4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butyric acid | 130288-93-6

• 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-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butyric acid
• 英文别名: 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid；4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid；4-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yloxy)-butyric acid；4-[(2-oxo-1,3-dihydroimidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid
• CAS: 130288-93-6
• 化学式: C₁₄H₁₃N₃O₄
• 分子量: 287.275
• InChiKey: XNHZEJRZFBXTOB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butyric acid 在 4-二甲氨基吡啶 、 sodium hydroxide 、 二苯基磷酸 、 三乙胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 {Cyclohexyl-[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yloxy)-butyryl]-amino}-acetic acid
  参考文献：
  名称：

  血小板cAMP磷酸二酯酶抑制剂。2.与被官能化侧链取代的1，3-二氢-2H-咪唑并[4，5-b]喹啉-2-酮相关的结构活性关系。

  摘要：

  合成了一系列在7位被官能化侧链取代的1,3-二氢-2H-咪唑并[4,5-b]喹啉-2-酮衍生物，并将其评估为人血小板cAMP磷酸二酯酶的抑制剂（ PDE）以及ADP和胶原蛋白诱导的血小板聚集。结构修饰集中于侧链末端，侧链长度和侧链连接原子的变化。在侧链末端结合的官能团包括羧酸，酯和酰胺，醇，乙酸酯，腈，四唑和苯基砜部分。cAMP PDE抑制能力各不相同，并取决于侧链末端及其与杂环核的关系。杂环的N-1或N-3处的甲基化降低了cAMP PDE抑制能力。该结构类别的几个代表证明了对ADP和胶原蛋白诱导的血小板凝集的有效抑制作用，并且在低纳摩尔浓度下最大程度地发挥了最大作用。酰胺13d，13f，13h，13k，13m和13w比相对简单取代的化合物具有更大的效力。但是，血小板抑制特性在整个系列中并不总是与cAMP PDE抑制相关，这可能是由于膜通透性的变化所致。口服给予大鼠后，离体测量的几种化合物

  DOI：

  10.1021/jm00092a019
• 作为产物：
  描述：

  methyl 4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butanoate 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 1.0h， 以88%的产率得到4-<(2,3-dihydro-2-oxo-1H-imidazo<4,5-b>quinolin-7-yl)oxy>butyric acid
  参考文献：
  名称：

  血小板cAMP磷酸二酯酶抑制剂。2.与被官能化侧链取代的1，3-二氢-2H-咪唑并[4，5-b]喹啉-2-酮相关的结构活性关系。

  摘要：

  合成了一系列在7位被官能化侧链取代的1,3-二氢-2H-咪唑并[4,5-b]喹啉-2-酮衍生物，并将其评估为人血小板cAMP磷酸二酯酶的抑制剂（ PDE）以及ADP和胶原蛋白诱导的血小板聚集。结构修饰集中于侧链末端，侧链长度和侧链连接原子的变化。在侧链末端结合的官能团包括羧酸，酯和酰胺，醇，乙酸酯，腈，四唑和苯基砜部分。cAMP PDE抑制能力各不相同，并取决于侧链末端及其与杂环核的关系。杂环的N-1或N-3处的甲基化降低了cAMP PDE抑制能力。该结构类别的几个代表证明了对ADP和胶原蛋白诱导的血小板凝集的有效抑制作用，并且在低纳摩尔浓度下最大程度地发挥了最大作用。酰胺13d，13f，13h，13k，13m和13w比相对简单取代的化合物具有更大的效力。但是，血小板抑制特性在整个系列中并不总是与cAMP PDE抑制相关，这可能是由于膜通透性的变化所致。口服给予大鼠后，离体测量的几种化合物

  DOI：

  10.1021/jm00092a019

文献信息

• Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives
  作者：Nicholas A. Meanwell、Piyasena Hewawasam、Jeanine A. Thomas、J. J. Kim Wright、John W. Russell、Marianne Gamberdella、Harold J. Goldenberg、Steven M. Seiler、George B. Zavoico

  DOI：10.1021/jm00074a005

  日期：1993.10

  effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of

  1-（环己基甲基）-4- [4-[（2,3-二氢-2-氧代-1H-咪唑并[4,5-b]喹啉-7-基）氧基] -1-氧丁基]哌嗪（2）以前被鉴定为是人血小板cAMP磷酸二酯酶和体外诱导聚集的有效水溶性抑制剂，在血栓形成动物模型中显示出有效的抗血栓形成活性。尽管2在大鼠中表现出25％的口服生物利用度，但在猴子中进行的药代动力学研究表明，母体化合物的生物利用度低于5％，这是肝脏中广泛的首过生物转化的结果。为了鉴定具有增强的代谢稳定性的有效血小板凝集抑制剂，将2的侧链酰胺部分替换为化学上更稳定的尿素（6a-s），磺酰胺（13a-m），砜（19a-r）和四唑（23a-s）部分。来自每种结构类型的许多代表在体外以优异的水溶性有效地有效抑制了ADP诱导的人血小板凝集，其中一些优于2。在每个系列中，N-（环己基甲基）-，N-（2-通过与猴肝的S-9级分温育2小时来评估乙基丁基）-，N-苄基-和N-（4-氟
• Imidazoquinolinylether derivatives useful as phosphodiesterase and blood
  申请人：Bristol-Myers Company

  公开号：US04775674A1

  公开（公告）日：1988-10-04

  Novel series of 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinyl ether derivatives of formula ##STR1## wherein R.sub.1 is hydrogen, lower alkly, benzyl; R.sub.2 is hydrogen, halogen, lower alkyl, lower alkoxy; Alk is alkylene; Y is hydroxy and alkanoic or aralkanoic esters thereof, oxo ketone, dialkylamino, carboxylic acid and esters, carboxamides, alkoxy, ethanolamines and cyclic carbamates thereof, tetrazolyl, and optionally substituted phenylsulfonyl. The compounds are cyclic AMP phosphodiesterase inhibitors and are particularly useful as inhibitors of blood platelet aggregation and/or as cardiotonic agents.

  2,3-二氢-2-氧基-1H-咪唑并[4,5-b]喹啉基醚衍生物的小说系列，其化学式为##STR1##其中R.sub.1为氢、低烷基、苄基；R.sub.2为氢、卤素、低烷基、低烷氧基；Alk为烷基；Y为羟基和羧酸酯、酮基、二烷基胺、羧酸和酯、羧酰胺、烷氧基、乙醇胺和环状碳酸酯、四唑基，以及可选择地取代的苯磺酰基。这些化合物是环磷酸腺苷磷酸二酯酶抑制剂，特别适用于抑制血小板聚集和/或作为心力衰竭药物。
• Imidazo[4,5-b]quinolinyloxyalkanoic acid amides with enhanced water
  申请人：Bristol-Myers Squibb Company

  公开号：US04943573A1

  公开（公告）日：1990-07-24

  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 ##STR1## wherein n is 3 to 5; R.sub.1 is alkyl of 1 to 4 carbon atoms; R.sub.2 is hydrogen; R.sub.3 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; R.sub.2 and R.sub.3 together with the nitrogen atom to which they are attached form 4-R.sub.4 -piperazin-1-yl wherein R.sub.4 is alkyl of 1 to 7 carbon atoms, alkoxyethyl of 3 to 7 carbon atoms, pyridinyl, pyrimidinyl, tetrahydropyranylmethyl, thienylmethyl, cycloalkyl-(CH.sub.2).sub.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.

  揭示了一种增强水溶性的2,3-二氢-2-氧基-1H-咪唑[4,5-b]喹啉氧烷酸酰胺的小说系列，其化学式为n为3到5；R.sub.1为1到4个碳原子的烷基；R.sub.2为氢；R.sub.3为1-哌啶基乙基，1-苄基哌啶-4-基，4-(1-哌啶基)哌啶，(1-烷基-2-吡咯啉基)烷基，其中烷基为1到4个碳原子，3-喹啉基；R.sub.2和R.sub.3与它们连接的氮原子一起形成4-R.sub.4-哌嗪-1-基，其中R.sub.4为1到7个碳原子的烷基，3到7个碳原子的烷氧乙基，吡啶基，嘧啶基，四氢吡喃基甲基，噻吩基甲基，环烷基-(CH.sub.2).sub.m，其中m为零或一，环烷基为5到7个碳原子，当环烷基为7个碳原子时m为零，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到4个碳原子。这些化合物是环磷酸腺苷磷酸二酯酶抑制剂，特别适用作为血小板聚集抑制剂和/或作为心力学药剂。
• 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。
• 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.