3-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide
• 英文别名: 3-amino-N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methylbenzamide
• 化学式: C₁₅H₁₂ClF₃N₂O
• 分子量: 328.721
• InChiKey: FMQLKEINBUWRPO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide 在 三甲基铝 作用下， 以 甲苯 为溶剂， 反应 2.0h， 生成 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methyl-3-(1-(2-(methylamino)pyrimidin-4-yl)cyclopropane-1-carboxamido)benzamide
  参考文献：
  名称：

  克服阻力的Pan-Raf抑制剂的合理设计，合成和生物学评估†

  摘要：

  具有DFG-in构象的选择性BRaf V600E抑制剂已被证明对黑色素瘤的一部分有效。然而，代表性抑制剂维罗非尼通过CRaf或BRAf WT依赖性方式迅速获得BRAf WT细胞的抗性。同时靶向Raf蛋白的所有亚型提供了增强功效以及降低获得性抗药性的前景。本文中，我们基于具有DFG-out构象的嘧啶支架作为泛Raf抑制剂，描述了一系列化合物I-01–I-22的设计和表征。其中，I-15结合所有Raf启动子，IC 50值为12.6 nM（BRaf V600E），30.1 nM（ARaf），19.7 nM（BRaf WT）和17.5 nM（CRaf），并证明了针对BRaf WT表型黑素瘤和BRaf V600E表型结直肠癌细胞的细胞活性。Western blot检测人黑素瘤SK-Mel-2细胞系中P-Erk的抑制作用表明，I-15在低至400 nM的浓度下抑制SK-Mel-2细胞系的增殖，而没有E

  DOI：

  10.1039/c7ob00518k
• 作为产物：
  描述：

  4-甲基-3-硝基苯甲酸 在 草酰氯 、 铁粉 、 氯化铵 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 3-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide
  参考文献：
  名称：

  设计，合成和评估基于嘧啶骨架的衍生物，作为有效的Pan-Raf抑制剂来克服耐药性。

  摘要：

  同时靶向所有Raf同工型提供了增强的功效以及降低的抗药性的前景。本文描述了一系列具有强力泛肽抑制剂的具有DFG-out构象的嘧啶支架的发现和表征。其中，具有优异泛泛效能的I-41表现出对BRafWT表型黑素瘤和BRafV600E表型结肠细胞的抑制活性。Western blotting结果显示，人黑素瘤SK-Mel-2细胞系中Erk的抑制作用表明I-41抑制了SK-Mel-2细胞的增殖而没有Erk的反常激活，这支持I-41可能成为良好的候选化合物。克服黑素瘤对当前BRafV600E抑制剂疗法的耐药性。I-41在大鼠中也具有良好的药代动力学特征。合成，SAR，线索选择，

  DOI：

  10.1016/j.ejmech.2017.02.041

文献信息

• Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
  作者：Lu Wang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Yanle Zhi、Li Zhang、Tianxiao Mao、Xiang Zhou、Yadong Chen、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2017.02.041

  日期：2017.4

  isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western

  同时靶向所有Raf同工型提供了增强的功效以及降低的抗药性的前景。本文描述了一系列具有强力泛肽抑制剂的具有DFG-out构象的嘧啶支架的发现和表征。其中，具有优异泛泛效能的I-41表现出对BRafWT表型黑素瘤和BRafV600E表型结肠细胞的抑制活性。Western blotting结果显示，人黑素瘤SK-Mel-2细胞系中Erk的抑制作用表明I-41抑制了SK-Mel-2细胞的增殖而没有Erk的反常激活，这支持I-41可能成为良好的候选化合物。克服黑素瘤对当前BRafV600E抑制剂疗法的耐药性。I-41在大鼠中也具有良好的药代动力学特征。合成，SAR，线索选择，
• COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
  申请人：Chen Weirong

  公开号：US20090036419A1

  公开（公告）日：2009-02-05

  The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.

  本发明提供了作为Raf蛋白激酶抑制剂有用的化合物。本发明还提供了这些化合物的组合物，以及治疗Raf介导疾病的方法。
• AN ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE AGONIST
  申请人：Farmar Licensing Co., Ltd.

  公开号：US20190194142A1

  公开（公告）日：2019-06-27

  The present invention discloses a compound of the formula (I), which acts as an agonist of adenosine monophosphate-activated protein kinase, which induce phosphorylation and activation of AMPKα, thereby further regulating downstream signaling pathways, inhibiting growth and proliferation of liver cancer cells and breast cancer cells, and also inducing apoptosis of adipocytes. Therefore, the compound provided by the present invention can be utilised for treatment and preparation of pharmaceutical composition for cancer, and lipid metabolism-related diseases or syndromes mediated by AMPK.

  本发明公开了一种化合物(I)的公式，该化合物作为腺苷单磷酸激活蛋白激酶的激动剂，诱导AMPKα的磷酸化和激活，从而进一步调节下游信号通路，抑制肝癌细胞和乳腺癌细胞的生长和增殖，并诱导脂肪细胞凋亡。因此，本发明提供的化合物可用于癌症的治疗和制备药物组合物，以及由AMPK介导的脂质代谢相关疾病或综合征。
• Adenosine monophosphate-activated protein kinase agonist
  申请人：NATIONAL YANG-MING UNIVERSITY

  公开号：US10793527B2

  公开（公告）日：2020-10-06

  The present invention discloses a compound of the formula (I), which acts as an agonist of adenosine monophosphate-activated protein kinase, which induce phosphorylation and activation of AMPKα, thereby further regulating downstream signaling pathways, inhibiting growth and proliferation of liver cancer cells and breast cancer cells, and also inducing apoptosis of adipocytes. Therefore, the compound provided by the present invention can be utilised for treatment and preparation of pharmaceutical composition for cancer, and lipid metabolism-related diseases or syndromes mediated by AMPK.

  本发明公开了一种式（I）化合物，它作为单磷酸腺苷激活蛋白激酶的激动剂，可诱导AMPKα磷酸化和活化，从而进一步调节下游信号通路，抑制肝癌细胞和乳腺癌细胞的生长和增殖，还可诱导脂肪细胞凋亡。因此，本发明提供的化合物可用于治疗和制备 AMPK 介导的癌症和脂质代谢相关疾病或综合征的药物组合物。
• Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors
  作者：Weimin Yang、Yadong Chen、Xiang Zhou、Yazhou Gu、Wenqi Qian、Fan Zhang、Wei Han、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2014.10.039

  日期：2015.1

  By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-Raf(V600E) inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-Raf(V600E)) cell lines with IC50 values of 3.190, 2276, 1.856, 1.632 mu M and 1.839 mu M, respectively, comparable with the positive control Vemurafenib (IC50 = 3.32 mu M). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-Raf(V600E)) and SK-MEL-2 (B-Raf(WT)) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-Raf(V600E)) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-Rat(WT)). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss. (C) 2014 Elsevier Masson SAS. All rights reserved.