ethyl 2-cyclopentyl-2-(pyridin-2-yl)acetate | 192800-87-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ethyl 2-cyclopentyl-2-(pyridin-2-yl)acetate
• 英文别名: Ethyl 2-cyclopentyl-2-(pyridin-2-yl)acetate；ethyl 2-cyclopentyl-2-pyridin-2-ylacetate
• CAS: 192800-87-6
• 化学式: C₁₄H₁₉NO₂
• 分子量: 233.31
• InChiKey: JHIKCCADGHAVHR-UHFFFAOYSA-N

物化性质

• 沸点：
  322.6±17.0 °C(Predicted)
• 密度：
  1.090±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  39.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 2-cyclopentyl-2-(pyridin-2-yl)acetate 在 sodium hydroxide 、 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 2.5h， 以43%的产率得到2-cyclopentyl-2-(pyridin-2-yl)acetic acid
  参考文献：
  名称：

  The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents

  摘要：

  The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI(50) < 0.1 mu M), displayed low off-target activity (>500X), and microsomal stability (T-1/2 > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

  DOI：

  10.1021/jm501740a
• 作为产物：
  描述：

  溴代环戊烷 、 2-吡啶乙酸乙酯 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以52%的产率得到ethyl 2-cyclopentyl-2-(pyridin-2-yl)acetate
  参考文献：
  名称：

  [EN] INDAZOLE COMPOUNDS AS KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
  [FR] COMPOSÉS INDAZOLE UTILISÉS COMME INHIBITEURS DE KINASE ET MÉTHODE DE TRAITEMENT DU CANCER AVEC LESDITS COMPOSÉS

  摘要：

  本教学提供了由结构式（I）或（I'）表示的吲唑化合物或其药用可接受的盐。还描述了这些药物组合物及其用作蛋白激酶抑制剂的方法，如对乳腺癌细胞、结肠癌细胞和卵巢癌细胞具有抗癌活性的TTK蛋白激酶、极化样激酶4（PLK4）和极化激酶。

  公开号：

  WO2013053051A1

文献信息

• [EN] INDAZOLE COMPOUNDS AS KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME<br/>[FR] COMPOSÉS INDAZOLE UTILISÉS COMME INHIBITEURS DE KINASE ET MÉTHODE DE TRAITEMENT DU CANCER AVEC LESDITS COMPOSÉS
  申请人：UNIV HEALTH NETWORK

  公开号：WO2013053051A1

  公开（公告）日：2013-04-18

  The present teaching provide indazole compounds represented by Structural Formulae (I) or (I') or a pharmaceutically acceptable salt thereof. Also described are pharmaceutical compositions and methods of use thereof as protein kinase inhibitors, such as TTK protein kinase, polo-like kinase 4 (PLK4) and Aurora kinases having anticancer activity against breast cancer cells, colon cancer cells, and ovarian cancer cells.

  本教学提供了由结构式（I）或（I'）表示的吲唑化合物或其药用可接受的盐。还描述了这些药物组合物及其用作蛋白激酶抑制剂的方法，如对乳腺癌细胞、结肠癌细胞和卵巢癌细胞具有抗癌活性的TTK蛋白激酶、极化样激酶4（PLK4）和极化激酶。
• INDAZOLE COMPOUNDS AS KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
  申请人：University Health Network

  公开号：US20140371202A1

  公开（公告）日：2014-12-18

  The present teaching provide indazole compounds represented by Structural Formulae (I) or (I′) or a pharmaceutically acceptable salt thereof. Also described are pharmaceutical compositions and methods of use thereof as protein kinase inhibitors, such as TTK protein kinase, polo-like kinase 4 (PLK4) and Aurora kinases having anticancer activity against breast cancer cells, colon cancer cells, and ovarian cancer cells.

  本教学提供由结构式（I）或（I'）所代表的吲唑化合物或其药学上可接受的盐。还描述了制备药物组合物和使用方法，作为蛋白激酶抑制剂，例如TTK蛋白激酶，极化样激酶4（PLK4）和极化激酶，对乳腺癌细胞，结肠癌细胞和卵巢癌细胞具有抗癌活性。
• KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
  申请人：UNIVERISTY HEALTH NETWORKS

  公开号：US20140051679A1

  公开（公告）日：2014-02-20

  The present teachings provide a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. Also described are pharmaceutical compositions and methods of use thereof.

  本文提供了一种由结构式（I）表示的化合物，或其药学上可接受的盐。还描述了这些药物组合物的制备方法和使用方法。
• US9580390B2
  申请人：——

  公开号：US9580390B2

  公开（公告）日：2017-02-28
• The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1<i>H</i>-indazole-5-carboxamides as Anticancer Agents
  作者：Yong Liu、Yunhui Lang、Narendra Kumar Patel、Grace Ng、Radoslaw Laufer、Sze-Wan Li、Louise Edwards、Bryan Forrest、Peter B. Sampson、Miklos Feher、Fuqiang Ban、Donald E. Awrey、Irina Beletskaya、Guodong Mao、Richard Hodgson、Olga Plotnikova、Wei Qiu、Nickolay Y. Chirgadze、Jacqueline M. Mason、Xin Wei、Dan Chi-Chia Lin、Yi Che、Reza Kiarash、Brian Madeira、Graham C. Fletcher、Tak W. Mak、Mark R. Bray、Henry W. Pauls

  DOI：10.1021/jm501740a

  日期：2015.4.23

  The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI(50) < 0.1 mu M), displayed low off-target activity (>500X), and microsomal stability (T-1/2 > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.