4-Anilidopiperidine analgesics. 2. A study of the conformational aspects of the analgesic activity of the 4-anilidopiperidines utilizing isomeric N-substituted 3-(propananilido)nortropane analogs

Abstract

Relatively little information is available concerning the influence of conformational factors on the potent analgesic actions of the 4-anilidopiperidines. A series of N-substituted 3 alpha- and 3 beta-(propananilido)nortropanes have been designed, synthesized, and stereochemically characterized as semirigid analogues of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. Conformational analysis of 3 alpha-propananilides (4) reveals a boat conformation for the preferred conformation of the piperidine ring of these tropane analogues. Evaluation of the analgesic potencies of the isomeric N-substituted 3-(propananilido)nortropanes of this study indicates greater potency for the 3 beta-(propananilido) isomers (5) with N-benzyl and N-phenethyl substitution as compared to the corresponding N-substituted 3 alpha-propananilides. Analysis of relative solubility differences among these isomers suggests that both structural and stereochemical influences predominate in affecting analgesic potency.