2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide | 1084332-21-7

• 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: 2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide
• 英文别名: 2-(3-aminophenoxy)-4-fluoro-6-(2-fluoro-4-iodoanilino)benzamide
• CAS: 1084332-21-7
• 化学式: C₁₉H₁₄F₂IN₃O₂
• 分子量: 481.24
• InChiKey: ZHLNWTCZQUZDSX-UHFFFAOYSA-N

物化性质

• 沸点：
  501.8±50.0 °C(Predicted)
• 密度：
  1.733±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  90.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide 在 甲酸 、 氯磺酰异氰酸酯 、 N,N-二甲基乙酰胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 2-[3-[[(amino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide
  参考文献：
  名称：

  Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties

  摘要：

  Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.11.004
• 作为产物：
  描述：

  3-羟基苯基氨基甲酸叔丁酯 在 sodium hydroxide 、 potassium tert-butylate 、 sodium hydride 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 45.83h， 生成 2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide
  参考文献：
  名称：

  WO2008/138639

  摘要：

  公开号：

文献信息

• Substituted phenylamino-benzene derivatives useful for treating hyper-proliferative disorders and diseases associated with mitogen extracellular kinase activity
  申请人：Li Yingfu

  公开号：US20090082328A1

  公开（公告）日：2009-03-26

  This invention relates to novel substituted phenylamino-benzene compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

  本发明涉及新颖的取代苯基氨基苯化合物、含有这些化合物的药物组合物以及将这些化合物或组合物作为唯一活性成分或与其他活性成分联合使用治疗增生和/或血管生成异常的用途。
• SUBSTITUTED PHENYLAMINO-BENZENE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH MITOGEN EXTRACELLULAR KINASE ACTIVITY
  申请人：Rudolph Joachim

  公开号：US20110071125A1

  公开（公告）日：2011-03-24

  This invention relates to novel substituted phenylamino-benzene compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

  本发明涉及新型取代苯胺基苯化合物、含有这种化合物的制药组合物以及将这些化合物或组合物用于治疗增殖过度和/或血管生成障碍，作为单一药物或与其他活性成分联合使用的用途。
• SUBSTITUTED SULPHONAMIDO PHENOXYBENZAMIDES
  申请人：Hartung Ingo

  公开号：US20110218219A1

  公开（公告）日：2011-09-08

  The present invention relates to substituted sulphonamido phenoxybenzamide compounds of general formula (I): in which A, R1, R2, R3, R4, R5, R6, R7, R8 and n are as defined in the claims, to pharmaceutical compositions and combinations containing said compounds, to methods of preparing said compounds, and to the use of said compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式（I）的取代磺酰胺基苯氧基苯甲酰胺化合物，其中A、R1、R2、R3、R4、R5、R6、R7、R8和n如权利要求中所定义，以及包含所述化合物的制药组合物和组合物，制备所述化合物的方法，以及使用所述化合物或组合物治疗过度增生和/或血管生成障碍，作为唯一药剂或与其他活性成分组合使用。
• SUBSTITUTED AMIDO PHENOXYBENZAMIDES
  申请人：Hartung Ingo

  公开号：US20110237592A1

  公开（公告）日：2011-09-29

  The present invention relates to substituted amido phenoxybenzamide compounds of general formula (I): in which A, R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined in the claims, to pharmaceutical compositions and combinations containing said compounds, to methods of preparing said compounds, and to the use of said compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式（I）的取代氨基苯氧基苯酰胺化合物，其中A，R1，R2，R3，R4，R5，R6，R7，R8，R9和n如权利要求所定义，以及包含所述化合物的制药组合物和组合物，制备所述化合物的方法以及使用所述化合物或组合物治疗增生性和/或血管生成障碍的用途，作为单一制剂或与其他活性成分组合使用。
• Substituted sulphonamido phenoxybenzamides
  申请人：Hartung Ingo

  公开号：US08993630B2

  公开（公告）日：2015-03-31

  The present invention relates to substituted sulphonamido phenoxybenzamide compounds of general formula (I): in which A, R1, R2, R3, R4, R5, R6, R7, R8 and n are as defined in the claims, to pharmaceutical compositions and combinations containing said compounds, to methods of preparing said compounds, and to the use of said compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式（I）的取代磺酰胺基苯氧基苯甲酰胺化合物，其中A，R1，R2，R3，R4，R5，R6，R7，R8和n如权利要求所定义，以及包含所述化合物的制药组合物和组合物，制备所述化合物的方法，以及使用所述化合物或组合物治疗增生过度和/或血管生成障碍作为唯一药物或与其他活性成分组合使用。