9-(1-aminodibenzofuran-4-yl)-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one | 912824-78-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 9-(1-aminodibenzofuran-4-yl)-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one
• CAS: 912824-78-3
• 化学式: C₂₄H₂₀N₄O₃
• 分子量: 412.448
• InChiKey: PRUSDQBFCYVZRD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  84.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  9-(1-aminodibenzofuran-4-yl)-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one 在 三乙胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 22.0h， 生成 2-(4-methylpiperazin-1-yl)-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzofuran-1-yl]acetamide
  参考文献：
  名称：

  DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

  摘要：

  Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]-pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1 H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n) NR1 R-2, where n = 1 or 2 and the moiety (RRN)-R-1-N-2 was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]-pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

  DOI：

  10.1021/jm100608j
• 作为产物：
  描述：

  9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 9-O-triflate 在 四(三苯基膦)钯 、 potassium carbonate 、 溶剂黄146 、 锌 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.5h， 生成 9-(1-aminodibenzofuran-4-yl)-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

  摘要：

  Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]-pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1 H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n) NR1 R-2, where n = 1 or 2 and the moiety (RRN)-R-1-N-2 was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]-pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

  DOI：

  10.1021/jm100608j

文献信息

• DNA-PK inhibitors
  申请人：Smith Cameron Murray Graeme

  公开号：US20060264427A1

  公开（公告）日：2006-11-23

  Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N;and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(═O), CH 2 and NH are disclosed for use in inhibiting DNA-PK.

  式I的化合物： 其中A、B和D分别从以下组中选择：(i) CH、NH、C；(ii) CH、N、N；和(iii) CH、O、C；虚线表示适当位置上的两个双键；Z从S、O、C(═O)、CH2和NH中选择，用于抑制DNA-PK。
• WO2006/109081
  申请人：——

  公开号：——

  公开（公告）日：——
• DNA-PK INHIBITORS
  申请人：Kudos Pharmaceuticals Ltd

  公开号：EP1869021A1

  公开（公告）日：2007-12-26
• US7696203B2
  申请人：——

  公开号：US7696203B2

  公开（公告）日：2010-04-13
• [EN] DNA-PK INHIBITORS<br/>[FR] INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2006109081A1

  公开（公告）日：2006-10-19

  [EN] Compounds of formula: (I) wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N; and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(=O), CH₂ and NH are disclosed for use in inhibiting DNA-PK.
  [FR] Composés de formule: (I) dans laquelle A, B et D sont respectivement choisis parmi le groupe composé de: (i) CH, NH, C; (ii) CH, N, N; et (iii) CH, O, C; les lignes pointillées représentent deux doubles liaisons dans les emplacements appropriés; et Z est choisi parmi S, O, C(=O), CH₂ et NH. Les composés sont décrits pour une utilisation dans l'inhibition de l'ADN-PK.