2-(2,6-dichlorophenylamino)-7-(1-acetoxyprop-3-en-1-yl)-1,6-dimethyl-1,8-dihydroimidazo[4,5-h]isoquinolin-9-one | 333455-34-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-(2,6-dichlorophenylamino)-7-(1-acetoxyprop-3-en-1-yl)-1,6-dimethyl-1,8-dihydroimidazo[4,5-h]isoquinolin-9-one
• 英文别名: acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester；1-[2-(2,6-dichloroanilino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allyl acetate；1-[2-(2,6-dichloroanilino)-1,6-dimethyl-9-oxo-8H-imidazo[4,5-h]isoquinolin-7-yl]prop-2-enyl acetate
• CAS: 333455-34-8
• 化学式: C₂₃H₂₀Cl₂N₄O₃
• 分子量: 471.343
• InChiKey: HXNZWMGLASBTBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  85.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(2,6-dichlorophenylamino)-7-(1-acetoxyprop-3-en-1-yl)-1,6-dimethyl-1,8-dihydroimidazo[4,5-h]isoquinolin-9-one 在 tris(dibenzylideneacetone)dipalladium (0) 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 3.33h， 生成 2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-pyrrolidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-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-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one 在 selenium(IV) oxide 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 21.0h， 生成 2-(2,6-dichlorophenylamino)-7-(1-acetoxyprop-3-en-1-yl)-1,6-dimethyl-1,8-dihydroimidazo[4,5-h]isoquinolin-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

文献信息

• Method of identifying inhibitors of Lck
  申请人：——

  公开号：US20030175935A1

  公开（公告）日：2003-09-18

  The present invention relates to polypeptides which comprise the ligand binding domain of Lck, crystalline forms of these polypeptides, and the use of these crystalline forms to determine the three dimensional structure of the catalytic domain of Lck. The invention also relates to the use of the three dimensional structure of the Lck catalytic domain both alone, or in complex with inhibitors, in methods of designing and/or identifying potential inhibitors of Lck activity, for example, compounds which inhibit the binding of a native substrate to the Lck catalytic domain. The invention also relates to the use of the three dimensional structure of the Lck catalytic domain both alone, or in complex with inhibitors, in methods of designing and/or identifying potential selective inhibitors of Lck activity, for example, compounds which inhibit the binding of a native substrate to the Lck catalytic domain selectively.

  本发明涉及包含Lck配体结合域的多肽、这些多肽的结晶形式，以及使用这些结晶形式来确定Lck催化域的三维结构。本发明还涉及使用Lck催化域的三维结构，单独或与抑制剂复合物一起，设计和/或识别Lck活性的潜在抑制剂的方法，例如抑制天然底物与Lck催化域的结合的化合物。本发明还涉及使用Lck催化域的三维结构，单独或与抑制剂复合物一起，设计和/或识别Lck活性的潜在选择性抑制剂的方法，例如选择性抑制天然底物与Lck催化域的结合的化合物。
• 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：——
• US7400979B2
  申请人：——

  公开号：US7400979B2

  公开（公告）日：2008-07-15