N-[2-(1,3-dioxoisoindol-2-yl)oxy-1-(3,4,5-trifluorophenyl)ethyl]-N-(2-hydroxypropyl)-3-methylbut-2-enamide | 1227306-89-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: N-[2-(1,3-dioxoisoindol-2-yl)oxy-1-(3,4,5-trifluorophenyl)ethyl]-N-(2-hydroxypropyl)-3-methylbut-2-enamide
• CAS: 1227306-89-9
• 化学式: C₂₄H₂₃F₃N₂O₅
• 分子量: 476.452
• InChiKey: QMRXOECFQXGRAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  87.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-[2-(1,3-dioxoisoindol-2-yl)oxy-1-(3,4,5-trifluorophenyl)ethyl]-N-(2-hydroxypropyl)-3-methylbut-2-enamide 在 hydrazine hydrate 、 氧气 、 臭氧 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 C₁₃H₁₃F₃N₂O₃
  参考文献：
  名称：

  Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease

  摘要：

  Fused oxadiazines (3) were discovered as selective and orally bioavailable gamma-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall gamma-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.

  DOI：

  10.1021/ml300209g
• 作为产物：
  描述：

  2-[Tert-butyl(dimethyl)silyl]oxy-1-(3,4,5-trifluorophenyl)ethanamine 在 2-氯丙酰氯 、 三丁基膦 、 氯化锆(IV) 、 三乙胺 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 生成 N-[2-(1,3-dioxoisoindol-2-yl)oxy-1-(3,4,5-trifluorophenyl)ethyl]-N-(2-hydroxypropyl)-3-methylbut-2-enamide
  参考文献：
  名称：

  Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease

  摘要：

  Fused oxadiazines (3) were discovered as selective and orally bioavailable gamma-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall gamma-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.

  DOI：

  10.1021/ml300209g

文献信息

• [EN] GAMMA SECRETASE MODULATORS<br/>[FR] MODULATEURS DE GAMMA SÉCRÉTASE
  申请人：SCHERING CORP

  公开号：WO2010056849A1

  公开（公告）日：2010-05-20

  In its many embodiments, the present invention provides a novel class of heterocyclic compounds of Group A or Group, as defined herein, as modulators of gamma secretase, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the central nervous system using such compounds or pharmaceutical compositions.

  在其多种实施方式中，本发明提供了一类新型的杂环化合物，属于A组或B组，如本文所定义，作为γ-分泌酶调节剂，以及制备这类化合物的方法，含有一种或多种这类化合物的药物组合物，制备含有一种或多种这类化合物的药物配方的方法，以及利用这类化合物或药物组合物治疗、预防、抑制或改善与中枢神经系统相关的一种或多种疾病的方法。
• GAMMA SECRETASE MODULATORS
  申请人：Zhu Zhaoning

  公开号：US20110294756A1

  公开（公告）日：2011-12-01

  In its many embodiments, the present invention provides a novel class of heterocyclic compounds of Group A or Group, as defined herein, as modulators of gamma secretase, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the central nervous system using such compounds or pharmaceutical compositions.
• US8673900B2
  申请人：——

  公开号：US8673900B2

  公开（公告）日：2014-03-18
• Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease
  作者：Xianhai Huang、Wei Zhou、Xiaoxiang Liu、Hongmei Li、George Sun、Mihirbaran Mandal、Monica Vicarel、Xiaohong Zhu、Chad Bennett、Troy McCraken、Dmitri Pissarnitski、Zhiqiang Zhao、David Cole、Gioconda Gallo、Zhaoning Zhu、Anandan Palani、Robert Aslanian、John Clader、Michael Czarniecki、William Greenlee、Duane Burnett、Mary Cohen-Williams、Lynn Hyde、Lixin Song、Lili Zhang、Inhou Chu、Alexei Buevich

  DOI：10.1021/ml300209g

  日期：2012.11.8

  Fused oxadiazines (3) were discovered as selective and orally bioavailable gamma-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall gamma-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.