5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid | 1259396-25-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid
• 英文别名: 2-(4-Carboxy-5-methylthiophen-2-yl)pyrrolidine-1-carboxylic acid t-butyl ester；2-methyl-5-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]thiophene-3-carboxylic acid
• CAS: 1259396-25-2
• 化学式: C₁₅H₂₁NO₄S
• 分子量: 311.402
• InChiKey: SPQFQYYHVTVNTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  95.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid 在 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 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 N-(5-chlorothiazol-2-yl)-2-methyl-5-(pyrrolidin-2-yl)thiophene-3-carboxamide
  参考文献：
  名称：

  Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus

  摘要：

  Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.06.060
• 作为产物：
  描述：

  3-噻吩甲酸 在 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 氯化亚砜 、 lithium hydroxide monohydrate 、 水 、 异丙基溴化镁 、 甲基磺酰氯 、 三乙胺 、 二异丙胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.42h， 生成 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid
  参考文献：
  名称：

  NOVEL THIOPHENECARBOXAMIDE DERIVATIVE AND PHARMACEUTICAL USE THEREOF

  摘要：

  本发明的目的是提供一种具有激活葡萄糖激酶作用的化合物。一种包含以下通式（I）所表示的化合物或其药学上可接受的盐为活性成分的药物组合物：其中X代表一个氮原子或CR6，其中R6代表氢原子或卤素原子；R1代表氢原子、C1-C6烷基、C1-C6烷氧基或C1-C6烷硫基；R2代表氢原子或氟原子；R3代表氢原子或C1-C6烷基；而R4和R5中的一个代表氢原子或C1-C6烷基，另一个代表C1-C6烷基羧酸、C1-C6烷基磺酰基、C1-C6烷基羰基或CONH2。

  公开号：

  US20120101137A1

文献信息

• NOVEL THIOPHENECARBOXAMIDE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
  申请人：Yamashita Tokuyuki

  公开号：US20120101137A1

  公开（公告）日：2012-04-26

  The object of the present invention is to provide a compound having a glucokinase-activating effect. A pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: wherein X means a nitrogen atom or CR 6 , wherein R 6 means a hydrogen atom or a halogen atom; R 1 means a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group; R 2 means a hydrogen atom or a fluorine atom; R 3 means a hydrogen atom or a C1-C6 alkyl group; and one of R 4 and R 5 means a hydrogen atom or a C1-C6 alkyl group, and the other means a C1-C6 alkylenecarboxylic acid, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl group, or CONH 2 .

  本发明的目的是提供一种具有激活葡萄糖激酶作用的化合物。一种包含以下通式（I）所表示的化合物或其药学上可接受的盐为活性成分的药物组合物：其中X代表一个氮原子或CR6，其中R6代表氢原子或卤素原子；R1代表氢原子、C1-C6烷基、C1-C6烷氧基或C1-C6烷硫基；R2代表氢原子或氟原子；R3代表氢原子或C1-C6烷基；而R4和R5中的一个代表氢原子或C1-C6烷基，另一个代表C1-C6烷基羧酸、C1-C6烷基磺酰基、C1-C6烷基羰基或CONH2。
• New synthetic route to the important <i>(S)</i>-5-(1-(<i>tert</i>-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid intermediate for the synthesis of a novel glucokinase activator
  作者：Hiroki Fujieda、Koji Maeda

  DOI：10.1080/00397911.2019.1570267

  日期：2019.3.19

  Abstract To obtain an efficient and practical route to a novel glucokinase activator, we investigated a novel synthetic method for the preparation of its key intermediate (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid through the asymmetric transfer hydrogenation of a pyrroline derivative. The hydrogenation of this pyrroline derivative using the iridium (III)-prolinamide

  摘要 为了获得一种高效实用的新型葡萄糖激酶激活剂途径，我们研究了一种制备其关键中间体(S)-5-(1-(叔丁氧基羰基)吡咯烷-2-基)-2-的新型合成方法。甲基噻吩-3-羧酸通过吡咯啉衍生物的不对称转移氢化。在大气压下使用铱 (III)-脯氨酰胺复合物 Cp*IrCl[(R)-PA] 氢化该吡咯啉衍生物，提供了约 50% ee 的初始中间体。通过重结晶进一步纯化提供了具有优异对映纯度的所需关键中间体，这适用于实际应用。图形概要
• NOVEL THIOPHENE CARBOXAMIDE DERIVATIVE AND MEDICINAL USE OF SAME
  申请人：Sanwa Kagaku Kenkyusho Co., Ltd

  公开号：EP2447265A1

  公开（公告）日：2012-05-02

  The object of the present invention is to provide a compound having a glucokinase-activating effect. A pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: wherein X means a nitrogen atom or CR6 wherein R6 means a hydrogen atom or a halogen atom; R1 means a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group; R2 means a hydrogen atom or a fluorine atom; R3 means a hydrogen atom or a C1-C6 alkyl group; and one of R4 and R5 means a hydrogen atom or a C1-C6 alkyl group, and the other means a C1-C6 alkylenecarboxylic acid, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl group, or CONH2.

  本发明的目的是提供一种具有葡萄糖激酶激活作用的化合物。 一种药物组合物，其活性成分包括通式（I）代表的化合物或其药学上可接受的盐： 其中 X 指氮原子或 CR6，其中 R6 指氢原子或卤素原子； R1 指氢原子、C1-C6 烷基、C1-C6 烷氧基或 C1-C6 烷硫基； R2 指氢原子或氟原子 R3 指氢原子或 C1-C6 烷基；以及 R4 和 R5 中的一个指氢原子或 C1-C6 烷基，另一个指 C1-C6 烷烯羧酸、C1-C6 烷基磺酰基、C1-C6 烷基羰基或 CONH2。
• Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus
  作者：Hiroki Fujieda、Masakazu Kogami、Masao Sakairi、Noriyasu Kato、Mitsuhiro Makino、Naoki Takahashi、Toshiyuki Miyazawa、Satoko Harada、Tokuyuki Yamashita

  DOI：10.1016/j.ejmech.2018.06.060

  日期：2018.8

  Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. (C) 2018 Elsevier Masson SAS. All rights reserved.