1-neopentyl-1'-(2-nitrophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline] | 917898-66-9

• 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-nitrophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]
• 英文别名: 1'-(2,2-Dimethylpropyl)-1-(2-nitrophenyl)spiro[2,3-dihydroquinoline-4,4'-piperidine]
• CAS: 917898-66-9
• 化学式: C₂₄H₃₁N₃O₂
• 分子量: 393.529
• InChiKey: NFCVYDXJNZIHAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  29
• 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：
  52.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-neopentyl-1'-(2-nitrophenyl)-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline] 在 氯化铵 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 为溶剂， 反应 88.0h， 生成 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 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 甲苯 为溶剂， 反应 52.0h， 生成 1-neopentyl-1'-(2-nitrophenyl)-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
• [EN] N-LINKED HETEROCYCLIC ANTAGONISTS OF P2Y1 RECEPTOR USEFUL IN THE TREATMENT OF THROMBOTIC CONDITIONS<br/>[FR] ANTAGONISTES HETEROCYCLIQUES A LIAISON N DU RECEPTEUR P2Y1, UTILES POUR TRAITER DES ETATS PATHOLOGIQUES THROMBOTIQUES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2007002637A1

  公开（公告）日：2007-01-04

  [EN] 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 defined herein. These compounds are selective inhibitors of the human P2Y, receptor which can be used as medicaments for treating thromboembolic disorders.
  [FR] La présente invention concerne de nouvelles urées contenant des hétérocycles substitués par N-aryle ou N-hétéroaryle de formule (I), ou un stéréoisomère, un tautomère ou un sel ou une forme solvatée de ceux-ci, acceptable d'une point de vue pharmaceutique, les variables A, B, D et W étant définies dans l'invention. Ces composés sont des inhibiteurs sélectifs du récepteur P2Y humain et peuvent être utilisés comme médicaments pour traiter des troubles thromboemboliques.