3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole | 775344-72-4

• 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: 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole
• 英文别名: 3-(5-Chlorofuran-2-yl)-4-phenyl-5-methylisoxazole；3-(5-chlorofuran-2-yl)-5-methyl-4-phenyl-1,2-oxazole
• CAS: 775344-72-4
• 化学式: C₁₄H₁₀ClNO₂
• 分子量: 259.692
• InChiKey: IPAVFMUBTIUYBW-UHFFFAOYSA-N

物化性质

• 熔点：
  71-73 °C
• 沸点：
  330.8±42.0 °C(Predicted)
• 密度：
  1.254±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  39.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 四丁基硫酸氢铵 作用下， 以 四氯化碳 、 二氯甲烷 、 水 为溶剂， 反应 5.0h， 生成 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetonitrile
  参考文献：
  名称：

  Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2013.12.023
• 作为产物：
  描述：

  帕瑞昔布中间体 在 sodium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 以60%的产率得到3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole
  参考文献：
  名称：

  [EN] ISOXAZOLE DERIVATIVES AND THEIR USE AS CYCLOOXYGENASE INHIBITORS
  [FR] DERIVES ISOXAZOLE ET UTILISATION EN TANT QU'INHIBITEURS DE CYCLOOXYGENASE

  摘要：

  公开号：

  WO2005068442A3

文献信息

• 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。
• Use of isoxazole derivatives as cyclooxygenase inhibitors
  申请人：Universita' degli Studi di Bari

  公开号：EP2246337A1

  公开（公告）日：2010-11-03

  The present invention refers to the use of a compound selected from 3,4-diphenyl-5-ethylisoxazole and 3,4-diphenyl-5-methylisoxazole as inhibitors of cyclooxygenase, in particular of cyclooxygenase 1 and 2 (COX-1) (COX-2).

  本发明涉及一种选自 3,4-二苯基-5-乙基异噁唑和 3,4-二苯基-5-甲基异噁唑的化合物作为环氧化酶，特别是环氧化酶 1 和 2（COX-1）（COX-2）的抑制剂的用途。
• MOFEZOLAC DERIVATIVES AS MULTI-FUNCTIONS SELECTIVE COX-1 INHIBITORS
  申请人：Università degli Studi di Bari "Aldo Moro"

  公开号：EP3782990A1

  公开（公告）日：2021-02-24

  The invention relates to a new class of compounds targeting COX-1. The invention also relates to the use of some of such compounds as a tool to investigate the structure and function of the enzyme, in the treatment targeting COX-1 or detection of COX-1 in relating disorders or diseases such as cancer and neuroinflammation, in particular in neurological (e.g. autism spectrum disorders) and neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases), and in gynecological tumour (e.g. ovarian cancer), neck and head tumor, and haematological tumours (e.g. multiple myeloma) and in the detection of COX-1 in "in vitro" (cells and tissues) and in "in vivo".

  本发明涉及一类靶向 COX-1 的新型化合物。本发明还涉及将其中一些化合物用作研究酶的结构和功能的工具，用于靶向 COX-1 的治疗或检测 COX-1 在癌症和神经炎症等相关紊乱或疾病中的作用，特别是在神经系统疾病（如自闭症谱系障碍）和神经退行性疾病（如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症（ALS）、多发性硬化症（MLS））中的作用。阿尔茨海默病、帕金森病、肌萎缩性脊髓侧索硬化症（ALS）、多发性硬化症（MS）、创伤性脑损伤（TBI）、艾滋病痴呆症和朊病毒病），以及妇科肿瘤（如卵巢癌）、颈部和头部肿瘤和血液肿瘤（如多发性骨髓瘤），以及在 "体外"（细胞和组织）和 "体内 "检测 COX-1。
• Synthesis, Pharmacological Characterization, and Docking Analysis of a Novel Family of Diarylisoxazoles as Highly Selective Cyclooxygenase-1 (COX-1) Inhibitors
  作者：Paola Vitale、Stefania Tacconelli、Maria Grazia Perrone、Paola Malerba、Laura Simone、Antonio Scilimati、Antonio Lavecchia、Melania Dovizio、Emanuela Marcantoni、Annalisa Bruno、Paola Patrignani

  DOI：10.1021/jm301905a

  日期：2013.6.13

  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)).
• PET radiotracer [18F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: Preliminary investigation
  作者：Maria Grazia Perrone、Paola Malerba、Md. Jashim Uddin、Paola Vitale、Andrea Panella、Brenda C. Crews、Cristina K. Daniel、Kebreab Ghebreselasie、Mike Nickels、Mohammed N. Tantawy、H. Charles Manning、Lawrence J. Marnett、Antonio Scilimati

  DOI：10.1016/j.ejmech.2014.04.074

  日期：2014.6

  Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.