Synthesis, Hydrolytic Refractivity and Initial Bioevaluation of (R)-Etomidate Analogs. Part 1. Synthesis and Hydrolytic Refractivity of (R)-Etomidate Analogs

摘要

Five (R)-etomidate analogs with the following ester substitutents were synthesized, purified, and structurally characterized: ethyl (etomidate), benzyl, diethylaminoethyl, neopentyl, and + or - pinacolyl. The chiral centers of the 1-phenethyl functions in these compounds were shown to have the (R) configuration in enantiomeric purities in excess of 98 percent. The injectable solutions of all (R)-etomidate analogs were shown to be stable over the maximum expected time frame between solution preparation and injection into test animals. Kinetic studies of these five compounds under physiological conditions (pH 7.3 buffer at 37 C) indicated that only the (R)-diethylaminoethyl derivative underwent hydrolysis at a rate sufficient for its half life to be determined. The half life for this compound under these conditions was found to be 17.4 + or - 0.16 hours. A specific case of anchimeric assistance is proposed to explain the rapid hydrolysis of the diethylaminoethyl analog at pH 7.3. The other four (R)-etomidate analogs were not sufficiently reactive to allow the determination of their half lives.