4-(7-benzyloxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester | 205259-42-3

• 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-(7-benzyloxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester
• 英文别名: tert-butyl 4-[6-methoxy-7-phenylmethoxyquinazolin-4-yl]piperazinecarboxylate；Tert-butyl 4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)piperazine-1-carboxylate；tert-butyl 4-(6-methoxy-7-phenylmethoxyquinazolin-4-yl)piperazine-1-carboxylate
• CAS: 205259-42-3
• 化学式: C₂₅H₃₀N₄O₄
• 分子量: 450.538
• InChiKey: YRCIAPNTKLLWEM-UHFFFAOYSA-N

物化性质

• 沸点：
  603.5±55.0 °C(Predicted)
• 密度：
  1.220±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 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：

  4-(7-benzyloxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester 在 palladium dihydroxide 盐酸 、 氢气 、 caesium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 65.0~70.0 ℃ 、344.74 kPa 条件下， 反应 1.0h， 生成 6-methoxy-4-(piperazin-1-yl)-7-(3-(piperidin-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
• 作为产物：
  描述：

  香草酸 在 硝酸 、 乙酸酐 、 三氯化铁 、 铁粉 、 potassium carbonate 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 4-(7-benzyloxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester
  参考文献：
  名称：

  血小板衍生的生长因子受体磷酸化的有效和选择性抑制剂。3.替换喹唑啉部分并改善4- [4-（N-取代的（硫代）氨基甲酰基）-1-哌嗪基] -6，7-二甲氧基喹唑啉衍生物的代谢多态性。

  摘要：

  我们以前曾报道过，一系列的4- [4-（N-取代的（硫代）氨基甲酰基）-1-哌嗪基] -6,7-二甲氧基喹唑啉衍生物是有效的和选择性的血小板衍生生长因子受体（PDGFR）磷酸化抑制剂。并证明了多种生物学效应，例如通过口服给药抑制大鼠颈动脉球囊损伤后新内膜的形成。在这里，我们研究了6,7-二甲氧基喹唑啉基部分的结构活性关系。关于6,7-二甲氧基，乙氧基类似物显示出有效的活性（16b的IC（50）为0.04 microM； 17a的IC（50）为0.01 microM），烷基的进一步延伸降低了活性。有趣的是，甲氧基乙氧基（16j的IC（50）为0.02 microM; 17h的IC（50）为0.01 microM）和乙氧基乙氧基（17j的IC（50）为0。02 micro M）类似物显示出最有效的活性，表明插入的氧原子与β-PDGFR显着相互作用。在三环喹唑啉衍生物中，2-氧代咪唑并[4,5-

  DOI：

  10.1021/jm020505v

文献信息

• Nitrogen-containing heterocyclic compounds
  申请人：——

  公开号：US20020068734A1

  公开（公告）日：2002-06-06

  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 thus are useful for the prevention or treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis. The compounds are represented by general formula (I): 1 wherein V represents an oxygen atom or a sulfur atom; W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbons on the ring may be substituted by unsubstituted alkyl groups; X represents a nitrogen atom or C-R 9 ; Y represents a nitrogen atom or C-R 8 ; Z represents a nitrogen atom or C-R 7 (provided that at least one of X, Y and Z represents a nitrogen atom); R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, etc.; R 2 represents a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, etc.; R 3 , R 4 , R 5 and R 6 , which may be the same or different, each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a nitro group, a cyano group, OR 12 , —NR 15 R 16 , etc.; R 7 represents a halogen atom, etc.; R 8 has the same significance as R 7 , and R 9 represents a hydrogen atom or —COR 41 .

  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细胞游走，因此可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。所述化合物由通式（I）表示：其中V表示氧原子或硫原子；W表示1,4-哌嗪基或1,4-同源哌嗪基，其中环上的碳可以被未取代的烷基取代；X表示氮原子或C-R9；Y表示氮原子或C-R8；Z表示氮原子或C-R7（前提是X、Y和Z中至少有一个表示氮原子）；R1表示氢原子、取代或未取代的烷基、取代或未取代的脂环烷基等；R2表示取代的烷基、取代或未取代的脂环烷基等；R3、R4、R5和R6，可以相同也可以不同，每个表示氢原子、卤素原子、取代或未取代的烷基、硝基、氰基、OR12、—NR15R16等；R7表示卤素原子等；R8具有与R7相同的意义，且R9表示氢原子或—COR41。
• 1,3 diazines with platelet-derived growth factor receptor inhibitory activity
  申请人：Kyowa Hakko Kogyo Co., Ltd.

  公开号：US06207667B1

  公开（公告）日：2001-03-27

  1,3 Diazines according to formula (I): and pharmaceutically acceptable salts thereof inhibit phosphorylation of platelet-derived growth factor receptor and thereby hinder abnormal cell growth and cell wandering. The compounds may be used to treat or prevent cell-proliferative disorders such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

  根据公式（I）的1,3二氮杂环化合物及其药学上可接受的盐抑制血小板源性生长因子受体的磷酸化，从而阻碍异常细胞生长和细胞游走。这些化合物可用于治疗或预防细胞增殖性疾病，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：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。
• US6169088
  申请人：——

  公开号：——

  公开（公告）日：——