N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide | 1237750-46-7

• 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: N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide
• 英文别名: N-(4-methyl-3-((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)-methylamino)phenyl)-3-(trifluoromethyl)benzamide；N-(4-methyl-3-((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)phenyl)-3-(trifluoromethyl)benzamide；N-[4-methyl-3-[[4-(methylamino)-2-methylsulfanylpyrimidin-5-yl]methylamino]phenyl]-3-(trifluoromethyl)benzamide
• CAS: 1237750-46-7
• 化学式: C₂₂H₂₂F₃N₅OS
• 分子量: 461.511
• InChiKey: WGFOBTRVTKLOLG-UHFFFAOYSA-N

物化性质

• 沸点：
  561.4±50.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide 在 potassium carbonate 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 71.0h， 生成 tert-butyl (S)-3-(8-methyl-6-(2-methyl-5-(3-(trifluoromethyl)-benzamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-2-yloxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  摘要：

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

  DOI：

  10.1021/acs.jmedchem.5b01618
• 作为产物：
  描述：

  4-氯-2-甲硫基嘧啶-5-羧酸乙酯 在 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 21.75h， 生成 N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  [EN] PREPARATION AND USE OF NOVEL PROTEIN KINASE INHIBITORS
  [FR] PRÉPARATION ET UTILISATION DE NOUVEAUX INHIBITEURS DE PROTÉINE KINASE

  摘要：

  这项发明提供了新型化合物以及使用这些化合物来治疗或预防癌症的方法。

  公开号：

  WO2016168992A1

文献信息

• A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl
  作者：Hwan Geun Choi、Pingda Ren、Francisco Adrian、Fangxian Sun、Hyun Soo Lee、Xia Wang、Qiang Ding、Guobao Zhang、Yongping Xie、Jianming Zhang、Yi Liu、Tove Tuntland、Markus Warmuth、Paul W. Manley、Jürgen Mestan、Nathanael S. Gray、Taebo Sim

  DOI：10.1021/jm901808w

  日期：2010.8.12

  The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I “gatekeeper” mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant

  为克服伊马替尼耐药而开发的第二代 Bcr-Abl 抑制剂尼罗替尼、达沙替尼和博舒替尼对 T315I“看门人”突变没有活性。在这里，我们描述了一种 II 型 T315I 抑制剂2 ( GNF - 7 )，基于 3,4-二氢嘧啶并[4,5- d ]嘧啶-2(1 H )-一个支架，能够有效抑制野生型和 T315I Bcr-Abl 以及其他临床相关的 Bcr-Abl 突变体，如 G250E、Q252H、Y253H、E255K、E255V、F317L 和 M351T，用于生化和细胞检测。此外，化合物2使用具有稳定荧光素酶表达的转化 T315I-Bcr-Abl-Ba/F3 细胞系，在生物发光异种移植小鼠模型中显示出针对 T315I-Bcr-Abl 的显着体内功效，而没有明显的毒性。化合物2是第一批能够抑制T315I的II型抑制剂之一，将作为设计第三代Bcr-Abl激酶抑制剂的重要线索。
• Preparation and use of novel protein kinase inhibitors
  申请人：Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

  公开号：US10364247B2

  公开（公告）日：2019-07-30

  The invention provides novel compounds and methods of using such compounds to treat or prevent cancer.

  本发明提供了新型化合物和使用此类化合物治疗或预防癌症的方法。
• PREPARATION AND USE OF NOVEL PROTEIN KINASE INHIBITORS
  申请人：Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

  公开号：US20180105528A1

  公开（公告）日：2018-04-19

  The invention provides novel compounds and methods of using such compounds to treat or prevent cancer.