(Z)-2-(2-Chloro-4,5-difluoro-3-methyl-benzoyl)-3-ethoxy-acrylic acid ethyl ester | 126483-97-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (Z)-2-(2-Chloro-4,5-difluoro-3-methyl-benzoyl)-3-ethoxy-acrylic acid ethyl ester
• 英文别名: Ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate；ethyl 2-(2-chloro-4,5-difluoro-3-methylbenzoyl)-3-ethoxyprop-2-enoate
• CAS: 126483-97-4
• 化学式: C₁₅H₁₅ClF₂O₄
• 分子量: 332.732
• InChiKey: OJYHLMMNMXCRMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (Z)-2-(2-Chloro-4,5-difluoro-3-methyl-benzoyl)-3-ethoxy-acrylic acid ethyl ester 在 盐酸 、 potassium carbonate 、 溶剂黄146 、 三乙胺 、 lithium chloride 作用下， 以 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 7-(3-Aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-6-fluoro-8-methyl-4-oxoquinoline-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
• 作为产物：
  描述：

  ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate 、 原甲酸三乙酯 在 乙酸酐 作用下， 生成 (Z)-2-(2-Chloro-4,5-difluoro-3-methyl-benzoyl)-3-ethoxy-acrylic acid ethyl ester
  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

• Benzoheterocyclic compounds
  申请人：Otsuka Pharmaceutical Company, Ltd.

  公开号：US04935420A1

  公开（公告）日：1990-06-19

  Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.2 is a morpholino group which may be substituted by one to three C.sub.1 -C.sub.6 alkyl groups where each of the alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of --NH.sub.2 and a halogen atom, and R.sup.3 is a C.sub.1 -C.sub.6 alkyl, --CH.sub.2 OH, ##STR2## (C.sub.1 -C.sub.6)alkylthiomethyl and --CH.sub.2 -halogen, or a pharmaceutically acceptable salt thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

  化合物的名称为Novel 4-oxoquinoline-3-carboxylic acid，其化学式为：##STR1## 其中，R.sup.2是一个morpholino基团，可以被1至3个C.sub.1-C.sub.6烷基基团取代，其中每个烷基基团可以被1至3个取代基所取代，所述取代基选自--NH.sub.2和卤素原子，R.sup.3是一个C.sub.1-C.sub.6烷基，--CH.sub.2 OH，##STR2## (C.sub.1-C.sub.6)烷基硫甲基和--CH.sub.2-卤素，或其药学上可接受的盐。这些化合物具有优异的抗微生物活性，因此可用作抗微生物剂，以及含有该化合物作为活性成分的制药组合物。
• 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic
  申请人：Otsuka Pharmaceutical Company, Limited

  公开号：US04855292A1

  公开（公告）日：1989-08-08

  Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.2 is 1-pyrrolidinyl which may have 1 to 2 substituents selected from the group consisting of (i) C.sub.1 -C.sub.6 alkyl, (ii) amino-(C.sub.1 -C.sub.6)alkyl, said amino being optionally substituted by 1 or 2 substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkanoyl, and C.sub.1 -C.sub.6 alkoxycarbonyl, (iii) amino which may be substituted by 1 or 2 substituents selected from C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6 alkoxycarbonyl, and C.sub.1 -C.sub.6 alkanoyl, and (iv) 2-oxo-1,3-dioxolenemethylamino which is substituted by C.sub.1 -C.sub.6 alkyl; or 1-piperidinyl which may have 1 to 3 substituents selected from oxo, hydroxy, halogen and C.sub.1 -C.sub.6 alkyl, and R.sup.3 is C.sub.1 -C.sub.6 alkyl, or a pharmaceutically acceptable salt thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

  化合物的结构式为：##STR1##其中，R.sup.2是1-吡咯烷基，可以有1至2个取自下列组的取代基：(i) C.sub.1 -C.sub.6烷基，(ii) 氨基-(C.sub.1 -C.sub.6)烷基，该氨基可以被1或2个取自C.sub.1 -C.sub.6烷基、C.sub.1 -C.sub.6酰基和C.sub.1 -C.sub.6烷氧羰基的取代基取代，(iii) 氨基，可以被1或2个取自C.sub.1 -C.sub.6烷基、苯基(C.sub.1 -C.sub.6)烷基、C.sub.1 -C.sub.6烷氧羰基和C.sub.1 -C.sub.6酰基的取代基取代，以及(iv) 2-氧代-1,3-二氧杂环戊烷甲基氨基，该氨基被C.sub.1 -C.sub.6烷基取代；或1-哌啶基，可以有1至3个取自氧代、羟基、卤素和C.sub.1 -C.sub.6烷基的取代基，R.sup.3是C.sub.1 -C.sub.6烷基，或其药学上可接受的盐。这些化合物具有优异的抗微生物活性，因此可用作抗微生物剂，并且含有上述化合物作为活性成分的制药组合物。
• 1-Cyclopropyl-6-fl
  申请人：Otsuka Pharmaceutical Company, Limited

  公开号：US04880806A1

  公开（公告）日：1989-11-14

  Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.2 is a heterocyclic group: ##STR2## in which R.sup.A is H, C.sub.1 -C.sub.6 alkyl or phenyl (C.sub.1 -C.sub.6) alkyl, R.sup.B is 2-oxo-1,3-dioxolenemethyl substituted by C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.8 cycloalkyl, R.sup.C is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxycarbonyl, or phenyl(C.sub.1 -C.sub.6)alkyl, R.sup.D is H or C.sub.1 -C.sub.6 alkyl, R.sup.G is C.sub.1 -C.sub.6 alkyl, and R.sup.H is C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl, or C.sub.1 C.sub.6 alkanoyl, and R.sup.3 is C.sub.1 -C.sub.6 alkyl, or R.sup.3 is C.sub.1 -C.sub.6 alkyl having 1 to 3 substituents selected from OH, C.sub.1 -C.sub.6 alkoxy and halogen when R.sup.2 is ##STR3## or a salt thereof, said compounds having excellent antimicrobial activity and being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

  化合物的化学式为：##STR1## 其中R.sup.2是一个杂环基：##STR2## 其中R.sup.A为H，C.sub.1-C.sub.6烷基或苯基（C.sub.1-C.sub.6）烷基，R.sup.B为2-氧代-1,3-二氧杂环甲基，被C.sub.1-C.sub.6烷基或C.sub.3-C.sub.8环烷基取代，R.sup.C为H，C.sub.1-C.sub.6烷基，C.sub.1-C.sub.6烷氧羰基或苯基（C.sub.1-C.sub.6）烷基，R.sup.D为H或C.sub.1-C.sub.6烷基，R.sup.G为C.sub.1-C.sub.6烷基，R.sup.H为C.sub.1-C.sub.6烷基，苯基（C.sub.1-C.sub.6）烷基或C.sub.1-C.sub.6脂肪酰基，R.sup.3为C.sub.1-C.sub.6烷基，或当R.sup.2为##STR3##时，R.sup.3为具有1-3个取代基的C.sub.1-C.sub.6烷基，所述化合物具有优异的抗微生物活性，可用作抗微生物剂，并且一种含有该化合物作为活性成分的药物组合物。