5-[(1E)-3-({2-[2,4-dichloro(methyl)-3-({[2-methyl-4-(4-morpholinyl)-8-quinolinyl]oxy}methyl)anilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-2-pyridinecarboxylic acid | 179624-69-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 5-[(1E)-3-({2-[2,4-dichloro(methyl)-3-({[2-methyl-4-(4-morpholinyl)-8-quinolinyl]oxy}methyl)anilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-2-pyridinecarboxylic acid
• 英文别名: 8-[3-[N-[(E)-3-(6-Carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-4-(morpholino)quinoline；5-[(E)-3-[[2-[2,4-dichloro-N-methyl-3-[(2-methyl-4-morpholin-4-ylquinolin-8-yl)oxymethyl]anilino]-2-oxoethyl]amino]-3-oxoprop-1-enyl]pyridine-2-carboxylic acid
• CAS: 179624-69-2
• 化学式: C₃₃H₃₁Cl₂N₅O₆
• 分子量: 664.545
• InChiKey: BLXCJXITUNFTIA-YRNVUSSQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  46
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  盐酸甲胺 、 5-[(1E)-3-({2-[2,4-dichloro(methyl)-3-({[2-methyl-4-(4-morpholinyl)-8-quinolinyl]oxy}methyl)anilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-2-pyridinecarboxylic acid 在 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 以65.4%的产率得到5-[(1E)-3-({2-[2,4-dichloro(methyl)-3-({[2-methyl-4-(4-morpholinyl)-8-quinolinyl]oxy}methyl)anilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-N-methyl-2-pyridinecarboxamide
  参考文献：
  名称：

  A New Class of Nonpeptide Bradykinin B₂ Receptor Ligand, Incorporating a 4-Aminoquinoline Framework. Identification of a Key Pharmacophore To Determine Species Difference and Agonist/Antagonist Profile

  摘要：

  Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B-2 receptor antagonists afforded highly potent ligands for human B-2 receptor with various affinities for guinea pig B-2 receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B-2 receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 mug/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B-2 receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B-2 receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B-2 agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

  DOI：

  10.1021/jm030326t
• 作为产物：
  描述：

  4-氯-8-羟基-2-甲基喹啉 在 sodium hydroxide 、 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride 、 potassium carbonate 、 1-羟基苯并三唑 、 一水合肼 、 苯酚 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成 5-[(1E)-3-({2-[2,4-dichloro(methyl)-3-({[2-methyl-4-(4-morpholinyl)-8-quinolinyl]oxy}methyl)anilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-2-pyridinecarboxylic acid
  参考文献：
  名称：

  A New Class of Nonpeptide Bradykinin B₂ Receptor Ligand, Incorporating a 4-Aminoquinoline Framework. Identification of a Key Pharmacophore To Determine Species Difference and Agonist/Antagonist Profile

  摘要：

  Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B-2 receptor antagonists afforded highly potent ligands for human B-2 receptor with various affinities for guinea pig B-2 receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B-2 receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 mug/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B-2 receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B-2 receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B-2 agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

  DOI：

  10.1021/jm030326t

文献信息

• [EN] PYRIDOPYRIMIDONES, QUINOLINES AND FUSED N-HERETOCYCLES AS BRADYKININ ANTAGONISTS<br/>[FR] PYRIDOPYRIMIDONES, QUINOLEINES ET HETEROCYCLES AZOTES FUSIONNES COMME ANTAGONISTES DE LA BRADYKININE
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：WO1996013485A1

  公开（公告）日：1996-05-09

  (EN) The invention relates to Pyridopyrimidones, Quinolines and fused N-heterocyclic compounds of formula (I) wherein Z is a group of the formula (a) or (b) in which X1 is N or C-R1, X2 is N or C-R9, X3 is N or C-R2, R1 is lower alkyl, R2 is hydrogen, lower alkyl, etc., R9 is hydrogen or lower alkyl, R3 is halogen, etc., R4 is halogen, etc., R5 is a group of formula (c), etc., A is lower alkylene, and Y is O, etc., and pharmaceutically acceptable salts thereof, to processes for preparation thereof, to a pharmaceutical composition comprising the same, and to methods of using the same therapeutically in the prevention and/or the treatment of bradykinin or its analogues mediated diseases in human being or animals.(FR) L'invention concerne des composés de la formule (I) dans laquelle Z est un groupe de la formule (a) ou (b). Dans ces formules, X1 est N ou C-R1, X2 est N ou C-R9, X3 est N ou C-R2, R1 est un alkyle inférieur, R2 est un hydrogène, un alkyle inférieur etc; R9 est un hydrogène ou un alkyle inférieur, R3 est un halogène, etc., R4 est un halogène, etc; R5 est un groupe de la formule (c) etc., dans laquelle A est un alkylène inférieur et Y est O, etc. L'invention concerne également les sels de ces composés acceptables sur le plan pharmaceutique, des procédés pour leur préparation, des compositions pharmaceutiques les contenant, ainsi que l'utilisation de ces compositions pour prévenir et/ou traiter les maladies associées à un métabolisme perturbé de la bradykinine ou de ses analogues, chez les humains ou les animaux.

  本发明涉及式(I)的吡啶吡咯酮、喹啉和融合的N-杂环化合物，其中Z是式(a)或(b)的基团，其中X1是N或C-R1，X2是N或C-R9，X3是N或C-R2，R1是低碳基，R2是氢，低碳基等，R9是氢或低碳基，R3是卤素等，R4是卤素等，R5是式(c)等基团，A是低碳基，Y是O等，以及其药学上可接受的盐，其制备方法，包括其的制药组合物，以及在人类或动物中预防和/或治疗缓激肽或其类似物介导的疾病的方法。
• PYRIDOPYRIMIDONES, QUINOLINES AND FUSED N-HERETOCYCLES AS BRADYKININ ANTAGONISTS
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0807105A1

  公开（公告）日：1997-11-19
• QUINOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0900203A1

  公开（公告）日：1999-03-10
• US5994368A
  申请人：——

  公开号：US5994368A

  公开（公告）日：1999-11-30
• US6083959A
  申请人：——

  公开号：US6083959A

  公开（公告）日：2000-07-04