2-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-imidazole-5-carboxylic acid | 385785-53-5

• 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: 2-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-imidazole-5-carboxylic acid
• 英文别名: 2-((6-Methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)imidazole-5-carboxylic acid；2-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-1H-imidazole-5-carboxylic acid
• CAS: 385785-53-5
• 化学式: C₂₀H₂₄N₆O₅
• 分子量: 428.448
• InChiKey: HLABPTHFFJECQY-UHFFFAOYSA-N

物化性质

• 沸点：
  726.0±70.0 °C(Predicted)
• 密度：
  1.401±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-imidazole-5-carboxylic acid 、 4-氟苯胺 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 二甲胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以39%的产率得到N-(4-fluorophenyl)-2-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-imidazole-5-carboxamide
  参考文献：
  名称：

  Discovery of Novel and Potent Thiazoloquinazolines as Selective Aurora A and B Kinase Inhibitors

  摘要：

  The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

  DOI：

  10.1021/jm050786h
• 作为产物：
  描述：

  N-(3-氯丙基)吗啉 在 sodium hydroxide 、 sodium dithionite 、 盐酸羟胺 、 四丁基氯化铵 、 硝酸 、 sodium acetate 、 sodium hydride 、 potassium carbonate 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 2-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-imidazole-5-carboxylic acid
  参考文献：
  名称：

  Discovery of Novel and Potent Thiazoloquinazolines as Selective Aurora A and B Kinase Inhibitors

  摘要：

  The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

  DOI：

  10.1021/jm050786h

文献信息

• Substituted quinazoline derivatives and their use as inhibitors
  申请人：AstraZeneca AB

  公开号：US20030187002A1

  公开（公告）日：2003-10-02

  The use of a compound of formula (I) 1 or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O) 2 , or NR 6 where R 6 is hydrogen or C 1-6 alkyl,; R 5 is an optionally substituted 5-membered heteroaromatic ring, R 1 , R 2 , R 3 , R 4 are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed.

  使用式(I)的化合物或其盐、酯或酰胺； 其中X为O、S、S(O)或S(O)2，或NR6，其中R6为氢或C1-6烷基； R5为可选择取代的5-成员杂芳环， R1、R2、R3、R4分别选自各种指定的基团，在制备用于抑制aurora 2激酶的药物中使用。 某些化合物是新颖的，这些化合物以及含有它们的药物组合物也有描述和声明。
• SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS
  申请人：AstraZeneca AB

  公开号：EP1299381A1

  公开（公告）日：2003-04-09
• US6919338B2
  申请人：——

  公开号：US6919338B2

  公开（公告）日：2005-07-19
• [EN] SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS<br/>[FR] DERIVES DE LA QUINAZOLINE SUBSTITUES ET LEUR UTILISATION COMME INHIBITEURS
  申请人：ASTRAZENECA AB

  公开号：WO2002000649A1

  公开（公告）日：2002-01-03

  The use of a compound of formula (I) or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C¿1-6?alkyl; R?5¿ is an optionally substituted 5-membered heteroaromatic ring, R?1, R2, R3, R4¿ are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed.
• Discovery of Novel and Potent Thiazoloquinazolines as Selective Aurora A and B Kinase Inhibitors
  作者：Frédéric H. Jung、Georges Pasquet、Christine Lambert-van der Brempt、Jean-Jacques M. Lohmann、Nicolas Warin、Fabrice Renaud、Hervé Germain、Chris De Savi、Nicola Roberts、Trevor Johnson、Cyril Dousson、George B. Hill、Andrew A. Mortlock、Nicola Heron、Robert W. Wilkinson、Stephen R. Wedge、Simon P. Heaton、Rajesh Odedra、Nicholas J. Keen、Stephen Green、Elaine Brown、Katherine Thompson、Stephen Brightwell

  DOI：10.1021/jm050786h

  日期：2006.2.1

  The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.