1-neopentyl-1'-(2-aminophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-neopentyl-1'-(2-aminophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]
• 英文别名: 2-[1'-(2,2-Dimethylpropyl)spiro[2,3-dihydroquinoline-4,4'-piperidine]-1-yl]aniline
• 化学式: C₂₄H₃₃N₃
• 分子量: 363.546
• InChiKey: ZJMAVUDDTPJVLT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  32.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-neopentyl-1'-(2-aminophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline] 、 4-三氟甲氧基苯基异氰酸酯 以 四氢呋喃 为溶剂， 反应 72.0h， 以15 mg的产率得到1-(2-(1-Neopentyl-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-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
• 作为产物：
  描述：

  1'-(2,2,2-trifluoroacetyl)spiro[indene-1,4'-piperidin]-3(2H)-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium aluminium tetrahydride 、 sodium azide 、 硫酸 、 氯化铵 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 、 potassium hydroxide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 乙酸乙酯 、 甲苯 为溶剂， 反应 68.0h， 生成 1-neopentyl-1'-(2-aminophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]
  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

• N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
  申请人：Qiao Jennifer

  公开号：US20060293281A1

  公开（公告）日：2006-12-28

  The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y 1 receptor which can be used as medicaments.

  本发明提供了含有式(I)的N-芳基或N-杂芳基取代的杂环的新型脲类化合物： 或其立体异构体、互变异构体、药学上可接受的盐或溶剂化合物形式，其中变量A、B、D和W如本文所定义。这些化合物是人类P2Y1受体的选择性抑制剂，可用作药物。
• N-LINKED HETEROCYCLIC ANTAGONISTS OF P2Y1 RECEPTOR USEFUL IN THE TREATMENT OF THROMBOTIC CONDITIONS
  申请人：Qiao Jennifer

  公开号：US20100197716A1

  公开（公告）日：2010-08-05

  The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y 1 receptor which can be used as medicaments.

  本发明提供了一种新型尿素，包含式（I）中的N-芳基或N-杂环芳基取代的杂环，或其立体异构体、互变异构体、药学上可接受的盐或溶剂形式，其中变量A、B、D和W如本文所定义。这些化合物是人类P2Y1受体的选择性抑制剂，可用作药物。
• US7728008B2
  申请人：——

  公开号：US7728008B2

  公开（公告）日：2010-06-01
• US8329718B2
  申请人：——

  公开号：US8329718B2

  公开（公告）日：2012-12-11
• 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.