ethyl 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1Hpyrrole-3-acetate | 853055-06-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: ethyl 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1Hpyrrole-3-acetate
• 英文别名: ethyl 2-[1-phenyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate；ethyl-[2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-1H-pyrrol-3-yl]acetate；ethyl 2-(2-methyl-5-(4-(methylsulfonyl)phenyl)-1-phenyl-1H-pyrrol-3-yl)acetate；ethyl 2-[2-methyl-5-(4-methylsulfonylphenyl)-1-phenylpyrrol-3-yl]acetate
• CAS: 853055-06-8
• 化学式: C₂₂H₂₃NO₄S
• 分子量: 397.495
• InChiKey: WYCFFUNCVUEJEH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  73.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1Hpyrrole-3-acetate 在 甲醇 、 sodium hydroxide 作用下， 反应 1.0h， 以71%的产率得到2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrol-3-acetic acid
  参考文献：
  名称：

  1,5-二芳基吡咯骨架的新型酯和酸衍生物作为抗炎和镇痛药。合成及体外和体内生物学评估

  摘要：

  开发了新一代的选择性环氧合酶2（COX-2）抑制剂（coxibs），以规避环氧合酶1（COX-1）和COX-2抑制剂的主要副作用（胃溃疡和肾毒性）。结果，考昔布在治疗急性和慢性炎性疾病中非常有价值。但是，由于心血管不良事件的高风险，已停止使用罗非昔布（Vioxx）等考昔布。最近的临床发现强调了通过适当的COX-1与COX-2选择性可以如何缓解Coxib的心血管毒性。我们先前报道了一组对COX-2有选择性的取代的1,5-二芳基吡咯衍生物。在这里，我们描述了新的1,5-二芳基吡咯的合成及其在体外，离体的抑制作用，以及体内对COX同工酶及其止痛活性的研究。异丙基-2-甲基-5- [4-（甲基磺酰基）苯基] -1-苯基-1选择该系列的代表成员H-吡咯-3-乙酸酯（10a）进行药代动力学和代谢研究。

  DOI：

  10.1021/jm901269y
• 作为产物：
  描述：

  2-methyl-5-(4-(methylsulfonyl)phenyl)-1-phenyl-1H-pyrrole 在 三乙基硅烷 、 四氯化钛 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 ethyl 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1Hpyrrole-3-acetate
  参考文献：
  名称：

  Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties

  摘要：

  The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.

  DOI：

  10.1021/jm200715n

文献信息

• Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation
  作者：Mariangela Biava、Giulio C. Porretta、Giovanna Poce、Claudio Battilocchio、Fabrizio Manetti、Maurizio Botta、Stefano Forli、Lidia Sautebin、Antonietta Rossi、Carlo Pergola、Carla Ghelardini、Nicoletta Galeotti、Francesco Makovec、Antonio Giordani、Paola Anzellotti、Paola Patrignani、Maurizio Anzini

  DOI：10.1021/jm901269y

  日期：2010.1.28

  (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More

  开发了新一代的选择性环氧合酶2（COX-2）抑制剂（coxibs），以规避环氧合酶1（COX-1）和COX-2抑制剂的主要副作用（胃溃疡和肾毒性）。结果，考昔布在治疗急性和慢性炎性疾病中非常有价值。但是，由于心血管不良事件的高风险，已停止使用罗非昔布（Vioxx）等考昔布。最近的临床发现强调了通过适当的COX-1与COX-2选择性可以如何缓解Coxib的心血管毒性。我们先前报道了一组对COX-2有选择性的取代的1,5-二芳基吡咯衍生物。在这里，我们描述了新的1,5-二芳基吡咯的合成及其在体外，离体的抑制作用，以及体内对COX同工酶及其止痛活性的研究。异丙基-2-甲基-5- [4-（甲基磺酰基）苯基] -1-苯基-1选择该系列的代表成员H-吡咯-3-乙酸酯（10a）进行药代动力学和代谢研究。
• Synthesis, Biological Evaluation, and Enzyme Docking Simulations of 1,5-Diarylpyrrole-3-Alkoxyethyl Ethers as Selective Cyclooxygenase-2 Inhibitors Endowed with Anti-inflammatory and Antinociceptive Activity
  作者：Maurizio Anzini、Michele Rovini、Andrea Cappelli、Salvatore Vomero、Fabrizio Manetti、Maurizio Botta、Lidia Sautebin、Antonietta Rossi、Carlo Pergola、Carla Ghelardini、Monica Norcini、Antonio Giordani、Francesco Makovec、Paola Anzellotti、Paola Patrignani、Mariangela Biava

  DOI：10.1021/jm800084s

  日期：2008.8.1

  comparable COX-2 selectivity to valdecoxib, while it was more selective than celecoxib but less selective than rofecoxib. The potential anti-inflammatory and antinociceptive activities of compounds 7a, 8a, and 8d were evaluated in vivo, where they showed a very good activity against both carrageenan-induced hyperalgesia and edema in the rat paw test. In the abdominal constriction test compound 7a, 8a, and

  合成了一系列取代的1,5-二芳基吡咯-3-烷氧基乙基醚（6、7和8），目的是评估先前报道的1,5-二芳基吡咯衍生物（5）是否取代了乙酸酯具有烷氧基乙基的部分仍可产生新的，高选择性和有效的COX-2抑制剂。在体外细胞培养测定中，所有化合物均被证明是有效的选择性COX-2抑制剂。在人全血（HWB）分析中，化合物8a对valdecoxib具有相当的COX-2选择性，而比celecoxib更具选择性，但与rofecoxib相比选择性较低。在体内评估了化合物7a，8a和8d的潜在抗炎和镇痛活性，在鼠爪试验中，它们对角叉菜胶引起的痛觉过敏和浮肿均显示出非常好的活性。在腹部收缩试验中，化合物7a，8a和8d能够以统计学上显着的方式减少扭曲的次数。此外，这些化合物的亲和力数据已通过酶对接模拟，通过与Autoxock 3.0.5，GRID 21和MacroModel 8.5结合使用的复合物软件包，与COX-
• 3-SUBSTITUTED-1,5-DIARLY-2-ALKYL-PYRROLES HIGHLY SELECTIVE AND ORALLY EFFECTIVE COX-2 INHIBITORS
  申请人：Cappelli Andrea

  公开号：US20090264500A1

  公开（公告）日：2009-10-22

  This invention relates to 3-substituted-1,5-diaryl-2-alkyl-pyrroles of Formula I, pharmaceutical compositions containing them, and to their use for the pharmacological treatment of pain and COX-2 over-activation associated disorders. Compounds of this invention are new pyrrole derivatives bearing in position-3 of the pyrrole ring, several variously functionalized, not aliphatic, side chains which confer to the compounds a relevant COX-2 potency and selectivity along with a remarkable oral efficacy. Phenyl rings in position-1 and -5 are variously substituted, but compounds of particular interest are those substituted in position-5 with 4-methylsulphonyl-phenyl or with 4-aminosulphonyl-phenyl groups.

  本发明涉及式I的3-取代-1,5-二芳基-2-烷基-吡咯衍生物，包含它们的药物组合物，以及它们用于治疗与疼痛和COX-2过度激活相关的疾病的药理学治疗。本发明的化合物是新的吡咯衍生物，在吡咯环的3位上带有几个不同官能团化的非脂肪侧链，这些侧链赋予化合物显著的COX-2效力和选择性以及卓越的口服效力。在1位和5位的苯环上有不同的取代基，但特别感兴趣的化合物是在5位上用4-甲基磺酰基苯基或4-氨基磺酰基苯基基团取代的化合物。
• 1,5-Diarylpyrrole-3-acetic Acids and Esters as Novel Classes of Potent and Highly Selective Cyclooxygenase-2 Inhibitors
  作者：Mariangela Biava、Giulio Cesare Porretta、Andrea Cappelli、Salvatore Vomero、Fabrizio Manetti、Maurizio Botta、Lidia Sautebin、Antonietta Rossi、Francesco Makovec、Maurizio Anzini

  DOI：10.1021/jm049121q

  日期：2005.5.1

  A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
• WO2008/14821
  申请人：——

  公开号：——

  公开（公告）日：——