Novel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives
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- Kanamitsu Norimasa
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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- Osaki Takashi
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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- Itsuji Yutaka
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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- Yoshimura Masakazu
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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- Tsujimoto Hisashi
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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- Soga Manabu
- Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.
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Abstract
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.
Journal
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- Chemical and Pharmaceutical Bulletin
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Chemical and Pharmaceutical Bulletin 55 (12), 1682-1688, 2007
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390282679145365376
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- NII Article ID
- 110006532108
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- NII Book ID
- AA00602100
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- COI
- 1:CAS:528:DC%2BD1cXht1ymu7g%3D
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- ISSN
- 13475223
- 00092363
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- NDL BIB ID
- 9273849
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- PubMed
- 18057740
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed