Analgesic narcotic antagonists. 1. 8 beta-Alkyl-, 8 beta-acyl-, and 8 beta-(tertiary alcohol)dihydrocodeinones and -dihydromorphinones.
Conjugate addition of lithium dialkyl cuprates to codeinone (3) gave as the major product a series of 8 beta-alkyldihydrocodeinones 4a-m. A low yield of the 8 alpha-isomer 6 was isolated in several cases. 8 beta-Acyldihydrocodeinones 10 were prepared by the addition of acyl carbanion equivalents (protected cyanohydrin method or lithium bis(alpha-ethoxyvinyl)cuprate) to 3 followed by hydrolysis. 8 beta-Acetyldihydrocodeine (12) was reacted with MeLi or n-BuLi to give tertiary alcohols 13, which were oxidized to target dihydrocodeinones 14. The 8 beta-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 8 beta-methyl (4a) and 8 beta-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)-8 beta-ethyldihydronorcodeinone (17b), has been selected for further study in man.
D000085:Acetates / Q000037:antagonists & inhibitors; D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives*; D006853:Hydrocodone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004091:Hydromorphone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors; D009292:Narcotic Antagonists / Q000138:chemical synthesis*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D013329:Structure-Activity Relationship
D000085:Acetates; D000700:Analgesics; D009292:Narcotic Antagonists; D006853:Hydrocodone; D009020:Morphine; D004091:Hydromorphone; D003061:Codeine