Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents

Abstract

Following discovery of the i.v. anesthetic activity of 2,6-diethylphenol in mice, a series of alkylphenols was examined in this species and the most active analogs were evaluated in rabbits. The synthesis of compounds which were not commercially available was accomplished by adaptations of standard ortho-alkylation procedures for phenols. Structure-activity relationships were complex, but potency and kinetics appeared to be a function of both the lipophilic character and the degree of steric hindrance exerted by ortho substituents. The most interesting compounds were found in the 2,6-dialkyl series and the greatest potency was associated with 2,6-di-sec-alkyl substitution. 2,6-Diisopropylphenol (ICI 35868) emerged as a candidate for further development and was subsequently shown to be an effective i.v. anesthetic agent in man.