2-(4-bromo-2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester | 147194-02-3

• 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: 2-(4-bromo-2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester
• 英文别名: 2-(4-Bromo 2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester；ethyl 4-(2-amino-2-oxoethyl)-2-[(4-bromo-2-fluorophenyl)methyl]-1,3-dioxopyrrolo[1,2-a]pyrazine-4-carboxylate
• CAS: 147194-02-3
• 化学式: C₁₉H₁₇BrFN₃O₅
• 分子量: 466.263
• InChiKey: BNITVQMRXRZDTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(4-bromo-2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.3h， 以40%的产率得到AS-3201
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  (R)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners

  摘要：

  A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a][1,2a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)enantiomer 44 (SX-3202): From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

  DOI：

  10.1021/jm9802968
• 作为产物：
  描述：

  2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester 在 ammonium hydroxide 、 氯化亚砜 、 sodium hydride 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.5h， 生成 2-(4-bromo-2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  (R)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners

  摘要：

  A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a][1,2a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)enantiomer 44 (SX-3202): From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

  DOI：

  10.1021/jm9802968

文献信息

• Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives,
  申请人：Dainippon Pharmaceutical Co., Ltd.

  公开号：US05258382A1

  公开（公告）日：1993-11-02

  Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen, halogen, trifluoromethyl, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or nitro, and R.sup.3 is hydrogen, halogen or alkyl having 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof, processes for preparation thereof, and pharmaceutical composition containing the same. Said compounds and their salts show excellent aldose reductase inhibitory activity and are useful for the prevention and treatment of diabetic complications.

  该文献介绍了一种公式为 ##STR1## 的四氢吡咯并[1,2-a]吡嗪-4-螺-3'-吡咯啉衍生物，其中R.sup.1和R.sup.2分别为氢、卤素、三氟甲基、碳链为1至6的烷基、碳链为1至6的烷氧基或硝基，R.sup.3为氢、卤素或碳链为1至6的烷基，以及其药学上可接受的盐，制备方法和含有它们的药物组合物。这些化合物及其盐具有出色的醛还原酶抑制活性，并可用于预防和治疗糖尿病并发症。
• Tetrahydropyrrolo 1,2-a pyrazine-4-spiro-3'-pyrrolidine derivatives, processes for the preparation thereof and pharaceutical compositions containing the same
  申请人：DAINIPPON PHARMACEUTICAL CO., LTD.

  公开号：EP0520320A2

  公开（公告）日：1992-12-30

  Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives of the formula: wherein R¹ and R² are independently hydrogen, halogen, trifluoromethyl, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or nitro, and R³ is hydrogen, halogen or alkyl having 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof, processes for preparation thereof, and pharmaceutical composition containing the same. Said compounds and their salts show excellent aldose reductase inhibitory activity and are useful for the prevention and treatment of diabetic complications.

  式中的四氢吡咯并[1,2-a]吡嗪-4-螺-3'-吡咯烷衍生物： 其中R¹和R²独立地为氢、卤素、三氟甲基、具有1至6个碳原子的烷基、具有1至6个碳原子的烷氧基或硝基，R³为氢、卤素或具有1至6个碳原子的烷基，及其药学上可接受的盐、其制备工艺和含有这些物质的药物组合物。上述化合物及其盐类显示出优异的醛糖还原酶抑制活性，可用于预防和治疗糖尿病并发症。
• Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same
  申请人：Dainippon Pharmaceutical Co., Ltd.

  公开号：EP0520320B1

  公开（公告）日：1997-09-10
• US5258382A
  申请人：——

  公开号：US5258382A

  公开（公告）日：1993-11-02