ethyl 7-(benzyloxy)-2-(2-methylpropyl)-1-oxo-4-{[(trifluoromethyl)sulfonyl]oxy}-1,2-dihydroisoquinoline-3-carboxylate | 447425-61-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: ethyl 7-(benzyloxy)-2-(2-methylpropyl)-1-oxo-4-{[(trifluoromethyl)sulfonyl]oxy}-1,2-dihydroisoquinoline-3-carboxylate
• 英文别名: Ethyl 2-(2-methylpropyl)-1-oxo-7-phenylmethoxy-4-(trifluoromethylsulfonyloxy)isoquinoline-3-carboxylate
• CAS: 447425-61-8
• 化学式: C₂₄H₂₄F₃NO₇S
• 分子量: 527.518
• InChiKey: SOWNKBXOSHSSPL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  ethyl 7-(benzyloxy)-2-(2-methylpropyl)-1-oxo-4-{[(trifluoromethyl)sulfonyl]oxy}-1,2-dihydroisoquinoline-3-carboxylate 在 sodium tetrahydroborate 、 四(三苯基膦)钯 、 氯化亚砜 、 草酰氯 、 5%-palladium/activated carbon 、 1,3-双(二苯基膦)丙烷 、 氢气 、 palladium diacetate 、 sodium hydride 、 sodium carbonate 、 一水合肼 、 三乙胺 、 N,N-二甲基甲酰胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 乙醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 48.5h， 生成 methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-7-carboxylate
  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：

  N-苯基双(三氟甲烷磺酰)亚胺 、 ethyl 7-(benzyloxy)-4-hydroxy-2-(2-methylpropyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylate 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 以91%的产率得到ethyl 7-(benzyloxy)-2-(2-methylpropyl)-1-oxo-4-{[(trifluoromethyl)sulfonyl]oxy}-1,2-dihydroisoquinoline-3-carboxylate
  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

文献信息

• Fused heterocyclic compounds
  申请人：——

  公开号：US20040082607A1

  公开（公告）日：2004-04-29

  The present invention provides a compound of the formula: wherein ring A is an optionally substituted 5 to 10-membered aromatic ring; R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond and the like; and L is a divalent hydrocarbon group, and a salt thereof, except 3-(aminomethyl)-2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-2-methyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-6-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinone and 3-(aminomethyl)-2-isopropyl-4-phenyl-1(2H)-isoquinolinone. The compound shows a superior peptidase-inhibitory activity and is useful as an agent for the prophylaxis or treatment of diabetes and the like. 1

  本发明提供了一种化合物，其化学式如下：其中环A是一个可选择取代的5至10成员芳香环；R1和R2相同或不同，每个都是一个可选择取代的碳氢化合物基团或可选择取代的杂环基团；X是一个键等；L是一个二价碳氢基团，以及其盐，但不包括3-(氨甲基)-2,6,7-三甲基-4-苯基-1(2H)-异喹啉酮，3-(氨甲基)-2-甲基-4-苯基-1(2H)-异喹啉酮，3-(氨甲基)-6-氯-2-甲基-4-苯基-1(2H)-异喹啉酮和3-(氨甲基)-2-异丙基-4-苯基-1(2H)-异喹啉酮。该化合物表现出优越的肽酶抑制活性，并可用作糖尿病的预防或治疗剂等。
• FUSED HETEROCYCLIC COMPOUNDS
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1355886B1

  公开（公告）日：2007-07-11
• US7034039B2
  申请人：——

  公开号：US7034039B2

  公开（公告）日：2006-04-25
• [EN] FUSED HETEROCYCLIC COMPOUNDS<br/>[FR] COMPOSES HETEROCYCLIQUES CONDENSES
  申请人：——

  公开号：WO2002062764A9

  公开（公告）日：2002-10-10

  [EN] The present invention provides a compound of the formula: wherein ring A is an optionally substituted 5 to 10-membered aromatic ring; R<1> and R<2> are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond and the like; and L is a divalent hydrocarbon group, and a salt thereof, except 3-(aminomethyl)-2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-2-methyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-6-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinone and 3-(aminomethyl)-2-isopropyl-4-phenyl-1(2H)-isoquinolinone. The compound shows a superior peptidase-inhibitory activity and is useful as an agent for the prophylaxis or treatment of diabetes and the like.
  [FR] L'invention concerne un composé représenté par la formule (I), dans laquelle le noyau A est un noyau aromatique doté de 5 à 10 chaînons éventuellement substitué ; R<1> et R<2> sont identiques ou différents, et chacun représente un groupe hydrocarbure éventuellement substitué ou un groupe hétérocyclique éventuellement substitué ; X représente une liaison et analogue ; et L représente un groupe hydrocarbure divalent. L'invention concerne aussi un sel du composé, à l'exception de 3-(aminométhyl)-2,6,7-triméthyl-4-phényl-1(2H)-isoquinolinone, 3-(aminométhyl)-2-méthyl-4-phényl-1(2H)-isoquinolinone, 3-(aminométhyl)-6-chloro-2-méthyl-4-phényl-1(2H)-isoquinolinone et 3-(aminométhyl)-2-isopropyl-4-phényl-1(2H)-isoquinolinone. Ce composé possède une activité supérieure d'inhibition de la peptidase et est utile comme agent pour prévenir ou traiter le diabète et analogue.
• 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.