The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.
Evolution of the 4-Anilidopiperidine Class of Opioid Analgesics -(80 refs.). -(BAGLEY, J. R.; KUDZMA, L. V.; LALINDE, N. L.; COLAPRET, J. A.; HUANG, B.-S.; LIN, B.-S.; JERUSSI, T. P.; BENVENGA, M. J.; DOORLEY, B. M.; OSSIPOV, M. H.; SPAULDING, T. C.; SPENCER, H. K.; Med. Res. Rev. 11 (1991) 4, 403-436; Dep. Chem. Dep. Pharm.,
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