Morphinan-6-ones

Naltrexone hydrochloride dihydrate (l-7V-cyclopropylmethyl-7,8-dihydro-14-hydroxy-morphinan-6-one hydrochloride) [16676-29-2] M 413.9, m 274-276°, [a] -173° (c 1, H2O), pKEst(i) 6 (N-cyclopropylmethyl), pKEst(i) (phenolic OH). This narcotic antagonist has been purified by recrystn from MeOH and dried air. The free base has m 168-170° after recrystn from Me2CO. [Cone et al. J Pharm Sci 64 618 7975 Gold et al. Med Res Rev 2 211 7952.]... 

Chemical Name 17-allyl-4,5a -epoxv-3,14-dihydroxv-morphinan-6-one Common Name N-allylnoroxymorphone N-allvl-1,4-hvdroxydihvdronormorphinone Structural Formula ... 

MORPHINAN-6-ONE, 4,5-alpha-EPOXr-3-METHOXY-17-METHYL-, TARTRATE (1U)... 

Chemical Name Morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5a)-... 

Chemical Name 17-Allyl-4,5a-epoxy-3,14-dihydroxy-morphinan-6-one... 

Morphinan-6-ones with hydroxyl groups at positions C-l, C-2, and C-4 have been prepared and their chemistry and pharmacology have been reviewed/501 These compounds will be discussed in a later section (p. 121). 

Stimulated by these observations, Brossi s group at NIH undertook an extensive investigation of morphinan-6-ones oxygenated in each available... 

Hydroxy-N-methylmorphinan was also found to bind to opioid receptors), but its analgesic activity in the MW assay was of doubtful significance. Related morphinan-6-ones were synthesized via 3-methoxyphenylethyl-amide(76,77) (e.g., Scheme 3.10). Resolution at the 2-benzyltetrahydroiso-quinoline stage afforded (-)-2-hydroxy-N-methylmorphinan-6-one (75a) and the corresponding methyl ether (75b). Neither compound exhibited significant MHP activity,(50) with the ether being only about i x morphine. The (+)-enantiomorphs were prepared in a similar manner.<50)... 

Brossi s group at NIH has also investigated morphinan-6-ones lacking aromatic substitution. The availability of (-) 64 (R = H, R = OH) gave access to the desired product (-) 77 by catalytic reduction of the... 

In a manner similar to that outlined previously, dihydrothebaine (80) gave on reaction with Me2CuLi the morphinan-6-one enol ether (81), which, on mild acid hydrolysis, yielded the 7a-methylmorphinan-6-one (82a) (B/C cis). The same product was obtained from 79 by first, acid hydrolysis of the enol-ether to a 3 1 mixture of B/C cis (morphinan) and B/C trans (isomor-phinan) isomers, followed by catalytic hydrogenation of the appropriate isomer to a mixture of 82a and 82b. 

Morphinan-6-ones substituted in both the 5- and 7-positions resulted from the calcium hydroxide-induced reaction of formaldehyde with 3-methoxy-N-methylmorphinan-6-one (97).<93) Scheme 3.13 illustrates the reaction sequences followed, including the products given by the reductive cleavage of the oxetane moiety (98). No interesting antinociceptive activity was found. 

The morphinan-6-one (99), available from thebaine,<36,94,95) has been reacted with lithium dialkylcuprates to give 8/3-alkylmorphinan-6-ones(96) (100) (Scheme 3.14). Variation of the N-substituent was effected by standard procedures, and reductive removal of the carbonyl under Huang-Minlon conditions to 101 also caused some 3-O-demethylation. Similar pathways were used for isomorphinan-6-ones and isomorphinans (102). 

Morphinan-6-one derivatives are usually more active as analgesics or antagonists than their morphinan counterparts, and replacement of oxygen at... 

Introduction of a 14-Alkoxy Group into Morphinan-6-ones Without 7,8 Double Bond... 

O-Alkylation can also be achieved using oxymorphone-derived morphinan-6-ones without a 7,8 double bond employing dimethyl or diethyl sulfate under... 

O-Benzylation can also be achieved using oxymorphone and derivatives thereof (e.g. naltrexone). Since 14-0-alkvlation of morphinan-6-ones without 7,8 double bond does not proceed as smoothly when other alkylating reagents than dimethyl or diethyl sulfate (see above) are used, the 6-keto function was protected by ketaliza-tion [47, 48]. For instance, 3-O-benzyl-protected ketals 32 and 33 were 14-0-alkylated with different benzyl bromides in DMF in the presence of NaH to afford compounds 34 and 35, respectively. Removal of the protecting groups... 

Among the most indispensable analgesics, morphinan-6-ones such as oxymor-phone, oxycodone, and dihydromorphinone have their main importance in clinical use. As earlier shown, hydrazone, oxime, carbazone, and semicarbazone derivatives of these morphinan-6-ones exhibit high affinity at the p-opioid receptor [54-56] and exhibit high antinociceptive potency in addition to less pronounced side effects [19, 57-60]. Therefore, it remains a promising synthetic task to convert the carbonyl group into various functionalities. 

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