SYNTHESIS,ANALGESIC ACTIVITY AND STUCTUREACTIVITY RELATIONSHIP OF 4-N-PROPIONYL ANALOGS OF CIS-3-METHYL FENTANYL

The synthesis of some 4-N-propionyl analogs of cis-3-methylfentanyl by acyl chloride method, anhydride method, mixed anhydride method and DCCmethod is reported. The ethyl group in 4-N-propionyl portion of cis-3-methylfentanyl was substituted by some groups with different electronic property. In mouse hotplate test. all compounds showed typical morphine-like action with analgesic potency cor-responding to 49～1963 times that of morphine. Compound 3 was found to exhibit higheranalgesic activity than cis-3-methyl fentanyl. Semiempirical INDO calculationshave been undertaken for 4 typical compounds and it was found that as a result of in-troduction of chlorovinyl, compound 3 exhibited characteristics of electronic structuredifferent from that of cis-3-methyl fentanyl. The relationships between analgesic activityand the electronic structure of these compounds were discussed.