ethyl 8-[(2-aminophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate | 1034732-72-3

• 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-[(2-aminophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate
• 英文别名: ethyl 1-methyl-8-(2-aminophenylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate；Ethyl 8-(2-aminoanilino)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxylate
• CAS: 1034732-72-3
• 化学式: C₁₉H₂₀N₆O₂
• 分子量: 364.407
• InChiKey: LQMSZSLTBOFTHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 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：
  108
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 8-[(2-aminophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 在 ammonium hydroxide 作用下， 以 乙醇 为溶剂， 反应 12.0h， 以17%的产率得到8-[(2-aminophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo-[4,3-h]quinazoline-3-carboxamide
  参考文献：
  名称：

  Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline Derivatives as a New Class of Orally and Selective Polo-Like Kinase 1 Inhibitors

  摘要：

  Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo-[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 mu M) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with 1050 values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.

  DOI：

  10.1021/jm901713n
• 作为产物：
  描述：

  ethyl 8-({2-[(tert-butoxycarbonyl)amino]phenyl}amino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 2.0h， 以96%的产率得到ethyl 8-[(2-aminophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate
  参考文献：
  名称：

  Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline Derivatives as a New Class of Orally and Selective Polo-Like Kinase 1 Inhibitors

  摘要：

  Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo-[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 mu M) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with 1050 values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.

  DOI：

  10.1021/jm901713n

文献信息

• SUBSTITUTED PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  申请人：Caruso Michele

  公开号：US20100216808A1

  公开（公告）日：2010-08-26

  Pyrazolo-quinazoline derivatives of formula (I) 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（I）中所定义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；本发明中的化合物在治疗与蛋白激酶活性失调相关的疾病，如癌症中可能有用。
• [EN] SUBSTITUTED PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLO-QUINAZOLINE SUBSTITUÉS, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION EN TANT QU'INHIBITEURS DES KINASES
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2008074788A1

  公开（公告）日：2008-06-26

  [EN] Pyrazolo-quinazoline derivatives of formula (I) 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.
  [FR] La présente invention concerne des dérivés de pyrazolo-quinazoline de formule (I) tels que définis dans le mémoire descriptif et leurs sels pharmaceutiquement acceptables, leur procédé de préparation et des compositions pharmaceutiques qui les comprennent. Les composés selon l'invention ont une utilisation thérapeutique pour le traitement de maladies associée à une activité protéine-kinase déréglée telles que le cancer.
• Identification of 4,5-Dihydro-1<i>H</i>-pyrazolo[4,3-<i>h</i>]quinazoline Derivatives as a New Class of Orally and Selective Polo-Like Kinase 1 Inhibitors
  作者：Italo Beria、Dario Ballinari、Jay Aaron Bertrand、Daniela Borghi、Roberto Tiberio Bossi、Maria Gabriella Brasca、Paolo Cappella、Michele Caruso、Walter Ceccarelli、Antonella Ciavolella、Cinzia Cristiani、Valter Croci、Anna De Ponti、Gabriele Fachin、Ronald Dale Ferguson、Jacqueline Lansen、Jurgen Karl Moll、Enrico Pesenti、Helena Posteri、Rita Perego、Maurizio Rocchetti、Paola Storici、Daniele Volpi、Barbara Valsasina

  DOI：10.1021/jm901713n

  日期：2010.5.13

  Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo-[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 mu M) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with 1050 values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.