4-{2-[3-(1-methylpyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenylamino]-1H-benzimidazol-5-yloxy}-pyridine-2-carboxylic acid methyl amide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-{2-[3-(1-methylpyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenylamino]-1H-benzimidazol-5-yloxy}-pyridine-2-carboxylic acid methyl amide
• 英文别名: N-methyl-4-({2-[(3-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-4-(trifluoromethyl)phenyl)amino]-1H-1,3-benzodiazol-5-yl}oxy)pyridine-2-carboxamide；N-methyl-4-[[2-[3-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-4-(trifluoromethyl)anilino]-3H-benzimidazol-5-yl]oxy]pyridine-2-carboxamide
• 化学式: C₂₇H₂₇F₃N₆O₃
• 分子量: 540.545
• InChiKey: CNFXCXPJZGOMBX-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-碘基-5-硝基苯甲醚 在 palladium on activated charcoal 吡啶 、 氢气 、 吡啶盐酸盐 、 铜 、 sodium cyanoborohydride 、 三苯基膦 、 三氟乙酸 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 65.0h， 生成 4-{2-[3-(1-methylpyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenylamino]-1H-benzimidazol-5-yloxy}-pyridine-2-carboxylic acid methyl amide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors

  摘要：

  Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).

  DOI：

  10.1021/jm070034i

文献信息

• US7531553B2
  申请人：——

  公开号：US7531553B2

  公开（公告）日：2009-05-12
• Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors
  作者：Michele H. Potashman、James Bready、Angela Coxon、Thomas M. DeMelfi,、Lucian DiPietro、Nicholas Doerr、Daniel Elbaum、Juan Estrada、Paul Gallant、Julie Germain、Yan Gu、Jean-Christophe Harmange、Stephen A. Kaufman、Rick Kendall、Joseph L. Kim、Gondi N. Kumar、Alexander M. Long、Seshadri Neervannan、Vinod F. Patel、Anthony Polverino、Paul Rose、Simon van der Plas、Douglas Whittington、Roger Zanon、Huilin Zhao

  DOI：10.1021/jm070034i

  日期：2007.9.1

  Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).