tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate | 401819-63-4

• 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: tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate
• 英文别名: tert-butyl 4-[7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl]piperazine-1-carboxylate
• CAS: 401819-63-4
• 化学式: C₂₀H₂₇ClN₄O₄
• 分子量: 422.912
• InChiKey: WGSDUDVZXFOJAZ-UHFFFAOYSA-N

物化性质

• 沸点：
  563.5±50.0 °C(Predicted)
• 密度：
  1.257±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  77
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 6-甲氧基-7-[2-(4-甲基-哌嗪-1-基)-乙氧基]-4-哌嗪-1-基-喹唑啉
  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：

  香草酸 在 palladium dihydroxide 氯化亚砜 、 氢气 、 硝酸 、 甲酸铵 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0~150.0 ℃ 、344.74 kPa 条件下， 反应 8.0h， 生成 tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate
  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 heterocyclic compounds
  申请人：——

  公开号：US20040176594A1

  公开（公告）日：2004-09-09

  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 glomeruloscierosis.

  本发明涉及含氮杂环化合物及其药用盐，具有对激酶磷酸化具有抑制活性，从而抑制这些激酶的活性。本发明还涉及通过抑制激酶的磷酸化来抑制激酶和治疗哺乳动物中的疾病状态的方法。在一个特定方面，本发明提供含氮杂环化合物及其药用盐，其抑制PDGF受体的磷酸化以阻碍异常细胞生长和细胞游走，并提供了一种预防或治疗细胞增殖性疾病（如动脉粥样硬化、血管再阻塞、癌症和肾小球硬化）的方法。
• Quinazoline derivatives as kinase inhibitors
  申请人：Pandey Anjali

  公开号：US20050101609A1

  公开（公告）日：2005-05-12

  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 ol inhibiling kinascs and tre ating disease states in a mammal by inhibiting the phosphorylation of kinases. In a particular aspect the present invention prtvides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a 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，其具有对激酶磷酸化的抑制活性，从而抑制这些激酶的活性。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，其抑制PDGF受体的磷酸化以阻碍异常细胞生长和游走，并提供了一种预防或治疗细胞增殖性疾病，如动脉硬化、血管再狭窄、癌症和肾小球硬化的方法。
• QUINAZOLINE DERIVATIVES AS KINASE INHIBITORS
  申请人：Pandey Anjali

  公开号：US20100113468A1

  公开（公告）日：2010-05-06

  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.

  本发明涉及一种氮杂环化合物及其药学上可接受的盐，其具有对激酶的磷酸化抑制活性，从而抑制了这种激酶的活性。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，本发明提供了一种氮杂环化合物及其药学上可接受的盐，用于抑制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：US20090176780A1

  公开（公告）日：2009-07-09

  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和治疗哺乳动物疾病状态的方法。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，用于抑制PDGF受体的磷酸化，以阻碍异常细胞生长和游走，并防止或治疗细胞增殖性疾病，如动脉硬化、血管再狭窄、癌症和肾小球硬化的方法。