1-methyl-1,8-diazaspiro[4.5]decan-2-one dihydrochloride | 1609407-01-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 1-methyl-1,8-diazaspiro[4.5]decan-2-one dihydrochloride
• 英文别名: 1-Methyl-1,8-diazaspiro[4.5]decan-2-one hydrochloride；1-methyl-1,8-diazaspiro[4.5]decan-2-one;hydrochloride
• CAS: 1609407-01-3
• 化学式: C₉H₁₆N₂O*2ClH
• 分子量: 241.161
• InChiKey: LJWYXKGGRCPQJQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.78
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine 、 1-methyl-1,8-diazaspiro[4.5]decan-2-one dihydrochloride 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one
  参考文献：
  名称：

  Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases

  摘要：

  Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.

  DOI：

  10.1016/j.bmcl.2019.03.014