benzyl 1-(2-(3-(4-(Trifluoromethoxy)phenyl)ureido)phenyl)-spiro[indoline-3,4′-piperidine]-1′-carboxylate

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: benzyl 1-(2-(3-(4-(Trifluoromethoxy)phenyl)ureido)phenyl)-spiro[indoline-3,4′-piperidine]-1′-carboxylate
• 英文别名: 1,2-dihydro-1-[2-[[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]phenyl]-spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid phenylmethyl ester；benzyl 1-[2-[[4-(trifluoromethoxy)phenyl]carbamoylamino]phenyl]spiro[2H-indole-3,4'-piperidine]-1'-carboxylate
• 化学式: C₃₄H₃₁F₃N₄O₄
• 分子量: 616.64
• InChiKey: GPTSTWODEIAOAF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  45
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  83.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  benzyl 1-(2-(3-(4-(Trifluoromethoxy)phenyl)ureido)phenyl)-spiro[indoline-3,4′-piperidine]-1′-carboxylate 在 palladium 10% on activated carbon 氢气 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以96%的产率得到1-(2-(spiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
  参考文献：
  名称：

  Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions

  摘要：

  本发明提供了含有N-芳基或N-杂环芳基取代的杂环化合物及其类似物的新型脲类化合物，这些化合物是人类P2Y1受体的选择性抑制剂。该发明还提供了相应的各种药物组合物以及调节P2Y1受体活性治疗对其敏感的疾病的方法。

  公开号：

  US20050261244A1
• 作为产物：
  描述：

  螺[吲哚啉-3,4’-哌啶]-1’-羧酸苄酯 在 氯化铵 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 18.5h， 生成 benzyl 1-(2-(3-(4-(Trifluoromethoxy)phenyl)ureido)phenyl)-spiro[indoline-3,4′-piperidine]-1′-carboxylate
  参考文献：
  名称：

  Conformationally Constrained ortho-Anilino Diaryl Ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y₁ Antagonist

  摘要：

  Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y(1) antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y(12) antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y(1) antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 31 will also be presented. Compound 31 was our first P2Y(1) antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.

  DOI：

  10.1021/jm4013906

文献信息

• Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
  申请人：Tuerdi Huji

  公开号：US20050261244A1

  公开（公告）日：2005-11-24

  The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y 1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y 1 receptor activity.

  本发明提供了含有N-芳基或N-杂环芳基取代的杂环化合物及其类似物的新型脲类化合物，这些化合物是人类P2Y1受体的选择性抑制剂。该发明还提供了相应的各种药物组合物以及调节P2Y1受体活性治疗对其敏感的疾病的方法。
• Conformationally Constrained <i>ortho-</i>Anilino Diaryl Ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y₁ Antagonist
  作者：Jennifer X. Qiao、Tammy C. Wang、Réjean Ruel、Carl Thibeault、Alexandre L’Heureux、William A. Schumacher、Steven A. Spronk、Sheldon Hiebert、Gilles Bouthillier、John Lloyd、Zulan Pi、Dora M. Schnur、Lynn M. Abell、Ji Hua、Laura A. Price、Eddie Liu、Qimin Wu、Thomas E. Steinbacher、Jeffrey S. Bostwick、Ming Chang、Joanna Zheng、Qi Gao、Baoqing Ma、Patricia A. McDonnell、Christine S. Huang、Robert Rehfuss、Ruth R. Wexler、Patrick Y. S. Lam

  DOI：10.1021/jm4013906

  日期：2013.11.27

  Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y(1) antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y(12) antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y(1) antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 31 will also be presented. Compound 31 was our first P2Y(1) antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.