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

Improved procedures have been developed for the synthesis of 2,4-diamino-6,7-dihydro-5H-pyrrolo3,4-d]pyrimidine ( 2a ), its 7-mcthyl derivative ( 2b ), and 6-(chloro-substituted phenyl) derivatives of 2,4-diamino-6,7-dihydro-5H-pyrrolo3,4-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.