Study of the syn and anti isomerism of the long-lasting opiate antagonist naloxazone and related compounds.

A 13C-NMR study of the long-acting opiate antagonists naloxazone (I) and naltrexazone (II) and the long-acting opiate agonist oxymorphazone (III) revealed that these compounds are formed as mixtures of their anti and syn isomers. The less crowded anti isomer was found to be the major product in all cases (ca. 80%). N,N-Dimethyl derivatives of naloxazone (IV), naltrexazone (V), and oxymorphazone (VI), which are sterically more crowded than the corresponding unsubstituted hydrazones I-III, were formed as almost exclusively anti isomers. Pure anti isomer of II was obtained as a 1:1 complex with ethanol. No syn-anti equilibration was observed during the 13C-NMR experiment in any of the cases studied. The relevance of our finding about the syn-anti isomerism of the opiate hydrazones to the understanding of their interactions with the opiate receptor is discussed.