Morphinane

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

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.]... 

In an extension of this work, Schnider and his colleagues condensed the salt (36) with the Grignard reagent from p-methoxy-benzyi chloride. The product (40), on reduction (41) and cycliza tion, affords the methoxylated morphinan (41). Removal of the methyl ether affords the narcotic analgesic racemorphan (43)... 

As an alternate route to functionalized morphinans, the intermediate, 38, is first nitrated, the group entering para to the methylene bridge (44). Reduction of the nitro to the aniline (45) followed then by diazotization and replacement by hydroxyl gives intermediate, 46. Cyclization as above again gives racemorphan. 

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

D,L-3-Hydroxy-N-methyl-morphinan Phenyl trimethyl ammonium chloride D-Tartaric acid... 

The methylation of 51.4 parts by weight of D,L-3-hydroxy-N-methyl-morphinan is carried out with a methylating solution obtained from 51.5 parts by weight of phenyl-trimethyl-ammonium-chloride. The D,L-3-methoxy-N-methyl-morphinan is isolated in the form of its hydrobromide, which melts with 1 mol of water at 92°-94°C, without water at 239°-240°C. The base isolated from the aqueous solution by means of sodium carbonate melts at 81°-83 C. 

Chemical Name 7,8-didehydro-4,5-epoxy-17 (2-propenyl)morphinan-3,6-diol Common Name N-allyInormorphine Structural Formula ... 

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

CN (5a,6a)-7,8-didehydro-4,5-epoxy-17-methyl-3-[2-(4-morpholinyl)ethoxy]morphinan-6-ol... 

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

A major study on 13C-NMR spectroscopy of hasubanan alkaloids was carried out by Matsui et al. (5) (Table III). They proposed assignments of all carbon atoms including the direct and long-range hetero coupling. The C-9 and JV-methyl carbons of hasubanan alkaloids reveal shifts of 6 and 20 ppm higher frequency than those reported for morphinan alkaloids (9). On the other hand, the iV-methyl carbons of hasubanans exhibit a lower frequency shift of 10 ppm relative to those of hasubanalactam-type alkaloids (5). These results have been utilized for structure elucidation in later works (4,7,10-12). 

The Diels-Alder reaction of morphinan-6,8-dienes with nitroethene affords a novel type of opium alkaloids (Eq. 8.3).10a High reactivity of nitroethylene is demonstrated for the Diels-Alder reaction with thermally unstable dienes, and this is used for synthesis of polycyclic kopsane-like alkaloids.1013... 

Numerous patents have appeared describing derivatives of 5 and 6 as potential PAMOR antagonists. With the exception of 5 and 6, there are no peer-reviewed publications on structure-activity relationships, in vivo activity, or other preclinical data for the new agents. As viewed from the patent literature, introduction of polar substitutents into the morphinan scaffold is the preferred peripheralization strategy. 

Analogs 11-13 are representative of new morphinan-derived zwitter-ions. The orally active 14-substituted ether (11) is 10-fold more potent than 2 in reversing morphine-induced decrease in GI motility in rat [41]. 

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