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

Patent metadata

Field	Value
Publication number	US-9809553-B2
Application number	US-201515119173-A
Country	US
Kind code	B2
Filing date	Feb 20, 2015
Priority date	Feb 21, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

A compound of formula (I):

wherein the substituents are as defined in the description.

Medicinal products containing the same which are useful in treating or preventing pathologies which are the result of activation of the RhoA/ROCK pathway and phosphorylation of the myosin light chain.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
X represents —C(═O), —CH(OH)— or —CH 2 —,
Ri 1 represents a hydrogen atom or a hydroxyl group,
it being understood that the compound of formula (I) wherein Ri 1 represents a hydroxyl group may be represented by the following tautomeric form:

Ri 2 and Ri 3 , which may be identical or different, each represent a hydrogen atom, a (C 1 -C 6 )alkyl group or a halogen atom,
Ri 6 , Ri 7 and Ri 8 , which may be identical or different, each represent a hydrogen atom or a halogen atom,
Ra 1 and Ra 5 , which may be identical or different, each represent a hydrogen atom, a halogen atom, an —O(C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkyl group,
Ra 2 represents a hydrogen or halogen atom, a hydroxyl group, a —O(C 1 -C 6 )alkyl group, a —(C 1 -C 6 )alkyl group, a nitrogen-containing heterocycle having from 3 to 7 ring members, or —O—(CH2) m —NR′R″,
Ra 3 represents a hydrogen atom, an —O(C 1 -C 6 )alkyl group, a —(C 1 -C 6 )alkyl group, a nitrogen-containing heterocycle having from 3 to 7 ring members, or —CRy 1 Ry 2 NH(Ry 3 ),
Ra 4 represents a hydrogen atom a halogen atom, an —O(C 1 -C 6 )alkyl group, a —(C 1 -C 6 )alkyl group, or —CRy 1 Ry 2 NH(Ry 3 ),
it being understood that:
Ra 1 , Ra 2 , Ra 3 , Ra 4 and Ra 5 may not simultaneously represent a hydrogen atom,
Ra 3 and Ra 4 may not simultaneously represent —CRy 1 Ry 2 NH(Ry 3 ),
Ra 1 and Ra 2 , together with the carbon atoms carrying them, may form a heterocycle having from 4 to 7 ring members chosen from tetrahydrofuran, 1,4-dioxane, tetrahydropyran, tetrahydro-2H-pyran-4-amine and 1-(tetrahydro-2H-pyran-4-yl)methanamine, and
Ra 2 and Ra 3 , together with the carbon atoms carrying them, may form a hydrocarbon ring having from 4 to 7 ring members chosen from cyclopentane, cyclopentanamine, N-cyclopentylglycinamide and 1-methylcyclopentanamine,

m is an integer, the value of which is fixed at 1, 2 or 3,
R′ and R″, which may be identical or different, each represent —(C 1 -C 6 )alkyl groups or, together with the nitrogen atom carrying them, form a heterocycle having from 3 to 7 ring members,
Ry 1 represents a hydrogen atom, a —(C 1 -C 6 )alkyl group, a —CH 2 -cyclohexyl group, or a 3-methoxyphenyl group,
Ry 2 represents a hydrogen atom or a —(C 1 -C 6 )alkyl group,
Ry 3 represents:
a hydrogen atom,
—C(═O)—CHRy 4 -NHRy 5 wherein Ry 4 represents a hydrogen atom or a (C 1 -C 6 )alkyl group and Ry 5 represents a hydrogen atom or a methyl group, or
a —(C 1 -C 6 )alkyl group which may be substituted by a hydroxyl group, an —O(C 1 -C 3 )alkyl group, a cyclohexyl group or a methylsulphonyl group,

or Ry 1 and Ry 2 , together with the carbon atom carrying them, form a cyclopropane, cyclobutane or tetrahydropyran group,
or Ry 2 and Ry 3 , together with the carbon and nitrogen atoms carrying them, respectively, form a pyrrolidine or piperidine group,

or an optical isomer thereof, where it exists, an addition salt thereof with a pharmaceutically acceptable acid or a hydrate thereof.

2. The compound according to claim 1 , wherein X represents —C(═O).

3. The compound of according to claim 1 , wherein Ri 1 represents a hydroxyl group, it being understood that said compound may be represented in its tautomeric form.

4. The compound according to claim 1 , wherein Ri 2 , Ri 6 , Ri 7 and Ri 8 each represent a hydrogen atom.

5. The compound according to claim 1 , Wherein Ra 1 and Ra 5 each represent a fluorine atom.

6. The compound according to claim 1 , wherein Ra 3 or Ra 4 represents —CRy 1 Ry 2 NH(Ry 3 ).

7. The compound according to claim 6 , wherein:
Ry 1 represents a hydrogen atom or a —(C 1 -C 6 )alkyl group,
Ry 2 represents a —(C 1 -C 6 )alkyl group, and
Ry 3 represents a hydrogen atom.

8. The compound according to claim 1 , wherein:
X represents —C(═O)—,
Ri 1 represents a hydrogen atom or a hydroxyl group,
Ri 2 , Ri 6 , Ri 7 and Ri 8 each represent a hydrogen atom and Ri 3 represents a hydrogen atom or a (C 1 -C 6 )alkyl group,
Ra 1 and Ra 5 , which may be identical or different, each represent a hydrogen atom, a fluorine atom or a (C 1 -C 6 )alkyl group,
Ra 2 represents a hydrogen atom or a —(C 1 -C 6 )alkyl group,
Ra 3 represents a hydrogen atom, a piperidine group or —CRy 1 Ry 2 NH(Ry 3 ),
Ra 4 represents a hydrogen atom or —CRy 1 Ry 2 NH(Ry 3 ), it being understood that Ra 3 and Ra 4 may not simultaneously represent —CRy 1 Ry 2 NH(Ry 3 ), and that:
when Ra 3 represents —CRy 1 Ry 2 NH(Ry 3 ), Ra 1 and Ra 2 , together with the carbon atoms carrying them, may form a tetrahydrofuran, 1,4-dioxane or tetrahydropyran group, or
when Ra 3 represents a hydrogen atom, Ra 1 and Ra 2 , together with the carbon atoms carrying them, may form a tetrahydro-2H-pyran-4-amine or 1-(tetrahydro-2H-pyran-4-yl)methanamine group, or
Ra 2 and Ra 3 , together with the carbon atoms carrying them, may form a cyclopentanamine or 1-methylcyclopentanamine group,

Ry 1 represents a hydrogen atom, a —(C 1 -C 6 )alkyl group or —CH 2 -cyclohexyl group,
Ry 2 represents a hydrogen atom or a —(C 1 -C 6 )alkyl group,
Ry 3 represents a hydrogen atom or a —(C 1 -C 6 )alkyl group which may be substituted by a hydroxyl group.

9. The compound according to claim 1 , which is selected from:
[4-(1-aminoethyl)-2,6-difluorophenyl](isoquinolin-5-yl)methanone,
[4-((1R)-1-aminoethyl)-2,6-difluorophenyl](isoquinolin-5-yl)methanone,
[4-(1-aminoethyl)-2,6-difluorophenyl](1-hydroxyisoquinolin-5-yl)methanone,
1-[3,5-difluoro-4-(isoquinolin-5-ylmethyl)phenyl]ethanamine,
{4-[(1S)-1-aminoethyl]-2,6-difluorophenyl}(isoquinolin-5-yl)methanol,
[4-(2-aminopropan-2-yl)-2,6-difluorophenyl](isoquinolin-5-yl)methanone,
5-[4-(2-aminopropan-2-yl)-2,6-difluorobenzoyl]isoquinolin-1(2H)-one,
5-[4-(1-aminoethyl)-2-fluoro-3-methoxybenzoyl]isoquinolin-1(2H)-one,
5-({5-[(1R)-1-aminoethyl]-3,4-dihydro-2H-chromen-8-yl}carbonyl)isoquinolin-1(2H)-one,
5-{4-[(1R)-1-aminoethyl]-2-methylbenzoyl}isoquinolin-1(2H)-one,
5-(2,6-difluoro-4-{1-[(2-hydroxyethyl)amino]ethyl}benzoyl)isoquinolin-1(2H)-one,
5-{4-[(1R)-1-aminoethyl]-2,6-difluorobenzoyl}-4-methylisoquinolin-1(2H)-one,
5-{3-[(1R)-1-aminoethyl]-2,6-difluorobenzoyl}isoquinolin-1(2H)-one,
5-[(1-amino-4,6-difluoro-2,3-dihydro-1H-inden-5-yl)carbonyl]isoquinolin-1(2H)-one,
5-{[(3R)-3-amino-4,6-difluoro-2,3-dihydro-1H-inden-5-yl]carbonyl}isoquinolin-1(2H)-one,
5-({8-[(1R)-1-aminoethyl]-2,3-dihydro-1,4-benzodioxin-5-yl}carbonyl)isoquinolin-1(2H)-one,
5-[2,6-difluoro-4-(piperidin-2-yl)benzoyl]isoquinolin-1(2H)-one,
5-[4-(1-amino-2-cyclohexylethyl)-2,6-difluorobenzoyl]isoquinolin-1(2H)-one, and
5-{[4-(aminomethyl)-3,4-dihydro-2H-chromen-8-yl]carbonyl}isoquinolin-1(2H)-one,
or an optical isomer thereof, where it exists, an addition salt thereof with a pharmaceutically acceptable acid or a hydrate thereof.

10. The compound according to claim 1 , which is 5-({5-8 (1R)-1-Aminoethyl]-3,4- dihydro-2H-chromen-8-yl}carbonyl)isoquinolin-1(2H)-one or an addition salt thereof with a pharmaceutically acceptable acid or a hydrate thereof.

11. The compound according to claim 1 , which is 5-{4-[(1R)-1-Aminoethyl]-2-methylbenzoyl}isoquinolin-1(2H)-one or an addition salt thereof with a pharmaceutically acceptable acid or a hydrate thereof.

Assignees

• Servier Lab

Inventors

• Chimenti Stéfano
• Courchay Christine
• Dessinges Aimee
• Gellibert Françoise
• Goument Bertrand
• Konnert Marc
• Peglion Jean-Louis
• Poitevin Christophe
• Vilaine Jean-Paul
• Villeneuve Nicole

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title