Novel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives

• Kanamitsu Norimasa

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

• Osaki Takashi

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

• Itsuji Yutaka

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

• Yoshimura Masakazu

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

• Tsujimoto Hisashi

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

• Soga Manabu

  Central Research Laboratory, Maruishi Pharmaceutical Co., Ltd.

抄録

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.

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 55 (12), 1682-1688, 2007

  公益社団法人 日本薬学会

キーワード

• isoindolin-1-one derivative
• sedative-hypnotic
• nonbenzodiazepine
• water-soluble

詳細情報

• CRID: 1390282679145365376
• NII論文ID: 110006532108
• NII書誌ID: AA00602100
• DOI: 10.1248/cpb.55.1682
• COI: 1:CAS:528:DC%2BD1cXht1ymu7g%3D
• ISSN: 13475223
• ISSN: 00092363
• NDL書誌ID: 9273849
• PubMed: 18057740
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I9273849
• Web Site: http://www.jstage.jst.go.jp/article/cpb/55/12/55_12_1682/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2008132426
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可