Studies on antispasmodics. I. Synthesis and anticholinergic activity of 1-, 2-, and 3-diarylmethylenequinolizidine quaternary ammonium salts.

Abstract

As part of a search for new antispasmodic agents, we have synthesized 1-, 2-, and 3-diarylmethylenequinolizidine quaternary ammonium salts (4-15), which can be regarded as conformationally rigid derivatives of diphemanil methylsulfate (1) or timepidium bromide (2). The Grignard reaction of ethoxycarbonylquinolizidines (16, 21, and 30) with phenyllithium or 2-thienylmagnesiumbromide, followed by dehydration, afforded diarylmethylenequinolizidines (19, 20, 24, 25, 33, and 34). Quaternization of the 1-substituted derivatives (19 and 20) with methyl bromide afforded only the cis methobromides (4 and 6). On similar treatment, the 2-substituted derivatives (24 and 25) each afforded two isomeric methobromides, the trans (8a and 9a) and cis (8b and 9b), and the 3-substituted derivatives also afforded trans (12a and 13a) and cis methobromides (12b and 13b). The stereochemistry of these methobromides was confirmed by thermal isomerization experiments and the chemical shifts of N+-methyl signals in the 1H-and 13C-nuclear magnetic resonance spectra. The quaternary ammonium salts (4-15) exhibited more potent anticholinergic activity than 1 and 2, and the activities of several compounds (8, 9, and 13) were equal to or greater than that of atropine. The structure-activity relationships of these compounds are discussed.