5-methyl-3-phenylisoquinolin-1(2H)-one | 1260150-57-9

• 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-methyl-3-phenylisoquinolin-1(2H)-one
• 英文别名: 5-methyl-3-phenyl-2H-isoquinolin-1-one
• CAS: 1260150-57-9
• 化学式: C₁₆H₁₃NO
• 分子量: 235.285
• InChiKey: MTORTMDPZWJMPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  18
• 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：
  29.1
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  2,3-二甲基苯甲酸 在 正丁基锂 、 氯化亚砜 、 二异丙胺 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 21.0h， 生成 5-methyl-3-phenylisoquinolin-1(2H)-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

• LiN(SiMe₃)₂/KO^tBu-Promoted Synthesis of Isoquinolone Derivatives from 2-Methylaryl Aldehydes and Nitriles
  作者：Peng Ma、Yuhang Wang、Jianhui Wang、Ning Ma

  DOI：10.1021/acs.joc.3c00698

  日期：2023.6.2

  A convenient method is proposed for the synthesis of isoquinolone derivatives from 2-methylaryl aldehydes and nitriles through LiN(SiMe3)2/KOtBu-promoted formal [4 + 2] cycloaddition reaction, featuring high atomic economy, good functional group tolerance, and easy operation. It enables the efficient formation of new C–C and C–N bonds toward isoquinolones without using preactivated amides.

  提出了一种由2-甲基芳基醛和腈通过LiN(SiMe 3 ) 2 /KO t Bu-促进的正式[4 + 2]环加成反应合成异喹诺酮类衍生物的简便方法，具有原子经济性高、官能团耐受性好、操作方便。它能够在不使用预活化酰胺的情况下有效地形成新的 C-C 和 C-N 键。
• 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.