Diels-Alder adduct analgesics

To extend this methodology, Diels-Alder reactions of several (Z)-4-arylidene (heteroarylidene)-2-phenyl-5(47/)-oxazolones with butadiene, 2,3-dimethylbuta-diene, cyclopentadiene and Danishefsky s diene have been studied. This work demonstrated that the products depended on the nature of the aromatic ring and the diene used. " An interesting application of this methodology is the synthesis of racemic epibatidine 729, a new alkaloid with a 7-azabicyclo[2.2.1]heptane skeleton that has proven to be a very potent analgesic. Preparation of 729 began with the Diels-Alder adduct 726 obtained from (Z)-4-[5 -(2 -chloropyridyhnethylene)]-2-... 

As early as 1956(323) it had been demonstrated that the benzoquinone Diels-Alder adduct, 211, was about equivalent to pethidine (about one seventh times morphine) in rodent analgesic assays. However, at that time, appropriate pharmacological evaluation was not readily available to the investigators and the project remained fallow for several years. 

Bentley and his colleagues7 describe the structure-activity relationships of a wide variety of structures derived from Diels-Alder adducts of thebaine. Among this group are found some of the most potent analgesics known. Particular attention should be directed toward the fine application of nuclear magnetic resonance spectroscopy, by Fulmor and his associates to elucidate the stereochemical configurations of these interesting compounds. 

A semisynthetic route to morphine analogs was found (10) from thebaine (8) using Diels-Alder reactions in the C-ring. Adducts such as (9)have the distinction of enormous potency (U), sufficient to immobilize rhinoceroses at moderate dose levels Unfortunately, the addictive liability runs parallel to the increase in analgesic potency, a tendency that was partly overcome (12) in the analog buprenorphine (10). 

Thebaine-maleimide adducts have been prepared, and the Diels-Alder reaction of thebaine with cyclic azo-dienophiles has been investigated. " Nitrosation of thebaine hydrochloride with nitrosyl chloride or pentyl nitrite in methanol or ethanol gives 7-hydroxyiminoneopinone dimethyl or diethyl acetal. " The chemistry of 14-bromocodeinone and its dimethyl acetal has been studied in some detail, including catalytic hydrogenation, "" methanoly-sis, " debromination, "" dehydrobromination, " and solvolysis.Efforts are continuing in the preparation of novel analgesics in the morphine-thebaine series. 

Thebaine acts as diene component in Diels-Alder reactions with methyl vinyl sulphone or divinyl sulphone. 1 1 Adducts are formed in both cases. The analgesic properties of some elaboration products of these adducts, e.g. (136), equal the potency of codeine. Cyclopentadiene adds... 

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