Azabicycloalkanes as analgetics. 3. Structure-activity relations of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative

Abstract

A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (I) was tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxyphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgetic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)-8] was established by the X-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivative [(+)-7] by chemical transformation and CD[circular dichroic] measurement. Certain structural and stereochemical correlations between these compounds and other known antagonist-analgetics are discussed. Tests were run in rabbits and monkeys.