1-(3-(2-Hydroxyethyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile | 1160501-79-0

• 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: 1-(3-(2-Hydroxyethyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile
• 英文别名: 1-[3-(2-hydroxyethyl)-5-[3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]phenyl]cyclopropane-1-carbonitrile
• CAS: 1160501-79-0
• 化学式: C₁₉H₁₅F₃N₄O
• 分子量: 372.35
• InChiKey: MTGNUTFABAEBRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  85.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(3-(2-Hydroxyethyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile 在 2,2,6,6-tetramethyl-piperidine-N-oxyl 、 sodium hypochlorite 、 sodium bromide 作用下， 以 水 、 丙酮 为溶剂， 反应 0.33h， 以57%的产率得到2-[3-(1-cyanocyclopropyl)-5-[3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]phenyl]acetic acid
  参考文献：
  名称：

  Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors

  摘要：

  Extensive phase II metabolism of an advanced PKC epsilon inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PR and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.082
• 作为产物：
  描述：

  1,3-二溴-5-氟苯 在 lithium chloro-isopropyl-magnesium chloride 、 丁腈 、 二(三叔丁基膦)钯 、 2-[[三(羟甲基)甲基]氨基]乙磺酸 、 四丁基溴化铵 、 palladium diacetate 、 sodium hydride 、 叔丁胺 、 N,N-二异丙基乙胺 、 1,4-双(二苯基膦)丁烷 、 三氟乙酸 、 lithium chloride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 甲苯 为溶剂， -20.0~165.0 ℃ 、101.33 kPa 条件下， 反应 85.0h， 生成 1-(3-(2-Hydroxyethyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile
  参考文献：
  名称：

  Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors

  摘要：

  Extensive phase II metabolism of an advanced PKC epsilon inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PR and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.082

文献信息

• KINASE INHIBITORS
  申请人：Jimenez Juan-Miguel

  公开号：US20090291937A1

  公开（公告）日：2009-11-26

  The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

  本发明涉及用作蛋白激酶抑制剂的化合物。本发明还提供了包含上述化合物的药学上可接受的组合物以及使用该组合物治疗各种疾病、病况或障碍的方法。本发明还提供了制备本发明化合物的方法。
• US8173635B2
  申请人：——

  公开号：US8173635B2

  公开（公告）日：2012-05-08
• US8367697B2
  申请人：——

  公开号：US8367697B2

  公开（公告）日：2013-02-05
• Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors
  作者：Jeremy J. Clemens、Timothy Coon、Brett B. Busch、Juliana L. Asgian、Sarah Hudson、Andreas Termin、Tina B. Flores、Dao Tran、Peggy Chiang、Sam Sperry、Ray Gross、Jeffrey Abt、Roger Heim、Sandra Lechner、Heather Twin、John Studley、Guy Brenchley、Philip N. Collier、Francoise Pierard、Andrew Miller、Chau Mak、Vadims Dvornikovs、Juan-Miguel Jimenez、Dean Stamos

  DOI：10.1016/j.bmcl.2014.05.082

  日期：2014.8

  Extensive phase II metabolism of an advanced PKC epsilon inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PR and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. (C) 2014 Elsevier Ltd. All rights reserved.