Heterocyclic analogues of benzamide antiarrhythmic agents

A series of heterocyclic N-[(diethylamino)alkyl]arenamides related to acecainide was prepared and examined for antiarrhythmic activity. The compounds were synthesized from the corresponding known heterocyclic carboxylic acids or esters by using standard amide formation methods. The effects of the compounds on the electrophysiological properties of canine Purkinje fibers and ventricular muscle strips were determined. Most of the compounds showed effects consistent with weak class I activity. Two compounds, N-[2-(diethylamino)ethyl]-3,4,5-trimethyl-1H-pyrrole-2-carboxamide and N-[2-(diethylamino)ethyl]-1H-indole-2-carboxamide, displayed prolongation of the action potential duration and functional refractory period indicative of modest class III electrophysiological activity. Representative compounds were examined by using molecular modeling techniques. Compounds of differing activity classes displayed qualitatively different electrostatic potential maps.