1-(4-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(4-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea
• 英文别名: 1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(4-methyl-3-trifluoromethyl-phenyl)-urea；1-[4-(6-chloropyrimidin-4-yl)oxyphenyl]-3-[4-methyl-3-(trifluoromethyl)phenyl]urea
• 化学式: C₁₉H₁₄ClF₃N₄O₂
• 分子量: 422.794
• InChiKey: KFGJMZXOWMPANT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  76.1
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(4-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea 在 盐酸 、 对甲苯磺酸 作用下， 以 甲醇 、 叔丁醇 为溶剂， 反应 6.0h， 生成 (R)-1-(4-methyl-3-(trifluoromethyl)phenyl)-3-(4-((6-(2-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)phenyl)urea
  参考文献：
  名称：

  Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

  摘要：

  Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.

  DOI：

  10.1021/acs.jmedchem.8b01594
• 作为产物：
  描述：

  对氨基苯酚 在 potassium carbonate 、 N,N-二异丙基乙胺 、 copper(ll) bromide 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 18.17h， 生成 1-(4-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea
  参考文献：
  名称：

  Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

  摘要：

  Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.

  DOI：

  10.1021/acs.jmedchem.8b01594

文献信息

• Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases
  申请人：Floersheimer Andreas

  公开号：US20060128734A1

  公开（公告）日：2006-06-15

  The invention relates to the use of diaryl urea derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceutical preparations comprising diaryl urea derivatives for the treatment of said diseases, diaryl urea derivatives for use in the treatment of said diseases, novel diaryl urea derivatives, pharmaceutical preparations comprising these novel diaryl urea derivatives, processes for the manufacture of the novel diaryl urea derivatives, the use or methods of use of the novel diaryl urea derivatives as mentioned above, and/or these novel diaryl urea derivatives for use in the treatment of the animal or human body.

  本发明涉及在蛋白激酶依赖性疾病的治疗中使用二芳基脲衍生物或用于制造用于治疗该类疾病的药物组合物，二芳基脲衍生物在治疗该类疾病中的使用方法，包含二芳基脲衍生物的制备用于治疗该类疾病的制药制剂，用于治疗该类疾病的二芳基脲衍生物，新型的二芳基脲衍生物，包含这些新型二芳基脲衍生物的制药制剂，制造这些新型二芳基脲衍生物的方法，上述新型二芳基脲衍生物的使用或使用方法，以及/或这些新型二芳基脲衍生物用于治疗动物或人体。
• US7652022B2
  申请人：——

  公开号：US7652022B2

  公开（公告）日：2010-01-26
• Discovery of <i>N</i>-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia
  作者：Xiaofei Liang、Beilei Wang、Cheng Chen、Aoli Wang、Chen Hu、Fengming Zou、Kailin Yu、Qingwang Liu、Feng Li、Zhenquan Hu、Tingting Lu、Junjie Wang、Li Wang、Ellen L. Weisberg、Lili Li、Ruixiang Xia、Wenchao Wang、Tao Ren、Jian Ge、Jing Liu、Qingsong Liu

  DOI：10.1021/acs.jmedchem.8b01594

  日期：2019.1.24

  Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.