Stereochemical Studies on Medicinal Agents. 13. Correlation of the Solid-State Conformations of 1,3,5-Trimethyl- and 1,3-Dimethyl-4-phenyl-4-propionoxypiperidine Enantiomers with Their Absolute Stereoselectivity at Analgetic Receptors

Abstract

Optical antipodes of γ-1,3,5-trimethyl-4-phenyl-4-propionoxypiperidine (4) were prepared and the absolute configuration was determined by degradation to (R)-3-dimethylamino-2-methylpropiophenone. Analgetic testing in mice by the sc route indicated that the (+)-3S,5S isomer is equipotent with morphine and five times more potent than its (-) antipode. X-Ray studies of 4 · HCl indicate that the conformational features of the more active enantiomers of 4· HCl and α- and β-prodine HCl are very similar. It is suggested that the methyl groups adjacent to the C-4 center in the more active enantiomers of 4 and the prodines induce a preferred, chiral arrangement of the phenyl and OCO groups which allow more facile association with analgetic receptors. © 1973, American Chemical Society. All rights reserved.