2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester | 942905-05-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester
• 英文别名: methyl 2-(3-chloro-4-fluorophenyl)sulfonyl-3-ethoxyprop-2-enoate
• CAS: 942905-05-7
• 化学式: C₁₂H₁₂ClFO₅S
• 分子量: 322.742
• InChiKey: KFRVTLNHLZBFJL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  78
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester 在 四(三苯基膦)钯 、 potassium carbonate 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙醚 为溶剂， 反应 21.0h， 生成 3-((3-chloro-4-fluorophenyl)sulfonyl)-4-(4-chlorophenyl)-7-fluoroquinoline
  参考文献：
  名称：

  Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications

  摘要：

  Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.

  DOI：

  10.1021/acs.jmedchem.6b01858
• 作为产物：
  描述：

  sodium 3-chloro-4-fluorobenzenesulfinate 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester
  参考文献：
  名称：

  Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications

  摘要：

  Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.

  DOI：

  10.1021/acs.jmedchem.6b01858

文献信息

• Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu 5 ) receptor negative allosteric modulators
  作者：János Galambos、Attila Bielik、Gábor Wágner、György Domány、János Kóti、Zoltán Béni、Áron Szigetvári、Zsuzsanna Sánta、Zoltán Orgován、Amrita Bobok、Béla Kiss、Mónika L. Mikó-Bakk、Mónika Vastag、Katalin Sághy、Mikhail Krasavin、Krisztina Gál、István Greiner、Zsolt Szombathelyi、György M. Keserű

  DOI：10.1016/j.ejmech.2017.03.071

  日期：2017.6

  optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant

  代谢型谷氨酸受体5（mGlu5）的负变构调节剂在许多不同的中枢神经系统疾病（包括焦虑症和抑郁症）的动物模型中均显示出功效。实际上，到达临床的所有化合物都属于具有连接（杂）环部分的炔属接头的相同化学型。在寻找新的化学型时，我们通过筛选公司复合甲板确定了吗啉代-磺基喹啉衍生物（1）。命中率高的HTS对mGlu5受体表现出合理的亲和力和选择性，但是其较差的代谢稳定性阻碍了其体内测试。在化学程序中，我们旨在探究命中的三个区域，以改善亲和力，理化性质和代谢稳定性。4位（区域I）上不同胺的系统变化导致鉴定出4-甲基-哌啶基类似物。通过平行合成绘制了喹啉核心（II区）和苯磺酰基部分（III区）的取代基。对约270种衍生物的吗啉代和4-甲基-哌啶基-磺基喹啉文库的评估显示，区域II和III中具有有益的取代基组合。然而，优化的4-甲基-哌啶基-磺基喹啉的血药浓度仍不足以实现强大的体内功效。最后，将4-羟甲基
• Sulfonyl-Quinoline Derivatives
  申请人：Galambos Janos

  公开号：US20090042934A1

  公开（公告）日：2009-02-12

  The present invention relates to new mGluR1 and mGluR5 receptor subtype preferring ligands of formula (I) and/or salts and/or hydrates and/or solvates and/or polymorphs thereof. The invention also relates to processes and intermediates for their preparation, to pharmaceutical compositions containing these compounds and to their use in treatment and/or prevention of conditions which require modulation of mGluR1 and mGluR5 receptors.

  本发明涉及公式（I）及/或其盐和/或水合物和/或溶剂化物和/或多晶型的新型mGluR1和mGluR5受体亚型偏爱配体。本发明还涉及它们的制备过程和中间体，包含这些化合物的制药组合物以及它们在需要调节mGluR1和mGluR5受体的情况下的治疗和/或预防的用途。
• QUINOLINE DERIVATIVES USEFUL IN THE TREATMENT OF MGLUR5 RECEPTOR-MEDIATED DISORDERS
  申请人：Keseru Gyorgy

  公开号：US20090270371A1

  公开（公告）日：2009-10-29

  Compounds of formula (I): and/or enantiomers and/or racemates and/or diastereomers and/or pharmaceutically acceptable salts thereof formed with acids or bases, to the process for their preparation, to the intermediates of the preparation process, to the pharmaceutical formulations containing these compounds and to their use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.

  公式(I)的化合物：及/或其对映体和/或外消旋体和/或非对映异构体和/或与酸或碱形成的药学上可接受的盐，其制备过程，制备过程中间体，包含这些化合物的制药配方以及它们在预防和/或治疗mGluR5受体介导的疾病中的用途。
• Sulfonyl-quinoline derivatives
  申请人：Richter Gedeon Nyrt.

  公开号：US08063220B2

  公开（公告）日：2011-11-22

  The present invention relates to new mGluR1 and mGluR5 receptor subtype preferring ligands of formula (I) and/or salts and/or hydrates and/or solvates and/or polymorphs thereof. The invention also relates to processes and intermediates for their preparation, to pharmaceutical compositions containing these compounds and to their use in treatment and/or prevention of conditions which require modulation of mGluR1 and mGluR5 receptors.

  本发明涉及公式（I）的新型mGluR1和mGluR5受体亚型优先配体和/或其盐和/或水合物和/或溶剂化物和/或多晶体。本发明还涉及制备这些化合物的过程和中间体，含有这些化合物的制药组合物以及它们在需要调节mGluR1和mGluR5受体的疾病的治疗和/或预防中的使用。
• Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications
  作者：János Galambos、Attila Bielik、Mikhail Krasavin、Zoltán Orgován、György Domány、Katalin Nógrádi、Gábor Wágner、György T. Balogh、Zoltán Béni、János Kóti、Zoltán Szakács、Amrita Bobok、Sándor Kolok、Mónika L. Mikó-Bakk、Mónika Vastag、Katalin Sághy、Judit Laszy、Attila Sándor Halász、Ottilia Balázs、Krisztina Gál、István Greiner、Zsolt Szombathelyi、György M. Keserű

  DOI：10.1021/acs.jmedchem.6b01858

  日期：2017.3.23

  Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.