4-piperazinyl-7-(2-methoxyethoxy)quinazoline | 461428-14-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-piperazinyl-7-(2-methoxyethoxy)quinazoline
• 英文别名: 7-(2-Methoxyethoxy)-4-piperazin-1-ylquinazoline
• CAS: 461428-14-8
• 化学式: C₁₅H₂₀N₄O₂
• 分子量: 288.349
• InChiKey: IYFJNURLBRHUJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  59.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-氰基苯异氰酸酯 、 4-piperazinyl-7-(2-methoxyethoxy)quinazoline 以 乙腈 为溶剂， 反应 2.0h， 生成 N-(4-cyanophenyl){4-[7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide
  参考文献：
  名称：

  Identification of Orally Active, Potent, and Selective 4-Piperazinylquinazolines as Antagonists of the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Family

  摘要：

  We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed against members of PDGFR receptor have been developed through modifications of the novel quinazoline template I. Systematic modifications in the A-bicyclic ring and D-rings of protype I were carried out to afford potent analogues, which display IC50 values of <250 nM in cellular betaPDGFR phosphorylation assays. An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC50 values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed. This analogue also inhibits autophosphorylation of Flt-3 ligand-stimulated wild-type Flt-3 and a constitutively activated Flt-3/internal tandem duplication (ITD) with IC50 values of 30-100 nM. Through this optimization process, 75 was found to be metabolically stable and has desirable pharmacokinetic properties in all animal species studied (F% > 50%, T-1/2 > 8 h). Oral administration of 75 promotes mice survival and significantly delayed disease progression in a Flt-3/ITD-mediated leukemia mouse model and shows efficacy in a nude mouse model of chronic myelomonocytic leukemia.

  DOI：

  10.1021/jm020143r
• 作为产物：
  描述：

  7-(2-methoxyethoxy)-4-quinazolinone 在 三氯氧磷 作用下， 以 异丙醇 为溶剂， 反应 4.0h， 生成 4-piperazinyl-7-(2-methoxyethoxy)quinazoline
  参考文献：
  名称：

  Identification of Orally Active, Potent, and Selective 4-Piperazinylquinazolines as Antagonists of the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Family

  摘要：

  We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed against members of PDGFR receptor have been developed through modifications of the novel quinazoline template I. Systematic modifications in the A-bicyclic ring and D-rings of protype I were carried out to afford potent analogues, which display IC50 values of <250 nM in cellular betaPDGFR phosphorylation assays. An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC50 values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed. This analogue also inhibits autophosphorylation of Flt-3 ligand-stimulated wild-type Flt-3 and a constitutively activated Flt-3/internal tandem duplication (ITD) with IC50 values of 30-100 nM. Through this optimization process, 75 was found to be metabolically stable and has desirable pharmacokinetic properties in all animal species studied (F% > 50%, T-1/2 > 8 h). Oral administration of 75 promotes mice survival and significantly delayed disease progression in a Flt-3/ITD-mediated leukemia mouse model and shows efficacy in a nude mouse model of chronic myelomonocytic leukemia.

  DOI：

  10.1021/jm020143r

文献信息

• Nitrogenous heterocylic compounds
  申请人：——

  公开号：US20040186110A1

  公开（公告）日：2004-09-23

  The present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention is also related to a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases. In a particular aspect the present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a PDGF receptor to hinder abnormal cell growth and cell wandering, and a method for preventing or treating cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

  本发明涉及含氮杂环化合物及其药学上可接受的盐，具有对激酶磷酸化的抑制活性，从而抑制了这些激酶的活性。本发明还涉及一种通过抑制激酶的磷酸化来抑制激酶并治疗哺乳动物疾病状态的方法。在特定方面，本发明提供了含氮杂环化合物及其药学上可接受的盐，抑制PDGF受体的磷酸化，以阻止异常细胞生长和细胞游走，并预防或治疗细胞增殖性疾病，如动脉硬化、血管再狭窄、癌症和肾小球硬化。
• Nitrogenous heterocyclic compounds
  申请人：Pandey Anjali

  公开号：US20060063770A1

  公开（公告）日：2006-03-23

  The present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention is also related to a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases. In a particular aspect the present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a PDGF receptor to hinder abnormal cell growth and cell wandering, and a method for preventing or treating cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

  本发明涉及一种含氮杂环化合物及其药学上可接受的盐，具有对激酶磷酸化的抑制活性，从而抑制这些激酶的活性。该发明还涉及通过抑制激酶的磷酸化来抑制激酶并治疗哺乳动物的疾病状态的方法。在特定方面，本发明提供了一种含氮杂环化合物及其药学上可接受的盐，其抑制PDGF受体的磷酸化，以阻碍异常细胞生长和细胞游走，并用于预防或治疗细胞增殖性疾病，如动脉粥样硬化、血管再狭窄、癌症和肾小球硬化。
• N-aryl-{4-[7-(alkoxy)quinazolin-4-yl]piperazinyl}carboxamide derivatives as PDGFRs inhibitors
  申请人：MILLENNIUM PHARMACEUTICALS, INC.

  公开号：EP1309569B1

  公开（公告）日：2010-10-06
• NITROGENOUS HETEROCYCLIC COMPOUNDS
  申请人：Millennium Pharmaceuticals, Inc.

  公开号：EP1309569A2

  公开（公告）日：2003-05-14
• US6956039B2
  申请人：——

  公开号：US6956039B2

  公开（公告）日：2005-10-18