6-benzyl-2-(4-pyridyl)-5,6,7,8-tetrahydro-3H-pyrido<4,3-d>pyrimidin-4-one | 139452-52-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-benzyl-2-(4-pyridyl)-5,6,7,8-tetrahydro-3H-pyrido<4,3-d>pyrimidin-4-one
• 英文别名: 6-benzyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one；6-benzyl-2-(4-pyridyl)-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-one；6-Benzyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol；6-benzyl-2-pyridin-4-yl-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-one
• CAS: 139452-52-1
• 化学式: C₁₉H₁₈N₄O
• 分子量: 318.378
• InChiKey: XGTSOQJTXUBYRQ-UHFFFAOYSA-N

物化性质

• 沸点：
  512.1±60.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-benzyl-2-(4-pyridyl)-5,6,7,8-tetrahydro-3H-pyrido<4,3-d>pyrimidin-4-one 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 甲醇 为溶剂， 反应 10.0h， 以87%的产率得到2-(4-pyridyl)-5,6,7,8-tetrahydro-3H-pyrido<4,3-d>pyrimidin-4-one
  参考文献：
  名称：

  Huber, Imre; Fueloep, Ferenc; Lazar, Janos, Journal of the Chemical Society. Perkin transactions I, 1992, # 1, p. 157 - 162

  摘要：

  DOI：
• 作为产物：
  描述：

  4-吡啶基偕胺肟 在 1% Pd on activated carbon 、 甲酸铵 、 sodium methylate 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 106.0h， 生成 6-benzyl-2-(4-pyridyl)-5,6,7,8-tetrahydro-3H-pyrido<4,3-d>pyrimidin-4-one
  参考文献：
  名称：

  Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases

  摘要：

  The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl) ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with beta-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused > 1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50 = 2 nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.005

文献信息

• [EN] 4-AMINO-2-PYRIDO-BICYCLIC PYRIMIDINES AND USE THEREOF AS TOPOISOMERASE II INHIBITORS<br/>[FR] PYRIMIDINES 4-AMINO-2-PYRIDO-BICYCLIQUES ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE LA TOPOISOMÉRASE II
  申请人：FONDAZIONE ST ITALIANO TECNOLOGIA

  公开号：WO2018114700A1

  公开（公告）日：2018-06-28

  The present invention concerns 4-amino-2-pyrido-bicyclic pyrimidines as type II topoisomerase inhibitors and use thereof as medicaments especially in the treatment of cancer. The invention also provides a method for the manufacture of 4- amino-2-pyrido bicyclic pyrimidines.

  本发明涉及4-氨基-2-吡啶双环嘧啶作为II型拓扑异构酶抑制剂及其用途作为药物，特别是在癌症治疗中的用途。该发明还提供了一种制备4-氨基-2-吡啶双环嘧啶的方法。
• 4-amino-2-pyrido-bicyclic pyrimidines and use thereof as topoisomerase II inhibitors
  申请人：FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA

  公开号：US10889560B2

  公开（公告）日：2021-01-12

  The present invention concerns 4-amino-2-pyrido-bicyclic pyrimidines of Formula (I) that function as type II topoisomerase inhibitors and their use thereof as medicaments especially in the treatment of cancer. The invention also provides a method for the manufacture of 4-amino-2-pyrido bicyclic pyrimidines of Formula (I).

  本发明涉及作为II型拓扑异构酶抑制剂的式(I)的4-氨基-2-吡啶双环嘧啶及其作为药物的用途，特别是在癌症治疗中的用途。 本发明还提供了一种制造式（I）的4-氨基-2-吡啶双环嘧啶的方法。
• Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3-<i>d</i>]pyrimidines for the Potential Treatment of Cystic Fibrosis
  作者：Elisabetta Pesci、Laura Bettinetti、Paola Fanti、Luis J. V. Galietta、Salvatore La Rosa、Letizia Magnoni、Nicoletta Pedemonte、Gian Luca Sardone、Laura Maccari

  DOI：10.1021/acs.jmedchem.5b00771

  日期：2015.12.24

  Cystic fibrosis (CF) is a lethal genetic disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) with a prevalence of the Delta F508 mutation. Whereas the detailed mechanisms underlying disease have yet to be fully elucidated, recent breakthroughs in clinical trials have demonstrated that CFTR dysfunction can be corrected by drug-like molecules. On the basis of this success, a screening campaign was carried out, seeking new drug-like compounds able to rescue Delta F508-CFTR that led to the discovery of a novel series of correctors based on a tetrahydropyrido[4,3-d]pyrimidine core. These molecules proved to be soluble, cell-permeable, and active in a disease relevant functional-assay. The series was then further optimized with emphasis on biological data from multiple cell systems while keeping physicochemical properties under strict control. The pharmacological and ADME profile of this corrector series hold promise for the development of more efficacious compounds to be explored for therapeutic use in CF.
• 4-AMINO-2-PYRIDO-BICYCLIC PYRIMIDINES AND USE THEREOF AS TOPOISOMERASE II INHIBITORS
  申请人：Fondazione Istituto Italiano di Tecnologia

  公开号：EP3558964A1

  公开（公告）日：2019-10-30
• Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases
  作者：Katerina Kumpan、Amit Nathubhai、Chenlu Zhang、Pauline J. Wood、Matthew D. Lloyd、Andrew S. Thompson、Teemu Haikarainen、Lari Lehtiö、Michael D. Threadgill

  DOI：10.1016/j.bmc.2015.05.005

  日期：2015.7

  The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl) ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with beta-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused > 1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50 = 2 nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2. (C) 2015 Elsevier Ltd. All rights reserved.