Substituted Morphinans

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]. 

Somewhat more effective catalysts are obtained by replacing BINAP with TolBINAP, which is 2,2 -bis(di-p-tolylphosphino)-l,l -binaphthyl.4 The presently preferred catalysts are complexes of Ru(OCOCF3)2 with (R)- or (S)-TolBINAP, obtained by treatment of Ru(OAc)2TolBINAP with 2 equiv. of trifluoroacetic acid. Such catalysts promote hydrogenation of typical enamides in 98% ee and 98% yield. This reaction can be used to provide asymmetric synthesis of isoquinoline alkaloids as well as of morphinans used as substitutes for morphine. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

Again, substitution on the nitrogen with a cyclobutylmethyl group on the morphinan scaffold produces mixed agonist-antagonist activity [18]. The resultant compound is known as butorphanol (21 Stadol Fig. 11.11) [56], and this has increased potency when compared to morphine. It is mainly utilized in the form... 

Other 3-substituted morphinans were isolated during attempts to prepare 3-hydroxymorphinans by sequential nitration, hydrogenation to the amine, and diazotization of the unsubstituted precursor/381 A mixture of 2- and 3-nitromorphinans was isolated, but no biological data were reported. 

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... 

The preparation of a 7-substituted morphinan in high yield was first accomplished in 1980.(82) Thebaine (78) was reacted with lithium dimethyl-cuprate to yield (90%) 7/3-methyldihydrothebaine- > (79) together with 4% of the 7a-epimer. Previously, dihydrothebaine(83) and the enol acetate of dihydrocodeinone(84) had been shown to react with methyl Grignard reagents affording predominantly 5-methyldihydrothebainone with only a trace of the 7-methyl isomer.(85) The production of 79 gave entry into a new series of morphinans. 

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. 

Morphman-6-ones are, as a rule, more active than corresponding morphinans, and it would appear that C-ring geometry and substitution patterns play a role in the drug-receptor union... 

An attempt has been made to synthesize the morphinane ring-system in this way, and l-(/3-diethylaminoethyl)-2-keto-1 2 3 4-tetrahydro-naphthalene was converted to [oxxvm] by condensation with the appropriate Mannich base methiodide, the product brominated with N-bromosuccinimide, and finally converted to the quaternary salt [cxxix]. Work on the corresponding N-dimethyl series was abandoned when it was found impossible to obtain the requisite substituted /3-tetralone in a state even approaching purity. The synthesis of [cxxx] has been accomplished by the same method, its production being accompanied by the production of [cxxxi] as a result of further ring-extension [43]. 

Because of the low reactivity of the tertiary alcohol, alkylation of the 014-hydroxyl with alkyl halides such as propyl or isoamyl halides was unsuccessful [Schmidhammer H, unpublished observations]. Therefore, allylic halides were employed to introduce 14-O-alkenyl substituents using similar conditions as described above [ 43—461. Catalytic hydrogenation afforded the corresponding 14-O-alkyl derivatives [43 -5]. Thus, 14-hydroxy-5-methylcodeinone (20) was treated with 3,3-dimethylallyl bromide in DMF in the presence of NaH to give compound 21, which underwent catalytic hydrogenation to yield 14-O-isoamyl-substituted morphinan 24 (Scheme 5) [43]. Similarly 14-phenylpropoxymorphinans 25 and 26 were prepared from 14-hydroxycodeinone (3) and 21, respectively, via intermediates 22 and 23, which were obtained by alkenylation using cinnamyl bromide (Scheme 5) [44, 45],... 

The reaction of Ru-binap complexes applied to tetrahydroisoquinoline compounds that have an exocyclic enamide double bond produces 1-substituted tetrahydroisoqui-nolines nearly quantitatively and with optical yield close to 100%. This procedure served in industrial production of benzomorphans, morphinans, and various isoquinoline alkaloids ... 

Syntheses of N-substituted-moiphinan dihydronormethines and O-alkylisoureas related to morphinan, norpethidine, or phenethylamine... 

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