Synthesis and Structural, Conformational, and Pharmacological Study of Some Esters Derived from 3-Phenethyl- 3-azabicyclo[3.2.1]octan-8-/3-ol and the Corresponding M-Endo-methyl Quaternary Derivatives

Abstract

A series of 8-/3-acyloxy-3-phenethyl-3-azabicyclo[3.2.1 ] octane and its W-endo methiodides were synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 8-ß-p- chlorobenzoyloxy-3-phenethyl-3-azabicyclo[3.2.1 Joctane methiodide (2c) was determined by X-ray diffraction. In CDCI3 solution, 1b-1e display the same preferred conformation. The cyclopentane and piperi- dine rings adopt an envelope conformation flattened at C-8 and a distorted chair conformation puckered at C-8 and flattened at N-3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. In all cases, methylation takes place from the endo position. The ability of the title compounds to antagonize the acetylcho- line-induced contraction of guinea pig ileum is also reported. An initial structure-activity relationship is proposed.