N-t-butoxycarbonyl-5-chloro-2-nitroaniline | 388571-30-0

• 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: N-t-butoxycarbonyl-5-chloro-2-nitroaniline
• 英文别名: tert-Butyl (5-chloro-2-nitrophenyl)carbamate；tert-butyl N-(5-chloro-2-nitrophenyl)carbamate
• CAS: 388571-30-0
• 化学式: C₁₁H₁₃ClN₂O₄
• 分子量: 272.688
• InChiKey: LOEZZJGKZFOPKK-UHFFFAOYSA-N

物化性质

• 沸点：
  327.1±32.0 °C(Predicted)
• 密度：
  1.348±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  84.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-t-butoxycarbonyl-5-chloro-2-nitroaniline 在 sodium dithionite 、 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.67h， 以99%的产率得到tert-butyl N-(2-amino-5-chlorophenyl)carbamate
  参考文献：
  名称：

  通过虚拟筛选发现选择性Aurora A激酶抑制剂

  摘要：

  在这里，我们报告发现了Aurora A选择性抑制剂的发现，Aurora A是细胞分裂和潜在抗癌靶标的关键调节剂。我们使用原子类别扩展配体重叠评分（xLOS），这是我们小组最近开发的一种基于3D配体的虚拟筛选方法，用于选择437种参考激酶抑制剂的形状和药效基团类似物。生化筛选发现了两个激酶抑制剂系列中空前的支架抑制剂系列。其中一种已通过基于结构的设计成功优化为有效的Aurora A抑制剂（IC 50= 2 nM），对Aurora激酶具有非常高的激酶组选择性。该抑制剂将Aurora A锁定为非活性构象，并破坏与其激活蛋白TPX2的结合，从而削弱Aurora A在有丝分裂纺锤体上的定位并诱导细胞分裂缺陷。该表型可以通过抗抑制剂的Aurora A突变体挽救。此外，该抑制剂在细胞中不诱导Aurora B特异性作用。

  DOI：

  10.1021/acs.jmedchem.6b00709
• 作为产物：
  描述：

  tert-butyl N-tert-butoxycarbonyl-N-(5-chloro-2-nitro-phenyl)carbamate 在 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以94%的产率得到N-t-butoxycarbonyl-5-chloro-2-nitroaniline
  参考文献：
  名称：

  Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection

  摘要：

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.

  DOI：

  10.1021/acs.jmedchem.8b01523

文献信息

• Process for producing N-acylnitroaniline derivative
  申请人：Sumitomo Chemical Company, Limited

  公开号：EP1172356B1

  公开（公告）日：2004-10-06
• Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection
  作者：Kenneth L. Granberg、Zhong-Qing Yuan、Bo Lindmark、Karl Edman、Johan Kajanus、Anders Hogner、Marcus Malmgren、Gavin O’Mahony、Anneli Nordqvist、Jan Lindberg、Stefan Tångefjord、Michael Kossenjans、Christian Löfberg、Jonas Brånalt、Dongmei Liu、Nidhal Selmi、Grigorios Nikitidis、Peter Nordberg、Ahlke Hayen、Anna Aagaard、Eva Hansson、Majlis Hermansson、Ida Ivarsson、Rasmus Jansson-Löfmark、Ulla Karlsson、Ulrika Johansson、Lena William-Olsson、Judith Hartleib-Geschwindner、Krister Bamberg

  DOI：10.1021/acs.jmedchem.8b01523

  日期：2019.2.14

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.
• Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening
  作者：Falco Kilchmann、Maria J. Marcaida、Sachin Kotak、Thomas Schick、Silvan D. Boss、Mahendra Awale、Pierre Gönczy、Jean-Louis Reymond

  DOI：10.1021/acs.jmedchem.6b00709

  日期：2016.8.11

  with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division

  在这里，我们报告发现了Aurora A选择性抑制剂的发现，Aurora A是细胞分裂和潜在抗癌靶标的关键调节剂。我们使用原子类别扩展配体重叠评分（xLOS），这是我们小组最近开发的一种基于3D配体的虚拟筛选方法，用于选择437种参考激酶抑制剂的形状和药效基团类似物。生化筛选发现了两个激酶抑制剂系列中空前的支架抑制剂系列。其中一种已通过基于结构的设计成功优化为有效的Aurora A抑制剂（IC 50= 2 nM），对Aurora激酶具有非常高的激酶组选择性。该抑制剂将Aurora A锁定为非活性构象，并破坏与其激活蛋白TPX2的结合，从而削弱Aurora A在有丝分裂纺锤体上的定位并诱导细胞分裂缺陷。该表型可以通过抗抑制剂的Aurora A突变体挽救。此外，该抑制剂在细胞中不诱导Aurora B特异性作用。