1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-one | 1022957-96-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-one
• 英文别名: 1-Methoxy-2-nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one；4-methoxy-3-nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one
• CAS: 1022957-96-5
• 化学式: C₁₂H₁₃NO₄
• 分子量: 235.24
• InChiKey: NLYLNTORHPILIG-UHFFFAOYSA-N

物化性质

• 沸点：
  429.6±45.0 °C(Predicted)
• 密度：
  1.262±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  72.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-one 在 palladium on activated charcoal 、 氢气 、 三乙酰氧基硼氢化钠 作用下， 以 乙醇 为溶剂， 生成 1-methoxy-7-(morphoin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ylamine
  参考文献：
  名称：

  Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122

  摘要：

  Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.

  DOI：

  10.1021/op200313v
• 作为产物：
  描述：

  1,2-二溴甲基-3-甲氧基苯 在 四丁基碘化铵 、 碳酸氢钠 、 potassium nitrate 、 potassium hydroxide 作用下， 以 乙醇 、 乙腈 为溶剂， 生成 1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-one
  参考文献：
  名称：

  Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122

  摘要：

  Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.

  DOI：

  10.1021/op200313v

文献信息

• Discovery of an Orally Efficacious Inhibitor of Anaplastic Lymphoma Kinase
  作者：Diane E. Gingrich、Joseph G. Lisko、Matthew A. Curry、Mangeng Cheng、Matthew Quail、Lihui Lu、Weihua Wan、Mark S. Albom、Thelma S. Angeles、Lisa D. Aimone、R. Curtis Haltiwanger、Kevin Wells-Knecht、Gregory R. Ott、Arup K. Ghose、Mark A. Ator、Bruce Ruggeri、Bruce D. Dorsey

  DOI：10.1021/jm201550q

  日期：2012.5.24

  improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional

  间变性淋巴瘤激酶（ALK）是治疗癌症的有希望的治疗靶标，在过去的几年中，临床上和临床上均获得了有利的发展，并最终获得FDA批准的ALK抑制剂克唑替尼。通过对ALK抑制剂二氨基嘧啶骨架进行一系列有针对性的修饰，我们的研究小组推动了ALK效能，激酶选择性和整体药物特性的改善。该支架的优化已导致鉴定出有效且有效的ALK 25b抑制剂。25b优于先前描述的ALK抑制剂的显着特征是其对胰岛素受体（IR）（密切相关的激酶家族成员）的选择性> 600倍。最重要的是25b与化合物3相比，其在大鼠中显示出剂量比例递增，而化合物3遭受剂量限制的吸收，阻止了进一步的发展。在SCID小鼠的ALK阳性ALCL肿瘤异种移植模型中口服给药时，化合物25b表现出显着的体内抗肿瘤功效，因此有必要在先进的临床前模型中进行进一步评估。
• FUSED BICYCLIC DERIVATIVES OF 2,4-DIAMINOPYRIMIDINE AS ALK AND c-MET INHIBITORS
  申请人：Ahmed Gulzar

  公开号：US20090221555A1

  公开（公告）日：2009-09-03

  The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , and A 5 , are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供公式I或II化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A1、A2、A3、A4和A5如本文所定义。公式I或II化合物具有ALK和/或c-Met抑制活性，可用于治疗增殖性疾病。
• Fused Bicyclic Derivatives of 2,4-Diaminopyrimidine as ALK and c-MET Inhibitors
  申请人：Ahmed Gulzar

  公开号：US20120165519A1

  公开（公告）日：2012-06-28

  The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , and A 5 , are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供了式I或II的化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A1、A2、A3、A4和A5如本文所定义。式I或II的化合物具有ALK和/或c-Met抑制活性，并可用于治疗增生性疾病。
• Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors
  申请人：Ahmed Gulzar

  公开号：US08552186B2

  公开（公告）日：2013-10-08

  The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供了式I或II的化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A1、A2、A3、A4和A5的定义如本文所述。式I或II的化合物具有ALK和/或c-Met抑制活性，可用于治疗增殖性疾病。
• Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
  申请人：Cephalon, Inc.

  公开号：US08148391B2

  公开（公告）日：2012-04-03

  The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供了I或II式化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A1、A2、A3、A4和A5的定义如本文所述。I或II式化合物具有ALK和/或c-Met抑制活性，并可用于治疗增生性疾病。