Heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators

Patent metadata

Field	Value
Publication number	US-9255090-B2
Application number	US-201214367823-A
Country	US
Kind code	B2
Filing date	Dec 20, 2012
Priority date	Dec 21, 2011
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

The present invention relates to phenyl-substituted heterocyclyl derivatives of the formula (I),

wherein Z, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
R 1 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )alkylsulfonyl, halogen or cyano;
R 2 represents hydrogen or halogen;
one of R 3 , R 4 and R 5 represents carboxy-(C 1 -C 3 )alkyl, carboxy-cyclopropyl or carboxy-(C 1 -C 3 )alkoxy and the other two represent independently of each other hydrogen, (C 1 -C 4 )alkoxy or halogen;
R 6 represents hydrogen, (C 1 -C 4 )alkoxy or halogen;
R 7 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkyl-methoxy, (C 3 -C 6 )cycloalkyloxy, methoxy-ethoxy, di-[(C 1 -C 2 )alkyl]-amino, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, halogen or (C 1 -C 4 )alkylsulfonyl;
or R 6 and R 7 together represent methylendioxy or ethylendioxy;
R 8 represents
(C 2 -C 5 )alkyl;
(C 1 -C 5 )alkyl which is mono- or di-substituted wherein the substituents are independently selected from hydroxy, (C 1 -C 4 )alkoxy, oxo, —NR 9 R 10 , optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy or optionally substituted aryl-(C 1 -C 2 )alkoxy;
(C 3 -C 5 )alkenyl;
(C 2 -C 3 )alkenyl which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl;
(C 3 -C 5 )alkynyl;
(C 3 -C 6 )cycloalkyl which is unsubstituted, mono-, di-, tri- or tetra-substituted with methyl; mono-substituted with oxo; mono-substituted with optionally substituted aryl; or mono-substituted with optionally substituted heteroaryl; or
heterocyclyl which is optionally mono-substituted with oxo;

R 9 represents (C 1 -C 4 )alkyl;
R 10 represents optionally substituted diphenylmethyl;
n represents 1 or 2;
m represents 1 or 2; and
Z represents —NH—, —O— or a bond;
or a salt thereof.

2. The compound according to claim 1 , wherein
R 1 represents hydrogen or halogen;
R 2 represents hydrogen or halogen;
one of R 3 , R 4 and R 5 represents carboxy-(C 1 -C 3 )alkyl or carboxy-(C 1 -C 3 )alkoxy and the other two represent hydrogen;
R 6 represents hydrogen, methoxy or halogen;
R 7 represents hydrogen, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, halogen or methylsulfonyl;
R 8 represents
(C 1 -C 4 )alkyl which is mono-substituted with optionally substituted aryl, optionally substituted heteroaryl or optionally substituted aryl-(C 1 -C 2 )alkoxy; or
cyclopropyl which is mono-substituted with optionally substituted aryl;

n represents 1 or 2;
m represents 1 or 2; and
Z represents —NH—, —O— or a bond;
or a salt thereof.

3. The compound according to claim 1 , wherein
R 1 represents fluoro;
R 2 , R 3 , R 4 and R 6 represent hydrogen;
R 5 represents carboxy-methyl or 1-carboxy-ethyl;
R 7 represents methoxy, ethoxy, isopropoxy or 2,2,2-trifluoroethoxy;
R 8 represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with
phenyl, wherein the phenyl is unsubstituted, mono-substituted with fluoro, chloro, methyl or methoxy, di-substituted with fluoro, or di-substituted with fluoro and chloro; or
pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted, mono-substituted with methyl, or di-substituted with methyl and fluoro;

n represents 1;
m represents 2; and
Z represents —O— or a bond;
or a salt thereof.

4. The compound according to claim 1 , wherein
R 1 represents fluoro, chloro or cyano;
R 2 , R 3 , R 5 and R 6 represent hydrogen;
R 4 represents carboxy-methyl or 1-carboxy-ethyl;
R 7 represents methoxy, ethoxy, n-propoxy, iso-propoxy, iso-butoxy, tert-butoxy, cyclopropyl-methoxy, methoxy-ethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy;
R 8 represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with
phenyl, wherein the phenyl is unsubstituted, mono-substituted with fluoro, chloro or methoxy, di-substituted with fluoro, or di-substituted with fluoro and chloro; or
pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted, mono-substituted with methyl, or di-substituted with methyl and fluoro;

n represents 1;
m represents 2; and
Z represents —O— or a bond;
or a salt thereof.

5. The compound according to claim 1 , wherein
R 1 represents hydrogen, fluoro or chloro;
or a salt thereof.

6. The compound according to claim 1 , wherein
one of R 3 , R 4 and R 5 represents carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy;
or a salt thereof.

7. The compound according to claim 1 , wherein
R 7 represents (C 1 -C 4 )alkoxy or trifluoromethoxy;
or a salt thereof.

8. The compound according to claim 1 , wherein
Z represents —O— and R 8 represents (C 1 -C 4 )alkyl which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl; or
Z represents a bond and R 8 represents
(C 1 -C 4 )alkyl which is mono-substituted with optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy or optionally substituted aryl-methoxy; or
cyclopropyl which is mono-substituted with optionally substituted aryl;

or a salt thereof.

9. The compound according to claim 1 , wherein
Z represents a bond;
or a salt thereof.

10. The compound according to claim 1 , wherein the compound is:
(3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid;
(3-{2-[trans-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid;
(3-{2-[trans-2-(2-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid;
(3-{2-[trans-2-(3-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid;
(3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid;
{3-[5-Fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid;
8-(5-Carboxymethyl-2-methyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(5-Carboxymethyl-2-trifluoromethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(5-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(5-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-4-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-4-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-4-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-5-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;
6-(5-Carboxymethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester;
4-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester;
8-(3-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester;

Assignees

• Actelion Pharmaceuticals Ltd

Inventors

• Aissaoui Hamed
• Boss Christoph
• Richard-Bildstein Sylvia
• Siegrist Romain

Classifications

• A61P35/02

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• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

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• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title