tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate | 1123583-13-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate
• 英文别名: tert-butyl N-[3-(2-amino-3-methylbenzimidazol-5-yl)oxyphenyl]carbamate
• CAS: 1123583-13-0
• 化学式: C₁₉H₂₂N₄O₃
• 分子量: 354.409
• InChiKey: JYDMHOAIKBOEHS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  91.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate 在 吡啶 、 4-二甲氨基吡啶 、 三氟乙酸 作用下， 反应 17.0h， 生成 N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x
• 作为产物：
  描述：

  2,4-二氟硝基苯 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 105.75h， 生成 tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x

文献信息

• HETEROCYCLIC COMPOUND AND USE THEREOF
  申请人：Hirose Masaaki

  公开号：US20110172245A1

  公开（公告）日：2011-07-14

  Provided is a heterocyclic compound showing strong Raf inhibitory activity. A compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是一种具有强烈Raf抑制活性的杂环化合物。该化合物由以下式表示：其中每个符号如规范中定义，或其盐。
• Heterocyclic compound and use thereof
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08324395B2

  公开（公告）日：2012-12-04

  Provided is a heterocyclic compound showing strong Raf inhibitory activity. A compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是一种具有较强Raf抑制活性的杂环化合物。该化合物由下式所表示：其中每个符号如规范中所定义，或其盐。
• Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds
  作者：Masanori Okaniwa、Masaaki Hirose、Takashi Imada、Tomohiro Ohashi、Youko Hayashi、Tohru Miyazaki、Takeo Arita、Masato Yabuki、Kazuyo Kakoi、Juran Kato、Terufumi Takagi、Tomohiro Kawamoto、Shuhei Yao、Akihiko Sumita、Shunichirou Tsutsumi、Tsuneaki Tottori、Hideyuki Oki、Bi-Ching Sang、Jason Yano、Kathleen Aertgeerts、Sei Yoshida、Tomoyasu Ishikawa

  DOI：10.1021/jm300126x

  日期：2012.4.12

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.