3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazole

• 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: 3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazole
• 化学式: C₁₆H₁₈ClFN₂O₄
• 分子量: 356.781
• InChiKey: VSTJFFHZZSGJDZ-RKDXNWHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  57
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazole 在 吡啶 、 四氧化锇 、 碘苯二乙酸 、 盐酸羟胺 、 sodium hydride 、 溶剂黄146 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 35.67h， 生成 (4S)-3-[(2R,4S,4aS)-11-fluoro-2,4-dimethyl-2',4',6'-trioxo-1,1',2,3',4,4',4a,6'-octahdro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5'-pyrimidin]-8-yl]-2-oxo-1,3-oxazolidine-4-carbonitrile
  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
• 作为产物：
  描述：

  6,7-difluoro-1,2-benzisoxazol-3(2H)-one 在 2,2,6,6-四甲基哌啶 、 正丁基锂 、 对甲苯磺酸 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 正己烷 、 水 、 甲苯 为溶剂， 反应 11.75h， 生成 3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-(1,3-dioxolan-2-yl)-7-fluoro-1,2-benzoxazole
  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

• Antibacterial Spiropyrimidinetriones with N-Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase
  作者：Gregory S. Basarab、Peter Doig、Charles J. Eyermann、Vincent Galullo、Gunther Kern、Amy Kimzey、Amy Kutschke、Marshall Morningstar、Virna Schuck、Karthick Vishwanathan、Fei Zhou、Madhusudhan Gowravaram、Sheila Hauck

  DOI：10.1021/acs.jmedchem.0c01100

  日期：2020.10.22

  was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure–activity relationships including

  在本文中，我们报道了螺并嘧啶三酮（SPT）在苯并异恶唑支架上掺入N-连接的唑取代基，相对于先前描述的类似物，革兰氏阳性抗菌活性得到改善。SPT具有不寻常的螺环结构，代表了细菌DNA回旋酶和拓扑异构酶IV抑制剂的新型抗菌类别。它们对临床上使用的氟喹诺酮类和其他DNA促旋酶/拓扑异构酶IV抑制剂无交叉耐药性。评估了SPT的活性对DNA促旋酶的抑制作用，对在5位上被N-连接的1,2,4-三唑取代的革兰氏阳性和革兰氏阴性病原体的抗菌活性提供了最有价值的信息。开发了定向亲核和亲电化学以改变这5位碳，氮，或氧取代基，并探索结构与活性之间的关系，包括目标结合模型周围的关系。鉴定出具有良好药代动力学参数的化合物，并且两种化合物在小鼠模型中均显示出胞浆性金黄色葡萄球菌感染。
• Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)
  作者：Gregory S. Basarab、Peter Doig、Vincent Galullo、Gunther Kern、Amy Kimzey、Amy Kutschke、Joseph P. Newman、Marshall Morningstar、John Mueller、Linda Otterson、Karthick Vishwanathan、Fei Zhou、Madhusudhan Gowravaram

  DOI：10.1021/acs.jmedchem.5b00863

  日期：2015.8.13

  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.
• 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