N-(4-cyanophenyl){4-[6-(2-methoxyethoxy)-7-(2-pyrrolidinylethoxy)quinazolin-4-yl]piperazinyl}carboxamide

• 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: N-(4-cyanophenyl){4-[6-(2-methoxyethoxy)-7-(2-pyrrolidinylethoxy)quinazolin-4-yl]piperazinyl}carboxamide
• 英文别名: N-(4-cyanophenyl)-4-[6-(2-methoxyethoxy)-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]piperazine-1-carboxamide
• 化学式: C₂₉H₃₅N₇O₄
• 分子量: 545.641
• InChiKey: QXWHYCMMVAXLSX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  40
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  N-(2-羟乙基)-吡咯烷 在 palladium on activated charcoal 盐酸 、 氯化亚砜 、 硫酸 、 氢气 、 甲酸铵 、 sodium hydride 、 potassium nitrate 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 溶剂黄146 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 10.5h， 生成 N-(4-cyanophenyl){4-[6-(2-methoxyethoxy)-7-(2-pyrrolidinylethoxy)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

文献信息

• Nitrogenous heterocyclic compounds
  申请人：——

  公开号：US20040259881A1

  公开（公告）日：2004-12-23

  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 diseases 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 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，具有对激酶的磷酸化抑制活性，从而抑制这种激酶的活性。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的疾病状态的方法。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，可抑制PDGF受体的磷酸化，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，如动脉硬化，血管再狭窄，癌症和肾小球硬化的方法。
• NITROGENOUS HETEROCYCLIC COMPOUNDS
  申请人：Millenium Pharmaceuticals, Inc.

  公开号：EP1309567A2

  公开（公告）日：2003-05-14
• [EN] NITROGENOUS HETEROCYCLIC COMPOUNDS<br/>[FR] COMPOSES HETEROCYCLIQUES AZOTES
  申请人：COR THERAPEUTICS INC

  公开号：WO2002016360A2

  公开（公告）日：2002-02-28

  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.