2-(Hydroxymethyl)-4-[3-(difluoromethyl)-5-(3-methyl-4-methoxyphenyl)-1H-pyrazole-1-yl]benzenesulfonamide | 304647-94-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(Hydroxymethyl)-4-[3-(difluoromethyl)-5-(3-methyl-4-methoxyphenyl)-1H-pyrazole-1-yl]benzenesulfonamide
• 英文别名: 4-[3-(difluoromethyl)-5-(4-methoxy-3-methylphenyl)pyrazol-1-yl]-2-(hydroxymethyl)benzenesulfonamide
• CAS: 304647-94-7
• 化学式: C₁₉H₁₉F₂N₃O₄S
• 分子量: 423.44
• InChiKey: LIUNJVOSPPFGRN-UHFFFAOYSA-N

物化性质

• 熔点：
  164-166 °C
• 沸点：
  638.3±65.0 °C(predicted)
• 密度：
  1.44±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(Hydroxymethyl)-4-[3-(difluoromethyl)-5-(3-methyl-4-methoxyphenyl)-1H-pyrazole-1-yl]benzenesulfonamide 在 碳酸氢钠 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 4-[3-difluoromethyl-5-(4-methoxy-3-methylphenyl)-pyrazol-1-yl]-2-hydroxymethyl-N-propionylbenzenesulfonamide sodium salt
  参考文献：
  名称：

  N-Acylated sulfonamide sodium salt: A prodrug of choice for the bifunctional 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamide class of COX-2 inhibitors

  摘要：

  Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.05.028
• 作为产物：
  描述：

  2-甲基苯甲醚 在 盐酸 、 三氯化铝 、 sodium hydride 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 6.5h， 生成 2-(Hydroxymethyl)-4-[3-(difluoromethyl)-5-(3-methyl-4-methoxyphenyl)-1H-pyrazole-1-yl]benzenesulfonamide
  参考文献：
  名称：

  2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation

  摘要：

  在N1位含有新颖药效团的1,5-二芳基吡唑类类似物被设计、合成并对体外环氧合酶（COX-1/COX-2）抑制活性进行了评估。在C-5苯环的4位及其周围的变异与C-3位的CF3和CHF2基团结合，展现出高度的效力和选择性指数（SI），用于COX-2抑制。这些强效化合物的体内评估与先前的一些化合物相比，显示4-OMe-苯基类似物6和4-NHMe-苯基类似物9（C-3位含CF3），以及4-OEt-苯基类似物19（C-3位含CHF2）对COX-2的抑制效力超过了塞来昔布。除了出色的抗炎、解热、镇痛和抗关节炎特性外，化合物6（DRF-4367）被发现具有优秀的药代动力学特性，长期关节炎研究中的胃肠道安全性，以及在人体全血检测中的COX-2效力。因此，化合物6被选为口服活性的抗炎候选物进行临床前评估。

  DOI：

  10.1039/b402787f

文献信息

• [EN] PYRAZOLES HAVING ANTIINFLAMMATORY ACTIVITY<br/>[FR] PYRAZOLES PRESENTANT UNE ACTIVITE ANTI-INFLAMMATOIRE
  申请人：REDDY RESEARCH FOUNDATION

  公开号：WO2000066562A1

  公开（公告）日：2000-11-09

  The present invention relates to novel antiinflammatory compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel heterocyclic compounds of general the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

  本发明涉及新型抗炎化合物、它们的衍生物、类似物、互变异构体、立体异构体、区域异构体、多晶形态、药学上可接受的盐、药学上可接受的溶剂化合物以及含有它们的药学上可接受的组合物。更具体地说，本发明涉及一般式（I）的新型杂环化合物、它们的衍生物、类似物、互变异构体、立体异构体、区域异构体、多晶形态、药学上可接受的盐、药学上可接受的溶剂化合物以及含有它们的药学上可接受的组合物。
• 2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation
  作者：Sunil Kumar Singh、Saibaba Vobbalareddy、Srinivasa Rao Kalleda、Shaikh Abdul Rajjak、Seshagiri Rao Casturi、Srinivasa Raju Datla、Rao N. V. S. Mamidi、Ramesh Mullangi、Ravikanth Bhamidipati、Rajagopalan Ramanujam、Venkateswarlu Akella、Koteswar Rao Yeleswarapu

  DOI：10.1039/b402787f

  日期：——

  Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog 6 and the 4-NHMe-phenyl analog 9 with a CF3, and the 4-OEt-phenyl analog 19 with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound 6 (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound 6 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.

  在N1位含有新颖药效团的1,5-二芳基吡唑类类似物被设计、合成并对体外环氧合酶（COX-1/COX-2）抑制活性进行了评估。在C-5苯环的4位及其周围的变异与C-3位的CF3和CHF2基团结合，展现出高度的效力和选择性指数（SI），用于COX-2抑制。这些强效化合物的体内评估与先前的一些化合物相比，显示4-OMe-苯基类似物6和4-NHMe-苯基类似物9（C-3位含CF3），以及4-OEt-苯基类似物19（C-3位含CHF2）对COX-2的抑制效力超过了塞来昔布。除了出色的抗炎、解热、镇痛和抗关节炎特性外，化合物6（DRF-4367）被发现具有优秀的药代动力学特性，长期关节炎研究中的胃肠道安全性，以及在人体全血检测中的COX-2效力。因此，化合物6被选为口服活性的抗炎候选物进行临床前评估。
• N-Acylated sulfonamide sodium salt: A prodrug of choice for the bifunctional 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamide class of COX-2 inhibitors
  作者：Sunil Kumar Singh、Saibaba Vobbalareddy、Srinivasa Rao Kalleda、Seshagiri Rao Casturi、Ramesh Mullangi、Rajagopalan Ramanujam、Koteswar Rao Yeleswarapu、Javed Iqbal

  DOI：10.1016/j.bmcl.2006.05.028

  日期：2006.8

  Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration. (c) 2006 Elsevier Ltd. All rights reserved.