1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-<4'-<(chloromethoxy)carbonyl>-1'-piperazinyl>quinoline-3-carboxylic acid | 99106-29-3

• 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-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-<4'-<(chloromethoxy)carbonyl>-1'-piperazinyl>quinoline-3-carboxylic acid
• 英文别名: 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[1'-(4'-N-(chloromethyloxycarbonyl)piperazinyl)]-3-quinolinecarboxylic acid；7-(4-chloromethoxycarbonylpiperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid；norfloxacin chloromethyl carbamate；1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-chloromethoxycarbonyl-1-piperazinyl)-3-quinolinecarboxylic acid；7-[4-(Chloromethoxycarbonyl)piperazin-1-yl]-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid
• CAS: 99106-29-3
• 化学式: C₁₈H₁₉ClFN₃O₅
• 分子量: 411.817
• InChiKey: BHFGIOWKZDAGCC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  90.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-<4'-<(chloromethoxy)carbonyl>-1'-piperazinyl>quinoline-3-carboxylic acid 在 silver carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 (4R)-3-[3-[[4-[[4-(3-carboxy-1-ethyl-6-fluoro-4-oxoquinolin-7-yl)piperazine-1-carbonyl]oxymethoxy]-4-oxobutanoyl]amino]propyl]-2-[(4R)-2-(2-hydroxyphenyl)-4,5-dihydro-1,3-thiazol-4-yl]-1,3-thiazolidine-4-carboxylic acid
  参考文献：
  名称：

  Synthesis and biological properties of conjugates between fluoroquinolones and a N3′′-functionalized pyochelin

  摘要：

  吡咯菌素是一种常见于铜绿假单胞菌和其他几种致病菌的铁载体。先前合成了一种在N3″位点功能化的吡咯菌素，其末端连接了一个丙胺基团。在本研究中，我们证实这种类似物能够与吡咯菌素的外膜受体FptA结合，并高效地将铁(III)转运至细菌内部。这种功能化的吡咯菌素似乎是抗生素载体化的良好候选药物，适用于特洛伊木马前药策略。在此背景下，通过稳定的或可在体内水解的接头臂，将吡咯菌素与三种氟喹诺酮类抗生素（诺氟沙星、环丙沙星和N-脱甲基氧氟沙星）合成了共轭物。某些吡咯菌素-氟喹诺酮共轭物在一些铜绿假单胞菌菌株的生长抑制实验中展现出了抗菌活性。然而，这些活性弱于单一抗生素。这些特性似乎与共轭物的溶解性和生物利用度以及所用接头臂的稳定性有关。

  DOI：

  10.1039/c1ob06250f
• 作为产物：
  描述：

  诺氟沙星 在 吡啶 作用下， 以 氯仿 、 水 、 氯甲酸氯甲酯 为溶剂， 生成 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-<4'-<(chloromethoxy)carbonyl>-1'-piperazinyl>quinoline-3-carboxylic acid
  参考文献：
  名称：

  (Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties

  摘要：

  这项发明涉及新型（酰氧烷氧基）羰基衍生物，作为具有主要或次要胺基团的药物中的生物可逆前药基团。水解酶被用来触发碳酸酯前药基团的母体胺药物的再生。该案例还包括药物组合物、治疗方法和工艺要求。

  公开号：

  US04760057A1

文献信息

• (Acyloxyalkoxy) carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs, their preparation and pharmaceutical compositions containing said derivatives
  申请人：Merck & Co., Inc.

  公开号：EP0130119A2

  公开（公告）日：1985-01-02

  This invention relates to novel (acyloxyalkoxy) carbonyl derivatives as a bioreversible prodrug moieties for primary and secondary amine functions in drugs having a primary or secondary amine function thereon. Hydrolytic enzymes are used to trigger the regeneration of the parent amine drug of the carbamate prodrug moiety. The case also contains pharmaceutical composition, method of treatment and process claims.

  本发明涉及新型（酰氧基烷氧基）羰基衍生物，作为具有伯胺或仲胺功能的药物中伯胺和仲胺功能的生物可逆原药分子。使用水解酶可促使氨基甲酸酯原药分子的母胺药物再生。本案还包含药物组合物、治疗方法和工艺权利要求。
• (Acyloxy)alkyl carbamate prodrugs of norfloxacin
  作者：Jose Alexander、Robert A. Fromtling、Judith A. Bland、Barbara A. Pelak、Evamarie C. Gilfillan

  DOI：10.1021/jm00105a013

  日期：1991.1

  As a new prodrug approach to norfloxacin (NFLX) we prepared the acetoxyalkyl carbamates of the type NFLXCO-OCHR-OAc by the reaction of sodium or mercuric acetate on NFLX alpha-chloroalkyl carbamates. These prodrugs did not have the bitter taste of NFLX. In vitro, the acetoxyethyl carbamate exhibited activity only against Staphylococcus spp. and was inactive against Gram-negative organisms. However, in the presence of serum and intestinal homogenate, esterase-catalyzed hydrolysis of the ester bond in these modified carbamates led to a cascade reaction resulting in the rapid regeneration of NFLX. At high oral doses of the prodrug, the acetaldehyde produced as a side product in the breakdown of the promoiety caused a slight decrease in alcohol metabolism in a mouse model. The bioavailability of NFLX from the acetoxyethyl carbamate was lower compared to an equivalent dose of NFLX when given as an oral suspension in rhesus monkeys, presumably because of the lower aqueous solubility of the prodrug.
• Synthesis of pyochelin–norfloxacin conjugates
  作者：Freddy Rivault、Clémence Liébert、Alain Burger、Françoise Hoegy、Mohamed A. Abdallah、Isabelle J. Schalk、Gaëtan L.A. Mislin

  DOI：10.1016/j.bmcl.2006.11.005

  日期：2007.2

  Using synthetic functionalized analogues of pyochelin, a siderophore common to several pathogenic Pseudomonas and Burkholderia species, four fluoroquinolone-pyochelin conjugates were efficiently synthesized and evaluated for their biological activities. (c) 2006 Elsevier Ltd. All rights reserved.
• Synthesis and Activities of Pyoverdin−Quinolone Adducts: A Prospective Approach to a Specific Therapy Against <i>Pseudomonas a</i><i>eruginosa</i>
  作者：Christophe Hennard、Que Chi Truong、Jean-François Desnottes、Jean-Marc Paris、Nicole J. Moreau、Mohamed A. Abdallah

  DOI：10.1021/jm990508g

  日期：2001.6.1

  Pseudomonas aeruginosa is particularly resistant to most all the antibiotics presently available, essentially because of the very low permeability of its outer membrane. To overcome this, we synthesized four siderophore-based antibiotics formed by two quinolones - norfloxacin and benzonaphthyridone - bound to the pyoverdin of P. aeruginosa ATCC 15692 via two types of spacer arms: one stable and the other readily hydrolyzable. From the comparison of their antibacterial properties with those of the two unbound quinolones, we reached the following conclusions: (a) The adducts inhibit Escherichia: coli's gyrase showing that the dissociation of the compounds is not necessary for their activity. However, the presence of the pyoverdin moiety on the molecule decreases the inhibition activity compared to the antibiotic alone. (b) They facilitate the uptake of Fe-55 using the specific pyoverdin-mediated iron-transport system of the bacterium. No uptake was observed either with II? aeruginosa ATCC 27853, which produces a structurally different pyoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa ATCC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC determinations have shown that only strains P. aeruginosa ATCC 15692 and the derived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginosa IA1 mutant present higher susceptibility to the pyoverdin-quinolone adducts, whereas P. aeruginosa ATCC 27853 and K690 are much more resistant. (d) Growth inhibition by these adducts confirmed these results and showed that the adducts with the hydrolyzable spacer arm have better activity than those with the stable one and that the labile spacer arm adducts present much higher activity than the quinolones alone. These results show clearly that the penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate outer-membrane receptor present higher susceptibility to the adduct. In this case the antibiotic uses the pyoverdin-mediated iron-transport system. Furthermore, better efficiency is obtained when the spacer arm is liabile and favors the antibiotic release inside the cell, allowing better inhibition of gyrase.
• Design and synthesis of penicilloyl oxymethyl quinolone carbamates as a new class of dual-acting antibacterials
  作者：RR Alex、VM Kulkarni

  DOI：10.1016/0223-5234(96)88301-2

  日期：1995.1