(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]-oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione

• 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: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]-oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione
• 英文别名: (2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione；(4'R,6'S,7'S)-17'-fluoro-4',6'-dimethyl-13'-(2-oxo-1,3-oxazolidin-3-yl)spiro[1,3-diazinane-5,8'-5,15-dioxa-2,14-diazatetracyclo[8.7.0.02,7.012,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione
• 化学式: C₂₁H₂₀FN₅O₇
• 分子量: 473.418
• InChiKey: CDAHTPNJGHKIRM-CEFVDNRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  34
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde 在 sodium hydride 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 24.67h， 生成 (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]-oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione 、 (2R,4R,4aR)-11-fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]-oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione
  参考文献：
  名称：

  Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)

  摘要：

  A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Grampositive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro toxicity profile, including no genotoxicity and no bone marrow toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound lu was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile.

  DOI：

  10.1021/acs.jmedchem.5b00863

文献信息

• COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
  申请人：AstraZeneca AB

  公开号：US20140206677A1

  公开（公告）日：2014-07-24

  Compounds of formula (I), pharmaceutically acceptable salts thereof, and uses of the compounds of formula (I) for treating bacterial infections are disclosed.

  化合物的结构式（I），其药学上可接受的盐，以及利用该结构式（I）化合物治疗细菌感染的用途被披露。
• Compounds and methods for treating bacterial infections
  申请人：AstraZeneca AB

  公开号：US08889671B2

  公开（公告）日：2014-11-18

  Compounds of formula (I), pharmaceutically acceptable salts thereof, and uses of the compounds of formula (I) for treating bacterial infections are disclosed.

  公开了式（I）的化合物，其药学上可接受的盐，以及使用式（I）的化合物治疗细菌感染的用途。
• US8889671B2
  申请人：——

  公开号：US8889671B2

  公开（公告）日：2014-11-18
• US9187495B2
  申请人：——

  公开号：US9187495B2

  公开（公告）日：2015-11-17
• US9540394B2
  申请人：——

  公开号：US9540394B2

  公开（公告）日：2017-01-10