4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-pyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid | 623152-12-5

• 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: 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-pyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid
• 英文别名: 4-[5-(Cyclopropylcarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid
• CAS: 623152-12-5
• 化学式: C₁₉H₁₉N₅O₃
• 分子量: 365.392
• InChiKey: DYXDDIRPUUPAJK-UHFFFAOYSA-N

物化性质

• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-pyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid 在 氯化亚砜 、 氯化二乙基铝 作用下， 以 二氯甲烷 为溶剂， 生成 N-cyclopropyl-3-[[6-(1H-indole-3-carbonyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-4-methylbenzamide
  参考文献：
  名称：

  Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors

  摘要：

  Pyrrolo[2,1-f][1,2,4] triazine based inhibitors of p38 alpha have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.05.091
• 作为产物：
  描述：

  3-氨基-4-甲基苯甲酸 在 4-二甲氨基吡啶 、 sodium hydroxide 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-pyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid
  参考文献：
  名称：

  [EN] PYRROLO-TRIAZINE ANILINE COMPOUNDS USEFUL AS KINASE INHIBITORS
  [FR] COMPOSES PYRROLO-TRIAZINE ANILINE UTILES EN TANT QU'INHIBITEURS DE KINASE

  摘要：

  具有化学式（I）的化合物，以及其药学上可接受的盐、前药和溶剂化物，可用作激酶抑制剂，其中R1、R2、R3、R4、R5、R6、X和Z如规范中所述。

  公开号：

  WO2003090912A1

文献信息

• Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-<i>N</i>-propylpyrrolo[1,2-<i>f</i>][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38α MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases
  作者：Chunjian Liu、James Lin、Stephen T. Wrobleski、Shuqun Lin、John Hynes、Hong Wu、Alaric J. Dyckman、Tianle Li、John Wityak、Kathleen M. Gillooly、Sidney Pitt、Ding Ren Shen、Rosemary F. Zhang、Kim W. McIntyre、Luisa Salter-Cid、David J. Shuster、Hongjian Zhang、Punit H. Marathe、Arthur M. Doweyko、John S. Sack、Susan E. Kiefer、Kevin F. Kish、John A. Newitt、Murray McKinnon、John H. Dodd、Joel C. Barrish、Gary L. Schieven、Katerina Leftheris

  DOI：10.1021/jm100540x

  日期：2010.9.23

  discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of

  描述了7k（BMS-582949）的发现和表征，这是一种高度选择性的p38αMAP激酶抑制剂，目前正处于治疗类风湿关节炎的II期临床试验中。该发现的关键是在1a中用N-环丙基合理取代N-甲氧基，这是先前报道的临床候选p38α抑制剂。与烷基和其他环烷基不同，环丙基的sp 2特性可赋予直接取代的酰胺NH改善的氢键特性。抑制剂7k的活性略低于1a在p38α酶促分析中显示出良好的药代动力学特性，因此在急性小鼠炎症模型和假建立的大鼠AA模型中更有效。通过X射线晶体学分析证实了7k与p38α的结合模式。
• Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein
  申请人：Kim Soojin

  公开号：US20060235020A1

  公开（公告）日：2006-10-19

  Processes are provided for selectively preparing novel stable crystalline salt forms, selectively and consistently, namely, preparing Form N-1 of the methanesulfonic acid salt, and Form N-1 and Form N-4 of the hydrochloric acid salt of the p38 kinase inhibitor 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide. The processes preferably employ solvent systems including formic acid/acetone and formic acid/methylethyl ketone which produce crystals having suitable flow properties and desired particle size, and solvents such as N,N-dimethylformamide and N,N-dimethylacetamide may be employed as well. Novel Form N-1 crystals of the Form N-1 and Form N-4 crystals of the hydrochloride salt and Form N-1 crystals of the methanesulfonic acid salt of the above free base, pharmaceutical compositions containing such novel forms and a method of treating p38 kinase associated conditions, including rheumatoid arthritis are also provided.

  提供了用于选择性制备新型稳定晶体盐形式的方法，即选择性和一致地制备甲磺酸盐的N-1型和氯化氢盐的N-1型和N-4型的p38激酶抑制剂4-[[5-[(环丙基氨基甲酰)-2-甲基苯基]氨基]-5-甲基-N-丙基吡咯[2,1-f][1,2,4]三嗪-6-羧酰胺。这些方法首选采用包括甲酸/丙酮和甲酸/甲基乙酮等溶剂体系，产生具有适当流动性和所需粒径的晶体，也可以使用N,N-二甲基甲酰胺和N,N-二甲基乙酰胺等溶剂。还提供了该自由基的N-1型和N-4型氯化氢盐的N-1型晶体以及甲磺酸盐的N-1型晶体，含有这种新型形式的药物组合物，以及治疗p38激酶相关疾病的方法，包括类风湿关节炎。
• PROCESS FOR PREPARING PYRROLOTRIAZINE ANILINE COMPOUNDS USEFUL AS KINASE INHIBITORS
  申请人：Cann O. Reginald

  公开号：US20060035886A1

  公开（公告）日：2006-02-16

  A process is provided for the process for preparing a pyrrolotriazine aniline p38 kinase inhibitor such as amide II by the direct aminolysis of the ester I wherein ester I is reacted with a strong organometallic base, such as hexyllithium or n-butyllithium and the desired amine such as n-propylamine to form the amide II.

  提供了一种用于制备吡咯三嗪苯胺P38激酶抑制剂（例如酰胺II）的过程，通过酯I的直接胺解反应得到。其中，酯I与强有机金属碱（如己基锂或正丁基锂）和所需的胺（如正丙胺）反应，形成酰胺II。
• PROCESS FOR PREPARING SALTS OF 4-[[5-[(CYCLOPROPYLAMINO)CARBONYL]-2-METHYLPHENYL]AMINO]-5-METHYL-N-PROPYLPYRROLO[2,1-f][1,2,4]TRIAZINE-6-CARBOXAMIDE AND NOVEL STABLE FORMS PRODUCED THEREIN
  申请人：Kim Soojin

  公开号：US20090312331A1

  公开（公告）日：2009-12-17

  Processes are provided for selectively preparing novel stable crystalline salt forms, selectively and consistently, namely, preparing Form N-1 of the methanesulfonic acid salt, and Form N-1 and Form N-4 of the hydrochloric acid salt of the p38 kinase inhibitor 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide. The processes preferably employ solvent systems including formic acid/acetone and formic acid/methylethyl ketone which produce crystals having suitable flow properties and desired particle size, and solvents such as N,N-dimethylformamide and N,N-dimethylacetamide may be employed as well. Novel Form N-1 crystals of the Form N-1 and Form N-4 crystals of the hydrochloride salt and Form N-1 crystals of the methanesulfonic acid salt of the above free base, pharmaceutical compositions containing such novel forms and a method of treating p38 kinase associated conditions, including rheumatoid arthritis are also provided.

  提供了选择性制备新型稳定晶态盐形式的过程，即有选择性和一致性地制备甲磺酸盐的N-1型和盐酸盐的N-1型和N-4型的p38激酶抑制剂4-[[5-[(环丙基氨基)羰基]-2-甲基苯基]氨基]-5-甲基-N-丙基吡咯[2,1-f][1,2,4]三嗪-6-羧酰胺。该过程最好使用包括甲酸/丙酮和甲酸/甲基乙酮的溶剂体系，产生具有适当流动性和所需粒径的晶体，也可以使用N，N-二甲基甲酰胺和N，N-二甲基乙酰胺等溶剂。还提供了上述自由基的N-1型甲磺酸盐和盐酸盐的N-1型和N-4型晶体的新型晶体形式，含有这种新型形式的药物组合物以及治疗p38激酶相关疾病，包括类风湿性关节炎的方法。
• J. Med. Chem. 2010, 53, 6629-6639
  作者：

  DOI：——

  日期：——