methyl 2-[N-(2-chloro-4-fluorophenyl)sulfamoyl]benzoate

• 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: methyl 2-[N-(2-chloro-4-fluorophenyl)sulfamoyl]benzoate
• 英文别名: Methyl 2-[[(2-chloro-4-fluorophenyl)amino]sulfonyl]benzoate；methyl 2-[(2-chloro-4-fluorophenyl)sulfamoyl]benzoate
• 化学式: C₁₄H₁₁ClFNO₄S
• 分子量: 343.763
• InChiKey: VNSSPGBXASLQGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  80.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-[N-(2-chloro-4-fluorophenyl)sulfamoyl]benzoate 、 丙烯酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以17%的产率得到Methyl 2-[(2-chloro-4-fluorophenyl)-prop-2-enoylsulfamoyl]benzoate
  参考文献：
  名称：

  [EN] SULFONAMIDE OR AMIDE COMPOUNDS, COMPOSITIONS AND METHODS FOR THE PROPHYLAXIS AND/OR TREATMENT OF AUTOIMMUNE, INFLAMMATION OR INFECTION RELATED DISORDERS
  [FR] COMPOSÉS DE SULFONAMIDE OU D'AMIDE, COMPOSITIONS ET PROCÉDÉS POUR LA PROPHYLAXIE ET/OU LE TRAITEMENT DE TROUBLES AUTO-IMMUNS, D'INFLAMMATION OU D'INFECTION

  摘要：

  本发明涉及新型磺胺类或酰胺类作为TLR-4拮抗剂，以及含有这些化合物的药物配方和使用方法。本发明的新型磺胺类或酰胺类的用途包括但不限于自身免疫、炎症或感染相关疾病的预防和/或治疗。

  公开号：

  WO2018156297A1
• 作为产物：
  描述：

  2-氯-4-氟苯胺 、 2-(氯磺酰基)苯甲酸甲酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 84.0h， 以17%的产率得到methyl 2-[N-(2-chloro-4-fluorophenyl)sulfamoyl]benzoate
  参考文献：
  名称：

  Discovery of Novel and Potent Small-Molecule Inhibitors of NO and Cytokine Production as Antisepsis Agents:  Synthesis and Biological Activity of Alkyl 6-(N-Substituted sulfamoyl)cyclohex-1-ene-1-carboxylate

  摘要：

  To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-alpha, IL-6 and IL-1 beta] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound (R)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.

  DOI：

  10.1021/jm050623t

文献信息

• SULFONAMIDE OR AMIDE COMPOUNDS, COMPOSITIONS AND METHODS FOR THE PROPHYLAXIS AND/OR TREATMENT OF AUTOIMMUNE, INFLAMMATION OR INFECTION RELATED DISORDERS
  申请人：TAIWANJ PHARMACEUTICALS CO., LTD

  公开号：US20200247761A1

  公开（公告）日：2020-08-06

  The present invention related to novel sulfonamides or amides as TLR-4 antagonists, and pharmaceutical formulations containing the same and the methods of use thereof. Uses of the present novel sulfonamides or amides include, but are not limited to, the prophylaxis and/or treatment of autoimmune, inflammation, or infection related disorders.
• [EN] SULFONAMIDE OR AMIDE COMPOUNDS, COMPOSITIONS AND METHODS FOR THE PROPHYLAXIS AND/OR TREATMENT OF AUTOIMMUNE, INFLAMMATION OR INFECTION RELATED DISORDERS<br/>[FR] COMPOSÉS DE SULFONAMIDE OU D'AMIDE, COMPOSITIONS ET PROCÉDÉS POUR LA PROPHYLAXIE ET/OU LE TRAITEMENT DE TROUBLES AUTO-IMMUNS, D'INFLAMMATION OU D'INFECTION
  申请人：TAIWANJ PHARMACEUTICALS CO LTD

  公开号：WO2018156297A1

  公开（公告）日：2018-08-30

  The present invention related to novel sulfonamides or amides as TLR-4 antagonists, and pharmaceutical formulations containing the same and the methods of use thereof. Uses of the present novel sulfonamides or amides include, but are not limited to, the prophylaxis and/or treatment of autoimmune, inflammation, or infection related disorders.

  本发明涉及新型磺胺类或酰胺类作为TLR-4拮抗剂，以及含有这些化合物的药物配方和使用方法。本发明的新型磺胺类或酰胺类的用途包括但不限于自身免疫、炎症或感染相关疾病的预防和/或治疗。
• Discovery of Novel and Potent Small-Molecule Inhibitors of NO and Cytokine Production as Antisepsis Agents:  Synthesis and Biological Activity of Alkyl 6-(N-Substituted sulfamoyl)cyclohex-1-ene-1-carboxylate
  作者：Masami Yamada、Takashi Ichikawa、Masayuki Ii、Mie Sunamoto、Katsumi Itoh、Norikazu Tamura、Tomoyuki Kitazaki

  DOI：10.1021/jm050623t

  日期：2005.11.1

  To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-alpha, IL-6 and IL-1 beta] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound (R)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.