Synthesis, antinociceptive activity, and opioid receptor profiles of 10-substituted-6-oxamorphinans

Abstract

A concise synthesis of the 6-oxamorphinan ring system has been designed which allows introduction of functionality at the 10-position. This has provided a series of 10-methylene-, 10-oxo-, and 10α-methyl-6-oxamorphinans, (24a–e), (25a–d), and (26a–c) respectively. The enamine 8a-(3-methoxyphenyl)-6-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrano[4,3-c]pyridine (4a) is converted in three steps, via trans-8a-(3-methoxyphenyl)-6-methyloctahydropyrano[4,3-c]pyridine-5α-carbonitrile (7a) and the corresponding 5α-acetyl derivative (9a), to the tetracyclic 10-methylene-6-oxamorphinan (11a). Oxidative cleavage of the 10-exocyclic methylene group of (11a) provides entry into the 10-oxo series. The antinociceptive activity and opioid receptor profiles of (24a–e), (25a–d), and (26a–c) have been evaluated and structure–activity relationships are discussed.