Synthesis, antinociceptive activity and opioid receptor profiles of 3-(octahydro-1H-pyrano- and -thiopyrano[4,3-c]pyridin-8a-yl)phenols

Abstract

The synthesis of a series of novel cis- and trans-3-(octahydro-1H-pyrano[4,3-c]pyridin-8a-yl)phenols (13a–1), (15a, b), (20a–d), (21a–e) and the trans-3-(octahydro-1H-thiopyrano[4,3-c]pyridin-8a-yl)phenol (26) is described. Alkylation of 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) with 2-chloro-1-(chloromethoxy)ethane or 2-chloro-1-(chloromethoxy)propane, and subsequent cyclization, generated the bicyclic enamines (9a) and (9b) respectively. Hydrogenation of (9a, b) under neutral conditions provided the trans-fused octahydropyrano[4,3-c]pyridines (10a), (16a), and (17a), whereas hydrogenation of (9a) in acidic media gave the corresponding cis-fused system (11a). The trans-fused octahydrothiopyrano[4,3-c]pyridine (23) was synthesized via the analogous enamine (22). Selected N-substituents were introduced via a vinyl chloroformate N-demethylation/re-alkylation sequence and subsequent O-demethylation afforded the title phenols. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure activity relationships are discussed.