5-nitro-3-(4-trifluoromethylphenyl)isoquinolin-1-one | 1450605-75-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-nitro-3-(4-trifluoromethylphenyl)isoquinolin-1-one
• 英文别名: 5-nitro-3-[4-(trifluoromethyl)phenyl]-2H-isoquinolin-1-one
• CAS: 1450605-75-0
• 化学式: C₁₆H₉F₃N₂O₃
• 分子量: 334.254
• InChiKey: PRPZXRSDJLFZEQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-nitro-3-(4-trifluoromethylphenyl)isoquinolin-1-one 在 氯化亚锡 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以40%的产率得到5-amino-3-(4-trifluoromethylphenyl)isoquinolin-1-one
  参考文献：
  名称：

  One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs

  摘要：

  Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of beta-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/ v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50 = 0.23 mu M vs IC50 = 1.6 mu M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.031
• 作为产物：
  描述：

  3-bromo-1-methoxy-5-nitro-isoquinoline 在 2-双环己基膦-2',6'-二甲氧基联苯 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 氢溴酸 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 5-nitro-3-(4-trifluoromethylphenyl)isoquinolin-1-one
  参考文献：
  名称：

  [EN] TANKYRASE INHIBITORS
  [FR] INHIBITEURS DE TANKYRASE

  摘要：

  本发明涉及一种具有式I的化合物，其中X为C(R6)或N，Y为C或N，环A、环B、R1和R2具有本文中定义的含义，前提是当环B为碳环时，X为C(R6)；或其药学上可接受的盐或溶剂。这些化合物是坦克酶-1和坦克酶-2抑制剂，并可用于治疗多种疾病，包括癌症。

  公开号：

  WO2014087165A1

文献信息

• [EN] TANKYRASE INHIBITORS<br/>[FR] INHIBITEURS DE TANKYRASE
  申请人：UNIV BATH

  公开号：WO2014087165A1

  公开（公告）日：2014-06-12

  The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.

  本发明涉及一种具有式I的化合物，其中X为C(R6)或N，Y为C或N，环A、环B、R1和R2具有本文中定义的含义，前提是当环B为碳环时，X为C(R6)；或其药学上可接受的盐或溶剂。这些化合物是坦克酶-1和坦克酶-2抑制剂，并可用于治疗多种疾病，包括癌症。
• Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro
  作者：Helen A. Paine、Amit Nathubhai、Esther C.Y. Woon、Peter T. Sunderland、Pauline J. Wood、Mary F. Mahon、Matthew D. Lloyd、Andrew S. Thompson、Teemu Haikarainen、Mohit Narwal、Lari Lehtiö、Michael D. Threadgill

  DOI：10.1016/j.bmc.2015.06.061

  日期：2015.9

  Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl) ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/beta-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies. (C) 2015 Elsevier Ltd. All rights reserved.
• One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs
  作者：Esther C.Y. Woon、Peter T. Sunderland、Helen A. Paine、Matthew D. Lloyd、Andrew S. Thompson、Michael D. Threadgill

  DOI：10.1016/j.bmc.2013.06.031

  日期：2013.9

  Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of beta-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/ v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50 = 0.23 mu M vs IC50 = 1.6 mu M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling. (C) 2013 Elsevier Ltd. All rights reserved.