Analgesic activity of the epimeric tropane analogs of meperidine. Physical and pharmacological study

Abstract

Condensation of cis-N-benzyl-2,5-bis(chloromethyl)pyrrolidine and phenylacetonitrile afforded a mixture of epimers 7 and 8 [8-benzyl-3.xi.-phenyl-1.alpha.H, 5.alpha.H-nortropane-3.xi.-carbonitrile], one of which was readily converted to the meperidine analog 1 [ethyl 3.alpha.-phenyl-1.alpha.H,5.alpha.H-tropane-3.beta.-carboxylate] prepared earlier by Bell and Archer; the other was converted to a new tropane analog of meperidine, compound 3 [ethyl 3.beta.-phenyl-1.alpha.H,5.alpha.H-tropane-3.alpha.-carboxylate]. The ED50 of 1 and 3 in the D''Amour-Smith [mouse] "tail flick" test for narcotic type analgesia, which differs by a factor of only 3 or 4 in potency, supports the accumulated data that suggest that the analgesic activity of the meperidine type is not very sensitive to the conformation of the phenyl group in 4-phenylpiperidines. A proton and 13C NMR comparison of 1 and 3, as well as a reevaluation of the conformational requirements of other compounds of the same series, leads to the conclusion that the differences in conformation are due to the varying degrees of flattening of the piperidine ring. The 1H NMR and 13C NMR data are not consistent with the boat conformation suggested earlier.