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

Benzamides characterized by one or more 2,2,2-trifluoroethoxy ring substituents and a heterocyclic amide side chain have been 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 are active. Considerable variation in the heterocyclic ring is permissible, but antiarrhythmic activity is strongly influenced by the basicity of the amine nitrogen and the nature of the link between heterocycle and amide nitrogen. One of these compounds, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide acetate (flecainide acetate, USAN), was studied extensively in animals and selected for clinical trial as an antiarrhythmic.