4-(环丙基甲氧基)-N-(3-甲酰基-8-甲基喹啉-7-基)苯甲酰胺 | 1018856-62-6

• 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
• 中文名称: 4-(环丙基甲氧基)-N-(3-甲酰基-8-甲基喹啉-7-基)苯甲酰胺
• 英文名称: 4-(cyclopropylmethoxy)-N-(3-formyl-8-methylquinolin-7-yl)benzamide
• 英文别名: 4-cyclopropylmethoxy-N-(3-formyl-8-methylquinolin-7-yl)benzamide；4-(cyclopropylmethoxy)-N-[3-formyl-8-methylquinolin-7-yl]benzoic acid amide；4-(cyclopropylmethoxy)-N-[3-formyl-8-methylquinolin-7-yl]benzamide
• CAS: 1018856-62-6
• 化学式: C₂₂H₂₀N₂O₃
• 分子量: 360.412
• InChiKey: UJEOCUFGLPMRCB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  68.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(环丙基甲氧基)-N-(3-甲酰基-8-甲基喹啉-7-基)苯甲酰胺 在 manganese(IV) oxide 、 乙醇 、 叠氮磷酸二苯酯 、 palladium on activated charcoal 、 potassium tert-butylate 、 氢气 、 N,N-二异丙基乙胺 、 异丙醇 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 146.5h， 生成 N-{3-[(1R)-1-aminoethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities

  摘要：

  Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.

  DOI：

  10.1021/jm300167z
• 作为产物：
  描述：

  4-(环丙基-甲氧基)苯甲酸 在 盐酸 、 氯化亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 70.0h， 生成 4-(环丙基甲氧基)-N-(3-甲酰基-8-甲基喹啉-7-基)苯甲酰胺
  参考文献：
  名称：

  Synthesis of a stable triformylmethane synthon and its scalable application to 7-acylamino-3-formylquinoline syntheses

  摘要：

  Novel 2-iminiomethylvinamidinium trihalides were isolated as stable crystals and found to be useful triformylmethane synthons with non-deliquescent nature in air. They were easier to manufacture, handle, and store than the known 2-iminiomethylvinamidinium dichloride. By virtue of in situ aminal protection, a combination of the vinamidinium salt with a secondary amine achieved an efficient and scalable synthesis of 7-acylamino-3-formylquinoline, a versatile synthetic intermediate for potent anti-obesity drugs 7-acylamino-3-aminomethy1-8-methylquinolines. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2014.02.040

文献信息

• HETEROCYCLIC COMPOUND
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2261213A1

  公开（公告）日：2010-12-15

  The present invention provides to a compound having melanin-concentrating hormone receptor antagonistic action and low toxicity, and useful as a agent for the prophylaxis or treatment of obesity and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.

  本发明提供了一种具有黑色素浓集激素受体拮抗作用和低毒性的化合物，可用作预防或治疗肥胖等疾病的药剂。本发明涉及一种由下式（I）表示的化合物：其中每个符号如规范中定义的，或其盐。
• The MCH₁receptor, an anti-obesity target, is allosterically inhibited by 8-methylquinoline derivatives possessing subnanomolar binding and long residence times
  作者：T Sakurai、K Ogawa、Y Ishihara、S Kasai、M Nakayama

  DOI：10.1111/bph.12529

  日期：2014.3

  dissociating reversible MCH1 receptor blocker with a low Koff value. CONCLUSION AND IMPLICATIONS This is the first time that a slowly dissociating negative allosteric modulator of the MCH1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH1 receptor antagonists, making members

  背景和目的 黑色素浓缩激素受体 1（MCH1 受体）拮抗剂被认为是抗肥胖剂。本研究报告了一类具有 8-甲基喹啉支架的新型 MCH1 受体拮抗剂。研究了这些拮抗剂阻断 MCH1 受体的分子机制。实验方法通过使用多种生物物理和基于细胞的功能分析来评估 MQ1 所举例说明的 8-甲基喹啉的药理学特性。主要结果 MQ1 抑制了 Gαi 和 Gαq 以及 β-抑制蛋白的多个信号通路。此外，MQ1 产生了无法克服的拮抗作用，导致 MCH 浓度依赖性结合曲线向右移动，同时最大反应逐渐降低。MQ1 的解离动力学由冲洗实验以及亲和选择-MS 确定。简而言之，MQ1 被证明是一种缓慢解离的可逆 MCH1 受体阻滞剂，具有低 Koff 值。结论和意义 这是首次证明 MCH1 受体的缓慢解离负变构调节剂可抑制该受体的众多信号通路。MQ1 的特性优于先前报道的 MCH1 受体拮抗剂，使其成为具有吸引力的候选药物。结论和意义
• Heterocyclic compound
  申请人：Murata Toshiki

  公开号：US20110015225A1

  公开（公告）日：2011-01-20

  The present invention provides to a compound having melanin-concentrating hormone receptor antagonistic action and low toxicity, and useful as a agent for the prophylaxis or treatment of obesity and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.

  本发明提供了一种具有黑色素浓聚激素受体拮抗作用和低毒性的化合物，可用作预防或治疗肥胖等疾病的药剂。本发明涉及一种由公式（I）表示的化合物，其中每个符号如规范中所定义，或其盐。
• STABLE VINAMIDINIUM SALT AND NITROGEN-CONTAINING HETEROCYCLIC RING SYNTHESIS USING THE SAME
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2258676B1

  公开（公告）日：2016-02-17
• US8373007B2
  申请人：——

  公开号：US8373007B2

  公开（公告）日：2013-02-12