4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>-N-<2-(1-piperidinyl)ethyl>butanamide | 141929-25-1

• 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-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>-N-<2-(1-piperidinyl)ethyl>butanamide
• 英文别名: 4-[(2,3-dihydro2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]-N-[2-(1-piperidinyl)ethyl]butanamide；4-[(2-oxo-1,3-dihydroimidazo[4,5-b]quinolin-7-yl)oxy]-N-(2-piperidin-1-ylethyl)butanamide
• CAS: 141929-25-1
• 化学式: C₂₁H₂₇N₅O₃
• 分子量: 397.477
• InChiKey: DBSIFWOJERQDAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  95.6
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-(2-氨乙基)哌啶 、 methyl 4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butanoate 反应 1.25h， 生成 4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>-N-<2-(1-piperidinyl)ethyl>butanamide
  参考文献：
  名称：

  Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility

  摘要：

  Two series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation. The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility. From a series of 7-aminoimidazo[4,5-b]quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c. However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis. A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accommodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity. Structural modifications of this series focused on variation of the piperazine substituent and side-chain length. The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties. The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM, and ADP-induced platelet aggregation, IC50 = 0.51-mu-M after a 3-min exposure and 0.1-mu-M after a 15-min exposure of platelet-rich plasma to the drug. Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.

  DOI：

  10.1021/jm00092a020

文献信息

• Imidazo[4,5-b] quinolinyloxyalkanoic acid amides with enhanced water solubility
  申请人：Bristol-Myers Squibb Company

  公开号：EP0426180A2

  公开（公告）日：1991-05-08

  A novel series of 2,3-dihydro-2-oxo-1H-imidazo­[4,5-b]quinolinyloxyalkanoic acid amides having enhanced water solubility is disclosed of the formula wherein n is 3 to 5; R₁ is alkyl of 1 to 4 carbon atoms; R₂ is hydrogen; R₃ is 1-piperidinylethyl, 1-benzylpiperidin-4-­yl, 4-(1-piperidinyl)piperidine, (1-alkyl-2-pyrrolidinyl)­alkyl where alkyl is 1 to 4 carbon atoms, 3-quinuclidinyl; R₂ and R₃ together with the nitrogen atom to which they are attached form 4-R₄-piperazin-1-yl wherein R₄ is alkyl of 1 to 7 carbon atoms, alkoxyethyl of 3 to 7 carbon atoms, pyridinyl, pyrimidinyl, tetrahydropyranylmethyl, thienyl­methyl, cycloalkyl-(CH₂)m where m is zero or one and cycloalkyl is 5 to 7 carbon atoms except m is zero when cycloalkyl is 7 carbon atoms, benzyl, 4-fluorobenzyl, 3-trifluoromethylbenzyl, 4-alkoxybenzyl where alkoxy is 1 to 4 carbon atoms. The compounds are cyclic AMP phosphodiesterase inhibitors and are particularly useful as inhibitors of blood platelet aggregation and/or as cardiotonic agents.

  本发明公开了一系列新型 2,3-二氢-2-氧代-1H-咪唑并[4,5-b]喹啉氧基烷酸酰胺，它们具有更强的水溶性，其式为 其中 n 为 3 至 5；R₁ 为 1 至 4 个碳原子的烷基；R₂ 为氢；R₃ 为 1-哌啶乙基、1-苄基哌啶-4-基、4-(1-哌啶基)哌啶、(1-烷基-2-吡咯烷基)烷基(其中烷基为 1 至 4 个碳原子)、3-奎宁环基；R₂ 和 R₃ 与它们所连接的氮原子一起形成 4-R₄-哌嗪-1-基，其中 R₄ 是 1 至 7 个碳原子的烷基、3 至 7 个碳原子的烷氧基乙基、吡啶基、嘧啶基、四氢吡喃基甲基、噻吩基甲基、环烷基-(CH₂)m，其中 m 为 0 或 1，环烷基为 5 至 7 个碳原子，但当环烷基为 7 个碳原子时，m 为 0；苄基、4-氟苄基、3-三氟甲基苄基、4-烷氧基苄基，其中烷氧基为 1 至 4 个碳原子。 这些化合物是环 AMP 磷酸二酯酶抑制剂，尤其可用作血小板聚集抑制剂和/或强心剂。
• JPH03169880A
  申请人：——

  公开号：JPH03169880A

  公开（公告）日：1991-07-23
• US4943573A
  申请人：——

  公开号：US4943573A

  公开（公告）日：1990-07-24
• Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility
  作者：Nicholas A. Meanwell、Ronald D. Dennis、Herbert R. Roth、Michael J. Rosenfeld、Edward Smith、J. J. Kim Wright、John O. Buchanan、Catherine L. Brassard、Marianne Gamberdella

  DOI：10.1021/jm00092a020

  日期：1992.7

  Two series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation. The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility. From a series of 7-aminoimidazo[4,5-b]quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c. However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis. A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accommodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity. Structural modifications of this series focused on variation of the piperazine substituent and side-chain length. The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties. The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM, and ADP-induced platelet aggregation, IC50 = 0.51-mu-M after a 3-min exposure and 0.1-mu-M after a 15-min exposure of platelet-rich plasma to the drug. Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.