7-(2-chlorophenyl)-5-methyl-1,2,4-benzotriazine-3-ylamine | 915145-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: 7-(2-chlorophenyl)-5-methyl-1,2,4-benzotriazine-3-ylamine
• 英文别名: 7-(2-Chlorophenyl)-5-methylbenzo[e][1,2,4]triazin-3-amine；7-(2-chlorophenyl)-5-methyl-1,2,4-benzotriazin-3-amine
• CAS: 915145-15-2
• 化学式: C₁₄H₁₁ClN₄
• 分子量: 270.721
• InChiKey: GDPDTPOGGCFUBE-UHFFFAOYSA-N

物化性质

• 沸点：
  468.3±37.0 °C(Predicted)
• 密度：
  1.360±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  64.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-(2-chlorophenyl)-5-methyl-1,2,4-benzotriazine-3-ylamine 、 1-(2-(4-溴苯氧基)乙基)吡咯烷 在 tris(dibenzylideneacetone)dipalladium (0) caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 为溶剂， 反应 12.0h， 以70%的产率得到[7-(2-chloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine
  参考文献：
  名称：

  The design and preliminary structure–activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes

  摘要：

  We describe the design, synthesis and structure-activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the alpha C-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 mu M) inhibitors into those with low nM potency. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.08.043
• 作为产物：
  描述：

  在 镍 sodium hydroxide 、 四(三苯基膦)钯 、 氢气 、 potassium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 7.5h， 生成 7-(2-chlorophenyl)-5-methyl-1,2,4-benzotriazine-3-ylamine
  参考文献：
  名称：

  Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine—a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays

  摘要：

  We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-l-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.11.006

文献信息

• 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
  作者：Moorthy S. S. Palanki、Hideo Akiyama、Peter Campochiaro、Jianguo Cao、Chun P. Chow、Luis Dellamary、John Doukas、Richard Fine、Colleen Gritzen、John D. Hood、Steven Hu、Shu Kachi、Xinshan Kang、Boris Klebansky、Ahmed Kousba、Dan Lohse、Chi Ching Mak、Michael Martin、Andrew McPherson、Ved P. Pathak、Joel Renick、Richard Soll、Naoyasu Umeda、Shiyin Yee、Katsutoshi Yokoi、Binqi Zeng、Hong Zhu、Glenn Noronha

  DOI：10.1021/jm7011276

  日期：2008.3.1

  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.
• Discovery and preliminary structure–activity relationship studies of novel benzotriazine based compounds as Src inhibitors
  作者：Glenn Noronha、Kathy Barrett、Jianguo Cao、Elena Dneprovskaia、Richard Fine、Xianchang Gong、Colleen Gritzen、John Hood、Xinshan Kang、Boris Klebansky、G. Li、W. Liao、Dan Lohse、Chi Ching Mak、Andrew McPherson、Moorthy S.S. Palanki、Ved P. Pathak、Joel Renick、Richard Soll、Ute Splittgerber、Wolfgang Wrasidlo、Binqi Zeng、Ningning Zhao、Y. Zhou

  DOI：10.1016/j.bmcl.2006.08.035

  日期：2006.11

  We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyI analogue (43) was identified as one of the most potent inhibitors of Src kinase. (c) 2006 Elsevier Ltd. All rights reserved.
• Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine—a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays
  作者：Glenn Noronha、Kathy Barrett、Antonio Boccia、Tessa Brodhag、Jianguo Cao、Chun P. Chow、Elena Dneprovskaia、John Doukas、Richard Fine、Xianchang Gong、Colleen Gritzen、Hong Gu、Ehab Hanna、John D. Hood、Steven Hu、Xinshan Kang、Jann Key、Boris Klebansky、Ahmed Kousba、Ge Li、Dan Lohse、Chi Ching Mak、Andrew McPherson、Moorthy S.S. Palanki、Ved P. Pathak、Joel Renick、Feng Shi、Richard Soll、Ute Splittgerber、Silva Stoughton、Suhan Tang、Shiyin Yee、Binqi Zeng、Ningning Zhao、Hong Zhu

  DOI：10.1016/j.bmcl.2006.11.006

  日期：2007.2

  We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-l-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth. (c) 2006 Elsevier Ltd. All rights reserved.
• The design and preliminary structure–activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes
  作者：Jianguo Cao、Richard Fine、Colleen Gritzen、John Hood、Xinshan Kang、Boris Klebansky、Dan Lohse、Chi Ching Mak、Andrew McPherson、Glenn Noronha、Moorthy S.S. Palanki、Ved P. Pathak、Joel Renick、Richard Soll、Binqi Zeng、Hong Zhu

  DOI：10.1016/j.bmcl.2007.08.043

  日期：2007.11

  We describe the design, synthesis and structure-activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the alpha C-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 mu M) inhibitors into those with low nM potency. (c) 2007 Elsevier Ltd. All rights reserved.