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

Condensation of cis-N-benzyl-2,5-bis(chloromethyl)pyrrolidine (6) and phenylacetonitrile afforded a mixture of epimers 7 and 8. Compound 8 was readily converted to the meperidine analog 1 prepared earlier by Bell and Archer. Compound 7 was converted to a new tropane analog of meperidine, compound 3. The ED50 of 1 and 3 in the D'Amour-Smith "tail flick" test for narcotic type analgesia, which differs by a factor of only 3 or 4 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 magnetic resonance spectral comparison of 1 and 3, as well as a reevaluation of the conformational requirements of 17-19, leads to the conclusion that the differences in conformation of 1,3,17, and 18 are due to the varying degrees of flattening of piperidine ring. The 1H NMR and 13C NMR data are not consistent with the boat conformation suggested earlier for compound 17.