Substituted fused pyrimidine compounds.

Abstract

Fused pyrimidine derivs., such as I [R1 = alkyl, alkenyl, hydroxyalkyl, etc.; R2 = H, CN, halogen, alkyl, haloalkyl, aryl, arylalkyl,etc.; R7 = H, alkyl, alkenyl, aryl, etc.; R8 = X-A-B, where X = arylene or heteroarylene, A = bond, alkylene, alkenylene, alkynylene, heteroalkylene, etc. and B = H, heterocyclyl, cycloalkyl, heteroaryl, acyl, amino, acylamino, etc.; Y = N, CR9 where R9 = H, OH, alkoxy, alkyl, aryl, etc.], were prepd. for therapeutic use in pharmaceutical compns. contg. them and methods of treating conditions and diseases that are mediated by adenosine receptor activity. This invention also provided tautomers, polymorphs, stereoisomers, prodrugs, solvates, and pharmaceutically acceptable salts of these fused pyrimidines. These compds. were claimed for use in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by antagonism of the adenosine receptor, such as asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation, reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinal tract disorders, autoimmune diseases, Parkinson's disease, Alzheimer's disease, restless leg syndrome, nocturnal myoclonus, cerebral ischemia, Huntington's disease, Wilson's disease, multiple system atrophy and/or corticobasal degeneration. These fused pyrimidines may be used in combination with one or more therapeutically active agents, such as an anti-inflammatory agent, antidiabetic agent, antihypertensive agent or anti-dyslipidemia agent. These fused pyrimidines, their tautomers, polymorphs, stereoisomers, prodrugs, solvate or a pharmaceutically acceptable salts thereof, which are adenosine A2A and A2B antagonist, or adenosine A1 and A2B antagonist, or Al, A2A and A2B antagonist thereby provide dual or pan antagonistic activity through additive or/and synergistic effect. Thus, 8-(1-benzyl-1H-pyrazol-4-yl)-1-propyl-1,4,5,7-tetrahydropurin-6-one II (R = CH2Ph) was prepd. via the disclosed method starting from 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione and 1-benzyl-1H-pyrazole-4-carboxylic acid. The prepd. fused pyrimidines were evaluated for binding activity for human adenosine A1, A2A, A2B and A3 receptors. [on SciFinder(R)]