First synthesis of important secondary oxidative metabolites of morphine and codeine with the Michael addition

Sándor Garadnay 1 , Zsuzsanna Gyulai 1 , Sándor Makleit 1 , and Attila Sipos 2
  • 1 Department of Organic Chemistry, University of Debrecen, H-4032, Debrecen, Hungary
  • 2 Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, H-4032, Debrecen, Hungary
  • 3 Gedeon Richter Plc., H-1475, Budapest, Hungary

Abstract

Abstract Morphine (1) and codeine (2) are two representatives of medically important, frequently used natural opiates, therefore the exploration of their metabolic pathways and the exact characterization of the metabolites are main targets of their pharmacological studies. These morphinans also play a crucial role in drug abuse; therefore, the analysis and preparation of the metabolites for identification and quantitation in human samples are considered important aims. In order to allow the in-depth analysis of metabolites derived from the oxidative pathways through morphinone (3) and codeinone (4), synthetic procedures have been elaborated for the gram-scale preparation of glutathione and N-acetylcysteine adducts. Primary pharmacological studies revealed the inactive nature of these metabolites in opioid receptor binding tests. Graphical abstract

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