Synthesis and antifungal properties of certain 7 alkylaminopyrazolo[1,5 a]pyrimidines

Article abstract of DOI:10.1021/jm00212a021

A series of 7-alkylaminopyrazolo[1,5-α]pyrimidines (5-25) and one 7-alkylthiopyrazolo[1,5-α]pyrimidine (4) were synthesized from the corresponding 7-chloro precursors 3, which were prepared in turn from the 7-hydroxy analogues 2, obtained via condensation of 3-aminopyrazoles with acetoacetate esters, malonate esters, or acetylenedicarboxylate ester. Compounds 4-25 were found to inhibit Trichophyton mentagrophytes (in vitro). The degree of inhibition increased with increasing 7-alkylamino chain length up to C₈ units and then began to decrease with longer chain lengths. Unsaturated chains were more fungitoxic than saturated chains, 5-methyl-7-oleylaminopyrazolo[1,5-α]pyrimidine [22, R⁷ = NH(CH₂)₈ CH=CH(CH₂)₇CH₃] being 4 times more inhibitory and 16 times more fungicidal (against T. mentagrophytes) than 5-methyl-7-n octylaminopyrazolo[1,5-α]pyrimidine [11,R⁷=NH(CH₂)₇CH₃]. Although 11 and 22 appeared to have some efficacy as topical antifungal agents, when applied to T. mentagrophytes infections in vivo, both caused irritation (of abraded and unabraded guinea pig skin) as did compound 4 (R⁵=Me; R⁷=SC₈H₁₇).