Antagonists opioid morphinan derivatives

Cyprodime is a morphinan derivative, a (p) OPIOID RECEPTOR ANTAGONIST. 

The 17-substituent of morphinans is believed to influence its agonistic or antagonistic activity towards the opioid receptor [5]. For example, 17-methyl morphinans, morphine, and oxymorphone are agonists. On the other hand, 17-aflyl and 17-cyclopropylmethyl (CPM) morphinans, naloxone and naltrexone (1) are antagonists [5]. Therefore, a dealkylation, especially demethylation reaction of 17-substituents has been widely used to synthesize morphinan derivatives that possess various 17-substituents [27-33]. However, the reaction with chloroformates has only been applied to 14-H-morphinans. Therefore, we were interested in the 17-dealkylation reaction in 14-OH-morphinans, like naltrexone (1). In the course of the study, we found a novel reaction that cleaved the C16-N17 bond in a naltrexone derivative 35 that produced oxazolidinone 36, which lacked a D-ring (Scheme 15). 

Apart from a few notable exceptions (see later), all known narcotic antagonists are based on the morphine, morphinan, or benzomorphan polycyclic systems, that is, on three closely related groups of opioid ligands that share many structure-activity relationships (see Chapters 2, 3, and 4). Details of antagonist representatives of each group will now be given, chiefly confined to N- allyl and N-cyclopropylmethy 1 (CPM) derivatives, with minimal chemical details. 

TRK-851 is a clinical candidate for an antitussive drug it has a novel, complex morphinan ring system. The development of TRK-851 was motivated by the finding that NTI, a selective 8 opioid receptor antagonist, showed antitussive effect. In this section we will describe the process of developing TRK-851, including the structure-activity relationship (SAR) studies on NTI derivatives and the difficulties encountered in overcoming a defect in the metabolism of a prototype clinical candidate, TRK-850. 

Neumeyer, J.L., Bidlack, J.M., Zong, R., Bakthavachalam, V., Gao, P., Cohen, D.J., Negus, S.S., Mello, N.K., 1999. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives. Mixed kappa agonists and mu agonists/antagonists as potential pharma-cotherapeutics for cocaine dependence. J. Med. Chem. (in press). 

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