methyl (E)-3-(4-((2(diethylamino)ethyl)amino)-3-nitrophenyl)acrylate | 929018-72-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: methyl (E)-3-(4-((2(diethylamino)ethyl)amino)-3-nitrophenyl)acrylate
• 英文别名: 04-PRAN；(E)-3-[4-(2-diethylaminoethylamino)-3-nitrophenyl]acrylic acid methyl ester；3-(4-(2-diethylaminoethylamino)-3-nitrophenyl)-acrylic acid methyl ester；methyl (E)-3-[4-[2-(diethylamino)ethylamino]-3-nitrophenyl]prop-2-enoate
• CAS: 929018-72-4
• 化学式: C₁₆H₂₃N₃O₄
• 分子量: 321.376
• InChiKey: YIJLIUBTCZOISZ-VQHVLOKHSA-N

物化性质

• 沸点：
  474.0±45.0 °C(Predicted)
• 密度：
  1.183±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  87.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (E)-3-(4-((2(diethylamino)ethyl)amino)-3-nitrophenyl)acrylate 在 tin(II) chloride dihdyrate 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

  摘要：

  A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC I enzyme and COLO 205 cellular IC50), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dos-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

  DOI：

  10.1021/jm2003552
• 作为产物：
  描述：

  4-氯-3-硝基肉桂酸 在 硫酸 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 生成 methyl (E)-3-(4-((2(diethylamino)ethyl)amino)-3-nitrophenyl)acrylate
  参考文献：
  名称：

  控制异羟肟酸的血浆稳定性：MedChem工具箱

  摘要：

  异羟肟酸是杰出的锌螯合基团，可用于设计各种治疗领域中的有效和选择性金属酶抑制剂。一些异羟肟酸显示出较高的血浆清除率，导致体内活性差，尽管它们在体外可能是非常有效的化合物。我们设计了一个由57名成员组成的异羟肟酸文库，以探索这些系列中结构与血浆的稳定性关系，并确定哪些酶和哪些药效团对血浆稳定性至关重要。芳基酯酶和羧酸酯酶被确定为异羟肟酸的主要代谢酶。最后，我们建议引入或删除结构特征以提高稳定性。因此，这项工作提供了第一个药物化学工具箱（实验程序和结构指导），用于评估和控制异羟肟酸的血浆稳定性，并充分发挥其作为体内药理探针和治疗剂的潜力。这项研究与临床前开发特别相关，因为它允许获得在人和啮齿动物模型中同样稳定的化合物。

  DOI：

  10.1021/acs.jmedchem.7b01444

文献信息

• Heterocyclic Compounds
  申请人：Chen Dizhong

  公开号：US20090048300A1

  公开（公告）日：2009-02-19

  The present invention relates to compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to heterocyclic compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase (HDAC) activities.

  本发明涉及一种组合物，该组合物是组蛋白去乙酰化酶的抑制剂。更具体地，本发明涉及杂环化合物及其制备方法。这些化合物可能作为药物用于治疗增殖性疾病以及涉及、与或与组蛋白去乙酰化酶（HDAC）活性有关的其他疾病。
• COMBINATION OF BENZIMIDAZOLE ANTI-CANCER AGENT AND A SECOND ANTI-CANCER AGENT
  申请人：Goh Kay Lin

  公开号：US20100098691A1

  公开（公告）日：2010-04-22

  The present invention relates to a pharmaceutical composition for the treatment of cancer as well as methods of treatment of cancer that are based on the finding that certain benzimidazole based anti-cancer agents can be used in combination with a second anti-cancer agent to achieve desirable therapeutic outcomes. More specifically the present invention relates to a pharmaceutical composition including a benzimidazole based anti-cancer agent and a second anti-cancer agent. The invention also relates to methods of treatment of cancer including administration of a benzimidazole based anti-cancer agent and a second anti-cancer agent to a patient in need thereof.

  本发明涉及一种用于癌症治疗的制药组合物，以及基于发现某些基于苯并咪唑的抗癌药物可以与第二种抗癌药物结合使用以达到理想的治疗效果的癌症治疗方法。更具体地，本发明涉及一种包括基于苯并咪唑的抗癌药物和第二种抗癌药物的制药组合物。本发明还涉及癌症治疗方法，包括向需要治疗的患者施用基于苯并咪唑的抗癌药物和第二种抗癌药物。
• N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: Design, synthesis, SAR studies, and in vivo antitumor activity
  作者：Haishan Wang、Niefang Yu、Hongyan Song、Dizhong Chen、Yong Zou、Weiping Deng、Pek Ling Lye、Joyce Chang、Melvin Ng、Stéphanie Blanchard、Eric T. Sun、Kanda Sangthongpitag、Xukun Wang、Kee Chuan Goh、Xiaofeng Wu、Hwee Hoon Khng、Lijuan Fang、Siok Kun Goh、Wai Chung Ong、Zahid Bonday、Walter Stünkel、Anders Poulsen、Michael Entzeroth

  DOI：10.1016/j.bmcl.2009.01.041

  日期：2009.3

  A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model. (C) 2009 Elsevier Ltd. All rights reserved.
• WO2007/30080
  申请人：——

  公开号：——

  公开（公告）日：——
• Minor structural modifications to Pracinostat produce big changes in its biological responses
  作者：Rong Jia、Pengju Sun、Yan Zhang、Youjin Ge、Niefang Yu

  DOI：10.1111/cbdd.13527

  日期：——

  AbstractA series of compounds similar to Pracinostat that contained benzimidazole ring and N‐hydroxyacrylamide attached at 5‐ or 6‐position were designed, synthesized, and evaluated as HDAC inhibitors. It was interesting to find that the corresponding derivative 1 with N‐hydroxyacrylamide attached at 5‐position was a potent HDAC inhibitor while the others at 6‐position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates.