methyl 3-(2-methoxyethoxy)-5-(4-(methylsulfonyl)phenoxy)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 3-(2-methoxyethoxy)-5-(4-(methylsulfonyl)phenoxy)benzoate
• 英文别名: Methyl 3-(2-methoxyethoxy)-5-(4-methylsulfonylphenoxy)benzoate
• 化学式: C₁₈H₂₀O₇S
• 分子量: 380.419
• InChiKey: PEPIBLDELYBGOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  96.5
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 3-(2-methoxyethoxy)-5-(4-(methylsulfonyl)phenoxy)benzoate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 tert-butyl 2-(3-(2-methoxyethoxy)-5-(4-(methylsulfonyl)phenoxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  参考文献：
  名称：

  Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

  摘要：

  Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected beta-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.07.051
• 作为产物：
  描述：

  4-溴苯甲砜 在 copper(l) iodide 、 2,2,6,6-四甲基-3,5-庚二酮 、 偶氮二甲酸二异丙酯 、 caesium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 methyl 3-(2-methoxyethoxy)-5-(4-(methylsulfonyl)phenoxy)benzoate
  参考文献：
  名称：

  Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

  摘要：

  Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected beta-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.07.051

文献信息

• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• US7910747B2
  申请人：——

  公开号：US7910747B2

  公开（公告）日：2011-03-22
• US8153677B2
  申请人：——

  公开号：US8153677B2

  公开（公告）日：2012-04-10
• [EN] NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME<br/>[FR] NOUVEAUX ACTIVATEURS DE LA GLUCOKINASE ET PROCÉDÉS D'UTILISATION DE CES ACTIVATEURS
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2008005964A2

  公开（公告）日：2008-01-10

  [EN] Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure of Formula (I), wherein Formula (II) is a heteroaryl ring; R₄ is -(CH₂)_n-Z-(CH₂)_m-PO(OR₇)(OR₈), -(CH₂)_nZ-(CH₂)_m-PO(OR₇)R₉, -(CH₂)_n-Z-(CH₂)_m-OPO(OR₇)R₉, -(CH₂)_nZ-(CH₂)_m-OPO(R₉)(R₁₀), or -(CH₂)_nZ-(CH₂)_m-PO(R₉)(R₁₀); R₅ and R6 are independently selected from H, alkyl and halogen; Y is R₇(CH₂)_s or is absent; and X, n, Z, m, R₄, R₅, R₆, R₇, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
  [FR] L'invention concerne des composés qui sont des activateurs de phosphonate et de phosphinate, qui sont donc utiles dans le traitement des diabètes et des maladies apparentées et qui possèdent la structure de la formule (I), où la formule (II) représente un noyau hétéroaryle ; R₄ représente un groupe -(CH₂)_n-Z-(CH₂)_m-PO(OR₇)(OR₈), -(CH₂)_nZ-(CH₂)_m-PO(OR₇)R₉, -(CH₂)_n-Z-(CH₂)_m-OPO(OR₇)R₉, -(CH₂)_nZ-(CH₂)_m-OPO(R₉)(R₁₀), ou -(CH₂)_nZ-(CH₂)_m-PO(R₉)(R₁₀) ; R₅ et R₆ sont indépendamment choisis parmi un atome H, un groupe alkyle et un atome d'halogène ; Y représente R₇(CH₂)_s ou est absent ; et X, n, Z, m, R₄, R₅, R₆, R₇, et s sont tels que définis ci-après ; ou un sel pharmaceutiquement acceptable de ces activateurs. L'invention concerne également un procédé pour traiter les diabètes et les maladies apparentées en employant les composés précédents.
• Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation
  作者：Zhengyu Wang、Xiaofan Shi、Huan Zhang、Liang Yu、Yanhua Cheng、Hefeng Zhang、Huibin Zhang、Jinpei Zhou、Jing Chen、Xu Shen、Wenhu Duan

  DOI：10.1016/j.ejmech.2017.07.051

  日期：2017.10

  Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected beta-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration. (C) 2017 Elsevier Masson SAS. All rights reserved.