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

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Abstract
As part of a search for new antispasmodic agents 1-, 2- and 3-diarylmethylenequinolizidine quaternary ammonium salts (4-15) were synthesized which can be regarded as conformationally rigid derivatives of diphemanil methylsulfate (1) or timepidium bromide (2). The Grignard reaction of ethoxycarbonylquinolizidines with phenyllithium or 2-thienylmagnesiumbromide, followed by dehydration, afforded diarylmethylenequinolizidines. Quaternization of the 1-substituted derivatives with methyl bromide afforded only the cis-methobromides. On similar treatment the 2-substituted derivatives each afforded 2 isomeric methobromides, the trans and cis and the 3-substituted derivatives afforded trans and cis methobromides. The stereochemistry of the methobromides was confirmed by thermal isomerization experiments and the chemical shifts of N+-methyl signals in the 1H- and 13C-NMR spectra. The quaternary ammonium salts (4-15) showed more potent anticholinergic activity [isolated guinea pig ileum] than 1 and 2, and the activities of several compounds were equal to or greater than that of atropine. The structure-activity relationships of these compounds are discussed.