4(1H)-Quinolinone, 2-ethyl-6-methoxy- | 135016-13-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4(1H)-Quinolinone, 2-ethyl-6-methoxy-
• 英文别名: 2-ethyl-6-methoxy-1H-quinolin-4-one
• CAS: 135016-13-6
• 化学式: C₁₂H₁₃NO₂
• 分子量: 203.241
• InChiKey: UYYINXKRZUQMMU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4(1H)-Quinolinone, 2-ethyl-6-methoxy- 在 盐酸 、 sodium hydride 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 22.0h， 生成 2-Ethyl-6-methoxy-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride
  参考文献：
  名称：

  New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives

  摘要：

  A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 muM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICID8731, has been selected for clinical evaluation.

  DOI：

  10.1021/jm00100a007
• 作为产物：
  描述：

  3-氧代戊酸甲酯 在 diphenyl ether-biphenyl eutectic 、 对甲苯磺酸 作用下， 以 环己烷 为溶剂， 反应 7.25h， 生成 4(1H)-Quinolinone, 2-ethyl-6-methoxy-
  参考文献：
  名称：

  New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives

  摘要：

  A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 muM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICID8731, has been selected for clinical evaluation.

  DOI：

  10.1021/jm00100a007

文献信息

• New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis
  作者：Bruno Couto Giacobbo、Kenia Pissinate、Valnês Rodrigues-Junior、Anne Drumond Villela、Estêvão Silveira Grams、Bruno Lopes Abbadi、Fernanda Teixeira Subtil、Nathalia Sperotto、Rogério Valim Trindade、Davi Fernando Back、Maria Martha Campos、Luiz Augusto Basso、Pablo Machado、Diógenes Santiago Santos

  DOI：10.1016/j.ejmech.2016.11.048

  日期：2017.1

  2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range

  2-（喹啉-4-基氧基）乙酰胺已被描述为结核分枝杆菌（Mtb）生长的有效和选择性体外抑制剂。在此，发现了一系列新的优化化合物，它们显示出强大的抗结核活性，并且对药物敏感性和耐药性结核分枝杆菌的抑菌浓度（MIC）值最小。亚微摩尔范围内的菌株。此外，最具活性的化合物对哺乳动物细胞没有明显的毒性，并且在Mtb感染的巨噬细胞模型中显示出与异烟肼和利福平相似的细胞内活性。使用棋盘法研究铅化合物与一线和二线抗结核药物的缔合谱表明，2-（喹啉-4-基氧基）乙酰胺与利福平具有协同作用。最终，一些合成化合物显示出良好的渗透性，适度的新陈代谢速率和较低的药物-药物相互作用风险，表明2-（喹啉-4-基氧基）乙酰胺可能为用于开发新的替代疗法的候选药物。结核病的治疗。
• Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties
  作者：Ana Flávia Borsoi、Laura Manzoli Alice、Nathalia Sperotto、Alessandro Silva Ramos、Bruno Lopes Abbadi、Fernanda Souza Macchi Hopf、Adilio da Silva Dadda、Raoní S. Rambo、Rodrigo Braccini Madeira Silva、Josiane Delgado Paz、Kenia Pissinate、Mauro Neves Muniz、Christiano Ev Neves、Luiza Galina、Laura Calle González、Marcia Alberton Perelló、Alexia de Matos Czeczot、Mariana Leyser、Sílvia Dias de Oliveira、Graziela de Araújo Lock、Bibiana Verlindo de Araújo、Teresa Dalla Costa、Cristiano Valim Bizarro、Luiz Augusto Basso、Pablo Machado

  DOI：10.1021/acsmedchemlett.2c00254

  日期：2022.8.11

  2-(quinoline-4-yloxy)acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure–activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous

  利用环烷基和给电子基团降低羰基亲电性，合成了一系列新型 2-(喹啉-4-基氧基)乙酰胺，并对其作为结核分枝杆菌 (Mtb) 生长的体外抑制剂进行了评估。结构-活性关系研究产生了选择性和有效的抗结核药物，其对药物敏感和耐药的结核分枝杆菌菌株的最低抑制浓度在亚微摩尔范围内。对先导化合物针对自发qcrB突变株的活性的评估表明，这些结构靶向细胞色素bc 1复合物。此外，选定的分子在结核感染的巨噬细胞模型中抑制结核分枝杆菌的生长。此外，根据具体情况，先导化合物具有化学稳定性，并表现出良好的动力学溶解度、高渗透性和低体外代谢率。最后，在小鼠口服给药后评估该化合物的药代动力学特征。据我们所知，首次在充分暴露的情况下获得了2-(喹啉-4-基氧基)乙酰胺，这可能使其具有体内有效性并进一步开发为抗结核候选药物。
• Exploring Scaffold Hopping for Novel 2-(Quinolin-4-yloxy)acetamides with Enhanced Antimycobacterial Activity
  作者：Ana Flávia Borsoi、Alessandro Silva Ramos、Nathalia Sperotto、Bruno Lopes Abbadi、Fernanda Souza Macchi Hopf、Adilio da Silva Dadda、Raoní Scheibler Rambo、Mauro Neves Muniz、Josiane Delgado Paz、Estevão Silveira Grams、Fernanda Fries da Silva、Kenia Pissinate、Luiza Galina、Laura Calle González、Lovaine Silva Duarte、Marcia Alberton Perelló、Alexia de Matos Czeczot、Cristiano Valim Bizarro、Luiz Augusto Basso、Pablo Machado

  DOI：10.1021/acsmedchemlett.3c00570

  日期：2024.4.11

  candidate telacebec, a novel series of 2-(quinolin-4-yloxy)acetamides was synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (Mtb) growth. These compounds demonstrated potent activity against drug-sensitive and multidrug-resistant strains (MIC ≤ 0.02 μM). Leading compounds were evaluated against a known qcrB resistant strain (T313A), and their loss in activity suggested that the cytochrome

  利用候选药物telacebec的支架跳跃策略，合成了一系列新型2-(喹啉-4-基氧基)乙酰胺，并对其作为结核分枝杆菌(Mtb)生长抑制剂进行了评估。这些化合物对药物敏感和多重耐药菌株表现出有效的活性（MIC ≤ 0.02 μM）。针对已知的qcrB抗性菌株 (T313A) 对主要化合物进行了评估，它们的活性丧失表明细胞色素bc 1复合物可能是目标。此外，这些结构对哺乳动物细胞表现出高选择性（选择性指数> 500）以及在不同水介质中的稳定性。此外，一些合成的喹啉的水溶性值超过了telacebec，同时保持了较低的代谢率。最后，在结核病 (TB) 感染的巨噬细胞模型中，选定的化合物可阻止 Mtb 生长超过 1.7 log 10菌落形成单位。这些发现验证了所提出的设计，并引入了新的 2-(喹啉-4-基氧基)乙酰胺，其在结核病药物发现活动中具有开发潜力。
• Quinoline derivatives, process for their preparation and their use as medicaments
  申请人：ZENECA LIMITED

  公开号：EP0412848B1

  公开（公告）日：1995-01-18
• US5444071A
  申请人：——

  公开号：US5444071A

  公开（公告）日：1995-08-22