8-Methoxy-2-(4'-cyanophenyl)quinazolin-4-[3 H]-one | 211172-78-0

• 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: 8-Methoxy-2-(4'-cyanophenyl)quinazolin-4-[3 H]-one
• 英文别名: 4-(4-Hydroxy-8-methoxy-2-quinazolinyl)benzonitrile；4-(8-methoxy-4-oxo-3H-quinazolin-2-yl)benzonitrile
• CAS: 211172-78-0
• 化学式: C₁₆H₁₁N₃O₂
• 分子量: 277.282
• InChiKey: NRHBAZUXKYNQEX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  74.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-Methoxy-2-(4'-cyanophenyl)quinazolin-4-[3 H]-one 在 sodium hydroxide 、 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 28.0h， 生成
  参考文献：
  名称：

  Resistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)

  摘要：

  Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A series of 2-alkyl- and 2-aryl-substituted 8-hydroxy-, 8-methoxy-, and 8-methylquinazolin-4(3H)-ones has been synthesized and evaluated for PARP inhibitory activity in permeabilized L1210 murine leukemia cells. 8-Methoxy- and 8-methylquinazolinones (14-34) were readily prepared by acylation of 3-substituted anthranilamides with the appropriate acid chloride, followed by base-catalyzed cyclization. The requisite 8-hydroxyquinazolinones (6, 35-39) were synthesized by demethylation of the corresponding 8-methoxyquinazolinones with BBr3. N-Methylation of 8-methoxy-2-methylquinazolinone (15) with Mel, followed by O-demethylation by BBr3, afforded the control N-3-methylquinazolinones 42 and 43, respectively. In general, an 8-hydroxy or 8-methyl substituent enhanced inhibitory activity in comparison with an 8-methoxy group. 2-Phenylquinazolinones were marginally less potent than the corresponding 2-methylquinazolinones, but the introduction of an electron-withdrawing or electron-donating 4'-substituent on the 2-aryl ring invariably increased potency. This was particularly evident in the 8-methylquinazolinone series (IC50 values 0.13-0.27 mu M), which are among the most potent PARP inhibitors reported to date. N-3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 mu M). In studies with L1210 cells in vitro, a concentration of 200 mu M 8-hydroxy-2-methylquinazolinone (6, NU1025) (IC50 value 0.40 mu M) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide and gamma-radiation 3.5- and 1.4-fold, respectively, at the 10% survival level.

  DOI：

  10.1021/jm980273t
• 作为产物：
  描述：

  3-甲氧基-2-氨基苯甲酰胺 、 对氰基苯甲酰氯 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 以27%的产率得到8-Methoxy-2-(4'-cyanophenyl)quinazolin-4-[3 H]-one
  参考文献：
  名称：

  Resistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)

  摘要：

  Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A series of 2-alkyl- and 2-aryl-substituted 8-hydroxy-, 8-methoxy-, and 8-methylquinazolin-4(3H)-ones has been synthesized and evaluated for PARP inhibitory activity in permeabilized L1210 murine leukemia cells. 8-Methoxy- and 8-methylquinazolinones (14-34) were readily prepared by acylation of 3-substituted anthranilamides with the appropriate acid chloride, followed by base-catalyzed cyclization. The requisite 8-hydroxyquinazolinones (6, 35-39) were synthesized by demethylation of the corresponding 8-methoxyquinazolinones with BBr3. N-Methylation of 8-methoxy-2-methylquinazolinone (15) with Mel, followed by O-demethylation by BBr3, afforded the control N-3-methylquinazolinones 42 and 43, respectively. In general, an 8-hydroxy or 8-methyl substituent enhanced inhibitory activity in comparison with an 8-methoxy group. 2-Phenylquinazolinones were marginally less potent than the corresponding 2-methylquinazolinones, but the introduction of an electron-withdrawing or electron-donating 4'-substituent on the 2-aryl ring invariably increased potency. This was particularly evident in the 8-methylquinazolinone series (IC50 values 0.13-0.27 mu M), which are among the most potent PARP inhibitors reported to date. N-3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 mu M). In studies with L1210 cells in vitro, a concentration of 200 mu M 8-hydroxy-2-methylquinazolinone (6, NU1025) (IC50 value 0.40 mu M) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide and gamma-radiation 3.5- and 1.4-fold, respectively, at the 10% survival level.

  DOI：

  10.1021/jm980273t

文献信息

• Quinazolinone compounds
  申请人：Newcastle University Ventures Limited

  公开号：US06156739A1

  公开（公告）日：2000-12-05

  Phosphate derivatives are disclosed of quinazolinone compounds having structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X' represent hydroxyl, alkyl, alkoxy, or O--Z where Z is a phosphate or phosphate derivative; Y' represents hydrogen, alkyl or an optionally substituted aryl group or optionally substituted aralkyl group; and R' is hydrogen, alkyl, or CH.sub.2 --O--Z where Z is again a phosphate or phosphate derivative; subject to the proviso that if neither X' nor R' contains Z, Y' is an aryl or aralkyl group having an O--Z substituent therein with Z once again being a phosphate or phosphate derivative as hereinabove defined. These compounds are useful as prodrugs for providing active PARP inhibiting substances for medical use in conjunction with a cytotoxic drug or radiotherapy in order to increase the effectiveness of the latter, especially in connection with antitumor treatment. ##STR1##

  磷酸盐衍生物被披露为具有结构式（I）的喹唑啉酮化合物或其药用可接受的盐，其中X'代表羟基、烷基、烷氧基或O-Z，其中Z是磷酸盐或磷酸盐衍生物；Y'代表氢、烷基或可选择取代的芳基或可选择取代的芳基烷基；R'是氢、烷基或CH.sub.2-O-Z，其中Z再次是磷酸盐或磷酸盐衍生物；但是如果X'和R'都不含Z，则Y'是具有O-Z取代基的芳基或芳基烷基，其中Z再次是磷酸盐或磷酸盐衍生物，如上所定义。这些化合物可用作前药，用于提供用于与细胞毒性药物或放疗一起用于医疗用途的活性PARP抑制物质，以增强后者的效果，特别是在抗肿瘤治疗方面。
• QUINAZOLINONE COMPOUNDS
  申请人：NEWCASTLE UNIVERSITY VENTURES LIMITED

  公开号：EP0966476A1

  公开（公告）日：1999-12-29
• [EN] QUINAZOLINONE COMPOUNDS<br/>[FR] COMPOSES DE QUINAZOLINONE
  申请人：NEWCASTLE UNIVERSITY VENTURES LIMITED

  公开号：WO1998033802A1

  公开（公告）日：1998-08-06

  (EN) Phosphate derivatives are disclosed of quinazolinone compounds having structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X' represent hydroxyl, alkyl, alkoxy, or O-Z where Z is a phosphate or phosphate derivative; Y' represents hydrogen, alkyl or an optionally substituted aryl group or optionally substituted aralkyl group; and R' is hydrogen, alkyl, or CH2-O-Z where Z is again a phosphate or phosphate derivative; subject to the proviso that if neither X' nor R' contains Z, Y' is an aryl or aralkyl group having an O-Z substituent therein with Z once again being a phosphate or phosphate derivative as hereinabove defined. These compounds are useful as prodrugs for providing active PARP inhibiting substances for medical use in conjunction with a cytotoxic drug or radiotherapy in order to increase the effectiveness of the latter, especially in connection with antitumor treatment.(FR) Dérivés de phosphate de composés de quinazolinone représentés par la formule (I) ou un de leurs sels acceptables sur le plan pharmaceutique, dans laquelle X' représente hydroxyle, alkyle, alkoxy ou O-Z dans laquelle Z représente un phosphate ou un dérivé de phosphate; Y' représente hydrogène, alkyle ou un groupe aryle éventuellement substitué ou un groupe aralkyle éventuellement substitué; R' représente hydrogène, alkyle ou CH2-O-Z dans laquelle Z représente à nouveau un phosphate ou un dérivé de phosphate; à condition que, si ni X', ni R' ne contiennent Z, Y' représente un groupe aryle ou aralkyle possédant un substituant de O-Z, Z représentant encore phosphate ou un dérivé de phosphate comme énoncé ci-dessus. Ces composés sont utiles en tant que promédicaments permettant d'obtenir des substances actives d'inhibition de PARP, poly(ADP-ribose)polymérase, à usage médical en combinaison avec un médicament cytotoxique ou une radiothérapie, de manière à augmenter l'efficacité de ces derniers, en particulier, en conjonction avec un traitement anti-tumeur.
• Resistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)
  作者：Roger J. Griffin、Sheila Srinivasan、Karen Bowman、A. Hilary Calvert、Nicola J. Curtin、David R. Newell、Louise C. Pemberton、Bernard T. Golding

  DOI：10.1021/jm980273t

  日期：1998.12.1

  Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A series of 2-alkyl- and 2-aryl-substituted 8-hydroxy-, 8-methoxy-, and 8-methylquinazolin-4(3H)-ones has been synthesized and evaluated for PARP inhibitory activity in permeabilized L1210 murine leukemia cells. 8-Methoxy- and 8-methylquinazolinones (14-34) were readily prepared by acylation of 3-substituted anthranilamides with the appropriate acid chloride, followed by base-catalyzed cyclization. The requisite 8-hydroxyquinazolinones (6, 35-39) were synthesized by demethylation of the corresponding 8-methoxyquinazolinones with BBr3. N-Methylation of 8-methoxy-2-methylquinazolinone (15) with Mel, followed by O-demethylation by BBr3, afforded the control N-3-methylquinazolinones 42 and 43, respectively. In general, an 8-hydroxy or 8-methyl substituent enhanced inhibitory activity in comparison with an 8-methoxy group. 2-Phenylquinazolinones were marginally less potent than the corresponding 2-methylquinazolinones, but the introduction of an electron-withdrawing or electron-donating 4'-substituent on the 2-aryl ring invariably increased potency. This was particularly evident in the 8-methylquinazolinone series (IC50 values 0.13-0.27 mu M), which are among the most potent PARP inhibitors reported to date. N-3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 mu M). In studies with L1210 cells in vitro, a concentration of 200 mu M 8-hydroxy-2-methylquinazolinone (6, NU1025) (IC50 value 0.40 mu M) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide and gamma-radiation 3.5- and 1.4-fold, respectively, at the 10% survival level.