Studies on antispasmodics. V. Synthesis and anticholinergic activity of N-alkyl 1- and 2-diarylmethylene-indolizidinium bromides.

Abstract

In a search for new antispasmodics, we have synthesized N-alkyl 2- and 1-diarylmethyleneindolizidinium bromides (6-13), which can be regarded as conformationally rigid derivatives of prifinium bromide (14) or the basic compound (15) of the pyrrolidine antispasmodics. Condensation of ethoxycarbonylindolizidines (20 and 26) with phenyllithium or 2-thienylmagnesium bromide, followed by dehydration, afforded diarylmethyleneindolizidines (23, 24, 29 and 30). Quaternization of the 2-substituted derivatives (23 and 24) with methyl bromide afforded two isomeric methobromides, the trans-(6a and 7a) and the cis-methobromides (6b and 7b), while the 1-substituted derivatives (29 and 30) afforded only the cis-methobromides (10 and 11). The stereochemistries of these methobromides were confirmed by the chemical shifts of the N+-methyl signals in the 1H- and 13C-NMR spectra. The stereochemistries of 2- and 1-diarylhydroxymethylindolizidines (21, 22, 27 and 28) were also determined from the IR spectra and by X-ray analysis. The quaternary ammonium salts (6-13) exhibited anticholinergic activity more potent than that of 15, and the activities of several compounds were equal to that of 14. The structure-activity relationships of these compounds are discussed.