Design, synthesis, and biological evaluation of C-9- and C-2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines as new A(2A) and A(3) adenosine receptors antagonists

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines such as I are prepd. as selective adenosine A2a and A3 receptor antagonists. Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines substituted at the 9-position retain receptor affinity but lose selectivity for the adenosine A2a and A3 receptors over other adenosine receptors. Replacement of the furan moiety present in the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine with a Ph or a substituted arom. ring abolishes affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface; replacement of the furan ring with an ortho-ethoxy-substituted arom. ring did not enhance affinity. Introduction of a N-methylpiperazinomethyl or morpholinomethyl function at the 5' position of the furanyl ring of I or introduction of a methylsulfanyl moiety at the 9-position of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines yields inhibitors with improved water solubilities but reduced affinities for adenosine A2a and A3 receptors.