ethyl 4-(5-chlorothiophen-2-yl)-2,4-dioxobutanoate | 323594-71-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: ethyl 4-(5-chlorothiophen-2-yl)-2,4-dioxobutanoate
• CAS: 323594-71-4
• 化学式: C₁₀H₉ClO₄S
• 分子量: 260.698
• InChiKey: DZGRSWOCHJWVCI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  16
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  88.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-(5-chlorothiophen-2-yl)-2,4-dioxobutanoate 在 盐酸 、 sodium tetrahydroborate 、 tin(II) chloride dihdyrate 、 偶氮二甲酸二异丙酯 、 盐酸羟胺 、 sodium cyanoborohydride 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 131.0h， 生成 N-[2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methoxy]phenyl]-1-propan-2-ylpiperidine-4-carboxamide
  参考文献：
  名称：

  Biarylmethoxy isonipecotanilides as potent and selective inhibitors of blood coagulation factor Xa

  摘要：

  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.

  DOI：

  10.1016/j.ejps.2010.11.010
• 作为产物：
  描述：

  2-乙酰基-5-氯噻酚 、 草酸二乙酯 在 potassium tert-butylate 作用下， 以 甲苯 为溶剂， 反应 12.0h， 以50%的产率得到ethyl 4-(5-chlorothiophen-2-yl)-2,4-dioxobutanoate
  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

• Probing the Subpockets of Factor Xa Reveals Two Binding Modes for Inhibitors Based on a 2-Carboxyindole Scaffold:  A Study Combining Structure-Activity Relationship and X-ray Crystallography
  作者：Marc Nazaré、David W. Will、Hans Matter、Herman Schreuder、Kurt Ritter、Matthias Urmann、Melanie Essrich、Armin Bauer、Michael Wagner、Jörg Czech、Martin Lorenz、Volker Laux、Volkmar Wehner

  DOI：10.1021/jm0490540

  日期：2005.7.1

  remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in

  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。
• 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
• [EN] SUBSTITUTED OXOAZAHETEROCYCLYL COMPOUNDS<br/>[FR] COMPOSES D'OXOAZAHETEROCYCLYLE SUBSTITUE
  申请人：AVENTIS PHARM PROD INC

  公开号：WO2001007436A2

  公开（公告）日：2001-02-01

  This invention is directed to oxoazaheterocyclyl compounds which inhibit Factor Xa, to oxoazaheterocyclyl compounds which inhibit both Factor Xa and Factor IIa, to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds, to a method of directly inhibiting Factor Xa and to a method of simultaneously directly inhibiting Factor Xa and Factor IIa.