tert-butyl 4-(4-{[7-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino}benzoyl)piperazine-1-carboxylate | 1018070-76-2

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: tert-butyl 4-(4-{[7-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino}benzoyl)piperazine-1-carboxylate
• 英文别名: Tert-butyl 4-[4-[[7-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]benzoyl]piperazine-1-carboxylate
• CAS: 1018070-76-2
• 化学式: C₃₁H₃₃ClN₆O₄
• 分子量: 589.094
• InChiKey: QKTPKCUSSCKQJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-{[7-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino}benzoyl)piperazine-1-carboxylate 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以99%的产率得到{4-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-phenyl}-piperazin-1-yl-methanone
  参考文献：
  名称：

  Development of Prodrug 4-Chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): A Topically Administered Therapeutic Candidate in Clinical Trials for the Treatment of Age-Related Macular Degeneration

  摘要：

  Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema associated with AMD. Therefore, we have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compounds is 4-chloro-3-{5-methyl-3-[4-(2-pytrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol (5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogues of 5 were prepared as prodrugs to improve the concentration of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concentrations of 5 are available in the back-of-the-eye tissues. From these studies, we identified 4-chloro-3-(5-methyl-3-{[4(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotfazin-7-yl)phenyl benzoate (12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compound 5 in the eye. This topically delivered compound exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compound 12 was advanced. It is currently in a clinical trial as a first in class, VEGFr2 targeting, topically applied compound for the treatment of AMD.

  DOI：

  10.1021/jm7011276
• 作为产物：
  描述：

  7-(2-氯-5-甲氧基苯基)-5-甲基-1,2,4-苯并三嗪-3-胺 、 4-(4-溴-苯甲酰基)-哌嗪-1-羧酸叔丁酯 在 palladium diacetate potassium tert-butylate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 xylene 为溶剂， 反应 0.25h， 以23%的产率得到tert-butyl 4-(4-{[7-(2-chloro-5-methoxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino}benzoyl)piperazine-1-carboxylate
  参考文献：
  名称：

  Development of Prodrug 4-Chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): A Topically Administered Therapeutic Candidate in Clinical Trials for the Treatment of Age-Related Macular Degeneration

  摘要：

  Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema associated with AMD. Therefore, we have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compounds is 4-chloro-3-{5-methyl-3-[4-(2-pytrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol (5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogues of 5 were prepared as prodrugs to improve the concentration of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concentrations of 5 are available in the back-of-the-eye tissues. From these studies, we identified 4-chloro-3-(5-methyl-3-{[4(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotfazin-7-yl)phenyl benzoate (12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compound 5 in the eye. This topically delivered compound exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compound 12 was advanced. It is currently in a clinical trial as a first in class, VEGFr2 targeting, topically applied compound for the treatment of AMD.

  DOI：

  10.1021/jm7011276