Analgesic narcotic antagonists. 15. Potent narcotic agonist 7 beta-(arylalkyl)-4,5 alpha-epoxymorphinans.

Structure-activity correlations in 7 beta-(arylalkyl)-3-methoxy- or hydroxy-4,5 alpha-epoxymorphinans have been investigated. 6 beta-Hydroxy-7 alpha-hydroxymethyl compounds 7 with 7 beta-substituents CH2CH2R [a, R = H; b, R = CH2CH3; c, R = C6H5; d, R = CH2C6H5; f, R = CH2CH2C6H5; g, R = (CH2)3C6H5; h, R = (CH2)4C6H5] were prepared. Wittig condensations with previously reported 4,5 alpha-epoxy-7 beta-formyl-7 alpha-(hydroxymethyl)-6 beta, 7 alpha-O-isopropylidene-3-methoxy-17-methylmorphinan-6 beta-ol (3), followed by dilute acid removal of the blocking group and then hydrogenation, gave saturated compounds 7. Compounds with a 6 alpha, 7 alpha-oxymethylene ring. 18c,d,f,g, were prepared from 7 beta-formyl derivative 16 and the appropriate Wittig reagent, followed by hydrogenation. Both the 6 beta-hydroxy-7 alpha-hydroxymethyl and 6 alpha, 7 alpha-oxymethylene series containing 7 beta-arylalkyl groups with an alkyl chain length of 2 to 4 ar potent narcotic agonists. The most potent 17-methyl compound, 4,5 alpha-epoxy-7 alpha-(hydroxymethyl)-17-methyl-17 beta-(4-phenylbutyl)morphinan-3,6 beta-diol (8f) was 700 times more potent than morphine in the acetic acid induced mouse writhing assay. 17-Methyl compounds in the c, d, f, g series were converted to 17-cyclopropylmethyl (P series) or 17-cyclobutylmethyl (B series) derivatives. Narcotic antagonistic activity could not be demonstrated for these potent agonist 17-cycloalkylmethyl derivatives. These pharmacological results parallel those previously reported for tertiary alcohol derivatives of the endo-ethenotetrahydrooripavines. Structureal considerations confirm the existence of a lipophilic site extending upward and outward from where the C ring of morphine and congeners bind to opiate receptors.

Analgesic narcotic antagonists. 8. 7 alpha-Alkyl-4,5 alpha-epoxymorphinan-6-ones.

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.

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.

Analgesic narcotic antagonists. 4. 7-Methyl-N-(cycloalkylmethyl)-3-hydroxymorphinan-6-ones and -isomorphinan-6-ones.

3,6-Dimethoxy-7 beta, 17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinan (2) was converted to the 4-deoxy compound 4 and hydrolyzed to a mixture of the B/C-cis (C series) and B/C-trans (T series) isomers of 7,8-didehydromorphinan-6-one, 5. Hydrogenation of the separated isomers gave 7-methyl-6-oxo derivatives 6a. 7,8-Dimethyl-(6b) or 7-methyl-8-ethylmorphinan-6-one (6c) was prepared by reaction of 5 with lithium organocuprates. The analgesic N-methyl compounds 6 were converted to 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 10--13. Some of these compounds had mixed profiles of narcotic agonist-antagonist effects. Studies with drug-dependent monkeys indicated that several of these compounds with an analgesic-antagonist ratio of less than 0.4 substitute for morphine.

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.