A process for the preparation of a compound of formula (I):

wherein:
Het represents a heteroaryl group,
T represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group optionally substituted by one to three halogen atoms, an alkyl(C 1 -C 4 )—NR 1 R 2 , group or an alkyl(C 1 -C 4 )—OR 6 group,
R 1 and R 2 independently of one another represent a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
or R 1 and R 2 together with the nitrogen atom carrying them, form a heterocycloalkyl group,

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 group may be linear branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated,
R 4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (C 1 -C 6 )alkyl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated,
R 5 represents a hydrogen atom or a 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 7 represents a group selected from R′ 7 , R′ 7 —CO—, R′ 7 —O—CO—, NR′ 7 R″ 7 —CO—, R′ 7 —SO 2 —, R′ 7 —NR″ 7 —SO 2 — wherein R′ 7 and R″ 7 independently of one another, 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, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl,
R 8 and R 9 represent, independently of one another, an oxo group or a halogen atom,
p and p′ are, independently of one another, integers equal to 0, 1, 2, 3 or 4,
q and q′ are, independently of one another, integers equal to 1, 2 or 3,

it being understood that when compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups: —PO(OM)(OM′), —PO(OM)(O − M 1 + ), —PO(O − M 1 + )(O − M 2 + ), —PO(O − )(O − )M 3 2+ , —PO(OM)(O[CH 2 CH 2 O] n CH 3 ), or —PO(O − M 1 + )(O[CH 2 CH 2 O] n CH 3 ), wherein M and M + independently of one another 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, a cycloalkyl or a heterocycloalkyl, both of the cycloalkyl and heterocycloalkyl being composed of from 5 to 6 ring members, M 1 + and M 2 + , independently of one another, represent a pharmaceutically acceptable monovalent cation, M 3 2+ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5,
it also 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 containing 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, which may include fused, bridged or spiro ring systems,
“heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and having from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO 2 and nitrogen, it being understood that bicycle group may be fused or spiro type,
wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, may be substituted by from 1 to 3 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; (C 3 -C 6 )spiro; optionally substituted linear or branched (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkyl-S—; hydroxyl; oxo (or N-oxide where appropriate); nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C 1 -C 6 )polyhaloalkyl; trifluoromethoxy, (C 1 -C 6 )alkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, wherein R′ and R″, independently of one another, represent a hydrogen atom, an optionally substituted, linear or branched (C 1 -C 6 )alkyl group or an aryl group,
its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
which process comprises subjecting a compound of formula (II);

wherein Alk represents a linear or branched (C 1 -C 6 )alkyl group,
the ester function of which compound of formula (II) is hydrolysed to yield the corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III):

to yield a compound of formula (IV):

which compound of formula (IV) is protected and subjected to an acylation or a sulfonylation reaction, and which can optionally be subjected to the action of a pyrophosphate or a phosphonate derivative in basic conditions, 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,
it being understood that at any moment considered appropriate during the course of the process described above, some groups (including hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis.

2 . The process according to claim 1 , wherein Het represents one of the following groups: 5,6,7,8-tetrahydroindolizine, indolizine or 1,2-dimethyl-1H-pyrrole.

3 . The process according to claim 1 , wherein q−1 and q′=1.

4 . The process according to claim 1 , wherein q=2 and q′=1.

5 . The process according to claim 1 , wherein T represents a hydrogen atom, a methyl group, a (morpholin-4-yl)methyl group, a 3-(morpholin-4-yl)propyl group, a dimethylaminomethyl group, or a (4-methylpiperazin-1-yl)methyl group.

6 . The process according to claim 1 , wherein R 3 represents a linear or branched (C 1 -C 6 )alkyl group, an aryl group or a heteroaryl group.

7 . The process according to claim 1 , wherein R 3 represents a group selected from phenyl, methyl, ethyl, propyl, butyl, 1-methyl-1H-pyrrolo[2,3-b]pyridine or 5-cyano-1,2-dimethyl-1H-pyrrole.

8 . The process according to claim 1 , wherein R 4 represents a linear or branched (C 1 -C 6 )alkyl group or an aryl group.

9 . The process according to claim 1 , wherein R 4 represents a phenyl or 4-hydroxyphenyl group.

10 . The process according to cl

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Davidson James Edward Paul
• Murray James Brooke
• Chen I-Jen
• Walmsley Claire
• Dodsworth Mark
• Meissner Johannes W G
• Brough Paul
• Fejes Lmre
• Tatai János
• Nyerges Miklós
• Kotschy András
• Szlávik Zoltán
• Geneste Olivier
• Le Tiran Arnaud
• Le Diguarher Thierry
• Henlin Jean-Michel
• Starck Jérôme-Benoît
• Guillouzic Anne-Françoise
• De Nanteuil Guillaume

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title