Conformationally restrained, chiral (phenylisopropyl)amino-substituted pyrazolo[3,4-d]pyrimidines and purines with selectivity for adenosine A1 and A2 receptors

Article abstract of DOI:10.1021/jm00095a024

Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)- 2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-propoxy-3H-imidazo[1,2-c]pyrazolo- [4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A₂ and A₁ adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl- 3,7-diphenyl-5-propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A₁ receptors, and were nonselective.