Synthesis and Analgesic Activity of 3,3-Dialkyl-Substituted Drotaverine Analogs

Abstract

Ritter reactions of 3,4-(R1)2-benzylcyanides with 1,1-(R2)2-2-[3,4-(R3)2-phenyl]ethanols synthesized 1-[3,4-(R1)2-benzyl]-3,3-(R2)2-6,7-(R3)2-3,4-dihydroisoquinolines (R1 = H, MeO, EtO; R2 = Alk; R3 = MeO, EtO). The obtained isoquinolines can be considered 3,3-dialkyl-substituted analogs of drotaverine. Aseries of benzo[f]isoquinolines were similarly prepared. Hydrochlorides of all isoquinolines were tested for analgesic activity. Ten of thirteen compounds were active in the hot-plate test. Four of them exhibited an analgesic effect in the acetic-acid-induced writhing test. The most active isoquinoline had R1 = MeO, R2 = Et, and R3 = EtO and inhibited acetic-acid-induced cramps by 71.01%. An analysis of the structure—activity relationship study showed that the analgesic effect was not related to variation of the R1 radical but was typical of structures with an ethoxy group on the isoquinoline ring. The effect increased upon substitution of ethyl for methyl groups (R2 radical) in the isoquinoline 3-position.