We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(−), 5(−), 27(−), and 47(−) [JM-1232(−)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD₅₀s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD₅₀s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD₅₀/HD₅₀) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(−) [JM-1232(−)] is being considered as the most potential candidate for clinical trials in humans.