N-(4-isopropoxyphenyl)-4-(6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)piperazine-1-carboxamide | 401903-53-5

• 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-isopropoxyphenyl)-4-(6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)piperazine-1-carboxamide
• 英文别名: 4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide
• CAS: 401903-53-5
• 化学式: C₃₀H₄₀N₆O₅
• 分子量: 564.685
• InChiKey: QRJUFNKCBDLAKR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  香草酸 在 palladium dihydroxide 盐酸 、 氯化亚砜 、 氢气 、 硝酸 、 甲酸铵 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 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 9.5h， 生成 N-(4-isopropoxyphenyl)-4-(6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)piperazine-1-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

• 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。
• Quinazoline derivatives as kinase inhibitors
  申请人：MILLENNIUM PHARMACEUTICALS, INC.

  公开号：EP1964839A2

  公开（公告）日：2008-09-03

  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.

  本发明涉及对激酶的磷酸化具有抑制活性的含氮杂环化合物及其药学上可接受的盐类，它们可抑制此类激酶的活性。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。在一个特定方面，本发明提供了含氮杂环化合物及其药学上可接受的盐类，它们可抑制PDGF受体的磷酸化，从而阻碍细胞异常生长和细胞游走，本发明还提供了一种预防或治疗细胞增殖性疾病如动脉硬化、血管再阻塞、癌症和肾小球硬化症的方法。
• Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
  申请人：Kanter James

  公开号：US20060167011A1

  公开（公告）日：2006-07-27

  The present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof and a process for making thereof. The compounds have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention also provides intermediate compounds useful in the process, as well as final products produced by the process, and salts or prodrugs thereof. The invention further provides a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases comprising administering an effective amount of a compound according to the invention to a patient in need thereof.

  本发明提供了含氮杂环化合物及其药学上可接受的盐类以及其制造工艺。这些化合物对激酶的磷酸化具有抑制活性，从而抑制此类激酶的活性。本发明还提供了在该工艺中有用的中间化合物，以及由该工艺生产的最终产品及其盐或原药。本发明进一步提供了一种通过抑制激酶的磷酸化来抑制哺乳动物体内的激酶和治疗疾病状态的方法，包括向有需要的患者施用有效量的根据本发明的化合物。
• NITROGENOUS HETEROCYCLIC COMPOUNDS AND PROCESS FOR MAKING NITROGENOUS HETEROCYCLIC COMPOUNDS AND INTERMEDIATES THEREOF
  申请人：Millennium Pharmaceuticals, Inc.

  公开号：EP1330444A2

  公开（公告）日：2003-07-30
• NITROGENOUS HETEROCYCLIC COMPOUNDS AND PROCESS FOR MAKING THEM
  申请人：MILLENNIUM PHARMACEUTICALS, INC.

  公开号：EP1330444B1

  公开（公告）日：2011-03-23