ethyl 2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate | 959632-81-6

• 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-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate
• 英文别名: ethyl [2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrol-3-yl]-acetate；ethyl 2-[1-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]acetate
• CAS: 959632-81-6
• 化学式: C₂₂H₂₂FNO₄S
• 分子量: 415.485
• InChiKey: QOHDGTMKQZCWJH-UHFFFAOYSA-N

物化性质

• 熔点：
  133 °C(Solv: hexane (110-54-3); ethyl acetate (141-78-6))
• 沸点：
  569.7±50.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  29
• 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：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate 在 4-二甲氨基吡啶 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 3-(nitrooxy)propyl 2-[1-(4-fluorophenyl)-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]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
• 作为产物：
  描述：

  1-[4-(methylsulfonyl)phenyl]pentane-1,4-dione 在 三乙基硅烷 、 四氯化钛 、 对甲苯磺酸 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 160.0 ℃ 、1.03 MPa 条件下， 反应 0.75h， 生成 ethyl 2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]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

• 1,5-Diaryl-2-alkylpyrrole-3-Substituted Nitro Esters, Selective COX-2 Inhibitors and Nitric Oxide Donors
  申请人：Giordani Antonio

  公开号：US20130165494A1

  公开（公告）日：2013-06-27

  1,5-diaryl-2-alkylpyrrole-3-substituted nitro esters, of Formula (I) are provided. Such compounds are potent and selective COX-2 inhibitors which are able to release NO in concentrations that make it possible to counteract the side effects due to selective COX-2 inhibition, without giving rise to hypotensive effects. Formula (I) includes compounds wherein the groups R′ and R″ are: —H, —F, —Cl, —Br, —CH 3 , —CF 3 , —OCH 3 , —SCH 3 , R1 is methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl and the substituent in position −3 of the pyrrole ring is a chain, where the groups X, Y, Z, W and R2 are: X is a carbonyl or a group —(CHR 3 )—, Y is an oxygen atom or the group —NR 3 — and Z is a carbonyl or a group —(CHR 3 )—, or a [—CH(COOH)—] group, or a group —(NR 3 )—, W is an aliphatic chain substituted with one or two (—O—NO 2 ) groups, R2 is: —H, —OH, —OCH 3 , or —NHR 3 . R 3 is: —H, —CH 3 , —CH 2 CH 3 , [—CH 2 (CH 3 ) 2 ]. R′″ is methylsulphonyl or sulphonamido. Pharmaceutical formulations and methods of making an using such formulations are also provided.

  提供的是1,5-二芳基-2-烷基吡咯-3-取代硝基酯，其分子式为(I)。这类化合物是强效且选择性的COX-2抑制剂，能够以在浓度上足以抵消由于选择性COX-2抑制引起的副作用的NO释放，而不会引起低血压效应。公式(I)包括的化合物中，基团R'和R"为：—H，—F，—Cl，—Br，—CH3，—CF3，—OCH3，—SCH3，R1为甲基，乙基，三氟甲基，羟甲基，甲氧甲基，且吡咯环上-3位的取代基为链状，其中X、Y、Z、W和R2分别为：X为羰基或—(CHR3)—基团，Y为氧原子或—NR3—基团，Z为羰基或—(CHR3)—基团，或[—CH(COOH)—]基团，或—(NR3)—基团，W为用一或两个(—O—NO2)基团取代的脂肪链，R2为：—H，—OH，—OCH3，或—NHR3。R3为：—H，—CH3，—CH2CH3，[—CH2(CH3)2]。R′″为甲基磺酰基或磺酰胺基。还提供了用于制备和使用此类化合物的药物配方和方法。
• Novel Analgesic/Anti-Inflammatory Agents: 1,5-Diarylpyrrole Nitrooxyalkyl Ethers and Related Compounds as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors
  作者：Maurizio Anzini、Angela Di Capua、Salvatore Valenti、Simone Brogi、Michele Rovini、Germano Giuliani、Andrea Cappelli、Salvatore Vomero、Luisa Chiasserini、Alessandro Sega、Giovanna Poce、Gianluca Giorgi、Vincenzo Calderone、Alma Martelli、Lara Testai、Lidia Sautebin、Antonietta Rossi、Simona Pace、Carla Ghelardini、Lorenzo Di Cesare Mannelli、Veronica Benetti、Antonio Giordani、Paola Anzellotti、Melania Dovizio、Paola Patrignani、Mariangela Biava

  DOI：10.1021/jm301370e

  日期：2013.4.25

  3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7–10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives

  设计了一系列带有连接到不同间隔基的硝基氧基烷基侧链的3-取代的1，5-二芳基吡咯。吡咯衍生的硝基氧基烷基逆酯，碳酸酯和醚（新类7 - 10），为COX-2选择性抑制剂和NO供体被合成并在本文中报告。通过考虑硝基氧基烷基醚（的代谢转化9，10）转换成相应的醇，衍生物17和18也进行了研究。硝基氧衍生物显示出NO依赖性血管舒张特性，而大多数化合物在体外实验模型中被证明是非常有效和选择性的COX-2抑制剂。对化合物9a的进一步体内研究，c和17a强调了良好的抗炎和抗伤害感受活性。化合物9c能够抑制白介素-1β（IL-1β）诱导的糖胺聚糖（GAG）释放，显示出软骨保护特性。最后，对化合物6c，d，9c和10b进行分子建模以及1 H和13 C-NMR研究，可以评估COX-2活性位点内这些分子的硝基氧基烷基酯和醚侧链的正确构型。
• 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-
• [EN] 1,5-DIARYL-2-ALKYLPYRROLE-3-SUBSTITUTED NITRO ESTERS, SELECTIVE COX-2 INHIBITORS AND NITRIC OXIDE DONORS<br/>[FR] NITROESTERS DE L,5-DIARYL-2-ALKYLPYRROLE 3-SUBSTITUÉS, INHIBITEURS SÉLECTIFS DE COX-2 ET DONNEURS D'OXYDE NITRIQUE
  申请人：ROTTAPHARM SPA

  公开号：WO2012032479A8

  公开（公告）日：2012-07-12
• Cyclooxygenase-2 Inhibitors. 1,5-Diarylpyrrol-3-acetic Esters with Enhanced Inhibitory Activity toward Cyclooxygenase-2 and Improved Cyclooxygenase-2/Cyclooxygenase-1 Selectivity
  作者：Mariangela Biava、Giulio Cesare Porretta、Giovanna Poce、Sibilla Supino、Stefano Forli、Michele Rovini、Andrea Cappelli、Fabrizio Manetti、Maurizio Botta、Lidia Sautebin、Antonietta Rossi、Carlo Pergola、Carla Ghelardini、Elisa Vivoli、Francesco Makovec、Paola Anzellotti、Paola Patrignani、Maurizio Anzini

  DOI：10.1021/jm0707525

  日期：2007.11.1

  The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new con pounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diary lpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.