5-chlorofuran-2-carbonitrile oxide

• 分子结构分类: 有机化合物 - 有机卤素化合物 - 芳基卤化物
• 英文名称: 5-chlorofuran-2-carbonitrile oxide
• 英文别名: 2-(5-chlorofuryl)carbonitrile oxide
• 化学式: C₅H₂ClNO₂
• 分子量: 143.529
• InChiKey: YRUNWWOIOMVMKD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  9
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  43.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-chlorofuran-2-carbonitrile oxide 在 sodium hydride 、 sodium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 13.0h， 生成 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole
  参考文献：
  名称：

  Synthesis, Pharmacological Characterization, and Docking Analysis of a Novel Family of Diarylisoxazoles as Highly Selective Cyclooxygenase-1 (COX-1) Inhibitors

  摘要：

  3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4-diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure activity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of S-methyl (or -CF3), 4-phenyl, and 5-chloro(-bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1-dependent thromboxane (TX) A(2). Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet-derived TXA(2) over protective vascular-derived prostac-yclin (PGI(2)).

  DOI：

  10.1021/jm301905a
• 作为产物：
  描述：

  5-chloro-2-furancarbohydroximoyl chloride 在 三乙胺 作用下， 生成 5-chlorofuran-2-carbonitrile oxide
  参考文献：
  名称：

  Synthesis, Pharmacological Characterization, and Docking Analysis of a Novel Family of Diarylisoxazoles as Highly Selective Cyclooxygenase-1 (COX-1) Inhibitors

  摘要：

  3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4-diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure activity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of S-methyl (or -CF3), 4-phenyl, and 5-chloro(-bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1-dependent thromboxane (TX) A(2). Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet-derived TXA(2) over protective vascular-derived prostac-yclin (PGI(2)).

  DOI：

  10.1021/jm301905a

文献信息

• 3-Aryl-5-vinyl-2-isoxazolines and 3-Aryl-5-vinylisoxazoles from Aryl Nitrile Oxides and Methyl Vinyl Ketone Lithium Enolate: Reaction Limits and Synthetic Utility Exploitation
  作者：Paola Vitale、Antonio Salomone、Antonio Scilimati

  DOI：10.1055/s-0034-1379640

  日期：——

  were synthesized by reacting aryl nitrile oxides with the lithium enolate of methyl vinyl ketone (MVK) at –78 °C. Fair to good yields are obtained in the case of aryl nitrile oxides bearing electron-withdrawing groups on the aryl moiety or less bulky groups. Conversely, lower yields or no reaction was observed in the presence of hindered aryl nitrile oxides. Such a behavior was confirmed by ab initio

  献给克劳迪奥·萨洛蒙（Claudio Salomone），2014年11月24日出生 抽象 3-芳基-5-羟基-5-乙烯基-2-异恶唑啉是通过使芳基腈氧化物与甲基乙烯基酮（MVK）的烯醇锂在–78°C下反应合成的。在芳基部分上带有吸电子基团或体积较小的基团的芳基腈氧化物的情况下，可获得相当好的收率。相反，在受阻芳基腈氧化物的存在下未观察到较低的产率或没有反应。通过从头算三个反应的活化能可以证实这种行为。通过在酸性条件下将相应的5-羟基-2-异恶唑啉脱水/芳香化，定量获得了许多3-芳基-5-乙烯基异恶唑。据报道，侧链精细化是一些乙烯基异恶唑和乙烯基异恶唑啉的合成工具。 3-芳基-5-羟基-5-乙烯基-2-异恶唑啉是通过使芳基腈氧化物与甲基乙烯基酮（MVK）的烯醇锂在–78°C下反应合成的。在芳基部分上带有吸电子基团或体积较小的基团的芳基腈氧化物的情况下，可获得相当好的收率。相反，在受阻芳基腈
• Functionalized diarylisoxazoles inhibitors of ciclooxygenase
  申请人：Scilimati Antonio

  公开号：US20090181970A1

  公开（公告）日：2009-07-16

  The present invention refers to isoxazole derivatives, in particular diarylisoxazole derivatives inhibitors of cyclooxygenase (COX), in particular cyclooxygenase-1 (COX-1), to their pharmaceutical compositions, the process for their preparation and their use for the chemoprevention and treatment of inflammatory syndromes and in the prevention and treatment of carcinomas, in particular intestinal, ovarian and cutaneous carcinomas, in the treatment of pain syndromes, in particular after surgery, and in the cardiovascular field as antithrombotics/vasoprotectives/cardioprotectives.

  本发明涉及异恶唑衍生物，特别是二芳基异恶唑衍生物，用作环氧合酶（COX）的抑制剂，特别是环氧合酶-1（COX-1）的抑制剂，以及它们的药物组合物、其制备方法以及用于化学预防和治疗炎症综合征以及预防和治疗癌症，特别是肠癌、卵巢癌和皮肤癌，在疼痛综合征的治疗中，特别是手术后，以及在心血管领域作为抗血栓/血管保护剂/心脏保护剂的用途。
• [EN] HETEROCYCLES AND THEIR RADIOLABELED ANALOGS USEFUL AS COX-1 SELECTIVE INHIBITORS<br/>[FR] HÉTÉROCYCLES ET LEURS ANALOGUES RADIOMARQUÉS UTILES EN TANT QU'INHIBITEURS SÉLECTIFS DE COX-1
  申请人：UNIV BARI

  公开号：WO2014115020A1

  公开（公告）日：2014-07-31

  The present invention relates to novel heterocycles which are potent and selective inhibitors of cyclooxygenase-1 (COX-1) and to their radiolabeled derivatives thereof which are both useful as theranostics of a number of pathologies.

  本发明涉及一种新型杂环化合物，这些化合物是环氧合酶-1（COX-1）的有效和选择性抑制剂，以及它们的放射标记衍生物，这些衍生物既可用作多种病理病变的诊疗药物。
• Salomone, Antonio; Scilimati, Antonio; Vitale, Paola, Synthesis, 2015, vol. 47, # 6, p. 807 - 816
  作者：Salomone, Antonio、Scilimati, Antonio、Vitale, Paola

  DOI：——

  日期：——
• Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles
  作者：Paola Vitale、Maria Grazia Perrone、Paola Malerba、Antonio Lavecchia、Antonio Scilimati

  DOI：10.1016/j.ejmech.2013.12.023

  日期：2014.3

  Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methy14-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 mu M; COX-2 IC50 > 50 mu M) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 mu M). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. (C) 2014 Published by Elsevier Masson SAS.