Azaindole acetic acid derivatives and their use as prostaglandin d2 receptor modulators

Patent metadata

Field	Value
Publication number	US-2017022196-A1
Application number	US-201515125018-A
Country	US
Kind code	A1
Filing date	Mar 16, 2015
Priority date	Mar 17, 2014
Publication date	Jan 26, 2017
Grant date	—

Abstract

The present invention relates to azaindole acetic acid derivatives of formula (I),

wherein R 1 and R 2 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

1 . A compound of formula (I):

wherein
R 1 represents hydrogen, (C 1-4 )alkyl, (C 1-2 )fluoroalkyl, (C 1-4 )alkoxy, or halogen; and
R 2 represents hydrogen or methyl;
or a salt thereof.

2 . The compound according to claim 1 , wherein
R 1 represents hydrogen, methyl, trifluoromethyl, methoxy, or fluoro; or a salt thereof.

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

4 . The compound according to claim 1 , wherein
R 1 represents hydrogen, methyl, or methoxy; or a salt thereof.

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

6 . The compound according to claim 1 , wherein
R 2 represents methyl; or a salt thereof.

7 . The compound of formula (I) according to claim 1 , wherein the absolute configuration of the stereogenic center is a compound of formula (I St1 )

or a salt thereof.

8 . The compound according to claim 1 , wherein the compound is:
2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; 2-(8((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; or 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; or a salt thereof.

9 . The compound according to claim 1 , wherein the compound is:
(S)-2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; or (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid; or a salt thereof.

10 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, formulated as a medicament.

12 . A method for preventing and/or treating a disease comprising administering to a subject in need thereof the compound according to claim 1 , wherein the disease is chronic and acute allergic/immune diseases/disorders; eosinophil-related diseases; or basophil-related diseases.

13 . The method according to claim 12 , wherein the chronic and acute allergic/immune disease/disorder is asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease or rheumatoid arthritis.

14 . The method according to claim 12 , wherein the eosinophil-related disease is small vessel vasculitides or hypereosinophilic syndromes.

15 . The method according to claim 14 , wherein the small vessel vasculitide is Churg Strauss syndrome, Wegener's granulomatosis, or microscopic polyangiitis and organ-specific subsets thereof.

16 . The method according to claim 14 , wherein the hypereosinophilic syndrome is eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia or DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).

17 . The method according to claim 12 , wherein the basophil-related diseases is basophilic leukemia or basophilic leukocytosis.

Assignees

• Actelion Pharmaceuticals Ltd

Inventors

• Aissaoui Hamed
• Boss Christoph
• Bouis Patrick
• Hazemann Julien
• Siegrist Romain

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P7/00

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