6-methoxy-4-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline | 741702-17-0

• 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: 6-methoxy-4-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
• 英文别名: 6-methoxy-4-piperazin-1-yl-7-(3-pyrrolidin-1-yl-propoxy)quinazoline；6-Methoxy-4-piperazin-1-yl-7-(3-pyrrolidin-1-ylpropoxy)quinazoline
• CAS: 741702-17-0
• 化学式: C₂₀H₂₉N₅O₂
• 分子量: 371.483
• InChiKey: ARLFUBFRSAUKPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  62.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  溴代环戊烷 、 6-methoxy-4-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以80%的产率得到4-(4-cyclopentylpiperazin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
  参考文献：
  名称：

  活性指导的强效选择性Toll样受体9拮抗剂的开发

  摘要：

  TLR9是人类pDC和B细胞内体中表达的主要先天免疫受体之一。异常的TLR9激活与几种自身免疫和代谢性疾病以及败血症有关，尽管特定的TLR9拮抗剂尚未可用于临床，但使该受体成为重要的治疗靶标。在这里，我们通过喹唑啉支架中的取代模式阐明特定生理化学特性的重要性，以在<50 nM时实现有效的hTLR9抑制以及对hTLR7的选择性> 600倍的选择性，这是另一种密切相关的TLR，与TLR9共享下游信号传导，但在生理学中起着不同的作用和病理学。使用hPBMC和报道细胞系进行测定。体外ADME资料良好，

  DOI：

  10.1016/j.ejmech.2018.09.058
• 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 9.0h， 生成 6-methoxy-4-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)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

• Identification of Orally Active, Potent, and Selective 4-Piperazinylquinazolines as Antagonists of the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Family
  作者：Anjali Pandey、Deborah L. Volkots、Joseph M. Seroogy、Jack W. Rose、Jin-Chen Yu、Joseph L. Lambing、Athiwat Hutchaleelaha、Stanley J. Hollenbach、Keith Abe、Neill A. Giese、Robert M. Scarborough

  DOI：10.1021/jm020143r

  日期：2002.8.1

  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.
• Activity-guided development of potent and selective toll-like receptor 9 antagonists
  作者：Barnali Paul、Oindrila Rahaman、Swarnali Roy、Sourav Pal、Sohal Satish、Ayan Mukherjee、Amrit R. Ghosh、Deblina Raychaudhuri、Roopkatha Bhattacharya、Sunny Goon、Dipyaman Ganguly、Arindam Talukdar

  DOI：10.1016/j.ejmech.2018.09.058

  日期：2018.11

  making this receptor an important therapeutic target, though specific TLR9 antagonists are yet to be available for clinical use. Here we elucidate the importance of specific physiochemical properties through substitution patterns in quinazoline scaffold to achieve potent hTLR9 inhibition at < 50 nM as well as > 600 fold selectivity against hTLR7, another closely related TLR that shares downstream signaling

  TLR9是人类pDC和B细胞内体中表达的主要先天免疫受体之一。异常的TLR9激活与几种自身免疫和代谢性疾病以及败血症有关，尽管特定的TLR9拮抗剂尚未可用于临床，但使该受体成为重要的治疗靶标。在这里，我们通过喹唑啉支架中的取代模式阐明特定生理化学特性的重要性，以在<50 nM时实现有效的hTLR9抑制以及对hTLR7的选择性> 600倍的选择性，这是另一种密切相关的TLR，与TLR9共享下游信号传导，但在生理学中起着不同的作用和病理学。使用hPBMC和报道细胞系进行测定。体外ADME资料良好，