Analgesic narcotic antagonists. 5. 7,7-Dimethyldihydrocodeinones and 7,7-dimethyldihydromorphinones.
Treatment of dihydrocodeinone (1a) or the 8 beta-methyl (1b) or 8 beta-ethyl (1c) analogues with formaldehyde-Ca(OH)2 in aqueous dioxane gave the corresponding 7,7-bis(hydroxymethyl)-6 beta-ols 2a-c. Ditosylation of 2, followed by LiEt3BH reduction, gave either the 7,7-dimethyl-6 beta-ol (6a) or 7 alpha-methyl-6 beta, 7 beta-oxetane compounds (5b,c). Compounds 5b and 5c were cleaved to 6b or 6c using LiAlH4-AlCl3. The configuration of the C6-alcohol group of 6a was confirmed by an oxidation-reduction sequence which gave the 7,7-dimethyl-5 alpha-ol 8a. Oxidation of 6 gave the C6-ketones 7a-c, which were converted to N-(cycloalkylmethyl) derivatives 11 and 12 and their corresponding 3-hydroxy compounds 14 and 15. The 3-methoxy-7,7-dimethyl-6-ones 7 were as active as dihydrocodeinone in agonist assays. One compound of this series, N-(cyclopropylmethyl)-7,7-dimethyldihydronorcodeinone (11a), was a potent mixed agonist-narcotic antagonist.
D000701:Analgesics, Opioid; D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives*; D006853:Hydrocodone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004091:Hydromorphone / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D051379:Mice; D009292:Narcotic Antagonists; D051381:Rats; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D006853:Hydrocodone; D004091:Hydromorphone; D003061:Codeine