Design, Synthesis, and Biological Evaluation of Novel CNS 7056 Derivatives as Sedatives in Rats and Rabbits

A new water‐soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast‐onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL‐001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL‐001 was chosen as the optimal compound for studies of ED50, LD50, latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL‐001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL‐001 has a shorter period of induction despite a slightly longer sedative duration and recovery time. A novel series of CNS 7056 derivatives were designed, synthesized, and evaluated for their sedative activity. EL‐001 has a shorter period of induction and a slightly longer sedative duration and recovery time compared with CNS 7056 and hence identified as a promising sedative candidate.