2-(3-ethanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide | 1226784-85-5

• 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-ethanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide
• 英文别名: 2-[3-(ethylsulfonylamino)phenoxy]-4-fluoro-6-(2-fluoro-4-iodoanilino)benzamide
• CAS: 1226784-85-5
• 化学式: C₂₁H₁₈F₂IN₃O₄S
• 分子量: 573.359
• InChiKey: WUDZJQWBTPHKFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  119
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(3-ethanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide 在 三氟甲磺酸N-吡啶鎓 作用下， 以 1,1,2-三氯乙烷 为溶剂， 以8%的产率得到C₂₁H₁₇F₃IN₃O₄S
  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：

  2-氟-4-碘苯胺 在 异丁酰胺 、 caesium carbonate 、 N,N-二异丙基乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(3-ethanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide
  参考文献：
  名称：

  Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories

  摘要：

  Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.02.028

文献信息

• 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 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。
• [EN] SUBSTITUTED SULPHONAMIDO PHENOXYBENZAMIDES<br/>[FR] SULFONAMIDO PHÉNOXYBENZAMIDES SUBSTITUÉS
  申请人：BAYER SCHERING PHARMA AG

  公开号：WO2010051933A3

  公开（公告）日：2010-07-15
• US8993630B2
  申请人：——

  公开号：US8993630B2

  公开（公告）日：2015-03-31
• Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties
  作者：Ingo V. Hartung、Stefanie Hammer、Marion Hitchcock、Roland Neuhaus、Arne Scholz、Gerhard Siemeister、Rolf Bohlmann、Roman C. Hillig、Florian Pühler

  DOI：10.1016/j.bmcl.2015.11.004

  日期：2016.1

  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.