3-((4-chloro-3-(trifluoromethyl)phenyl)amino)-3-oxopropanoic acid | 827029-04-9

• 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-((4-chloro-3-(trifluoromethyl)phenyl)amino)-3-oxopropanoic acid
• 英文别名: 3-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-propionic acid；3-[4-Chloro-3-(trifluoromethyl)anilino]-3-oxopropanoic acid
• CAS: 827029-04-9
• 化学式: C₁₀H₇ClF₃NO₃
• mdl: MFCD17946304
• 分子量: 281.619
• InChiKey: YGUUKWAFSDJGBV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-((4-chloro-3-(trifluoromethyl)phenyl)amino)-3-oxopropanoic acid 、 4-(4-吡啶甲基）苯胺 在 O-benzotriazol-1-yl-N,N,N',N'-bis(tetramethylene)uronium tetrafluoroborate 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 以23%的产率得到N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(pyridine-4-ylmethyl)phenyl]malonamid
  参考文献：
  名称：

  [EN] MALONAMIDE DERIVATIVES
  [FR] DERIVES DE MALONAMIDE

  摘要：

  公开号：

  WO2005005389A3
• 作为产物：
  描述：

  2-氯-5-氨基三氟甲苯 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 3-((4-chloro-3-(trifluoromethyl)phenyl)amino)-3-oxopropanoic acid
  参考文献：
  名称：

  Discovery of (E)-N¹-(3-Fluorophenyl)-N³-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

  摘要：

  Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.

  DOI：

  10.1021/acs.jmedchem.9b00176

文献信息

• Malonamide Derivatives
  申请人：Bruge David

  公开号：US20070213374A1

  公开（公告）日：2007-09-13

  The present invention relates to malonamide derivatives of formula A-D-B-1, as inhibitors of raf-kinase and the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition.

  本发明涉及公式A-D-B-1的马隆酰胺衍生物，作为raf-激酶的抑制剂，以及使用公式（I）化合物制备制药组合物的用途。
• [EN] MALONAMIDE DERIVATIVES<br/>[FR] DERIVES DE MALONAMIDE
  申请人：MERCK PATENT GMBH

  公开号：WO2005005389A3

  公开（公告）日：2005-03-24
• Discovery of (<i>E</i>)-<i>N</i>¹-(3-Fluorophenyl)-<i>N</i>³-(3-(2-(pyridin-2-yl)vinyl)-1<i>H</i>-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
  作者：Xuesong Liu、Beilei Wang、Cheng Chen、Ziping Qi、Fengming Zou、Junjie Wang、Chen Hu、Aoli Wang、Juan Ge、Qingwang Liu、Kailin Yu、Zhenquan Hu、Zongru Jiang、Wei Wang、Li Wang、Wenchao Wang、Tao Ren、Mingfeng Bai、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.9b00176

  日期：2019.5.23

  Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.