Functionalized aminotriazines

Abstract

The present invention relates to novel antagonists of the A2B adenosine receptor and pharmaceutical compositions comprising said antagonists as well as their uses for the treatment and prevention of disorders known to be susceptible to improvement by antagonism of the A2B receptor such as asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, vascular diseases, allergic diseases, hypertension, retinopathy, diabetes mellitus, inflammatory gastrointestinal tract disorders, inflammatory diseases, autoimmune diseases, renal diseases, neurological disorders and, in particular, cancers. In particular, the present invention relates to compounds of formula (I), wherein R1 represents 1 to 3 identical or different R1 substituents, wherein said R1 is independently at each occurrence selected from hydrogen, halogen, C1-C8alkyl, C1- C8haloalkyl, C1-C8alkoxy, C1-C8hydroxyalkyl and C1-C8alkoxyalkyl; Ra is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, thiodiazolyl, oxazolyl, pyrazolyl and triazolyl wherein said phenyl, pyridinyl, thiazolyl, thiodiazolyl, oxazolyl, pyrazolyl and triazolyl is independently optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cycloalkyl, C1-C4alkyl-substituted cycloalkyl, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8alkylaminocarbonyl, C1-C8hydroxyalkyl, C1- C8dialkylaminoC1-C8alkyl, C1-C8aminoalkyl and a heterocycle selected from oxiran, oxetane, aziridine and azetidine wherein said oxiran, oxetane, aziridine and azetidine are independently optionally substituted by halogen, hydroxyl, C1-C4alkyl, C1-C2haloalkyl, C1-C2alkoxy; or Ra is -CONHR' wherein R' is selected from C1-C8alkyl, cycloalkyl, aryl, heteroaryl and C1-C8alkyl-N-morpholino, wherein said aryl, heteroaryl and C1-C8alkyl-N-morpholino is independently optionally substituted by [one or more] substituents selected from halogen, cycloalkyl, C1-C8alkyl, C1-C8alkoxy, C1-C8hydroxalkyl and C1-C8alkoxyalkyl; Ar / Het is selected from pyridinyl, phenyl and oxazolyl wherein said pyridinyl, phenyl and oxazolyl is independently optionally substituted by one or more substituents independently selected from halogen, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl and C1-C8 alkoxyalkyl; or pharmaceutically acceptable salt, or hydrate thereof.

Description

[0001] The present invention relates to novel A2B adenosine receptor antagonists and pharmaceutical compositions comprising said antagonists, and their use for the treatment and prevention of disorders known to be amenable to amelioration by antagonism of A2B receptors, said disorders being Such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, vascular disease, allergic disease, hypertension, retinopathy, diabetes, inflammatory gastrointestinal disorder, inflammatory disease, autoimmune disease, renal disease, neurological disorder and especially cancer. Background technique [0002] Listing or discussion of apparently prior published documents in this specification [0003] It should not necessarily be taken as an admission that this document is part of the prior art or is common general knowledge. [0004] Adenosine is an endogenous regulator of many physiological responses, including vasodilation, pain and inflammation. Adenosine receptors belo...

Images