作者: Ryu, Jong Hoon ; Kim, Hyoung Ja ; Park, Jeong Ho ; Lim, Dami ; Lee, Kyung‐Tae ; Lee, Jeong‐Hun ; Pae, Ae Nim ; Shin, Ji Sun ; Lee, Hwi‐Ho ; Yoon, Hong Bin ; Lee, Jae Yeol ; Jung, Da Woon ; Kim, Sun Young
Alzheimer's disease (AD) is the most common degenerative brain disease that causes dementia of the elderly and is characterized by neuritic plaques and neurofibrillary tangles in the brain tissue of a patient with AD.Recently, we have reported the identification of phenylsulfonyl hydrazide derivatives including MPO-0063 (Scheme 1) as novel and selective mPGES-1 inhibitors through the screening of a chem. library and hit-to lead optimization.The synthesis of phenylsulfonamide 5 (MPO-0112) was carried out in a three-step reaction according to our reported procedure as illustrated in Scheme 1.15,16 N-Benzyl-4-chlorophenylsulfonamide 2 was prepared in 89% yield from the reaction of 4-chlorophenylsulfonyl chloride 1 with benzylamine in the presence of triethylamine (TEA).The reaction of 4-(benzyloxy)phenol 3 with 0.5 equivalent of triphosgene in the presence of N,N-diisopropylethylamine(DIPEA) gave 4-(benzyloxy)phenyl chloroformate 4 in quant. yield. The target phenylsulfonamide 5 (MPO-0112) was obtained in 73% yield by the nucleophilic substitution reaction of chloroformate 4 with sulfonamide 2 in the presence of TEA.These overall biol. results suggest that 5 (MPO-0112) as a selective mPGES-1 inhibitor may be useful for the treatment of cognitive impairment observed in Alzheimer's disease.
