4-Anilidopiperidine analgesics. 3. 1-Substituted 4-(propananilido)perhydroazepines as ring-expanded analogs

Abstract

A study of ring-expanded analog of the 4-(propananilido)piperidine analgesics was undertaken to evaluate the influence of the structural modification on both analgesic activity and physical-dependence capacity. A series of 1-substituted 4-(propananilido)perhydroazepine derivatives was synthesized and pharmacologically evaluated in mice for analgesic activity and physical-dependence capacity. The ring-expanded analogs of the 4-(propananilido)piperidines retain a relatively high degree of analgesic potency, except in the case of the 1-phenylethylated analog which is .apprx. 150-fold less potent than the correspondingly 1-substituted piperidine analgesic. Evaluation of physical-dependence capacity of the most potent 1-substituted 4-(propananilido)perhydroazepines reveals no significant difference for the compounds as compared with morphine. The 4-(propananilido)perhydroazepines having 1-substitutents in common with known opiate antagonists failed to exhibit antagonism of morphine analgesia.