4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole | 265113-82-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole
• 英文别名: 4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)-imidazole(73 % yield)；4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-imidazole
• CAS: 265113-82-4
• 化学式: C₁₇H₁₄ClFN₂O₃S
• 分子量: 380.827
• InChiKey: YVZIBNGIENXYSE-UHFFFAOYSA-N

物化性质

• 熔点：
  196 °C
• 沸点：
  584.4±50.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  69.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole 在 三溴化硼 、 potassium carbonate 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 、 乙腈 为溶剂， 生成
  参考文献：
  名称：

  NO-Donor COX-2 Inhibitors. New Nitrooxy-Substituted 1,5-Diarylimidazoles Endowed with COX-2 Inhibitory and Vasodilator Properties

  摘要：

  A series of NO-donor diarylimidazoles derived from the lead compound Cimicoxib were synthesized and evaluated for their COX-2 inhibitory activity and their stability in whole blood as well as for vasodilator properties. The products are partly transformed into the corresponding alcohols following 24-h incubation in whole blood. All of them display good COX-1/COX-2 selectivity, but are less potent than the lead; a molecular modeling study was carried out to investigate their binding mode. The compounds are also capable of relaxing rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism; this property could confer reduced cardiotoxicity with respect to traditional COX-2 inhibitors.

  DOI：

  10.1021/jm0607247
• 作为产物：
  描述：

  3-氟-4-甲氧基苯甲醛 在 N-氯代丁二酰亚胺 、 potassium carbonate 作用下， 以 甲醇 、 乙二醇二甲醚 、 甲苯 、 乙腈 为溶剂， 反应 24.0h， 生成 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole
  参考文献：
  名称：

  一系列新的COX-2选择性抑制剂：1，5-二芳基咪唑的合成及其构效关系。

  摘要：

  描述了开发为有效和选择性环氧合酶2（COX-2）抑制剂的一系列1,5-二芳基咪唑的合成和药理活性。在体外（在人全血中对COX-1和COX-2的抑制）和在体内（对角叉菜胶引起的爪水肿，气袋和痛觉过敏测试）均对新化合物进行了评估。修饰两个区域异构咪唑核的所有位置导致鉴定出最佳的4- [4-氯-5-（3-氟-4-甲氧基苯基）咪唑-1-基]苯磺酰胺（UR-8880，51f）候选者，目前正在进行I期临床试验。

  DOI：

  10.1021/jm030765s

文献信息

• Radiosynthesis and Evaluation of 11C-Labeled Diaryl-Substituted Imidazole and Indole Derivatives for Mapping Cyclooxygenase-2
  作者：Mariko Tanaka、Yoshihiko Fujisaki、Kazunori Kawamura、Kiichi Ishiwata、Qinggeletu、Fumihiko Yamamoto、Takahiro Mukai、Minoru Maeda

  DOI：10.1248/bpb.29.2087

  日期：——

  11C-Labeled analogs of 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole ([11C]1), 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide ([11C]2) and 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole ([11C]3), which have been shown to have excellent potency and high selectivity for cyclooxygenase isoform 2 (COX-2) inhibiting activity, were prepared and evaluated in rats as potential radiopharmaceuticals for imaging the COX-2 enzyme by positron emission tomography. These 11C-labeled COX-2 inhibitors were synthesized in high radiochemical yields by O-[11C]methylation of phenolic precursors with [11C]methyl triflate in acetone containing NaOH as a base. In vivo evaluation in rats bearing AH109A hepatoma showed no specific binding of any tracer to COX-2 in any tissue such as the brain, heart, lung, kidney, and AH109A hepatoma. In ex vivo autoradiography, [11C]1 showed regionally different distribution in the brain, while [11C]2 and [11C]3 were not substantially taken up by the brain. In in vitro monolayer efflux assays, compound 3 was found to be a substrate for the P-glycoprotein (P-gp) efflux pump, but pretreatment of rats with the potent P-gp inhibitor, cyclosporine A, did not have any significant influence on the cerebral uptake of [11C]3. These results indicate that all three tracers were not suitable for in vivo imaging of COX-2. There seem to be some obstacles to finding a useful candidate for in vivo imaging application of COX-2 selective inhibitors only by standard consideration of in vitro affinity and selectivity, and the lipophilicity of the compound.

  11C 标记的 4-氯-5-(3-氟-4-甲氧基苯基)-1-(4-甲磺酰基苯基)咪唑类似物（[11C]1）、4-[4-氯-5-(3-氟-4-甲氧基苯基)咪唑-1-基]苯磺酰胺类似物（[11C]2）和 2-(4-氨基磺酰基苯基)-3-(4-甲氧基苯基)吲哚类似物（[11C]3）、制备出了对环氧化酶同工酶 2（COX-2）抑制活性具有卓越效力和高选择性的 11C 标记 COX-2 放射性药物，并在大鼠体内进行了评估，以作为通过正电子发射断层扫描对 COX-2 酶进行成像的潜在放射性药物。这些 11C 标记的 COX-2 抑制剂是通过在含 NaOH 作为碱的丙酮中用 [11C]methyl triflate 对酚类前体进行 O-[11C]methylation 合成的，具有很高的放射化学收率。在患有 AH109A 肝瘤的大鼠身上进行的体内评估显示，在大脑、心脏、肺、肾和 AH109A 肝瘤等任何组织中，任何示踪剂都没有与 COX-2 发生特异性结合。在体外自显影中，[11C]1 在大脑中显示出不同的区域分布，而[11C]2 和[11C]3 并未被大脑大量吸收。在体外单层外排试验中，发现化合物 3 是 P-糖蛋白（P-gp）外排泵的底物，但用强效 P-gp 抑制剂环孢素 A 预处理大鼠并没有对大脑摄取 [11C]3 产生任何显著影响。这些结果表明，这三种示踪剂都不适合用于 COX-2 的体内成像。仅从体外亲和性和选择性以及化合物的亲脂性等标准考虑，要找到一种适用于 COX-2 选择性抑制剂体内成像应用的候选化合物似乎还存在一些障碍。
• NOVEL IMIDAZOLES WITH ANTI-INFLAMMATORY ACTIVITY
  申请人：J. Uriach y Compania S.A.

  公开号：EP1122243B1

  公开（公告）日：2004-09-08
• US6838476B1
  申请人：——

  公开号：US6838476B1

  公开（公告）日：2005-01-04
• Synthesis and Structure−Activity Relationship of a New Series of COX-2 Selective Inhibitors:  1,5-Diarylimidazoles
  作者：Carmen Almansa、José Alfón、Alberto F. de Arriba、Fernando L. Cavalcanti、Ignasi Escamilla、Luis A. Gómez、Agustí Miralles、Robert Soliva、Javier Bartrolí、Elena Carceller、Manuel Merlos、Julián García-Rafanell

  DOI：10.1021/jm030765s

  日期：2003.7.1

  The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole

  描述了开发为有效和选择性环氧合酶2（COX-2）抑制剂的一系列1,5-二芳基咪唑的合成和药理活性。在体外（在人全血中对COX-1和COX-2的抑制）和在体内（对角叉菜胶引起的爪水肿，气袋和痛觉过敏测试）均对新化合物进行了评估。修饰两个区域异构咪唑核的所有位置导致鉴定出最佳的4- [4-氯-5-（3-氟-4-甲氧基苯基）咪唑-1-基]苯磺酰胺（UR-8880，51f）候选者，目前正在进行I期临床试验。
• NO-Donor COX-2 Inhibitors. New Nitrooxy-Substituted 1,5-Diarylimidazoles Endowed with COX-2 Inhibitory and Vasodilator Properties
  作者：Konstantin Chegaev、Loretta Lazzarato、Paolo Tosco、Clara Cena、Elisabetta Marini、Barbara Rolando、Pierre-Alain Carrupt、Roberta Fruttero、Alberto Gasco

  DOI：10.1021/jm0607247

  日期：2007.4.1

  A series of NO-donor diarylimidazoles derived from the lead compound Cimicoxib were synthesized and evaluated for their COX-2 inhibitory activity and their stability in whole blood as well as for vasodilator properties. The products are partly transformed into the corresponding alcohols following 24-h incubation in whole blood. All of them display good COX-1/COX-2 selectivity, but are less potent than the lead; a molecular modeling study was carried out to investigate their binding mode. The compounds are also capable of relaxing rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism; this property could confer reduced cardiotoxicity with respect to traditional COX-2 inhibitors.