Conformationally Restricted Fentanyl Analogs

Synthesis, analgesic activity and preliminary molecular modeling studies of the cisand trans-fused octahydro-l,2,3,4,4a,5,11,1 la-pyrido[3,4-c][1,5]benzoxazepines 8 and 9, the first rigid fentanyl analogs with a conformationally restricted 4-anilido group that retain antinociceptive properties, are reported. Fentanyl (1) is the prototype of the highly potent 4-anilidopiperidine class of synthetic opioid analgesics. Although 1 lacks any obvious structural relationship to morphine, it is a significantly more potent analgesic 1, with specific affinity for the ~ opioid receptor. O ,JLcH2CH3 R' PhCH2CH2-N N. R N / " ' ~ l q 1 2 Attempts to define the bioactive conformation of 4-anilidopiperidines by synthesizing rigid analogs have generally been unsuccessful. 2 A noteworthy exception is a tropane derivative of fentanyl synthesized by Riley and Bagley 3 which retained high analgesic potency, suggesting that the piperidine ring adopts the chair form in • 4 the bioactive conformation of 4-anilidopiperidines. However, all attempts to tie back the prop~onyl group or the anilido phenyl ring 5 of 4-anilidopiperidines produced inactive compounds. Therefore, little remained known about the conformational requirements of the 4-propionanilido group for biological activity. In this paper, we report on the novel octahydro-l,2,3,4,4a,5,11,1 la-pyrido-[3,4-c][1,5]benzoxazepine ring system 2 in which the C-9a to C-1 la linkage effectively tethers the ortho position of the anilido phenyl ring to the C-3 position of the piperidine ring. We report the synthesis, analgesic activity and preliminary molecular modeling studies of both cisand trans-fused octahydro-l,2,3,4,4a,5,11,11a-pyrido[3,4-c][l,5]benzoxazepines 8 and 9, the first rigid 1177 1178 L.V. KUDZMA et al.