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

In the past few years, our group has been involved in the development of A2A and A3 adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine, 61), potent and very selective at the A2A receptor subtype, and N8-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines-N5-urea or amide (MRE series, b), very selective at the human A3 adenosine receptor subtype. We now describe a large series of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N8-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines-N5-urea or -amide. The substitution of the furanyl moiety of compound 61,...