(4R)-3-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazol-3-yl}-4-methyl-1,3-oxazolidin-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并异恶唑
• 英文名称: (4R)-3-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazol-3-yl}-4-methyl-1,3-oxazolidin-2-one
• 英文别名: (R)-3-(6-((2S,6R)-2,6-dimethylmorpholino)-5-(1,3-dioxolan-2-yl)-7-fluorobenzo[d]isoxazol-3-yl)-4-methyloxazolidin-2-one；(4R)-3-{6[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolane-2-yl)-7-fluoro-1,2-benzoxazol-3-yl}-4-methyl-1,3-oxazolidin-2-one；(4R)-3-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazol-3-yl]-4-methyl-1,3-oxazolidin-2-one
• 化学式: C₂₀H₂₄FN₃O₆
• 分子量: 421.425
• InChiKey: FHZONBWWDGRYDN-UTUOFQBUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  86.5
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  巴比妥酸 、 (4R)-3-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazol-3-yl}-4-methyl-1,3-oxazolidin-2-one 在 溶剂黄146 作用下， 反应 16.0h， 以12%的产率得到(2S,4r,4aR)-11-fluoro-2,4-dimethyl-8-[(4R)-4-methyl-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
• 作为产物：
  描述：

  3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde 在 4-甲基苯磺酸吡啶 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 28.67h， 生成 (4R)-3-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazol-3-yl}-4-methyl-1,3-oxazolidin-2-one
  参考文献：
  名称：

  COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS

  摘要：

  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。

  公开号：

  US20140206677A1

文献信息

• [EN] FUSED, SPIROCYCLIC HETEROAROMATIC COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS<br/>[FR] COMPOSÉS HÉTÉROAROMATIQUES SPIROCYCLIQUES FUSIONNÉS POUR LE TRAITEMENT D'INFECTIONS BACTÉRIENNES
  申请人：ENTASIS THERAPEUTICS LTD

  公开号：WO2015181637A1

  公开（公告）日：2015-12-03

  Disclosed are methods for treating various bacterial infections with (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-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, or a pharmaceutically acceptable salt thereof.

  披露了使用(2R,4S,4aS)-11-氟-2,4-二甲基-8-[(4S)-4-甲基-2-氧代-1,3-噁唑啉-3-基]-1,2,4,4a-四氢-2'H,6H-螺[1,4-噁唑啉[4,3-a][1,2]噁唑啉[4,5-g]喹啉-5,5'-嘧啶]-2',4',6' (1'H,3'H)-三酮或其药用可接受盐治疗各种细菌感染的方法。
• Fused, spirocyclic heteroaromatic compounds for the treatment of bacterial infections
  申请人：Entasis Therapeutics Limited

  公开号：US10238661B2

  公开（公告）日：2019-03-26

  Disclosed are methods for treating various bacterial infections with (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-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, or a pharmaceutically acceptable salt thereof.

  公开了用(2R,4S,4aS)-11-氟-2,4-二甲基-8-[(4S)-4-甲基-2-氧代-1,3-恶唑啉-3-基]-1,2,4,4a-四氢-2′H、6H-螺[1,4-恶嗪并[4,3-a][1,2]恶唑并[4,5-g]喹啉-5,5′-嘧啶]-2′,4′,6′(1′H,3′H)-三酮，或其药学上可接受的盐。
• FUSED, SPIROCYCLIC HETEROAROMATIC COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS
  申请人：Entasis Therapeutics Limited

  公开号：US20180169104A1

  公开（公告）日：2018-06-21

  Disclosed are methods for treating various bacterial infections with (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-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, or a pharmaceutically acceptable salt thereof.
• 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