1-(2-(1′-neopentylspiro[indoline-3,4′-piperidine]-1-yl)-phenyl)-3-(4-(trifluoromethoxy)phenyl)urea

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 1-(2-(1′-neopentylspiro[indoline-3,4′-piperidine]-1-yl)-phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
• 英文别名: Urea, N-[2-[1'-(2,2-dimethylpropyl)-1,2-dihydrospiro[3H-indole-3,4'-piperidin]-1-yl]phenyl]-N'-[4-(trifluoromethoxy)phenyl]-；1-[2-[1'-(2,2-dimethylpropyl)spiro[2H-indole-3,4'-piperidine]-1-yl]phenyl]-3-[4-(trifluoromethoxy)phenyl]urea
• 化学式: C₃₁H₃₅F₃N₄O₂
• 分子量: 552.64
• InChiKey: FDCUCZZKNTVJSB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  56.8
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  螺[吲哚啉-3,4’-哌啶]-1’-羧酸苄酯 在 palladium 10% on activated carbon 、 氢气 、 氯化铵 、 溶剂黄146 、 锌 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 为溶剂， 反应 26.5h， 生成 1-(2-(1′-neopentylspiro[indoline-3,4′-piperidine]-1-yl)-phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
  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

• 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.