6-(6-chloro-pyrimidin-4-yloxy)naphthalene-1-carboxylic acid(3-trifluoromethyl phenyl)amide | 890128-71-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-(6-chloro-pyrimidin-4-yloxy)naphthalene-1-carboxylic acid(3-trifluoromethyl phenyl)amide
• 英文别名: 6-(6-chloropyrimidin-4-yl)oxy-N-[3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide
• CAS: 890128-71-9
• 化学式: C₂₂H₁₃ClF₃N₃O₂
• 分子量: 443.812
• InChiKey: IRMRHQFPMZOYEI-UHFFFAOYSA-N

物化性质

• 沸点：
  503.6±50.0 °C(Predicted)
• 密度：
  1.455±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  64.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-(6-chloro-pyrimidin-4-yloxy)naphthalene-1-carboxylic acid(3-trifluoromethyl phenyl)amide 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium tetrahydroborate 、 三乙胺 作用下， 以 叔丁醇 为溶剂， 65.0~110.0 ℃ 、12.0 MPa 条件下， 反应 30.5h， 生成 6-(6-hydroxymethyl pyrimidin-4-yloxy)naphthalene-1-carboxylic acid (3-trifluoromethyl phenyl)amide
  参考文献：
  名称：

  A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis

  摘要：

  This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

  DOI：

  10.1021/acs.jmedchem.5b01582
• 作为产物：
  描述：

  6-羟基-1-萘甲酸 在 4-二甲氨基吡啶 、 1-丙基磷酸酐 、 三乙胺 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 4.0h， 生成 6-(6-chloro-pyrimidin-4-yloxy)naphthalene-1-carboxylic acid(3-trifluoromethyl phenyl)amide
  参考文献：
  名称：

  A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis

  摘要：

  This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

  DOI：

  10.1021/acs.jmedchem.5b01582

文献信息

• Pharmaceutical Compositions and Solid Forms
  申请人：BERGHAUSEN Joerg

  公开号：US20110112121A1

  公开（公告）日：2011-05-12

  The present invention relates to pharmaceutical compositions of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, to the use of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide and compositions of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in therapeutic applications, especially indications with a dysregulation/overexpression of VEFG, (neo)-vascularisation and VEGF driven angiogenesis and to methods for manufacturing such compositions, the invention further relates to specific forms of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide and to the manufacturing and use of such forms. The present invention also relates to a new process to produce 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide.

  本发明涉及6-(6-羟甲基嘧啶-4-氧基)-萘-1-羧酸(3-三氟甲基苯基)-酰胺的药物组合物，以及使用6-(6-羟甲基嘧啶-4-氧基)-萘-1-羧酸(3-三氟甲基苯基)-酰胺和6-(6-羟甲基嘧啶-4-氧基)-萘-1-羧酸(3-三氟甲基苯基)-酰胺的组合物在治疗应用中，尤其是在VEGF的失调/过度表达、(新生)血管生成和VEGF驱动的血管生成方面的适应症，并且涉及制造此类组合物的方法，本发明还涉及6-(6-羟甲基嘧啶-4-氧基)-萘-1-羧酸(3-三氟甲基苯基)-酰胺的特定形式以及制造和使用此类形式的方法。本发明还涉及一种生产6-(6-羟甲基嘧啶-4-氧基)-萘-1-羧酸(3-三氟甲基苯基)-酰胺的新工艺。
• WO2007/31265
  申请人：——

  公开号：——

  公开（公告）日：——
• WO2006/59234
  申请人：——

  公开号：——

  公开（公告）日：——
• US8026247B2
  申请人：——

  公开号：US8026247B2

  公开（公告）日：2011-09-27
• [EN] PHARMACEUTICAL COMPOSITIONS AND SOLID FORMS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES ET FORMES SOLIDES
  申请人：NOVARTIS AG

  公开号：WO2011003858A2

  公开（公告）日：2011-01-13

  The present invention relates to pharmaceutical compositions of 6-(6-hydroxymethyl- pyrimidin-4-yloxy)-naphthalene-1-carboxyfic acid (3-trifluoromethyl-phenyl)-amide, to the use of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthatene-1-carboxylic acid (3-trifluoromethyI- phenyl)-amide and compositions of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-naphthalene-1- carboxylic acid (3-trifluoromethyi-phenyi)-amide in therapeutic applications, especially indications with a dysregulation/overexpression of VEFG, (neo)-vascularisation and VEGF driven angiogenesis and to methods for manufacturing such compositions, the invention further relates to specific forms of 6-(6-hydroxymethyl-pyrimidin-4-yloxy)-πaphthalene-1- carboxyiic acid (3-trifluαromethyl-phenyl)-amide and to the manufacturing and use of such forms. The present invention also relates to a new process to produce 6-6-hydroxymethyl- pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide.