ethyl 1-[(2-aminothiazol-5-yl)methyl]piperidine-4-carboxylate | 1325708-57-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: ethyl 1-[(2-aminothiazol-5-yl)methyl]piperidine-4-carboxylate
• 英文别名: 1-(2-Amino-thiazol-5-ylmethyl)-piperidine-4-carboxylic acid ethyl ester；ethyl 1-[(2-amino-1,3-thiazol-5-yl)methyl]piperidine-4-carboxylate
• CAS: 1325708-57-3
• 化学式: C₁₂H₁₉N₃O₂S
• mdl: MFCD23343765
• 分子量: 269.368
• InChiKey: PSIPZVYUXNAJTG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.666
• 拓扑面积：
  96.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid 、 ethyl 1-[(2-aminothiazol-5-yl)methyl]piperidine-4-carboxylate 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 methyl 1-[[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetyl]amino]thiazol-5-yl]methyl]piperidine-4-carboxylate
  参考文献：
  名称：

  Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia

  摘要：

  Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.03.042
• 作为产物：
  描述：

  1-(2-tert-Butoxycarbonylamino-thiazol-5-ylmethyl)-piperidine-4-carboxylic acid ethyl ester 在 乙酸乙酯 、 水 、 Sodium sulfate-III 作用下， 以 二氯甲烷 、 三氟乙酸 为溶剂， 反应 12.0h， 生成 ethyl 1-[(2-aminothiazol-5-yl)methyl]piperidine-4-carboxylate
  参考文献：
  名称：

  Acetamide derivatives as glucokinase activators, their process and medicinal application

  摘要：

  本发明披露了乙酰胺衍生物及其立体异构体、互变异构体、前药、药物可接受的盐、多晶形态、溶剂化物及其制剂，用于预防、治疗、控制进展或辅助治疗激活葡萄糖激酶有益的疾病和/或医疗条件。本发明还提供了制备这些乙酰胺衍生物的方法。

  公开号：

  US08501955B2

文献信息

• ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND MEDICINAL APPLICATION
  申请人：Bhuniya Debnath

  公开号：US20100310493A1

  公开（公告）日：2010-12-09

  Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, are disclosed. The disclosure also provides process of preparation of these acetamide derivatives.

  乙酰胺衍生物，它们的立体异构体、互变异构体、前药、药用可接受盐、多型体、溶剂合物及其配方，用于预防、管理、治疗、控制疾病和/或医疗状况的进展，或者作为激活葡萄糖激酶有益时的辅助治疗，已被披露。该披露还提供了这些乙酰胺衍生物的制备方法。
• [EN] BENZAMIDE COMPOUNDS AS GLUCOKINASE ACTIVATORS AND THEIR PHARMACEUTICAL APPLICATION<br/>[FR] COMPOSÉS DE BENZAMIDE À TITRE D'ACTIVATEURS DE GLUCOKINASE ET LEUR APPLICATION PHARMACEUTIQUE
  申请人：ADVINUS THERAPEUTICS PRIVATE LTD

  公开号：WO2011095997A1

  公开（公告）日：2011-08-11

  Benzamide compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof useful as Glucokinase activators or modulators are disclosed. The disclosure further relates to process of preparation of the benzamide compounds.

  公开了化学式（I）的苯甲酰胺化合物，它们的立体异构体、互变异构体、前药、药用可接受的盐、多型体、溶剂合物和制剂，可用作葡萄糖激酶激活剂或调节剂。该公开还涉及苯甲酰胺化合物的制备过程。
• US8501955B2
  申请人：——

  公开号：US8501955B2

  公开（公告）日：2013-08-06
• Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia
  作者：Anil M. Deshpande、Debnath Bhuniya、Siddhartha De、Bhavesh Dave、Vinod P. Vyavahare、Santosh H. Kurhade、Sachin R. Kandalkar、Keshav P. Naik、Balasaheb S. Kobal、Rahul D. Kaduskar、Sujay Basu、Vaibhav Jain、Pratima Patil、Sandhya Chaturvedi Joshi、Ganesh Bhat、Amol A. Raje、Satyanarayana Reddy、Jayasagar Gundu、Vamsi Madgula、Suhas Tambe、Prasad Shitole、Dhananjay Umrani、Anita Chugh、Venkata P. Palle、Kasim A. Mookhtiar

  DOI：10.1016/j.ejmech.2017.03.042

  日期：2017.6

  Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Acetamide derivatives as glucokinase activators, their process and medicinal application
  申请人：Bhuniya Debnath

  公开号：US08501955B2

  公开（公告）日：2013-08-06

  Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, are disclosed. The disclosure also provides process of preparation of these acetamide derivatives.

  本发明披露了乙酰胺衍生物及其立体异构体、互变异构体、前药、药物可接受的盐、多晶形态、溶剂化物及其制剂，用于预防、治疗、控制进展或辅助治疗激活葡萄糖激酶有益的疾病和/或医疗条件。本发明还提供了制备这些乙酰胺衍生物的方法。