Synthesis, stereochemistry, and antiarrhythmic activity of some 8 substituted decahydroisoquinolines

Article abstract of DOI:10.1021/jm00257a002

The diastereoisomeric series of 8 substituted 2 methyldecahydroisoquinolines has been synthesized and evaluated as antiarrhythmic agents. Substituted benzoyloxy and benzamido derivatives were found to yield compounds with therapeutic indices considerably higher than that of quinidine. Optimal values were obtained with compounds possessing lipophilic substitutions, most notably the 3,4 dichlorobenzamido grouping. The previous observation of some correlation of trans ring junction stereochemistry with optimal potency was further substantiated by examples in this study. The coumpounds prepared were much less toxic than quinidine. A tetrahydroisoquinoline benzamide derivative was equivalent to quinidine but much less effective as an antiarrhythmic than its decahydro analogs, a finding compatible with earlier studies. Support is provided for the Topliss concept for maximizing activity within a series of compounds where the aromatic moiety is a necessary grouping.