Assuntos
Analgésicos , Morfinanos/farmacologia , Administração Oral , Analgésicos/efeitos adversos , Analgésicos Opioides , Animais , Haplorrinos , Humanos , Camundongos , Morfinanos/efeitos adversos , Morfina/farmacologia , Antagonistas de Entorpecentes , Ratos , Transtornos Relacionados ao Uso de Substâncias/etiologia , Fatores de TempoRESUMO
The preparation of a series of 7 alpha-alkylated dihydrocodeinones is described. N-(Cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 7 alpha-methyl (a series) or 7 alpha, 8 beta-dimethyl (b series) substituted dihydronorcodeinones (7) were prepared from the appropriately substituted N-(cycloalkylmethyl)-4-hydroxymorphinan-6-ones (5) by dibromination, 4,5-epoxy ring closure, and catalytic debromination. Treatment of 7 with BBr3 gave low yields of the corresponding 3-phenols 8. Alternatively, reaction of dihydrocodeinone (10) with dimethylformamide dimethyl acetal gave the 7-[(dimethylamino)methylene] adduct 11, which was hydrogenated to 7 alpha-methyl- (12) or 7 alpha-(hydroxymethyl)dihydrocodeinone (13). Treatment of 11 with lithium reagents, followed by hydrogenation, gave a mixture of 7 alpha-alkyl (15c-f) compounds and the corresponding 4,5-epoxy-cleaved products 16. Reaction of 11 with alpha-ethoxyvinyllithium gave intermediate 17, which on hydrolysis and hydrogenation yielded the 6,7-furyl (18) or pyrroyl (19) derivative. N-(Cycloalkylmethyl)-14-hydroxydihydronorcodeinones 23P,B reacted with dimethylformamide dimethyl acetal to give 25P,B, which were hydrogenated to the 7 alpha-methyl compounds 26P,B and O-demethylated to give 27P,B. The 7 alpha-methyl-N-methyl compounds were about equipotent with dihydrocodeinone. Derivatives with larger alkyl groups were less potent. Corresponding N-(cycloalkylmethyl) compounds did not show strong mixed agonist-narcotic antagonist activity.
Assuntos
Analgésicos/síntese química , Codeína/análogos & derivados , Hidrocodona/análogos & derivados , Antagonistas de Entorpecentes/síntese química , Animais , Fenômenos Químicos , Química , Hidrocodona/síntese química , Hidrocodona/farmacologia , Técnicas In Vitro , Camundongos , Ratos , Tempo de Reação/efeitos dos fármacosRESUMO
Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.
