2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester | 333458-45-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester
• 英文别名: 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester；ethyl 2-[4-cyano-2-(2,6-dichloroanilino)-3-methylbenzimidazol-5-yl]-2-methyl-3-oxobutanoate
• CAS: 333458-45-0
• 化学式: C₂₂H₂₀Cl₂N₄O₃
• 分子量: 459.332
• InChiKey: PSMNKRICEHLNGF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  97
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester 在 硫酸 、 溶剂黄146 作用下， 反应 2.5h， 以88%的产率得到2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one
  参考文献：
  名称：

  Optimization of 2-Phenylaminoimidazo[4,5-h]isoquinolin-9-ones:  Orally Active Inhibitors of lck Kinase

  摘要：

  The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.

  DOI：

  10.1021/jm020446l
• 作为产物：
  描述：

  2-(2-cyano-3-methylamino-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 29.0h， 生成 2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester
  参考文献：
  名称：

  Optimization of 2-Phenylaminoimidazo[4,5-h]isoquinolin-9-ones:  Orally Active Inhibitors of lck Kinase

  摘要：

  The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.

  DOI：

  10.1021/jm020446l

文献信息

• Heterocyclic compounds useful as inhibitors of tyrosine kinases
  申请人：——

  公开号：US20020016460A1

  公开（公告）日：2002-02-07

  Disclosed are novel compounds of formula (I): 1 wherein Ar 1 , R a , R 4 , R 5 , X and Y are defined below, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases associated with such kinases, for example, diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer, as well as conditions resulting from cerebral ischemia, such as stroke. Also disclosed are processes for preparing these compounds, novel intermediates useful in these processes and compositions comprising compounds of the formula (I).

  揭示了式（I）的新化合物：其中Ar1、Ra、R4、R5、X和Y的定义如下，这些化合物可用作某些蛋白酪氨酸激酶的抑制剂，因此可用于治疗与这些激酶相关的疾病，例如由于细胞不当增殖而导致的疾病，包括自身免疫疾病、慢性炎症性疾病、过敏疾病、移植排斥和癌症，以及由脑缺血引起的疾病，如中风。还披露了制备这些化合物的方法，这些方法中有用的新中间体以及包含式（I）化合物的组合物。
• INHIBITORS OF TYROSINE KINASES AND USES THEREOF
  申请人：Jankowski D. Orion

  公开号：US20080039426A1

  公开（公告）日：2008-02-14

  Disclosed herein are compounds that inhibit the activity of particular tyrosine kinases. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of tyrosine kinase-mediated diseases or conditions or tyrosine kinase-dependent diseases or conditions are provided.

  本文披露了一些抑制特定酪氨酸激酶活性的化合物。本文还披露了制备这些化合物的方法。此外，还披露了包括这些化合物的药物组合物。提供了使用这些化合物，单独或与其他治疗剂联合使用，用于治疗酪氨酸激酶介导的疾病或状况或酪氨酸激酶依赖性疾病或状况的方法。
• Inhibitors of tyrosine kinases and uses thereof
  申请人：Pharmacyclics, Inc.

  公开号：US08067395B2

  公开（公告）日：2011-11-29

  Disclosed herein are compounds that inhibit the activity of particular tyrosine kinases. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of tyrosine kinase-mediated diseases or conditions or tyrosine kinase-dependent diseases or conditions are provided.

  本文披露了一些抑制特定酪氨酸激酶活性的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。提供了使用这些化合物单独或与其他治疗剂联合治疗酪氨酸激酶介导的疾病或状况或酪氨酸激酶依赖性疾病或状况的方法。
• WO2007/87068
  申请人：——

  公开号：——

  公开（公告）日：——
• Isoquinolinone synthesis by SNAr reaction: a versatile route to imidazo[4,5-h]isoquinolin-9-ones
  作者：Roger J. Snow、Tanja Butz、Abdelhakim Hammach、Suresh Kapadia、Tina M. Morwick、Anthony S. Prokopowicz、Hidenori Takahashi、Jonathan D. Tan、Matt A. Tschantz、Xiao-Jun Wang

  DOI：10.1016/s0040-4039(02)01802-6

  日期：2002.10

  Reaction of 2-chlorobenzonitriles with beta-ketoesters in an SNAr reaction, followed by cyclization in acid provides a versatile route to isoquinolones. Starting from 2,6-dichloro-3-nitrobenzonitrile 7, sequential displacement of the chlorines by an amine and a beta-ketoester leads to imidazo[4,5-h]isoquinolin-9-ones 1, a new class of kinase inhibitor. (C) 2002 Elsevier Science Ltd. All rights reserved.