Analgesic narcotic antagonists. I. 8β-Alkyl-, 8β-acyl-, and 8β-(tertiary alcohol)dihydrocodeinones and -dihydromorphinones

Article abstract of DOI:10.1021/jm00176a016

Conjugate addition of lithium dialkyl cuprates to codeinone (3) gave as the major product a series of 8β-alkyldihydrocodeinones 4a-m. A low yield of the 8α-isomer 6 was isolated in several cases. 8β-Acyldihydrocodeinones 10 were prepared by the addition of acyl carbanion equivalents (protected cyanohydrin method or lithium bis(α-ethoxyvinyl)cuprate) to 3 followed by hydrolysis. 8β-Acetyldihydrocodeine (12) was reacted with MeLi or n-BuLi to give tertiary alcohols 13, which were oxidized to target dihydrocodeinones 14. The 8β-substituted compounds with unsaturated (4c,f,m), branched (4d,g,i-k), or large straight-chain (4h,l) alkyl groups, as well as the acyl (10a-d) and tertiary alcohol (14a,b) derivatives, were less active than dihydrocodeinone (4n) in the mouse writhing and rat tail-flick analgesic assays. The analgesically active 8β-methyl (4a) and 8β-ethyl (4b) compounds were converted to N-(cyclopropylmethyl)- and N-(cyclobutylmethyl)dihydronorcodeinones (17 and 18) and -dihydronormorphinones (19 and 20). Some of these compounds had mixed agonist-antagonist profiles of action. One of these compounds, N-(cyclopropylmethyl)-8β-ethylidihydronorcodeinone (17b), has been selected for further study in man.