BAY-438 | 1295505-76-8

• 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: BAY-438
• 英文别名: 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{3-[(sulfamoylamino)methyl]phenoxy}benzamide；3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-[3-[(sulfamoylamino)methyl]phenoxy]benzamide
• CAS: 1295505-76-8
• 化学式: C₂₀H₁₆F₃IN₄O₄S
• 分子量: 592.337
• InChiKey: KQYTZJXGFPXBER-UHFFFAOYSA-N

物化性质

• 沸点：
  570.1±60.0 °C(Predicted)
• 密度：
  1.798±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  145
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3,4,5-三氟苯硼酸 在 吡啶 、 氨 、 copper diacetate 、 N,N'-羰基二咪唑 、 三氟乙酸 、 lithium hexamethyldisilazane 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 BAY-438
  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

文献信息

• [EN] SUBSTITUTED HALOPHENOXYBENZAMIDE DERIVATIVES<br/>[FR] DÉRIVÉS D'HALOGÉNOPHÉNOXYBENZAMIDE SUBSTITUÉS
  申请人：BAYER SCHERING PHARMA AG

  公开号：WO2011047796A1

  公开（公告）日：2011-04-28

  The present invention relates to substituted halophenoxybenzamide derivative compounds of general formula (I) in which R1, R2, R3, R3a, R4, R5, R6, Ra, Rb, Rc, and X are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及通式（I）中R1、R2、R3、R3a、R4、R5、R6、Ra、Rb、Rc和X所定义的取代卤苯氧基苯甲酰衍生物化合物，以及制备该化合物的方法，包括含有该化合物的药物组合物和药物组合物的使用，用于制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分组合使用，治疗或预防增殖亢进和/或血管生成障碍。
• SUBSTITUTED HALOPHENOXYBENZAMIDE DERIVATIVES
  申请人：Hitchcock Marion

  公开号：US20120263714A1

  公开（公告）日：2012-10-18

  The present invention relates to substituted halophenoxybenzamide derivative compounds of general formula (I) in which R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , R a , R b , R c , and X are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式（I）的取代卤代苯氧基苯甲酰胺衍生物化合物，其中R1、R2、R3、R3a、R4、R5、R6、Ra、Rb、Rc和X如权利要求中所定义，以及制备所述化合物的方法，包括所述化合物的制药组合物和组合物，以及使用所述化合物制造治疗或预防疾病的制药组合物，特别是治疗或预防增生和/或血管生成异常的疾病，作为单独药物或与其他活性成分组合使用。
• 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.