(E)-6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one oxime

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (E)-6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one oxime
• 英文别名: (NE)-N-(6,8-difluoro-3,4-dihydro-2H-naphthalen-1-ylidene)hydroxylamine
• 化学式: C₁₀H₉F₂NO
• 分子量: 197.184
• InChiKey: QAKMXDVZZLTKBQ-UKTHLTGXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  32.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one oxime 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 22.42h， 生成 7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
  参考文献：
  名称：

  [EN] HETEROCYCLIC AMIDES AS KINASE INHIBITORS
  [FR] AMIDES HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE KINASE

  摘要：

  揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，用于治疗RIP1激酶介导的疾病或紊乱；特别揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，其中至少一种其他治疗活性药剂是免疫调节剂，用于治疗癌症。

  公开号：

  WO2018154520A1
• 作为产物：
  描述：

  6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 、 水 为溶剂， 反应 2.33h， 以96%的产率得到(E)-6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one oxime
  参考文献：
  名称：

  [EN] HETEROCYCLIC AMIDES AS KINASE INHIBITORS
  [FR] AMIDES HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE KINASE

  摘要：

  揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，用于治疗RIP1激酶介导的疾病或紊乱；特别揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，其中至少一种其他治疗活性药剂是免疫调节剂，用于治疗癌症。

  公开号：

  WO2018154520A1

文献信息

• [EN] HETEROCYCLIC AMIDES AS KINASE INHIBITORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE KINASE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2018154520A1

  公开（公告）日：2018-08-30

  Disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent for use in the treatment of a RIP1 kinase mediated disease or disorder; particularly disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent, wherein the at least one other therapeutically active agent is an immuno-modulator, for use in the treatment of cancer.

  揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，用于治疗RIP1激酶介导的疾病或紊乱；特别揭示了一种RIP1激酶抑制剂化合物与至少一种其他治疗活性药剂的组合，其中至少一种其他治疗活性药剂是免疫调节剂，用于治疗癌症。
• [EN] HETEROCYCLIC AMIDES AS KINASE INHIBITORS FOR USE IN THE TREATMENT CANCER<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QU'INHIBITEURS DE KINASES DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2020044206A1

  公开（公告）日：2020-03-05

  Disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg. Also disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg, and administering to the human a PD1 antagonist thereof at a dose of about 200 mg.

  揭示了一种治疗人类癌症的方法，该方法包括向患者施用大约50毫克至约1600毫克的RIP1激酶抑制剂。还揭示了一种治疗人类癌症的方法，该方法包括向患者施用大约50毫克至约1600毫克的RIP1激酶抑制剂，并向患者施用大约200毫克的PD1拮抗剂。
• HETEROCYCLIC AMIDES AS KINASE INHIBITORS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US20200062735A1

  公开（公告）日：2020-02-27

  Disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent for use in the treatment of a RIP1 kinase mediated disease or disorder; particularly disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent, wherein the at least one other therapeutically active agent is an immuno-modulator, for use in the treatment of cancer.
• Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer
  作者：Philip A. Harris、Jill M. Marinis、John D. Lich、Scott B. Berger、Anirudh Chirala、Julie A. Cox、Patrick M. Eidam、Joshua N. Finger、Peter J. Gough、Jae U. Jeong、James Kang、Viera Kasparcova、Lara K. Leister、Mukesh K. Mahajan、George Miller、Rakesh Nagilla、Michael T. Ouellette、Michael A. Reilly、Alan R. Rendina、Elizabeth J. Rivera、Helen H. Sun、James H. Thorpe、Rachel D. Totoritis、Wei Wang、Dongling Wu、Daohua Zhang、John Bertin、Robert W. Marquis

  DOI：10.1021/acsmedchemlett.9b00108

  日期：2019.6.13

  RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.