1-cyclopropyl-5-amino-6,8-difluoro-7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

• 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: 1-cyclopropyl-5-amino-6,8-difluoro-7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
• 英文别名: 5-amino-7-[(4Z)-3-(aminomethyl)-4-methoxyiminopyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid
• 化学式: C₁₉H₂₁F₂N₅O₄
• 分子量: 421.404
• InChiKey: MUDXGFVYJYJGIF-BHGWPJFGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  N-tert-butoxycarbonyl-2-(2-cyanoethyl)aminoacetic acid ethyl ester 在 甲醇 、 sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 乙醇 、 盐酸羟胺 、 sodium ethanolate 、 三氧化硫吡啶 、 碳酸氢钠 、 二甲基亚砜 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 乙酰氯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 、 乙腈 为溶剂， 反应 7.83h， 生成 1-cyclopropyl-5-amino-6,8-difluoro-7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  参考文献：
  名称：

  Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines:  Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro- 4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic Acid (LB20304)^,1

  摘要：

  New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C-5-NH2) > F (C-5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C-5-NH2) > naphthyridine = F (C-5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (mu g/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Acinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.

  DOI：

  10.1021/jm970202e

文献信息

• Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime)
  申请人：LG Chemical Ltd.

  公开号：US05633262A1

  公开（公告）日：1997-05-27

  The present invention relates to a novel quinolone compound having an excellent antibacterial activity. More specifically, the present invention relates to a novel quinoline(naphthyridine)carboxylic acid derivative represented by the following formula (I), which has an 4-aminomethyl-3-oximepyrrolidine substituent on 7-position of the quinolone nucleus and shows a superior antibacterial activity in contrast to the known quinolone antibacterial agents having a weak activity against gram-positive bacterial strains and also has a broad antibacterial spectrum and a highly improved pharmacokinetic property: ##STR1## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Q are defined as described in the specification.

  本发明涉及一种具有出色抗菌活性的新奎诺酮化合物。更具体地说，本发明涉及一种由以下式（I）所表示的新喹诺啉（萘啉）羧酸衍生物，该衍生物在喹诺酮核的7位具有一个4-氨甲基-3-羟肟吡咯烷取代基，并且与已知的抗革兰氏阳性细菌菌株具有较弱活性的喹诺酮抗菌剂相比，表现出优越的抗菌活性，同时具有广泛的抗菌谱和高度改进的药代动力学性能：其中R、R.sub.1、R.sub.2、R.sub.3、R.sub.4和Q如规范中所述。
• Novel quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituents and processes for their preparation
  申请人：LG Chemical Limited

  公开号：EP0688772A1

  公开（公告）日：1995-12-27

  The present invention relates to a novel quinolone compound having an excellent antibacterial activity. More specifically, the present invention relates to a novel quinoline(naphthyridine)carboxylic acid derivative represented by the following formula (I), which has an 4-aminomethyl-3-oximepyrrolidine substituent on 7-position of the quinolone nucleus and shows a superior antibacterial activity in contrast to the known quinolone antibactrial agents having a weak activity against gram-positive bacterial strains and also has a broad antibacterial spectrum and a highly improved pharmacokinetic property : wherein R, R₁, R₂, R₃, R₄ and Q are defined as described in the specification.

  本发明涉及一种具有优异抗菌活性的新型喹诺酮化合物。更具体地说，本发明涉及一种由下式（I）表示的新型喹啉（萘啶）羧酸衍生物，该衍生物在喹诺酮核的 7 位上具有 4-氨基甲基-3-氧亚甲基吡咯烷取代基，与对革兰氏阳性细菌菌株活性较弱的已知喹诺酮类抗菌剂相比，显示出更优越的抗菌活性，并且具有广泛的抗菌谱和高度改进的药代动力学特性： 其中 R、R₁、R₂、R₃、R₄ 和 Q 的定义如说明书所述。
• Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituents and processes for their preparation
  申请人：LG Chemical Limited

  公开号：EP0688772B1

  公开（公告）日：1999-05-06
• US5633262A
  申请人：——

  公开号：US5633262A

  公开（公告）日：1997-05-27
• US5698570A
  申请人：——

  公开号：US5698570A

  公开（公告）日：1997-12-16