ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate
• 英文别名: ethyl 8-amino-1,4,4-trimethyl-5H-pyrazolo[4,3-h]quinazoline-3-carboxylate
• 化学式: C₁₅H₁₉N₅O₂
• 分子量: 301.348
• InChiKey: LENMBZYRPFCKBQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  95.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 在 palladium diacetate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 氢氧化钾 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 cesium iodide 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 DMF (N,N-dimethyl-formamide) 、 乙醇 、 二乙二醇二甲醚 为溶剂， 反应 46.5h， 生成 N,1,4,4-tetramethyl-8-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide
  参考文献：
  名称：

  [EN] PYRAZOLO-QUINAZOLINE DERIVATIVES,PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  [FR] DERIVES DE PYRAZOLO-QUINAZOLINE, PROCEDE DE PREPARATION ASSOCIE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE KINASE

  摘要：

  公开了配方(Ia)或(Ib)中定义的吡唑喹唑啉衍生物及其药用盐，其制备方法以及包含它们的药物组合物；本发明的化合物可能在治疗中对与异常蛋白激酶活性相关的疾病，如癌症，具有用处。

  公开号：

  WO2004104007A1
• 作为产物：
  描述：

  ethyl (6E)-6-[(dimethylamino)methylidene]-1,4,4-trmethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate 、 盐酸胍 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以93%的产率得到ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate
  参考文献：
  名称：

  Identification of N,1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor

  摘要：

  The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described, Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesize cl, Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified its a drug candidate for further development. Compound 28 is Currently undergoing phase I and phase II clinical trials.

  DOI：

  10.1021/jm9006559

文献信息

• Pyrazolo-Quinazoline Derivatives, Process for Their Preparation and Their Use as Kinase Inhibitors
  申请人：Traquandi Gabriella

  公开号：US20090124605A1

  公开（公告）日：2009-05-14

  Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

  本发明公开了式(Ia)或(Ib)的吡唑喹唑啉衍生物及其药学上可接受的盐，以及其制备方法和包含它们的制药组合物；本发明的化合物在治疗与蛋白激酶活性失调有关的疾病，如癌症中可能有用。
• Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
  申请人：Traquandi Gabriella

  公开号：US20070185143A1

  公开（公告）日：2007-08-09

  Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention maybe useful in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer”.

  本发明公开了公式（Ia）或（Ib）中定义的吡唑并[3,4-d]喹唑啉衍生物及其药学上可接受的盐，其制备方法和包含它们的制药组合物；本发明中的化合物可能在治疗中有用，用于治疗与蛋白激酶活性失调有关的疾病，如癌症。
• PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  申请人：Traquandi Gabriella

  公开号：US20130338148A1

  公开（公告）日：2013-12-19

  Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

  本发明揭示了式(Ia)或(Ib)的吡唑并喹唑啉衍生物及其药学上可接受的盐，以及它们的制备方法和包含它们的制药组合物；本发明的化合物可能在治疗与蛋白激酶活性失调相关的疾病，如癌症方面有用。
• Pyrazolo quinazoline derivatives, process for their preparation and their use as kinase inhibitors
  申请人：Traquandi Gabriella

  公开号：US08541429B2

  公开（公告）日：2013-09-24

  Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

  本发明公开了式(Ia)或(Ib)的吡唑喹唑啉衍生物及其药学上可接受的盐，以及其制备方法和包含它们的药物组合物；本发明的化合物可能在治疗与蛋白激酶活性失调相关的疾病，如癌症方面有用。
• Identification of <i>N</i>,1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1<i>H</i>-pyrazolo[4,3-<i>h</i>]quinazoline-3-carboxamide (PHA-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor
  作者：Maria Gabriella Brasca、Nadia Amboldi、Dario Ballinari、Alexander Cameron、Elena Casale、Giovanni Cervi、Maristella Colombo、Francesco Colotta、Valter Croci、Roberto D’Alessio、Francesco Fiorentini、Antonella Isacchi、Ciro Mercurio、Walter Moretti、Achille Panzeri、Wilma Pastori、Paolo Pevarello、Francesca Quartieri、Fulvia Roletto、Gabriella Traquandi、Paola Vianello、Anna Vulpetti、Marina Ciomei

  DOI：10.1021/jm9006559

  日期：2009.8.27

  The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described, Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesize cl, Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified its a drug candidate for further development. Compound 28 is Currently undergoing phase I and phase II clinical trials.