Dialkyl bicyclic heterocycles with a bridgehead nitrogen as purine analogs possessing significant cardiac inotropic activity

Article abstract of DOI:10.1002/jhet.5570200345

A number of 5,7-dialkyl-s-triazolo[1,5-a]pyrimidines and 5,7-dialkylpyrazolo[1,5-a]pyrimidines and related heterocycles containing a bridgehead nitrogen have been prepared and studied as cardiovascular agents in the anesthetized dog. A number of these compounds have exhibited significant inotropic activity with little effct on heart rate. Especially active were 5,7-dialkyl-2-amino or 2-alkylthio-2-triazolo[1,5-a]pyrimidines. In contrast, highly polar purine analogs in these ring systems compounds such as 5,7-di-n-propyl-2-benzylthio-1,3,4-thiadiazolo[3,2-a]pyrimidine bromide 45 containing a charge on the bridgehead nitrogen, were inactive. The detailed structure activity relationship of the dialkyl derivatives of related ring systems are discussed. The presence of certain ring nitrogen atoms are vital to potent in vivo activity, presumably due to specific enzyme binding at these sites. Several of the compounds studied, showed oral activity and are excellent candidates for further evaluation in man.