(7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid methyl ester | 1256768-33-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid methyl ester
• 英文别名: Methyl 2-(7-fluoro-1,1-dioxo-2,3-dihydro-1lambda6,2,4-benzothiadiazin-4-yl)acetate；methyl 2-(7-fluoro-1,1-dioxo-2,3-dihydro-1λ6,2,4-benzothiadiazin-4-yl)acetate
• CAS: 1256768-33-8
• 化学式: C₁₀H₁₁FN₂O₄S
• 分子量: 274.273
• InChiKey: CVKGMJGQFSZSBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  84.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid methyl ester 、 1-溴-三氟对二甲苯 在 potassium carbonate 作用下， 以 acetonitrle 为溶剂， 反应 2.0h， 以77%的产率得到[2-(4-(trifluoromethyl)benzyl)-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl]acetic acid methyl ester
  参考文献：
  名称：

  Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors

  摘要：

  A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 mu M. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.

  DOI：

  10.1021/jm100962a
• 作为产物：
  描述：

  (7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid methyl ester 在 sodium tetrahydroborate 作用下， 以 异丙醇 、 乙腈 为溶剂， 反应 0.08h， 以67%的产率得到(7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid methyl ester
  参考文献：
  名称：

  Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors

  摘要：

  A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 mu M. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.

  DOI：

  10.1021/jm100962a

文献信息

• 一种苯并噻二嗪酮类衍生物，其制备方法和用 途
  申请人：深圳海王医药科技研究院有限公司

  公开号：CN107056731B

  公开（公告）日：2019-12-10

  本发明提供了具有如式(I)所示结构的化合物及其制备方法。本发明还提供了该类化合物在预防和治疗糖尿病并发症药物中的应用，以及含有这些化合物的药物组合物。本发明的化合物对ALR2抑制活性和ALR1抑制活性具有高选择性，在高糖环境下对细胞有保护作用，化合物在大鼠的体内药物半衰期较长，在血液中浓度较高，其对STZ诱导糖尿病大鼠的坐骨运动神经传导损伤、坐骨感觉神经传导损伤有明显修复作用且效果较好，明显加快了感觉神经纤维A‑fiber和C‑fiber的传导速度，显著降低了大鼠坐骨神经中山梨醇，表现出良好的动物安全性。
• Acetic Acid Derivatives of 3,4-Dihydro-2<i>H</i>-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors
  作者：Xin Chen、Changjin Zhu、Fan Guo、Xiaowei Qiu、Yanchun Yang、Shuzhen Zhang、Minlan He、Shagufta Parveen、Chaojun Jing、Yan Li、Bing Ma

  DOI：10.1021/jm100962a

  日期：2010.12.9

  A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 mu M. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.