1-Ethyl-6-fluoro-1,4-dihydro-7-<4-(cyanomethyl)-1-piperazinyl>-4-oxoquinoline-3-carboxylic acid | 99726-81-5

• 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-7-<4-(cyanomethyl)-1-piperazinyl>-4-oxoquinoline-3-carboxylic acid
• 英文别名: 7-<4-(cyanomethyl)-1-piperazinyl>-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid；1-Ethyl-6-fluoro-1,4-dihydro-7-[4-(cyanomethyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid；7-[4-(Cyanomethyl)piperazin-1-yl]-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid
• CAS: 99726-81-5
• 化学式: C₁₈H₁₉FN₄O₃
• 分子量: 358.372
• InChiKey: GEYRVSUXCGULRA-UHFFFAOYSA-N

物化性质

• 熔点：
  220-225 °C
• 沸点：
  596.5±50.0 °C(Predicted)
• 密度：
  1.360±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  87.9
• 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-7-<4-(cyanomethyl)-1-piperazinyl>-4-oxoquinoline-3-carboxylic acid 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 10.0h， 以83%的产率得到诺氟沙星
  参考文献：
  名称：

  Studies on prodrugs. 10. Possible mechanism of N-dealkylation of N-masked norfloxacins having several active methylene groups

  摘要：

  As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.

  DOI：

  10.1021/jm00123a031
• 作为产物：
  描述：

  氯乙腈 、 诺氟沙星 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 以72%的产率得到1-Ethyl-6-fluoro-1,4-dihydro-7-<4-(cyanomethyl)-1-piperazinyl>-4-oxoquinoline-3-carboxylic acid
  参考文献：
  名称：

  New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay

  摘要：

  A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyrido[2,3-d]pyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay. The results were correlated with minimum inhibitory concentrations (MICs) against a variety of organisms. Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side-by-side. The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent. The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyrido[2,3-d]pyrimidine, was also explored. In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth. Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.

  DOI：

  10.1021/jm00153a015

文献信息

• Artifacts Generated During Azoalkane Peroxy Radical Oxidative Stress Testing of Pharmaceuticals Containing Primary and Secondary Amines
  作者：Marcela Nefliu、Todd Zelesky、Patrick Jansen、Gregory W. Sluggett、Christopher Foti、Steven W. Baertschi、Paul A. Harmon

  DOI：10.1002/jps.24667

  日期：2015.12

  artifactual degradation of pharmaceutical compounds containing primary and secondary amines during peroxy radical-mediated oxidative stress carried out using azoalkane initiators. Two degradation products were detected when model drug compounds dissolved in methanol/water were heated to 40°C with radical initiators such as 2,2'-azobis(2-methylpropionitrile) (AIBN). The primary artifact was identified as an

  我们报告了在使用偶氮烷烃引发剂进行的过氧自由基介导的氧化应激过程中，含有伯胺和仲胺的药物化合物的人为降解。当使用自由基引发剂（例如2,2'-偶氮双（2-甲基丙腈）（AIBN））将溶于甲醇/水中的模型药物化合物加热至40°C时，检测到两种降解产物。最初的伪影被确定为由模型药物的胺基与甲醛和氰化氢反应生成的α-氨基腈，而甲醛和氰化氢是应激反应的副产物。胺基与异氰酸之间的反应产生了轻微的伪影，这也是应力反应的副产物。我们报告了pH，引发剂/药物摩尔比和偶氮烷烃引发剂类型对这些假象形成的影响。
• KONDO, HIROSATO;SAKAMOTO, FUMIO;INOUE, YOSHIMASA;TSUKAMOTO, GORO, J. MED. CHEM., 32,(1989) N, C. 679-682
  作者：KONDO, HIROSATO、SAKAMOTO, FUMIO、INOUE, YOSHIMASA、TSUKAMOTO, GORO

  DOI：——

  日期：——
• New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay
  作者：John M. Domagala、Lori Doyle Hanna、Carl L. Heifetz、Marland P. Hutt、Thomas F. Mich、Joseph P. Sanchez、Marjorie Solomon

  DOI：10.1021/jm00153a015

  日期：1986.3

  A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyrido[2,3-d]pyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay. The results were correlated with minimum inhibitory concentrations (MICs) against a variety of organisms. Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side-by-side. The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent. The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyrido[2,3-d]pyrimidine, was also explored. In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth. Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.
• Studies on prodrugs. 10. Possible mechanism of N-dealkylation of N-masked norfloxacins having several active methylene groups
  作者：Hirosato Kondo、Fumio Sakamoto、Yoshimasa Inoue、Goro Tsukamoto

  DOI：10.1021/jm00123a031

  日期：1989.3

  As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.