Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N-(piperidylalkyl)trifluoroethoxybenzamides

Abstract

Benzamides characterized by 1 or more 2,2,2-trifluoroethoxy ring substituents and a heterocyclic amide side chain were prepared and evaluated for oral antiarrhythmic activity in mice. The most potent compounds are derived from 2,5-bis(2,2,2-trifluoroethoxy)benzamide, and, within this group, both tertiary as well as secondary benzamides were active. Consdierable variation in the heterocyclic ring is permissible, but antiarrhythmic activity is strongly influenced by the basicity of the amine N and the nature of the link between heterocycle and amide nitrogen. The compound, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide acetate (flecainide acetate, USAN), was studied extensively in animals and selected for clinical [human] trial as an antiarrhythmic.