Syntheses of potential metabolites of a potent kappa-opioid receptor agonist, TRK-820 |
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Authors: | Kawamura Kuniaki Horikiri Hiromasa Hayakawa Jun Seki Chie Yoshizawa Ken-ichi Umeuchi Hideo Nagase Hiroshi |
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Institution: | Pharmaceutical Research Laboratories, Toray Industries Inc., 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Kuniaki_Kawamura@nts.toray.co.jp |
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Abstract: | Chemical syntheses of three kinds of potential metabolites of TRK-820, a potent kappa-opioid receptor agonist, were described. One of the potential metabolites 2, 17-N-dealkylated TRK-820, was synthesized starting from noroxycodone through 8 steps in 21% total yield. Glucuronidation of intermediate 10 and compound 1, the free base of TRK-820, was carried out stereoselectively to give 3-O-beta-D-glucuronides 15 and 16 in good yields, respectively. Syntheses of potential conjugated metabolites 3 and 4 were accomplished through 10 steps and 2 steps in 11% and 43% total yields, respectively. Among the potential metabolites of TRK-820, compounds 2 and 4 were identified as metabolites in human hepatocytes. The results of pharmacological studies of compounds 2, 3, and 4 are described. |
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