6-chloro-2-ethyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid

• 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: 6-chloro-2-ethyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid
• 英文别名: 6-Chloro-2-ethyl-1-oxo-4-phenylisoquinoline-3-carboxylic acid
• 化学式: C₁₈H₁₄ClNO₃
• 分子量: 327.767
• InChiKey: JNKNZYAEAQPQNO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-2-ethyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid 在 sodium tetrahydroborate 、 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 4.0h， 生成 6-chloro-2-ethyl-3-(hydroxymethyl)-4-phenylisoquinolin-1(2H)-one
  参考文献：
  名称：

  Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554

  摘要：

  The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl) oxy] acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.06.059
• 作为产物：
  描述：

  2-苯甲酰基-4-氯苯甲酸 在 sodium methylate 、 potassium carbonate 作用下， 以 1,3-二甲基-2-咪唑啉酮 、 DMF (N,N-dimethyl-formamide) 、 丙酮 为溶剂， 反应 52.17h， 生成 6-chloro-2-ethyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  JNK INHIBITOR

  摘要：

  一种含有异喹啉酮骨架或其盐的JNK抑制剂，例如由以下公式表示的化合物： 其中环A和环B分别是可选择取代的苯环，X是-O-，-N=，-NR3-或-CHR3-，R2是酰基，可选择酯化或硫酯化的羧基，可选择取代的氨基甲酰基或可选择取代的氨基等，虚线表示单键或双键，R1是氢原子，可选择取代的碳氢基团，可选择取代的杂环基团等。

  公开号：

  EP1484320A1

文献信息

• JNK INHIBITOR
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1484320A1

  公开（公告）日：2004-12-08

  A JNK inhibitor containing a compound having an isoquinolinone skeleton or a salt thereof, such as a compound represented by the formula wherein ring A and ring B are each an optionally substituted benzene ring, X is -O-, -N=, -NR3- or -CHR3-, R2 is an acyl group, an optionally esterified or thioesterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted amino group and the like, a broken line shows a single bond or a double bond, and R1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and the like, and the like.

  一种含有异喹啉酮骨架或其盐的JNK抑制剂，例如由以下公式表示的化合物： 其中环A和环B分别是可选择取代的苯环，X是-O-，-N=，-NR3-或-CHR3-，R2是酰基，可选择酯化或硫酯化的羧基，可选择取代的氨基甲酰基或可选择取代的氨基等，虚线表示单键或双键，R1是氢原子，可选择取代的碳氢基团，可选择取代的杂环基团等。
• Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554
  作者：Yoshihiro Banno、Yasufumi Miyamoto、Mitsuru Sasaki、Satoru Oi、Tomoko Asakawa、Osamu Kataoka、Koji Takeuchi、Nobuhiro Suzuki、Koji Ikedo、Takuo Kosaka、Shigetoshi Tsubotani、Akiyoshi Tani、Miyuki Funami、Michiko Tawada、Yoshio Yamamoto、Kathleen Aertgeerts、Jason Yano、Hironobu Maezaki

  DOI：10.1016/j.bmc.2011.06.059

  日期：2011.8

  The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl) oxy] acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.