5-(5-氯噻吩-2-基)异恶唑-3-羧酸乙酯 | 323594-72-5

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 中文名称: 5-(5-氯噻吩-2-基)异恶唑-3-羧酸乙酯
• 英文名称: ethyl 5-(5-chlorothiophen-2-yl)isoxazole-3-carboxylate
• 英文别名: ethyl 5-(5-chlorothiophen-2-yl)-1,2-oxazole-3-carboxylate
• CAS: 323594-72-5
• 化学式: C₁₀H₈ClNO₃S
• mdl: MFCD20131614
• 分子量: 257.697
• InChiKey: WDAZHKHLVOUBBY-UHFFFAOYSA-N

物化性质

• 沸点：
  399.9±42.0 °C(Predicted)
• 密度：
  1.381±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  80.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-(5-氯噻吩-2-基)异恶唑-3-羧酸乙酯 在 lithium hydroxide 、 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 PPh₃(polystyrene-bound) 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 生成 6-Chloro-1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
  参考文献：
  名称：

  探查因子Xa的子链揭示了基于2-羧基吲哚支架的抑制剂的两种结合模式：结合结构-活性关系和X射线晶体学的研究。

  摘要：

  描述了一系列结合了中性P1配体的高效能2-羧基吲哚基因子Xa抑制剂之间的结构活性关系，尤其着重于解决因子Xa酶亚口袋的结构要求。通过系统地取代2-羧基吲哚支架与优先的P1和P4取代基来探索与亚口袋的相互作用。在吲哚核上结合最有利的取代基导致发现显示K（i）值为0.07 nM的非常有效的Xa抑制剂。与因子Xa结合的抑制剂的X射线晶体学分析揭示了抑制剂结合模式的取代基依赖性转换，并为获得的SAR提供了理论依据。

  DOI：

  10.1021/jm0490540
• 作为产物：
  描述：

  ethyl 4-(5-chlorothiophen-2-yl)-2,4-dioxobutanoate 在 盐酸羟胺 作用下， 以 乙醇 为溶剂， 以90%的产率得到5-(5-氯噻吩-2-基)异恶唑-3-羧酸乙酯
  参考文献：
  名称：

  取代吲哚-碳酰肼的设计、合成、光谱表征、体外酪氨酸酶抑制、抗氧化评价、计算机模拟和动力学研究

  摘要：

  在目前的研究中，合理设计和合成了 25 种与不同芳基取代相连的吲哚-碳酰肼衍生物。所有衍生物的结构均使用不同的光谱技术进行了确认，包括1 H NMR、13 C NMR、质谱和元素分析。所有合成化合物的酪氨酸酶抑制活性均表现出 0.070 至 > 100 μM 范围内的 IC 50值。构效关系表明，化合物4f（R = 4-OH，IC 50  = 0.070 μM）、8f（R = 4-OH，IC 50  = 0.072 μM）和19e（IC 50  = 0.19 μM）对发现 R 位置的 -OH 取代基是所有三个测试系列中最活跃的成员。动力学研究表明，化合物4f、8f和19e是混合型抑制剂。此外，对最有效的衍生物进行了毒性和基于细胞的抗黑素生成评估，结果表明4f、8f和19e在 8 µM 时没有毒性，并且在 8 µM 时黑色素含量百分比降至 68.43、72.61、73.47 μM，分别。在计

  DOI：

  10.1016/j.bioorg.2022.106140

文献信息

• Biarylmethoxy isonipecotanilides as potent and selective inhibitors of blood coagulation factor Xa
  作者：Gianfranco Lopopolo、Filomena Fiorella、Modesto de Candia、Orazio Nicolotti、Sophie Martel、Pierre-Alain Carrupt、Cosimo Altomare

  DOI：10.1016/j.ejps.2010.11.010

  日期：2011.2

  New chloro-substituted biarylmethoxyphenyl piperidine-4-carboxamides were synthesized and assayed in vitro as inhibitors of the blood coagulation enzymes factor Xa (fXa) and thrombin. An investigation of effects of the amidine and isopropyl groups attached at the piperidine nitrogen and 5-(halogenoaryl)isoxazol-3-yl groups as biaryl substituents led us to identify new compounds which proved to be selective fXa inhibitors, with inhibition constants in the low nanomolar range. The most potent compound 21e, that incorporates 2-Cl-thiophen-5-yl group as the P1 motif and 1-isopropylpiperidine P4 group, inhibited fXa with K-i value of 0.3 nM and very high selectivity over thrombin and some other tested serine proteases, achieving moderate levels of anticoagulant activity in the low micromolar range, as assessed by the prothrombin time clotting assay (PT2 = 3.30 mu M). Based on reliable docking simulations, molecular modeling provided a rationale for interpreting structure-activity relationships. The predicted binding modes highlighted the structural requirements for addressing the subsites S1 and S4 of the fXa enzyme. (C) 2010 Elsevier B.V. All rights reserved.
• Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?
  作者：Guyan Liang、Yong Mi Choi-Sledeski、Xin Chen、Yong Gong、Eric W. MacMillan、Joseph Tsay、Keith Sides、Jennifer Cairns、Berndt Kulitzscher、David J. Aldous、Isabelle Morize、Henry W. Pauls

  DOI：10.1016/j.bmcl.2012.01.021

  日期：2012.5

  The tetrameric folding of beta-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for beta-tryptase. (C) 2012 Elsevier Ltd. All rights reserved.
• Factor Xa inhibitors based on a 2-carboxyindole scaffold: SAR of neutral P1 substituents
  作者：Marc Nazaré、Melanie Essrich、David W Will、Hans Matter、Kurt Ritter、Matthias Urmann、Armin Bauer、Herman Schreuder、Angela Dudda、Jörg Czech、Martin Lorenz、Volker Laux、Volkmar Wehner

  DOI：10.1016/j.bmcl.2004.06.020

  日期：2004.8

  A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated with the 2-carboxyindole scaffold. This privileged fragment assembly approach yielded a set of equipotent, selective inhibitors with structurally diverse neutral P1 substituents. (C) 2004 Elsevier Ltd. All rights reserved.
• Probing Factor Xa Protein–Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands
  作者：María Isabel Fernández-Bachiller、Songhwan Hwang、María Elena Schembri、Peter Lindemann、Mónica Guberman、Svenja Herziger、Edgar Specker、Hans Matter、David W. Will、Jörg Czech、Michael Wagner、Armin Bauer、Herman Schreuder、Kurt Ritter、Matthias Urmann、Volkmar Wehner、Han Sun、Marc Nazaré

  DOI：10.1021/acs.jmedchem.2c00865

  日期：2022.10.13
• SUBSTITUTED OXOAZAHETEROCYCLYL COMPOUNDS
  申请人：Aventis Pharmaceuticals Inc.

  公开号：EP1208097A2

  公开（公告）日：2002-05-29