Synthesis and structural, conformational and pharmacological study of some esters derived from 3-β-hydroxytropan-3-α-carboxylic acid

Abstract

A series of 3-β-hydroxy-3-α-alkoxycarbonyl tropanes has been synthesized and studied by IR, 1H and 13C NMR spectroscopy, and the crystal structure of ethyl-3-β-hydroxytropan-3-α-carboxylate ( VIb) and phenethyl-3-β-hydroxytropan-3-α-carboxylate ( VIc) have been determined by X-ray diffraction. The compounds studied display in chloroform- d the same preferred conformation. The pyrrolidine and piperidine rings adopt a flattened N8 envelope and a distorted chair conformation puckered at N8 and strongly flattened at C3, respectively, with the N-methyl and hydroxy groups in equatorial and pseudo-equatorial positions and the ester group in a pseudo-axial arrangement with respect to the piperidine ring. An intramolecular interaction between the hydroxy group and the nitrogen atom is proposed. However in CD 3OD solution the intramolecular hydrogen bond is broken and the hydroxy and ester groups adopt a different relative disposition, more sterically favourable, decreasing the flattening of the piperidine ring. With regard to the tropane skeleton, these results are in close agreement with those found for compounds VIb and VIc in the crystalline state. The inhibitory effect of the title compounds on 3H-GABA binding to a synaptosomal brain membranes is also reported.