d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate | 243983-44-0

• 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: d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
• 英文别名: ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate；d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]cyclohex-1-en-1-carboxylate；ethyl 6-[(2,4-difluorophenyl)sulfamoyl]cyclohexene-1-carboxylate
• CAS: 243983-44-0；352006-79-2；352006-80-5
• 化学式: C₁₅H₁₇F₂NO₄S
• 分子量: 345.367
• InChiKey: VSOMGDDXCKLSIG-UHFFFAOYSA-N

物化性质

• 熔点：
  123-124 °C(Solv: ethyl acetate (141-78-6); isopropyl ether (108-20-3))
• 沸点：
  435.3±55.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 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：
  7

反应信息

• 作为反应物：
  描述：

  d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate 在 硫酸 作用下， 以 丙醇 为溶剂， 生成 propyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
  参考文献：
  名称：

  Cycloalkene derivatives, process for producing the same, and use

  摘要：

  本发明提供了一种由以下公式表示的化合物：其中R代表一个具有取代基的脂肪烃基、一个具有取代基的芳香烃基、一个具有取代基的杂环基、一个由公式表示的基团：OR1（其中R1代表氢原子或具有取代基的脂肪烃基）或一个由公式表示的基团：其中R1b代表氢原子或具有取代基的脂肪烃基，R1c与R1b相同或不同，代表氢原子或具有取代基的脂肪烃基，R0代表氢原子或脂肪烃基，或者R和R0彼此之间形成键结合，Ar代表具有取代基的芳香烃基，n为1至4的整数，或其盐，用作预防或治疗心脏病、自身免疫疾病、感染性休克等疾病的药物。

  公开号：

  US06495604B1
• 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 28.0h， 生成 d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
  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

• Site-Selective Labeling of a Lysine Residue in Human Serum Albumin
  作者：Shigehiro Asano、James T. Patterson、Thomas Gaj、Carlos F. Barbas

  DOI：10.1002/anie.201405924

  日期：2014.10.27

  Conjugation to human serum albumin (HSA) has emerged as a powerful approach for extending the in vivo half‐life of many small molecule and peptide/protein drugs. Current HSA conjugation strategies, however, can often yield heterogeneous mixtures with inadequate pharmacokinetics, low efficacies, and variable safety profiles. Here, we designed and synthesized analogues of TAK‐242, a small molecule inhibitor

  与人血清白蛋白（HSA）的结合已成为延长许多小分子和肽/蛋白质药物在体内半衰期的有效方法。但是，当前的HSA偶联策略通常会产生药代动力学不足，功效低下和安全性变化不均的异质混合物。在这里，我们设计并合成了TAK-242的类似物，它是Toll样受体4的小分子抑制剂，主要与HSA的一个赖氨酸残基反应。这些基于TAK-242的环己烯化合物具有很强的反应活性，Lys64被确定为主要的缀合位点。还以位点特异性的方式制备了二价HSA共轭物。此外，与相应的马来酰亚胺缀合物相比，HSA-环己烯缀合物在人血浆和小鼠中均保持较高水平的稳定性。
• PHARMACEUTICAL AGENT
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2018855A1

  公开（公告）日：2009-01-28

  The present invention provides an agent for the prophylaxis or treatment of complications after coronary-artery bypass surgery or cardiac diseases, autoimmune diseases, central nervous system diseases, inflammatory diseases, sepsis, severe sepsis or septic shock in a patient who undergoes coronary-artery bypass surgery, which comprises a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a compound represented by the formula (II): wherein each symbol is as defined in the specification, or a salt thereof or a prodrug thereof, and an agent for the prophylaxis or treatment of sepsis and the like, as well as complications after coronary-artery bypass surgery, which is prepared for administration of ethyl (6R)-6-[(2-chloro-4-fluoroanilino)sulfonyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof in a specific dose at a specific administration time.

  本发明提供了一种用于预防或治疗冠状动脉旁路手术或心脏疾病、自身免疫疾病、中枢神经系统疾病、炎症性疾病、败血症、重型败血症或脓毒性休克后并发症的药剂，该药剂包括由式(I)表示的化合物：其中每个符号如规范中定义，或由式(II)表示的化合物：其中每个符号如规范中定义，或其盐或前药，以及一种用于预防或治疗败血症等并发症及冠状动脉旁路手术后并发症的药剂，该药剂用于在特定剂量和特定给药时间内给予乙酸乙酯(6R)-6-[(2-氯-4-氟苯胺基)磺酰]-1-环己烯-1-羧酸乙酯或其盐或前药。
• Substituted aromatic-ring compounds, process for producing the same and use
  申请人：Tamura Norikazu

  公开号：US20050176783A1

  公开（公告）日：2005-08-11

  A compound of the formula: wherein R 1 is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group of the formula: OR 1a wherein R 1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group of the formula: wherein R 1b and R 1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom, Y is an optionally substituted methylene group or an optionally substituted nitrogen atom, ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from (1) an aliphatic hydrocarbon group optionally having substituent(s), (2) an aromatic hydrocarbon group optionally having substituent(s), (3) a group of the formula: OR 2 wherein R 2 is a hydrogen atom, or an aliphatic hydrocarbon group optionally having substituent(s) and (4) a halogen atom, Ar is an aromatic hydrocarbon group optionally having substituent(s), a group of the formula: is a group of the formula: or the formula: m is an integer of 0 to 2, n is an integer of 1 to 3, and the sum of m and n is not more than 4, provided that when X is a methylene group, Y is an optionally substituted methylene group, and a salt thereof have an inhibitory activity on nitric oxide (NO) production and cytokine production, and are useful as an agent for the prophylaxis and/or treatment of diseases, such as cardiac disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock and the like.

  一种化合物的公式：其中R1是一个脂肪烃基，可以选择地具有取代基，或是一个芳香烃基，可以选择地具有取代基，或是一个杂环基，可以选择地具有取代基，或是一个公式为OR1a的基团，其中R1a是氢原子或是一个脂肪烃基，可以选择地具有取代基，或是一个公式为的基团，其中R1b和R1c相同或不同，且每个都是氢原子或是一个脂肪烃基，可以选择地具有取代基，X是一个亚甲基基团、氮原子、硫原子或是氧原子，Y是一个可以选择地具有取代基的亚甲基基团或是一个可以选择地具有取代基的氮原子，环A是一个5到8成员环，可以选择地进一步被1到4个取代基所取代，所述取代基被选择自(1)一个脂肪烃基，可以选择地具有取代基，(2)一个芳香烃基，可以选择地具有取代基，(3)一个公式为OR2的基团，其中R2是一个氢原子或是一个脂肪烃基，可以选择地具有取代基，以及(4)一个卤原子，Ar是一个芳香烃基，可以选择地具有取代基，一个公式为的基团，或是一个公式为的基团，其中m是0到2的整数，n是1到3的整数，且m和n的和不超过4，当X是一个亚甲基基团，Y是一个可以选择地具有取代基的亚甲基基团时，该化合物及其盐具有一种抑制一氧化氮（NO）产生和细胞因子产生的活性，可用作预防和/或治疗疾病的药剂，例如心脏疾病、自身免疫性疾病、炎症性疾病、中枢神经系统疾病、传染病、败血症、脓毒性休克等。
• Combination Drugs
  申请人：——

  公开号：US20040063685A1

  公开（公告）日：2004-04-01

  The present invention relates to a pharmaceutical agent containing an anti-sepsis drug (e.g., cycloalkene compound), and at least one kind of drug selected from the group consisting of an antibacterial agent, an antifungal agent, a non-steroidal antiinflammatory drug, a steroid and an anticoagulant in combination.

  本发明涉及一种药物制剂，其包含一种抗脓毒症药物（例如环烷化合物），并且与至少一种从抗菌药物、抗真菌药物、非甾体抗炎药、类固醇和抗凝剂中选择的药物组合使用。
• STABLE EMULSION COMPOSITION
  申请人：Asakawa Naoki

  公开号：US20100016381A1

  公开（公告）日：2010-01-21

  The present invention provides an emulsion composition comprising (A) a compound stable in an acidic range, and (B) a buffer, wherein the pH is adjusted from about 3.7 to about 5.5.

  本发明提供了一种乳液组合物，包括(A)在酸性范围内稳定的化合物和(B)缓冲剂，其中pH值调节在大约3.7到5.5之间。