9-cyclopropyl-6-fluoro-7-(isoindol-5-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione

• 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: 9-cyclopropyl-6-fluoro-7-(isoindol-5-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione
• 英文别名: 9-cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-6-fluoro-8-methoxy-[1,2]thiazolo[5,4-b]quinoline-3,4-dione
• 化学式: C₂₂H₁₈FN₃O₃S
• 分子量: 423.468
• InChiKey: INFOMPWYYGJYFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  96
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-溴邻苯二甲酰亚胺 在 四(三苯基膦)钯 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 四(三苯基膦)钯 、 三氟化硼乙醚 、 potassium acetate 、 碳酸氢钠 、 三氟乙酸 作用下， 以 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 9-cyclopropyl-6-fluoro-7-(isoindol-5-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione
  参考文献：
  名称：

  Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains:  Effects of Structural Modifications at the 6-, 7-, and 8-Positions

  摘要：

  We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 mu g/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.

  DOI：

  10.1021/jm060844e

文献信息

• New isothiazoloquinolones and related compounds as anti-infective agents
  申请人：Bradbury James Barton

  公开号：US20060235041A1

  公开（公告）日：2006-10-19

  The invention provides certain compounds and salts of Formula I and Formula II: which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables A 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A 8 and R 9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

  本发明提供了公式I和公式II的某些化合物和盐：具有抗微生物活性。本发明还提供了在制备公式I和公式II的化合物中有用的新型合成中间体。本文中定义了变量A1、R2、R3、R5、R6、R7、A8和R9。本文披露的公式I和公式II的某些化合物是细菌DNA合成和细菌复制的有效和选择性抑制剂。本发明还提供了抗微生物组合物，包括制药组合物，其中包含一个或多个公式I或公式II的化合物和一个或多个载体、赋形剂或稀释剂。这样的组合物可以仅包含公式I或公式II的化合物作为唯一的活性剂，也可以包含公式I或公式II的化合物和一个或多个其他活性剂的组合物。本发明还提供了治疗动物微生物感染的方法。
• NEW ISOTHIAZOLOQUINOLONES AND RELATED COMPOUNDS AS ANTI-INFECTIVE AGENTS
  申请人：Bradbury Barton James

  公开号：US20120114601A1

  公开（公告）日：2012-05-10

  The invention provides certain compounds and salts of Formula I and Formula II: which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables A 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A 8 and R 9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

  本发明提供了公式I和公式II的某些化合物和盐：具有抗微生物活性。该发明还提供了制备公式I和公式II化合物有用的新型合成中间体。变量A1、R2、R3、R5、R6、R7、A8和R9在此有定义。本文披露的公式I和公式II的某些化合物是强效和选择性的细菌DNA合成和细菌复制抑制剂。本发明还提供了抗微生物组合物，包括含有公式I或公式II的一个或多个化合物和一个或多个载体、赋形剂或稀释剂的制药组合物。这样的组合物可以仅包含公式I或公式II的化合物作为唯一活性剂，或者可以包含公式I或公式II的化合物和一个或多个其他活性剂的组合。本发明还提供了治疗动物微生物感染的方法。
• US8114888B2
  申请人：——

  公开号：US8114888B2

  公开（公告）日：2012-02-14
• Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains:  Effects of Structural Modifications at the 6-, 7-, and 8-Positions
  作者：Qiuping Wang、Edlaine Lucien、Akihiro Hashimoto、Godwin C. G. Pais、David M. Nelson、Yongsheng Song、Jane A. Thanassi、Christopher W. Marlor、Christy L. Thoma、Jijun Cheng、Steven D. Podos、Yangsi Ou、Milind Deshpande、Michael J. Pucci、Douglas D. Buechter、Barton J. Bradbury、Jason A. Wiles

  DOI：10.1021/jm060844e

  日期：2007.1.1

  We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 mu g/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.