Aromatic esters of nonquaternary carbon-4 piperidinols as analgesics.

ABSTRACT

Aromatic carboxylic esters of 1-methyl-4-piperidinol were prepared and evaluated for analgesic activity. In addition, aralkyl, alkyl, and cycloalkyl carboxylates of the 4-piperidinol system and 3,4-dimethoxybenzoates of isomeric piperidinols (24-26) were synthesized. The 3,4-dimethoxybenzoate 23 was nearly twice as active as codeine in the mouse hot-plate assay. In monkeys, 23 showed no morphine-like physical dependence liability, cis- and trans-1,3-dimethyl-4-piperidinol esters 24 and 25 showed no binding to the opiate receptor in rat brain homogenates. The 3- and 4-monosubstituted and the 3,4-disubstituted benzoate esters were examined for qualitative structure-activity relationships with respect to parameters Esc and pi. Various structural features of this series of compounds that may have an affinity for receptor binding sites are discussed.