7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-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: 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
• 英文别名: 7-(3-Aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid；7-(3-aminoazetidin-1-yl)-1-(3-amino-4,6-difluorophenyl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid；1-(3-Amino-4,6-difluorophenyl)-7-(3-aminoazetidin-1-yl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid；7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxoquinoline-3-carboxylic acid
• 化学式: C₁₉H₁₄ClF₃N₄O₃
• 分子量: 438.793
• InChiKey: ATHBCDQPZRXUNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  113
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N,N-二甲基甲酰胺 、 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 、 对甲苯磺酸一水合物 在 乙醇 、 乙醚 作用下， 以 乙醚 为溶剂， 以to give 340 mg of the title compound的产率得到1-(3-amino-4,6-difluorophenyl)-7-(3-aminoazetidin-1-yl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid p-toluenesulfonic acid salt
  参考文献：
  名称：

  Pyridonecarboxylic acid derivatives or salts thereof and antibacterial

  摘要：

  本发明提供了以下通式（1）的吡啶酮羧酸衍生物：##STR1## 其中，R.sup.1是氢原子或羧基保护基，R.sup.2是硝基或取代或未取代的氨基，R.sup.3是卤素原子，R.sup.4和R.sup.5分别是氢原子、卤素原子、低碳基或低烷氧基，可以相同也可以不同，A是氮原子或--CX.dbd.，其中X是氢原子、卤素原子、低碳基或低烷氧基，Z是卤素原子或饱和环状氨基，可以具有取代基或其盐，以及包含其的抗菌剂。

  公开号：

  US05910498A1
• 作为产物：
  描述：

  2,4-二氟苯甲酸 在 钯 盐酸 、 sodium azide 、 草酰氯 、 硫酸 、 氢气 、 potassium carbonate 、 溶剂黄146 、 potassium nitrate 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 116.33h， 生成 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  参考文献：
  名称：

  A Novel Antibacterial 8-Chloroquinolone with a Distorted Orientation of the N1-(5-Amino-2,4-difluorophenyl) Group

  摘要：

  Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 C1 atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.

  DOI：

  10.1021/jm0205090

文献信息

• NOVEL PYRIDONECARBOXYLIC ACID DERIVATIVE OR SALT THEREOF
  申请人：WAKUNAGA PHARMACEUTICAL CO., LTD.

  公开号：US20190276407A1

  公开（公告）日：2019-09-12

  A pyridonecarboxylic acid derivative or a salt thereof is represented by Formula (1), where R 1 is hydrogen, a halogen atom, a lower alkyl group, or an amino group; R 2 is —NH—R 6 , where R 6 is hydrogen, a lower alkyl group, an amino lower alkyl group, or the like; —O—R 7 , where R 7 is hydrogen, a lower alkyl group, or the like; —(CH 2 ) m —R 8 , where R 8 is an amino group or the like, m is 1, 2, 3 or 4; or a cyclic amino group of Formula (2), where Y represents NH or C—R 9a R 9b , where R 9a and R 9b are each independently hydrogen, a lower alkyl group, an amino group, a lower alkyl amino group, or the like; n and p are 1 or 2; R 3 is hydrogen, a halogen atom, a lower alkyl group, or the like; R 4 is hydrogen or a carboxyl group-protecting group; and R 5 is hydrogen or a hydroxyl group-protecting group.

  化合物或其盐可由以下式（1）表示，其中R1是氢、卤素原子、低烷基或氨基；R2是—NH—R6，其中R6是氢、低烷基、氨基低烷基或类似物；—O—R7，其中R7是氢、低烷基或类似物；—(CH2)m—R8，其中R8是氨基或类似物，m为1、2、3或4；或由以下式（2）的环状氨基团表示，其中Y代表NH或C—R9aR9b，其中R9a和R9b各自独立地是氢、低烷基、氨基、低烷基氨基或类似物；n和p为1或2；R3是氢、卤素原子、低烷基或类似物；R4是氢或羧基保护基团；R5是氢或羟基保护基团。
• Phenylenediamines and process for preparing the same
  申请人：Wakunaga Pharmaceutical Co., Ltd.

  公开号：US05994575A1

  公开（公告）日：1999-11-30

  Phenylenediamines represented by general formula (1): ##STR1## wherein R represents an alkyl group or an optionally substituted aralkyl group, X.sup.1 represents a hydrogen atom or a halogen atom, and X.sup.2 represents a halogen atom; salts thereof, and a process for preparing the same. The compounds are useful as intermediates for synthesis of pyridonecarboxylic acid derivatives useful as antibacterial agents.

  通式(1)表示的苯二胺类化合物：##STR1## 其中，R代表烷基或可选择取代的芳基烷基，X.sup.1代表氢原子或卤素原子，X.sup.2代表卤素原子；其盐以及制备它们的方法。这些化合物可用作合成吡啶酮羧酸衍生物的中间体，这些衍生物可用作抗菌剂。
• NOVEL PYRIDONECARBOXYLATE DERIVATIVE OR SALT THEREOF AND ANTIBACTERIAL CONTAINING THE SAME AS ACTIVE INGREDIENT
  申请人：WAKUNAGA SEIYAKU KABUSHIKI KAISHA

  公开号：EP0787720A1

  公开（公告）日：1997-08-06

  The invention provides a pyridonecarboxylic acid derivative of the following general formula (1): wherein R1 is a hydrogen atom or carboxy protecting group, R2 is a nitro or substituted or unsubstituted amino group, R3 is a halogen atom, each of R4 and R5, which may be the same or different, is a hydrogen atom, halogen atom, lower alkyl group or lower alkoxy group, A is a nitrogen atom or - CX= wherein X is a hydrogen atom, halogen atom, lower alkyl group or lower alkoxy group, and Z is a halogen atom or a saturated cyclic amino group which may have a substituent, or a salt thereof and an antibacterial agent comprising the same.

  本发明提供了以下通式(1)的吡啶甲酸衍生物： 其中 R1 是氢原子或羧基保护基团，R2 是硝基或取代或未取代的氨基，R3 是卤素原子，R4 和 R5（可以相同或不同）各自是氢原子、卤素原子、低级烷基或低级烷氧基，A 是氮原子或 - CX= 其中 X 是氢原子、卤素原子、低级烷基或低级烷氧基，Z 是卤素原子或饱和环状氨基（可以有取代基），或其盐以及由其组成的抗菌剂。
• NOVEL PHENYLENEDIAMINES AND PROCESS FOR PREPARING THE SAME
  申请人：WAKUNAGA PHARMACEUTICAL CO., LTD.

  公开号：EP0897909A1

  公开（公告）日：1999-02-24

  Phenylenediamines represented by general formula (1): wherein R represents an alkyl group or an optionally substituted aralkyl group, X1 represents a hydrogen atom or a halogen atom, and X2 represents a halogen atom; salts thereof, and a process for preparing the same. The compounds are useful as intermediates for synthesis of pyridonecarboxylic acid derivatives useful as antibacterial agents.

  由通式(1)代表的苯二胺： 其中 R 代表烷基或任选取代的芳烷基，X1 代表氢原子或卤素原子，X2 代表卤素原子；它们的盐及其制备方法。这些化合物可用作合成可用作抗菌剂的吡啶甲酸衍生物的中间体。
• PYRIDONECARBOXYLATE DERIVATIVE OR SALT THEREOF AND ANTIBACTERIAL CONTAINING THE SAME AS ACTIVE INGREDIENT
  申请人：WAKUNAGA SEIYAKU KABUSHIKI KAISHA

  公开号：EP0787720B1

  公开（公告）日：2003-07-16