3,4-bis(4-methoxyphenyl)-5-methylisoxazole | 78967-05-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3,4-bis(4-methoxyphenyl)-5-methylisoxazole
• 英文别名: 3,4-di(4-methoxyphenyl)-5-methylisoxazole；3,4-di(p-methoxyphenyl)-5-methylisoxazole；3,4-bis(4-methoxyphenyl)-5-methyl-1,2-oxazole
• CAS: 78967-05-2
• 化学式: C₁₈H₁₇NO₃
• 分子量: 295.338
• InChiKey: CKKXCPZQKHHECC-UHFFFAOYSA-N

物化性质

• 沸点：
  409.5±45.0 °C(Predicted)
• 密度：
  1.134±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  44.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,4-bis(4-methoxyphenyl)-5-methylisoxazole 在 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]ethyl 4-methylbenzenesulfonate
  参考文献：
  名称：

  Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability

  摘要：

  A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 inhibitor [COX-1 IC50 = 0.0079 mu M and COX-2 IC50 > 50 mu M, with a selectivity index (SI) in favor of COX-1 higher than 6300]. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. Sls ranged between 1 and higher than 11903,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 mu M and COX-2 IC50 > 50 mu M. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 mu M, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and apoptosis when co-administered with the proteasome inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.12.029
• 作为产物：
  描述：

  对甲氧基苯基丙酮 、 [(4-甲氧苯基)次甲基]氮烷氧化 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以50%的产率得到3,4-bis(4-methoxyphenyl)-5-methylisoxazole
  参考文献：
  名称：

  Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability

  摘要：

  A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 inhibitor [COX-1 IC50 = 0.0079 mu M and COX-2 IC50 > 50 mu M, with a selectivity index (SI) in favor of COX-1 higher than 6300]. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. Sls ranged between 1 and higher than 11903,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 mu M and COX-2 IC50 > 50 mu M. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 mu M, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and apoptosis when co-administered with the proteasome inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.12.029

文献信息

• [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。
• 3,4-Diarylisoxazol-5-acetic acids and process for making same
  申请人：CDC Life Sciences Inc.

  公开号：US04327222A1

  公开（公告）日：1982-04-27

  3,4-Diarylisoxazol-5-acetic acids of the formula ##STR1## in which Ar.sup.1 and Ar.sup.2 are the same or different and are selected from phenyl and naphthyl, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same or different and are selected from hydrogen, halogen, trifluoromethyl, lower alkyl, and lower alkoxy, and R.sup.5 is selected from hydrogen, lower alkyl, and lower alkoxy. The compounds have anti-inflammatory, analgesic, and anti-pyretic activities and a low order of toxicity, and methods for their preparation and use are also disclosed.

  化学式为##STR1##的3,4-二芳基异噁唑-5-乙酸，其中Ar.sup.1和Ar.sup.2相同或不同，可选自苯基和萘基，R.sup.1，R.sup.2，R.sup.3和R.sup.4相同或不同，可选自氢，卤素，三氟甲基，低碳基和低碳氧基，而R.sup.5可选自氢，低碳基和低碳氧基。这些化合物具有抗炎，镇痛和退热活性，并具有低毒性，还公开了它们的制备和使用方法。
• NITROSATED NONSTEROIDAL ANTIINFLAMMATORY COMPOUNDS, COMPOSITIONS AND METHODS OF USE
  申请人：EARL Richard A.

  公开号：US20100093671A1

  公开（公告）日：2010-04-15

  The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.

  该发明描述了新型亚硝酰化非甾体抗炎药（NSAIDs）及其药学上可接受的盐，并且描述了至少包含一种亚硝酰化NSAID和可选的至少一种化合物的新型组合物，该化合物捐赠、转移或释放一氧化氮，刺激内源性一氧化氮的合成，提高内源性内皮源性松弛因子的水平或是一氧化氮合酶的底物，并/或至少包含一种治疗剂。该发明还提供了至少包含一种亚硝酰化NSAID和至少一种化合物的新型组合物，该化合物捐赠、转移或释放一氧化氮，提高内源性内皮源性松弛因子的水平，刺激内源性一氧化氮的合成或是一氧化氮合酶的底物，并/或至少包含一种治疗剂。该发明还提供了至少包含一种亚硝酰化NSAID，可选的至少一种一氧化氮供体和/或至少一种治疗剂的新型试剂盒。该发明还提供了治疗炎症、疼痛和发热的方法；治疗胃肠道疾病的方法；促进伤口愈合的方法；治疗和/或预防使用非甾体抗炎化合物导致的胃肠道、肾脏和/或呼吸道毒性的方法；治疗炎症性疾病状态和/或疾病的方法；以及治疗和/或预防眼科疾病和/或疾病的方法。
• MANUFACTURING PROCESS FOR NO-DONATING COMPOUNDS SUCH AS NO-DONATING DICLOFENAC
  申请人：ANDERSSON Johan

  公开号：US20090170934A1

  公开（公告）日：2009-07-02

  The present invention relates to a new process for the preparation of NO-donating compounds using a sulfonated intermediate. The invention relates to new intermediates prepared therein suitable for large scale manufacturing of NO-donating compounds. The invention further relates to the use of the new intermediates for the manufacturing of pharmaceutically active NO-donating compounds. The invention further relates to a substantially crystalline form of NO-donating NSAIDs, especially 2-[2-(nitrooxy)ethoxy]ethyl 2-[(2,6-dichlorophenyl)amino]phenyl}acetate, the preparation thereof and to pharmaceutical formulations containing said crystalline form and to the use of said crystalline form in the preparation of a medicament.

  本发明涉及一种使用磺化中间体制备NO供体化合物的新工艺。该发明涉及其中制备的适用于NO供体化合物大规模生产的新中间体。本发明还涉及使用新中间体制造药用活性NO供体化合物。此外，本发明还涉及NO供体NSAIDs的实质晶体形式，特别是2-[2-(硝氧基)乙氧基]乙基2-[(2,6-二氯苯基)氨基]苯基}乙酸酯的制备，以及含有该晶体形式的制药配方和在制备药物时使用该晶体形式的用途。
• A further pocket or conformational plasticity by mapping COX-1 catalytic site through modified-mofezolac structure-inhibitory activity relationships and their antiplatelet behavior
  作者：Roberta Solidoro、Morena Miciaccia、Carmela Bonaccorso、Cosimo Gianluca Fortuna、Domenico Armenise、Antonella Centonze、Savina Ferorelli、Paola Vitale、Pryscila Rodrigues、Renilda Guimarães、Alana de Oliveira、Mariana da Paz、Luciana Rangel、Plínio Cunha Sathler、Angela Altomare、Maria Grazia Perrone、Antonio Scilimati

  DOI：10.1016/j.ejmech.2024.116135

  日期：2024.2

  respectively. The other symmetrically substituted alkoxyphenyl moietis were inactive at 50 μM final concentration. Among the asymmetrically substituted, only the (methoxyphenyl on C3-isoxazole and ethoxyphenyl on C4-isoxazole) and (methoxyphenyl on C3-isoxazole and -propoxyphenyl on C4-isoxazole) were active with SI = 1087 and 38, respectively. Among the set of compounds with the acetic moiety, structurally

  环氧合酶在心血管、神经系统和神经退行性疾病中具有独特的作用。它们在不同类型的癌症中表达不同。需要单独或联合治疗使用特异性和选择性 COX 抑制剂。完全了解两种环氧合酶 (COX) 亚型催化位点的差异仍有待研究。因此，使用高选择性 COX-1 抑制剂莫非唑酸作为先导化合物，以探索由极性残基 Q192、S353、H90 和 Y355 形成的 COX-1 区域，设计并合成了两个系列的新型化合物，收率相当至良好，如下所示：以及疏水性氨基酸 I523、F518 和 L352。根据COX-1:莫非唑酸复合物的结构，疏水性氨基酸似乎具有自由体积，最终比与莫非唑酸苯基连接的甲氧基更容易接近空间位阻基团，特别是C4-莫非唑酸异恶唑处的甲氧基苯基。 Mofezolac 带有两个与异恶唑核心环的 C3 和 C4 连接的甲氧基苯基。因此，在新化合物中，一个或两个甲氧基被更高级的同系乙氧基、正丙基和异丙基、正丁基和