Synthesis, antinociceptive activity and opioid receptor profiles of trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl)phenols

Abstract

The synthesis of a series of novel trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols (12a–g), (20a–c), (21), (22) and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl) phenols (28a, b), (34) is described. Construction of the pyrano[2,3-c]pyridines is achieved via annulation of the pyran ring onto the arylpiperidin-3-ones (6) and (14)(R = CO₂Ph). The pyrano[3,4-c]pyridines are synthesized by application of metallated enamine chemistry to 1-methyl-4-(3-methoxyphenyl)1,2,3,6-tetrahydropyridine (4) and proceeds via the novel 2-oxa-8-azabicyclo[3.3.1 ] nonane (23) and the bicyclic enamines (24) and (29). Manipulation of this general methodology has afforded a number of structural variants bearing strategic substitutions in the pyran ring as well as alternative N-groups. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure-activity relationships are discussed.