2-amino-6-(2-methylbenzyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | 651358-44-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 2-amino-6-(2-methylbenzyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one
• 英文别名: 2-amino-4-oxo-6-(2-methylbenzyl)-3,7-dihydropyrrolo[2,3-d]pyrimidine；2-amino-4-oxo-6-(2-methylbenzyl)pyrrolo[2,3-d]pyrimidine
• CAS: 651358-44-0
• 化学式: C₁₄H₁₄N₄O
• 分子量: 254.291
• InChiKey: OLGIMIITXYGGJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.73
• 重原子数：
  19.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  87.56
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2-amino-6-(2-methylbenzyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 在 N,N-二甲基苯胺 、 三氯氧磷 作用下， 反应 4.0h， 以28%的产率得到2-amino-4-chloro-6-(2-methylbenzyl)-pyrrolo[2,3-d]pyrimidine
  参考文献：
  名称：

  抗血管生成和抗肿瘤药物。设计，合成和评估新型2-氨基-4-（3-溴苯胺基）-6-苄基取代的吡咯并[2,3-d]嘧啶作为受体酪氨酸激酶的抑制剂。

  摘要：

  包含酪氨酸激酶（RTK）的几种不同类别的生长因子受体直接或间接参与血管生成。抑制这些RTKs通过限制其生长和转移为肿瘤的治疗提供了新的范例。我们设计，合成和评估了11种新颖的2-氨基-4-（3-溴苯胺基）-6-取代的苄基吡咯并[2,3-d]嘧啶，这是一系列RTK抑制剂中的第一个。通过与2，6-二氨基-4-嘧啶酮进行环缩合反应，由合适的α-溴甲基苄基酮合成这些类似物，得到2-氨基-4-氧代-6-取代的苄基吡咯并[2，3-d]嘧啶。将4-位氯化，然后用3-溴苯胺置换，得到目标化合物。在某些情况下，吡咯并[2，在氯化和置换然后脱保护之前，对3-d]嘧啶进行保护。这些化合物被评估为血管内皮生长因子受体VEGFR-2（Flk-1，KDR）和VEGFR-1（Flt-1）的抑制剂。表皮生长因子受体（EGFR）; 和血小板衍生的生长因子受体-β（PDGFR-beta）。还评估了选定的化合物对培养物中A43

  DOI：

  10.1016/j.bmc.2003.08.034
• 作为产物：
  描述：

  在 氢溴酸 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 73.0h， 生成 2-amino-6-(2-methylbenzyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one
  参考文献：
  名称：

  抗血管生成和抗肿瘤药物。设计，合成和评估新型2-氨基-4-（3-溴苯胺基）-6-苄基取代的吡咯并[2,3-d]嘧啶作为受体酪氨酸激酶的抑制剂。

  摘要：

  包含酪氨酸激酶（RTK）的几种不同类别的生长因子受体直接或间接参与血管生成。抑制这些RTKs通过限制其生长和转移为肿瘤的治疗提供了新的范例。我们设计，合成和评估了11种新颖的2-氨基-4-（3-溴苯胺基）-6-取代的苄基吡咯并[2,3-d]嘧啶，这是一系列RTK抑制剂中的第一个。通过与2，6-二氨基-4-嘧啶酮进行环缩合反应，由合适的α-溴甲基苄基酮合成这些类似物，得到2-氨基-4-氧代-6-取代的苄基吡咯并[2，3-d]嘧啶。将4-位氯化，然后用3-溴苯胺置换，得到目标化合物。在某些情况下，吡咯并[2，在氯化和置换然后脱保护之前，对3-d]嘧啶进行保护。这些化合物被评估为血管内皮生长因子受体VEGFR-2（Flk-1，KDR）和VEGFR-1（Flt-1）的抑制剂。表皮生长因子受体（EGFR）; 和血小板衍生的生长因子受体-β（PDGFR-beta）。还评估了选定的化合物对培养物中A43

  DOI：

  10.1016/j.bmc.2003.08.034

文献信息

• Synthesis and biological activity of N4-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents
  作者：Aleem Gangjee、Sonali Kurup、Michael A Ihnat、Jessica E. Thorpe、Satyendra S. Shenoy

  DOI：10.1016/j.bmc.2010.03.052

  日期：2010.5

  A series of eight N-4-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 8-15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N-4-phenylsubstituted-6-phenylmethylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines 16-20 were synthesized to evaluate the importance of the 2-NH2 moiety for multiple receptor tyrosine kinase (RTK) inhibition. Cyclocondensation of alpha-halomethylbenzylketones with 2,6-diamino-4-hydroxypyrimidine afforded 2-amino-6-(2,4-dichlorophenylmethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 23 and reaction of alpha-bromomethylbenzylketones with ethylamidinoacetate followed by cyclocondensation with formamide afforded the 6-phenylmethylsubstituted-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones, 40-42, respectively. Chlorination of the 4-position and displacement with appropriate anilines afforded the target compounds 8-20. Compounds 8, 10 and 14 were potent VEGFR-2 inhibitors and were 100-fold, 40-fold and 8-fold more potent than the standard semaxanib, respectively. Previously synthesized multiple RTK inhibitor, 5 and the VEGFR-2 inhibitor 8 from this study, were chosen for further evaluation in a mouse orthotopic model of melanoma and showed significant inhibition of tumor growth, angiogenesis and metastasis. (C) 2010 Elsevier Ltd. All rights reserved.
• Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents1
  作者：Aleem Gangjee、Ying Zhao、Sudhir Raghavan、Michael A. Ihnat、Bryan C. Disch

  DOI：10.1016/j.bmc.2010.05.049

  日期：2010.7

  A series of 2-amino-4-m-bromoanilino-6-benzyl pyrrolo[ 2,3-d] pyrimidines analogues 4-12 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). These analogues were synthesized from the appropriate alpha-bromomethylbenzylketones via cyclocondensation with 2,6-diamino-4-pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[ 2,3-d] pyrimidines. Chlorination at the 4-position followed by displacement with 3-bromoaniline or 3-bromo-N-methylaniline and methylation of the 7-NH afforded the target compounds. Remarkably, dimethylation of both the 4-N and N7 afford whole cell EGFR inhibitors that are more cytotoxic than clinically used erlotinib and mono-methylation at the 4-N or N7 affords more cytotoxic whole cell PDGFR-b inhibitors than clinically used sunitinib. Methylation at either the 4-N or N7 position was detrimental to whole cell VEGFR-2 inhibition. The inhibitory data against the RTKs in this study demonstrates that methylation of the 4-NH and/or the 7-NH influences both the specificity and potency of RTK inhibition. (C) 2010 Elsevier Ltd. All rights reserved.