Following our discovery of the intravenous (iv) anesthetic activity of 2, 6-diethylphenol in mice, a series of alkylphenols was examined in this species and the most active analogues were further 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 found to be complex, but, in general, potency and kinetics appeared to be a function of both the lipophilic characterand the degree of steric hindrance exerted by ortho substituents. The most interesting compounds were found in the 2, 6-dialkyl series, andthe greatest potency was associated with 2, 6-di-sec-alkyl substitution. In particular, 2, 6-diisopropylphenol (ICI 35868) emerged as a candidate for further development and has subsequently been shown to be an effective iv anesthetic agent in man.

The concept of total intravenous (iv) anesthesia has in recent years prompted attempts to improve on existing drugs, but alternative agents have not proved to be entirely satisfactory. 1 The use of the surfactant Cremophor EL for the formulation of compounds otherwise poorly soluble in water alone has enabled an examination of the anesth-etic potential of numerous structural types with high lipophilic character which could not previously have been administered by the intravenous route. This paper de-scribes the synthesis and biological evaluationof a series of alkyl-substituted phenols which resulted from the discovery of anesthetic activity in 2, 6-diethylphenol (8) in