6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yloxy)-3-methylbenzofuran-2-carboxylic acid | 1618131-32-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yloxy)-3-methylbenzofuran-2-carboxylic acid
• 英文别名: 3-methyl-5-[3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridine-4-oxy]-6-chlorobenzofuran-2-formic acid；6-Chloro-5-[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)pyridin-4-yl]oxy-3-methyl-1-benzofuran-2-carboxylic acid；6-chloro-5-[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)pyridin-4-yl]oxy-3-methyl-1-benzofuran-2-carboxylic acid
• CAS: 1618131-32-0
• 化学式: C₂₇H₂₂ClN₃O₅
• 分子量: 503.942
• InChiKey: MEVXQVCFUKETIW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  96.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yloxy)-3-methylbenzofuran-2-carboxylic acid 、 甘氨酸乙酯盐酸盐 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 为溶剂， 以83%的产率得到ethyl 2-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yloxy)-3-methylbenzofuran-2-carboxamido)acetate
  参考文献：
  名称：

  4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists

  摘要：

  A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.05.031
• 作为产物：
  描述：

  benzyl 4-chloronicotinate 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yloxy)-3-methylbenzofuran-2-carboxylic acid
  参考文献：
  名称：

  4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists

  摘要：

  A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.05.031

文献信息

• [EN] AMIDE COMPOUNDS AND PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF<br/>[FR] COMPOSÉS AMIDES ET PROCÉDÉS DE PRÉPARATION, COMPOSITIONS PHARMACEUTIQUES ET APPLICATIONS ASSOCIÉS
  申请人：SHANGHAI INST MATERIA MEDICA

  公开号：WO2014117292A1

  公开（公告）日：2014-08-07

  本发明涉及结构式（I）所示的一类酰胺类化合物，它是低吸收的TGR5激动剂，可用于治II型糖尿病、肥胖症、肝脏和肠道慢性炎症疾病。
• 4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists
  作者：Qingan Zou、Hongliang Duan、Mengmeng Ning、Jia Liu、Ying Feng、Liming Zhang、Junjie Zhu、Ying Leng、Jianhua Shen

  DOI：10.1016/j.ejmech.2014.05.031

  日期：2014.7

  A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19. (C) 2014 Elsevier Masson SAS. All rights reserved.