Synthesis of antifols related to 2,4‐diamino‐6,7‐dihydro‐5H‐pyrrolo[3,4‐d] pyrimidine. Enhancement of antiparasitic selectivity by nitrogen‐linked mono‐ and dichlorobenzoyl groups or the 3,4–dichlorophenylthiocarbamoyl group

Abstract

AbstractImproved procedures have been developed for the synthesis of 2,4‐diamino‐6,7‐dihydro‐5H‐pyrrolo[3,4‐d]pyrimidine (2a), its 7‐mcthyl derivative (2b), and 6‐(chloro‐substituted phenyl) derivatives of 2,4‐diamino‐6,7‐dihydro‐5H‐pyrrolo[3,4‐d]pyritnidine (4). Direct acylation of compounds 2a or 2b with acid chlorides or mixed anhydrides derived from chloro‐substituted benzoic or cinnamic acids gave 6‐(chloro‐substituted benzoyl or cinnamoyl) derivatives. Lithium aluminum hydride reduction of 6‐(chloro‐substituted benzoyl) derivatives under controlled conditions permitted preparation of 6‐(chloro‐substituted benzyl) derivatives (3). Compound 2a also reacted with aryl isothiocyanates to yield 6‐arylthiocarbamoyl derivatives. Antimalarial assays for in vivo activity against murine malaria (P. berghei) and avian malaria (P. gallinaceum) revealed that a somewhat enhanced in vivo antiparasitic effect above that of parent compound 2a without any evident increase in host toxicity was conferred by introduction of certain of the 6‐chloro‐substituted benzoyl groups or the 6‐(3,4‐dichlorophenylthiocarbamoyl) group. Corresponding 6‐(chloro‐substituted benzyl) derivatives more frequently displayed host toxicity.