Thebaine analogues

An efficient synthesis of the thebaine analogue (158), as outlined in Scheme 13, in which the nitrogen atom is translocated from C(17) to the 16-position has been reported.161 It was converted into the Bentley adduct (159) by successive Diels-Alder and Grignard reactions. Further work on the Diels-Alder reactions of morphine alkaloids is expected for example, the enamine (160) has been prepared specifically for this purpose.162... 

This approach was later extended to an enantioselective synthesis,5415 Scheme 10. Unfortunately, some racemization occurred during preparation of substrate 94, but not during cyclization to 95, this time mediated by iodosobenzene diacetate. Reduction/closure, followed by Barton radical decarboxylation yielded the known thebaine analogue 97.56... 

By conventional tests, secondary amine analogues of 4-phenylpiperidine analgesics lack activity (normorphine is equi-potent with morphine by the intra-cisternal route [48]) many secondary bases of the thebaines,(VII), however, are morphine-like analgesics. These findings lend support to the view that the low potencies reported for many nor-analogues of analgesics are due to distribution factors and not to the failure of such derivatives to associate at the receptor. 

The mechanistic aspects of the rearrangement of thebaine and codeine analogues in methanesulphonic acid have been clarified, and have led to an... 

Oripavine 3-ethyl ether (38), an unnatural analogue of thebaine (35), was found to be metabolized to morphine 3-ethyl ether and to morphine (36). The efficiency of the conversion was comparable to that of natural biosynthesis. (For an examination of other unnatural compounds as substrates for the enzymes of the biosynthesis of morphine alkaloids, see Vol. 4, p. 15.)... 

It has long been known that only morphine and codeine possess analgesic properties, whereas thebaine acts as a convulsant, similar to strychnine [16]. However, analogues produced from thebaine have provided some of the more interesting and clinically useful dmgs such as buprenorphine (see Section 11.5). Indeed, an early structure-activity relationship was realized between morphine and its methylated phenolic relative, codeine. Codeine (see below) is known to have about one-tenth the analgesic activity of morphine, and was also less likely to produce addiction. Additionally, an early diacetylated analogue of morphine, heroin (6) (Fig. 11.2), demonstrated an increased potency but also an increased addictive potential. 

Synthetic Analogues of Thebaine Further Define Morphinan SAR 266... 

EN 1639A UM 792 Nalorex " Trexan ) is one of the phenanthrene series and an analogue of oxymorphone and thebaine, and is also an analogue of the antagonist naloxone. It is a (largely subtype-unselective) opioid RECEPTOR antagonist, and is used orally in detoxification treatment for formerly opioid-dependent individuals to help prevent relapse. 

Attempts to convert oripavine (the 3-demethylated analogue of thebaine) to an analogue of thebenine failed to give clearly-defined products [26]. 

Whereas total syntheses of alkaloids have been few, a great deal of attention has been given to the modification of alkaloid skeletons and to the synthesis of alkaloid analogues in an effort to prepare new pharmacologically active compounds. To begin, the bromination product of thebaine (137), 14-bromocodein-one (138 R1 + R2 = O), has been the subject of a number of reports.147-154... 

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