2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinazoline | 1234707-19-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinazoline
• 英文别名: [(7R)-7-methyl-4-quinazolin-2-yl-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone
• CAS: 1234707-19-7
• 化学式: C₂₃H₂₃N₇O
• 分子量: 413.482
• InChiKey: BZCVKCOKZBGXCF-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  80
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氯喹唑啉 、 (7R)-7-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinazoline
  参考文献：
  名称：

  Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia

  摘要：

  Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

  DOI：

  10.1021/jm100541c

文献信息

• Discovery of the Dual Orexin Receptor Antagonist [(7<i>R</i>)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2<i>H</i>-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
  作者：Christopher D. Cox、Michael J. Breslin、David B. Whitman、John D. Schreier、Georgia B. McGaughey、Michael J. Bogusky、Anthony J. Roecker、Swati P. Mercer、Rodney A. Bednar、Wei Lemaire、Joseph G. Bruno、Duane R. Reiss、C. Meacham Harrell、Kathy L. Murphy、Susan L. Garson、Scott M. Doran、Thomayant Prueksaritanont、Wayne B. Anderson、Cuyue Tang、Shane Roller、Tamara D. Cabalu、Donghui Cui、George D. Hartman、Steven D. Young、Ken S. Koblan、Christopher J. Winrow、John J. Renger、Paul J. Coleman

  DOI：10.1021/jm100541c

  日期：2010.7.22

  Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.