SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF A SERIES OF NEW 3-METHYL-1,4-DISUBSTITUTED-PIPERIDINE ANALGESICS

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-methyl-4-[N-2-fluorophenyl)methoxyacetamido] piperidine hydrochloride (40) (Anaquest, A-3331.HC1, 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. © 1990, American Chemical Society. All rights reserved.