Analgesics of the orvinol type. 19-Deoxy and 6,20-epoxy derivatives

A series of new ethenotetrahydrooripavine derivatives has been prepared in which the C-19 hydroxyl group has been replaced by hydrogen. The syntheses proceed via the thioanisole adducts of the thevinones. These adducts are converted to 1,2-epoxides, which are rearranged to aldehydes and then reduced to primary alcohols. Further conversion of these alcohols result in the deoxy derivatives and the 6,20-epoxy analogues, which contain a fused tetrahydrofuran ring. The compounds in this series, some of which offer the possibility of strong hydrogen-bonding interactions and others of which contain sterically fixed lipophilic side chains, have been evaluated as analgesics by the rat tail-flick method. Based on these and previous results, a proposal is made for the interaction of the orvinols with the opiate receptor involving both lipophilic (L) and hydrophilic (H) subsites. This proposal can be extended to suggest an optimum conformation for the enkephalins.