Piperidines
Still further simplification of the structural requirements for central analgesic activity came from the serendipitous observation that the simple phenyl pi peri dine, meperidine
(34), shows biological activity almost indistinguishable from that of morphine. Further elaboration of that molecule led to one of the most potent opioid analgesics, fentanyl
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In-depth investigation of the structure activity relationships in the fentanyl meperidine series in the Janssen laboratories revealed that additional substitution of the amide nitrogen-bearing center resulted in still further enhancement of analgesic potency. Several compounds were obtained as a result of this work, which showed analgesic activity in animal models at doses some five decade orders of magnitude lower than morphine; the biological profile of these agents is, however, almost identical to that of the classical opioids.
Reaction of the carbonyl group of pi peri done j36 with cyanide and aniline leads to formation of a cyanohydrin-like function known as an a-aminonitrile (37); hydrolysis under strongly acidic conditions gives the corresponding amide 38. (Although aminonitriles are somewhat labile, particularly under basic conditions, the corresponding aminoamide is a quite stable function.) The benzyl amine protecting group is then removed by catalytic hydrogenation (39). Alkylation with 2-phenethyl bromide proceeds on the more nucleophilic aliphatic amine to afford jW. Ethanolysis of the amide function leads to the corresponding ester, 41. Acylation of the remaining secondary amine function with propionyl chloride affords carfentanyl (42).6 The same sequence starting with the corresponding 3-methylpi peri done (43)7 affords lofentanyl (44).
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Alkylation of intermediate with 2-(2-bromo-
ethyl)thiophene affords the corresponding thiophene-containing compound 4J5. Ethanolysis then leads to ethyl ester (46). Reduction of the carbonyl function affords the carbinol J7. Alkylation of the alkoxide obtained from the alcohol with methyl iodide gives the methyl ether 4^. Acylation with propionyl chloride leads to the very potent opioid analgesic sulfentanyl (49).^ In the absence of a specific reference, one may speculate that alkylation of heterocycle 50^ with l-bromo-2chloroethane would give the chloroethyl derivative 51. Use of this for alkylation of 39 would give the heterocycle substituted intermediate 52. A similar scheme via structures JW, 53a, and j>4_ would then afford alfentanil (55).
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