tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate
• 英文别名: Tert-butyl 6-chloro-3[(4-methoxyphenyl)sulfanyl]pyridine-2-carboxylate；tert-butyl 6-chloro-3-(4-methoxyphenyl)sulfanylpyridine-2-carboxylate
• 化学式: C₁₇H₁₈ClNO₃S
• 分子量: 351.854
• InChiKey: UXQKNAWHBYPTBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  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：
  0.29
• 拓扑面积：
  73.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate 在 potassium tert-butylate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 ({2-[({3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridin-2-yl}carbonyl)amino]-1,3-thiazol-5-yl}sulfanyl)acetic acid
  参考文献：
  名称：

  Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus

  摘要：

  Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic beta-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose -lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses >= 10 mpk, with >= 70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.088
• 作为产物：
  描述：

  2-氯-5-氟吡啶-6-羧酸 在 三氟化硼乙醚 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate
  参考文献：
  名称：

  Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus

  摘要：

  Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic beta-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose -lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses >= 10 mpk, with >= 70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.088

文献信息

• Novel 2-pyridinecarboxamide derivatives
  申请人：Mitsuya Morihiro

  公开号：US20060258701A1

  公开（公告）日：2006-11-16

  The present invention relates to a compound which has a glucokinase-activating effect and is useful as a therapeutic agent for diabetes mellitus, being represented by a formula (I): [wherein X 1 represents a nitrogen atom, sulfur atom, oxygen atom or the like; R 1 represents a 6- to 10-membered aryl group, 5- to 7-membered heteroaryl group or the like; D represents an oxygen atom or sulfur atom; R and R 3 are the same or different, each representing a hydrogen atom, lower alkyl group or the like; a formula (II) represents an optionally substituted 5- to 7-membered heteroaryl group or the like; a formula (III) represents a monocyclic or bicyclic heteroaryl group] or a pharmaceutically acceptable salt thereof.

  本发明涉及一种化合物，具有激活葡萄糖激酶的效果，并可用作糖尿病治疗剂，其化学式表示为（I）：[其中X1表示氮原子、硫原子、氧原子或类似物；R1表示6-至10-成员芳基基团、5-至7-成员杂芳基基团或类似物；D表示氧原子或硫原子；R和R3相同或不同，分别表示氢原子、低碳基或类似物；式（II）表示可选取代的5-至7-成员杂芳基团或类似物；式（III）表示单环或双环杂芳基团]或其药学上可接受的盐。
• 2-pyridinecarboxamide derivatives
  申请人：MSD K. K.

  公开号：US08344003B2

  公开（公告）日：2013-01-01

  The present invention relates to a compound which has a glucokinase-activating effect and is useful as a therapeutic agent for diabetes mellitus, being represented by a formula (I): [wherein X1 represents a nitrogen atom, sulfur atom, oxygen atom or the like; R1 represents a 6- to 10-membered aryl group, 5- to 7-membered heteroaryl group or the like; D represents an oxygen atom or sulfur atom; R2 and R3 are the same or different, each representing a hydrogen atom, lower alkyl group or the like; a formula (II) represents an optionally substituted 5- to 7-membered heteroaryl group or the like; a formula (III) represents a monocyclic or bicyclic heteroaryl group] or a pharmaceutically acceptable salt thereof.

  本发明涉及一种具有葡萄糖激酶激活作用的化合物，可用作糖尿病治疗剂，其化学式表示为（I）：[其中X1表示氮原子、硫原子、氧原子或类似物；R1表示6-至10-成员芳基基团、5-至7-成员杂芳基团或类似物；D表示氧原子或硫原子；R2和R3相同或不同，分别表示氢原子、较低的烷基基团或类似物；式（II）表示可选地取代的5-至7-成员杂芳基团或类似物；式（III）表示单环或双环杂芳基团]或其药学上可接受的盐。
• NOVEL 2-PYRIDINECARBOXAMIDE DERIVATIVES, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND METHODS OF TREATMENT
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20150336946A1

  公开（公告）日：2015-11-26

  Novel pyridine-2-carboxamide derivatives of formula I and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are effective as glucokinase activating agents. Pharmaceutical compositions and methods of treatment are also included. The present invention relates to novel pyridine-2-carboxamide derivatives and salts thereof which are effective as glucokinase activating agents. Moreover, it relates to compositions containing such compounds, and methods of treatment.

  本发明公开了式I的新型吡啶-2-羧酰胺衍生物及其药学上可接受的盐，用于治疗或预防2型糖尿病和类似疾病。这些化合物作为葡萄糖激酶激活剂具有有效性。本发明还涉及包含这些化合物的制药组合物和治疗方法。本发明涉及新型吡啶-2-羧酰胺衍生物及其盐，其作为葡萄糖激酶激活剂具有有效性。此外，涉及含有此类化合物的组合物和治疗方法。
• 2-pyridine carboxamide derivatives
  申请人：Banyu Pharmaceutical Co., Ltd.

  公开号：US07629362B2

  公开（公告）日：2009-12-08

  The present invention relates to a compound which has a glucokinase-activating effect and is useful as a therapeutic agent for diabetes mellitus, being represented by a formula (I): [wherein X1 represents a nitrogen atom, sulfur atom, oxygen atom or the like; R1 represents a 6- to 10-membered aryl group, 5- to 7-membered heteroaryl group or the like; D represents an oxygen atom or sulfur atom; R2 and R3 are the same or different, each representing a hydrogen atom, lower alkyl group or the like; a formula (II) represents an optionally substituted 5- to 7-membered heteroaryl group or the like; a formula (III) represents a monocyclic or bicyclic heteroaryl group] or a pharmaceutically acceptable salt thereof.

  本发明涉及一种具有葡萄糖激酶激活作用的化合物，可用作糖尿病治疗剂，其化学式为（I）：[其中X1表示氮原子、硫原子、氧原子或类似物；R1表示6-至10-成员的芳基基团、5-至7-成员的杂环芳基基团或类似物；D表示氧原子或硫原子；R2和R3相同或不同，分别表示氢原子、低碳基基团或类似物；化学式（II）表示可选取代的5-至7-成员的杂环芳基基团或类似物；化学式（III）表示单环或双环杂环芳基基团] 或其药学上可接受的盐。
• NOVEL 2-PYRIDINECARBOXAMIDE DERIVATIVES
  申请人：MSD K.K.

  公开号：EP1598349B1

  公开（公告）日：2011-07-27