cyclopropyl-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl]methanone | 1223444-66-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: cyclopropyl-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl]methanone
• 英文别名: cyclopropyl{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl}methanone；cyclopropyl-[4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl]methanone
• CAS: 1223444-66-3
• 化学式: C₁₇H₂₁F₂NO₃
• 分子量: 325.355
• InChiKey: XYPYBHCFRYWTPG-AOOOYVTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  cyclopropyl-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl]methanone 在 pyridinium chlorochromate 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 13.0h， 生成 (2R,4S,4aS)-8-(cyclopropanecarbonyl)-9,10-difluoro-2,4-dimethylspiro[2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a]quinoline-5,5′-hexahydropyrimidine]-2′,4′,6′-trione
  参考文献：
  名称：

  Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

  摘要：

  The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.

  DOI：

  10.1021/jm501174m
• 作为产物：
  描述：

  2,3,4-三氟苯甲酸 在 咪唑 、 sodium tetrahydroborate 、 四丁基氟化铵 、 碘 、 仲丁基锂 、 pyridinium chlorochromate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 环己烷 为溶剂， 反应 42.0h， 生成 cyclopropyl-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl]methanone
  参考文献：
  名称：

  Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

  摘要：

  The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.

  DOI：

  10.1021/jm501174m

文献信息

• FUSED, SPIROCYCLIC HETEROAROMATIC COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS
  申请人：Barvian Kevin

  公开号：US20110245224A1

  公开（公告）日：2011-10-06

  The present invention relates to compounds of Formula (I); to pharmaceutically acceptable salts thereof, to methods of using them to treat bacterial infections, and to methods for their preparation.

  本发明涉及式(I)的化合物；其药学上可接受的盐；使用它们治疗细菌感染的方法；以及它们的制备方法。
• CHEMICAL COMPOUNDS 542
  申请人：ASTRAZENECA AB

  公开号：US20140128371A1

  公开（公告）日：2014-05-08

  The present invention relates to compounds of Formula (I): to pharmaceutically acceptable salts thereof, to methods of using them to treat bacterial infections, and to methods for their preparation.

  本发明涉及式（I）的化合物，其中：制备这些化合物的方法，以及将其用于治疗细菌感染的方法和其制备方法的药学上可接受的盐。
• US8658641B2
  申请人：——

  公开号：US8658641B2

  公开（公告）日：2014-02-25
• US9040528B2
  申请人：——

  公开号：US9040528B2

  公开（公告）日：2015-05-26
• Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization
  作者：Gregory S. Basarab、Patrick Brassil、Peter Doig、Vincent Galullo、Howard B. Haimes、Gunther Kern、Amy Kutschke、John McNulty、Virna J. A. Schuck、Gregory Stone、Madhusudhan Gowravaram

  DOI：10.1021/jm501174m

  日期：2014.11.13

  The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.