6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid | 142256-43-7

• 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-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid
• 英文别名: 6-chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid；6-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid；6-Chloro-2-methyl-1-oxo-4-phenylisoquinoline-3-carboxylic acid
• CAS: 142256-43-7
• 化学式: C₁₇H₁₂ClNO₃
• 分子量: 313.74
• InChiKey: LHPNMPOYKUGVQI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 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-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid 在 盐酸 、 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 29.5h， 生成 3-amino-6-chloro-2-methyl-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 盐酸 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 64.0h， 生成 6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid
  参考文献：
  名称：

  Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine

  摘要：

  A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead la. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]7,8-dihydro-N, 7-dimethyl-8-oxo-5-(substituted phenyl)6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [I-125]- BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED(50) values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED(50) values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

  DOI：

  10.1021/jm00016a014

文献信息

• Heterocyclic amine, derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05198462A1

  公开（公告）日：1993-03-30

  A novel heterocyclic amine derivative of the general formula: ##STR1## wherein a ring A and a ring B stand independently for an optionally substituted benzene ring, Z.degree. stands for O or S or ##STR2## stands for --CH.sub.2 --, X stands for O, S or NR.sup.1 wherein R.sup.1 stands for hydrogen atom or an alkyl group, Y stands for NH, O or (CH.sub.2).sub.n wherein n denotes 0 to 2, and R.sup.2 stands for an optionally substituted hydrocarbon group, or their salts.

  一种新的杂环胺衍生物，其一般式为：##STR1## 其中环A和环B分别独立代表一个可选择取代的苯环，Z°代表O或S或##STR2## 代表--CH2 --，X代表O、S或NR1，其中R1代表氢原子或烷基，Y代表NH、O或(CH2)n，其中n为0至2，R2代表一个可选择取代的碳氢基团，或其盐。
• Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine
  作者：Hideaki Natsugari、Yoshinori Ikeura、Yutaka Kiyota、Yuji Ishichi、Takenori Ishimaru、Osamu Saga、Hideo Shirafuji、Toshimasa Tanaka、Izumi Kamo

  DOI：10.1021/jm00016a014

  日期：1995.8

  A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead la. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]7,8-dihydro-N, 7-dimethyl-8-oxo-5-(substituted phenyl)6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [I-125]- BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED(50) values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED(50) values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.
• Heterocyclic amine derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0481383B1

  公开（公告）日：1995-06-28
• US5198462A
  申请人：——

  公开号：US5198462A

  公开（公告）日：1993-03-30
• US5300646A
  申请人：——

  公开号：US5300646A

  公开（公告）日：1994-04-05