Modulators of protease activated receptors

Patent metadata

Field	Value
Publication number	US-9701711-B2
Application number	US-201414519383-A
Country	US
Kind code	B2
Filing date	Oct 21, 2014
Priority date	Jul 28, 2010
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present application 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 modulating Protease Activated Receptor-2 (PAR2) and for treating a subject at risk of—or susceptible to—a disease or disorder, or having a disease or disorder associated with undesirable PAR2 activity.

First claim

What is claimed:

1. A method for the therapeutic treatment of a disease or disorder associated with undesirable PAR2 activity selected from arthritis, colitis and inflammatory bowel disease, pancreatitis, stroke, gastric ulcer, asthma, epilepsy, Alzheimer's disease, diabetes, irritable bowel syndrome and cancers of the stomach, colon, bowel, breast, liver or pancreas, comprising administering to a subject in need thereof a compound of the formula (I):

wherein
R 1 is —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;
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 5 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 a group selected from 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, 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;
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
a salt 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] or 5-isoxazoyl-Cha-Ile-spiro[octahydro-1H-indene-1,4′-piperidine].

2. The method according to claim 1 , wherein the compound 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 or phenyl, wherein the phenyl group is 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, optionally substituted with a group selected from 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 a group selected from phenyl, benzyl, aminoalkyl, amidoalkyl or a heterocycle; wherein
the phenyl, benzyl or heterocycle may be further substituted with 1 to 3 substituents selected from alkyl, alkyloxy, aminoalkyl, amidoalkyl, hydroxy, halo, nitro, dioxalane, trihaloalkyl, or trihaloalkoxy; or
a salt thereof.

3. The method according to claim 1 , wherein the compound 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, 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 a group selected from 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; or
a salt thereof.

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

wherein
R a , R b and R c are each independently hydrogen, alkyl, aminoalkyl, alkoxy, C 4 -C 7 heterocycle, hydroxy, halo, nitro, 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 a and R b or R b and R c combined form dioxalane; or
a salt thereof.

5. The method according to claim 1 , wherein the compound is represented by the formula (Id):

wherein
R d , R e and R f are each independently phenyl, benzyl, aminoalkyl, amidoalkyl, aminoaryl or a heterocycle, or R d and R e or R e and R f combined, form a fused 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, alkoxy, aminoalkyl, amidoalkyl, hydroxy, halo, nitro, dioxalane, trihaloalkyl, or trihaloalkoxy; or salts thereof.

6. The method according to claim 1 , wherein said compound is:
5-isoxazoyl-Cha-Ile-aminomethylphenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(2-methoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(3-methoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(4-methoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(2-methyl)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(2-ethoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(2-propoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethyl-(2-isopropoxy)phenyl;
5-isoxazoyl-Cha-Ile-aminomethy

Assignees

• Univ Queensland

Inventors

• Fairlie David Paul
• Liu Ligong
• Yau Mei Kwan
• Suen Jacky Yung
• Reid Robert

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title