(6S)-6-[(2-氯-4-氟苯基)磺酰基]-1-环己烯-1-羧酸乙酯 | 243984-10-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (6S)-6-[(2-氯-4-氟苯基)磺酰基]-1-环己烯-1-羧酸乙酯
• 中文别名: (6S)-6-[[(2-氯-4-氟苯基)氨基]磺酰基]-1-环己烯-1-甲酸乙酯
• 英文名称: ethyl (6S)-6-[N-(2-chloro-4-fluoro-phenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate
• 英文别名: TAK-242；(6S)-6-({2-Chloro-4-fluoroanilino}sulfonyl)-1-cyclohexene-1-carboxylic acid ethyl ester；(S)-ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-enecarboxylate；ethyl (6S)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate
• CAS: 243984-10-3
• 化学式: C₁₅H₁₇ClFNO₄S
• 分子量: 361.822
• InChiKey: LEEIJTHMHDMWLJ-AWEZNQCLSA-N

物化性质

• 熔点：
  54-55℃
• 沸点：
  462.0±55.0 °C(Predicted)
• 密度：
  1.39

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  80.8
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P264,P270,P301+P312,P330
• 危险性描述：
  H302,H315,H320,H335

反应信息

• 作为产物：
  描述：

  2-(ethoxycarbonyl)cyclohex-1-ene-1-sulfonic acid 在 氯化亚砜 、 三乙胺 作用下， 以 乙酸乙酯 为溶剂， 反应 14.0h， 生成 (6S)-6-[(2-氯-4-氟苯基)磺酰基]-1-环己烯-1-羧酸乙酯
  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

• [EN] SUBSTITUTED CYCLOHEXENES<br/>[FR] CYCLOHEXÈNES SUBSTITUÉS
  申请人：AUSPEX PHARMACEUTICALS INC

  公开号：WO2009015028A1

  公开（公告）日：2009-01-29

  Disclosed herein are deuterated derivatives of TAK-242 of Formula (I) which are modulators of TLR4 signalling pathway, pharmaceutical compositions thereof and methods of use thereof. Formula (I)

  本公开涉及TAK-242的二氘代衍生物，其化学式为（I），这些衍生物是TLR4信号通路的调节剂，以及其药物组合物和使用方法。化学式（I）
• Convenient synthesis of antisepsis agent TAK-242 by novel optical resolution through diastereomeric N-acylated sulfonamide derivative
  作者：Atsuko Nishiguchi、Tomomi Ikemoto、Kiminori Tomimatsu

  DOI：10.1016/j.tet.2007.02.127

  日期：2007.5

  A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By condensation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39% yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from rac-1

  通过非对映异构体拆分，开发了一种简便的防腐剂TAK-242（（R）-1）的合成方法。通过使外消旋体rac - 1与手性酸（S）-O-乙酰基扁桃酸（6a）缩合，通过简单的结晶以39％的收率分离出所需的非对映异构体5a，收率为98％。用NaOH水溶液对5a进行脱酰，然后重结晶，得到具有99％ee的（R）-1，从rac - 1产率为20％。
• SUBSTITUTED CYCLOHEXENES
  申请人：Gant Thomas G.

  公开号：US20090022706A1

  公开（公告）日：2009-01-22

  Disclosed herein are substituted cyclohexene TLR4 signaling pathway modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文披露了化学式I的取代环己烯TLR4信号通路调节剂，其制备方法，制药组合物以及使用方法。
• PROCESS FOR PREPARATION OF OPTICALLY ACTIVE SULFONAMIDES AND INTERMEDIATES FOR THEIR SYNTHESIS
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1334966B1

  公开（公告）日：2011-05-04
• COMPOUNDS FOR SUPPRESSING A PERIPHERAL NERVE DISORDER INDUCED BY AN ANTI - CANCER AGENT
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2528598A1

  公开（公告）日：2012-12-05