Modulators of protease activated receptors

Patent metadata

Field	Value
Publication number	US-9868763-B2
Application number	US-201214235640-A
Country	US
Kind code	B2
Filing date	Jul 27, 2012
Priority date	Nov 7, 2011
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

The present invention provides novel compounds of the Formula (I), pharmaceutical compositions comprising such compounds and methods for using such compounds as tools for biological studies or as agents or drugs for therapies such as metabolic syndrome, obesity, type II diabetes, fibrosis and cardiovascular diseases, whether they are used alone or in combination with other treatment modalities.

First claim

The invention claimed is:

1. A method of treating a disease or disorder selected from metabolic syndrome, obesity, type II diabetes, fibrosis and cardiovascular diseases comprising administering to a subject in need thereof an effective amount of a PAR2 antagonist represented by formula (I):

wherein
R 1 is hydrogen, C 1 -C 6 alkyl, aminoalkyl, hydroxyalkyl, or —C(O)R 8 ;
R 8 is a 5- or 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O, optionally substituted with one or more substituents selected from alkyl, alkoxy, amine, aminoalkyl, amidoalkyl, halo, hydroxy, trihaloalkyl, trihaloalkoxy or phenyl, wherein the phenyl group is optionally substituted with 1 to 3 substituents selected from alkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl, or trihaloalkoxy; or

R 1 , together with the nitrogen atom to which it is attached, forms a mono- or bicyclic-nitrogen containing heterocycle, optionally substituted with alkyl;
R 2 is an aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group comprising 1 to 3 heteroatoms selected from N and O, wherein the C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group may be further substituted with one or more substituents selected from alkyl, amine, hydroxy, or the cyclic group or heterocyclic group is fused with an optionally substituted aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group;
R 3 is hydrogen or C 1 -C 6 alkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, aminoalkyl or amidoalkyl;
R 5 is a benzyl group optionally substituted with alkyl, aminoalkyl, alkoxy, C 4 -C 7 heterocycle, hydroxy, halo, nitro, dioxalane, trihaloalkyl, trihaloalkoxy or —C(O)NHCHR 9 R 10 ;
R 9 is —C(O)NH 2 and
R 10 is a C 2 -C 5 aminoalkyl;
or
R 4 and R 5 combined, together with the nitrogen to which they are attached, form piperidine, optionally substituted with phenyl, benzyl, aminoalkyl, aminoaryl, amidoalkyl or a heterocycle; or
R 4 and R 5 combined, together with the nitrogen to which they are attached, form piperidine fused with an aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group;
wherein the phenyl, benzyl, aminoaryl, heterocycle or the aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group fused with piperidine may be further substituted with 1 to 3 substituents selected from alkyl, alkylamine, alkylamide, alkylsulfonyl, alkoxy, aminoalkyl, aminoaryl, amidoalkyl, arylamine, hydroxy, halo, nitro, oxo, optionally substituted phenyl, optionally substituted piperidine, dioxalane, trihaloalkyl, or trihaloalkoxy; or the aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group fused with the piperidine is further fused with an additional C 6 -C 10 cyclic or C 6 -C 10 heterocyclic group;
R 6 is hydrogen or C 1 -C 6 alkyl;
R 7 is C 1 -C 6 alkyl, amino, hydroxy, alkoxy, aminoalkyl, amidoalkyl, saturated or unsaturated cycloalkyl, or heterocycle; or
R 6 and R 7 combined, together with the carbon to which they are attached, form C 5 -C 8 aromatic or aliphatic cyclic group or heterocyclic group, optionally substituted with a group selected from alkyl, aminoalkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl or trihaloalkoxy; and
R 12 is hydrogen or C 1 -C 6 alkyl; and
salts thereof;
provided that the compound is not 5-isoxazoyl-Cha-Ile-spiro[indene-1,4′-piperidine], 5-isoxazoyl-Cha-Ile-spiro[indane-1,4′-piperidine], 5-isoxazoyl-Cha-Ile-spiro[octahydro-1H-indene-1,4′-piperidine] or 5-isoxazoyl-Cha-Ile-1,2,3,4-tetrahydroisoquinoline.

2. The method according to claim 1 wherein for compounds of the formula (I)
R 1 is hydrogen or —C(O)R 8 ; wherein
R 8 is a 5- or 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O, optionally substituted with one or more substituents selected from alkyl, alkoxy, amine, aminoalkyl, amidoalkyl, halo, hydroxy, trihaloalkyl, trihaloalkoxy or phenyl, wherein the phenyl group may be further optionally substituted with 1 to 3 substituents selected from alkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl, or trihaloalkoxy;
R 6 is hydrogen or C 1 -C 6 alkyl; and
R 7 is C 1 -C 6 alkyl, amino, hydroxy, alkoxy, aminoalkyl, amidoalkyl, saturated or unsaturated cycloalkyl, or heterocycle; and
salts thereof.

3. The method according to claim 1 , wherein the compound of formula (I) is represented by the formula (Ia):

wherein
R 11 is a 5- or 6-membered unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O, optionally substituted with one or more groups selected from alkyl, amino, or phenyl, wherein the phenyl group may be further optionally substituted with 1 to 3 substituents selected from alkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl or trihaloalkoxy;
R 4 is hydrogen, C 1 -C 6 alkyl, aminoalkyl or amidoalkyl;
R 5 is a benzyl group substituted with alkyl, aminoalkyl, alkoxy, C 4 -C 7 heterocycle, hydroxy, halo, nitro, dioxalane, trihaloalkyl or trihaloalkoxy; or
R 4 and R 5 combined, together with the nitrogen to which they are attached, form piperidine, optionally substituted with phenyl, benzyl, aminoalkyl, aminoaryl, amidoalkyl or a heterocycle, or piperidine is fused with an aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group; wherein the phenyl, benzyl, aminoaryl, heterocycle or fused aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group may be further substituted with 1 to 3 substituents selected from alkyl, alkylamine, alkylamide, alkylsulfonyl, alkoxy, aminoalkyl, aminoaryl, amidoalkyl, arylamine, hydroxy, halo, nitro, oxo, optionally substituted phenyl, optionally substituted piperidine, dioxalane, trihaloalkyl, or trihaloalkoxy; or the fused aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group is fused with an additional C 6 -C 10 cyclic or C 6 -C 10 heterocyclic group; and
salts thereof.

4. The method according to claim 1 , wherein the compound of formula (I) is represented by the formula (Ib):

wherein
R 4 is hydrogen, C 1 -C 6 alkyl, aminoalkyl or amidoalkyl;
R 5 is a benzyl group, optionally substituted with a group selected from alkyl, aminoalkyl, alkoxy, C 4 -C 7 heterocycle, hydroxy, halo, nitro, dioxalane, trihaloalkyl or trihaloalkoxy; or
R 4 and R 5 combined, together with the nitrogen to which they are attached, form piperidine, optionally substituted with phenyl, benzyl, aminoalkyl, aminoaryl, amidoalkyl or a heterocycle, or piperidine is fused with an aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group; wherein the phenyl, benzyl, heterocycle or fused aromatic or aliphatic C 3 -C 8 cyclic group or C 3 -C 8 heterocyclic group may be further substituted with 1 to 3 substituents selected from alkyl, alkylamine, alkylamide, alkyloxy, aminoalkyl, amidoalkyl, hydroxy, halo, nitro, dioxalane, trihaloalkyl, or trihaloalkyloxy; and
salts thereof.

5. A method according to claim 1 , wherein the compound of formula (I) is represented by the formula (Ic):

wherein
R a , R b and R c individually represent a group selected from hydrogen, alkyl, aminoal

Assignees

• Fairlie David
• Liu Ligong
• Yau Mei-Kwan
• Suen Jacky Yung
• Reid Robert
• Lohman Rink-Jan
• Iyer Abishek Venkatasubramanian
• Lim Junxian
• Brown Lindsay Charles
• Univ Queensland

Inventors

• Fairlie David
• Liu Ligong
• Yau Mei-Kwan
• Suen Jacky Yung
• Reid Robert
• Lohman Rink-Jan
• Iyer Abishek Venkatasubramanian
• Lim Junxian
• Brown Lindsay Charles

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title