Novel water-soluble sedative-hypnotic agents: isoindolin-1-one derivatives.
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.
Kanamitsu
Norimasa
N
Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd, 2-2-18 Imazu-naka, Tsurumi-ku, Osaka 538-0042, Japan. nirimasa_kanamitu@maruishi-pharm.co.jp
Osaki
Takashi
T
Itsuji
Yutaka
Y
Yoshimura
Masakazu
M
Tsujimoto
Hisashi
H
Soga
Manabu
M
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006993:Hypnotics and Sedatives; D007275:Injections, Intravenous; D054833:Isoindoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012890:Sleep / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism
D006993:Hypnotics and Sedatives; D054833:Isoindoles