dimethyl carbamic acid 4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-chromen-7-yl ester | 393810-93-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: dimethyl carbamic acid 4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-chromen-7-yl ester
• 英文别名: 4-Methyl-3-(3-nitrobenzyl)-2-oxo-2h-chromen-7-yl dimethylcarbamate；[4-methyl-3-[(3-nitrophenyl)methyl]-2-oxochromen-7-yl] N,N-dimethylcarbamate
• CAS: 393810-93-0
• 化学式: C₂₀H₁₈N₂O₆
• 分子量: 382.373
• InChiKey: FOXZPGBYHXQIAK-UHFFFAOYSA-N

物化性质

• 沸点：
  577.8±50.0 °C(Predicted)
• 密度：
  1.343±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  dimethyl carbamic acid 4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-chromen-7-yl ester 在 吡啶 、 甲酸 、 氯磺酰异氰酸酯 、 tin(II) chloride dihdyrate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙酸乙酯 、 甲苯 为溶剂， 反应 9.0h， 生成 4-(fluoromethyl)-2-oxo-3-(3-(sulfamoylamino)benzyl)-2H-chromen-7-yl dimethylcarbamate
  参考文献：
  名称：

  Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

  摘要：

  A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound la and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead la and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.

  DOI：

  10.1021/ml4002419
• 作为产物：
  描述：

  3-硝基溴苄 在 硫酸 、 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 dimethyl carbamic acid 4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-chromen-7-yl ester
  参考文献：
  名称：

  偶联的mTOR / MEK双功能抑制剂作为潜在的多药理抗癌剂：原型化合物的发现

  摘要：

  mTOR / MEK双功能抑制剂具有克服PI3K / Akt / mTOR（PAM）与Ras / MEK / ERK途径之间的串扰引起的耐药性的潜力。在本文中，我们报告了共轭双靶分子化合物13作为原型mTOR / MEK双功能抑制剂的发现。它显示出对mTOR和MEK1的适度高抑制活性，IC 50值分别为0.19μM和0.98μM。特别是，它对A549（GI 50  = 4.66μM）和HCT116（GI 50）均表现出有吸引力的抗增殖活性 = 5.47μM）细胞系。据我们所知，它是mTOR / MEK共轭双功能抑制剂的第一个实例。此外，从这项原理验证研究中，很明显，可以通过将mTOR激酶抑制剂共价连接至变构MEK抑制剂来实现mTOR和MEK的单剂双重抑制。

  DOI：

  10.1007/s00044-020-02502-x

文献信息

• [EN] DUAL MEK/PI3K INHIBITORS AND THERAPEUTIC METHODS USING THE SAME<br/>[FR] INHIBITEURS DOUBLES DE MEK/PI3K ET PROCÉDÉS THÉRAPEUTIQUES LES UTILISANT
  申请人：UNIV MICHIGAN

  公开号：WO2014164942A1

  公开（公告）日：2014-10-09

  Dual inhibitors of MEK and PI3K and compositions containing the same are disclosed. Methods of using the dual MEK/PI3K inhibitors in the treatment of diseases and conditions wherein inhibition of MEK and PI3K provides a benefit, like cancers, also are disclosed.

  抑制MEK和PI3K的双重抑制剂和含有它们的组合物已被披露。还披露了在治疗需要抑制MEK和PI3K以获益的疾病和情况中使用双重MEK/PI3K抑制剂的方法，如癌症。
• Novel Coumarin Derivative Having Antitumor Activity
  申请人：Iikura Hitoshi

  公开号：US20110092700A1

  公开（公告）日：2011-04-21

  The present invention provides a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof: wherein: X is selected from heteroaryl etc., Y 1 and Y 2 are selected from —N═ etc., Y 3 and Y 4 are selected from —CH═ etc., A is selected from sulfamide etc., R 1 is selected from hydrogen etc., and R 2 is selected from C 1-6 alkyl etc. The compound or salt has sufficiently high antitumor activity, and is useful in the treatment of cell proliferative disorders, particularly cancers. The present invention also provides a pharmaceutical composition containing the compound or salt as an active ingredient.

  本发明提供一种由下式（1）或其药学上可接受的盐所表示的化合物：其中，X选自杂环芳基等；Y1和Y2选自—N═等；Y3和Y4选自—CH═等；A选自磺酰胺等；R1选自氢等；R2选自C1-6烷基等。该化合物或盐具有足够高的抗肿瘤活性，并可用于治疗细胞增殖性疾病，特别是癌症。本发明还提供一种含有该化合物或盐作为活性成分的制药组合物。
• p27 Protein Inducer
  申请人：Sakai Toshiyuki

  公开号：US20110009398A1

  公开（公告）日：2011-01-13

  The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G 1 , G 2 , G 3 and G 8 are each independently selected from —N═ etc., Ring G 6 is selected from divalent aryl etc., A is selected from amino etc., G 4 is selected from oxygen etc., G 5 is selected from oxygen etc., G 7 is selected from —CH 2 — etc., and R 2 is selected from C 1-6 alkyl etc.

  本发明提供了一种p27蛋白诱导剂，其包含以下通式（11）所表示的化合物或其药学上可接受的盐作为活性成分：其中G1，G2，G3和G8各自独立地选择自—N═等，环G6选择自双价芳基等，A选择自氨基等，G4选择自氧等，G5选择自氧等，G7选择自—CH2—等，R2选择自C1-6烷基等。
• p27 PROTEIN INDUCER
  申请人：Chugai Seiyaku Kabushiki Kaisha

  公开号：EP2172198B1

  公开（公告）日：2014-04-16
• Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning
  作者：Toshihiro Aoki、Ikumi Hyohdoh、Noriyuki Furuichi、Sawako Ozawa、Fumio Watanabe、Masayuki Matsushita、Masahiro Sakaitani、Kenji Morikami、Kenji Takanashi、Naoki Harada、Yasushi Tomii、Koji Shiraki、Kentaro Furumoto、Mitsuyasu Tabo、Kiyoshi Yoshinari、Kazutomo Ori、Yuko Aoki、Nobuo Shimma、Hitoshi Iikura

  DOI：10.1021/ml400379x

  日期：2014.4.10

  Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 1 la and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound I (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.