(6S)-2-nitro-6-(2-propynyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine | 1188334-60-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (6S)-2-nitro-6-(2-propynyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: (S)-2-nitro-6-prop-2-ynyloxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine；2-Nitro-6(S)-prop-2-ynyloxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine；(6S)-2-nitro-6-prop-2-ynoxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• CAS: 1188334-60-2
• 化学式: C₉H₉N₃O₄
• 分子量: 223.188
• InChiKey: PEEFIABMXLALNU-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6S)-2-nitro-6-(2-propynyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine 在 bis-triphenylphosphine-palladium(II) chloride 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 copper(l) iodide 、 potassium carbonate 、 三乙胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 16.0h， 生成 (6S)-6-({3-[5-(4-fluorophenyl)-2-pyridinyl]-2-propynyl}oxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationships of Varied Ether Linker Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

  摘要：

  New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both alpha-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating M. tb (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH2) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model.

  DOI：

  10.1021/jm200377r
• 作为产物：
  描述：

  在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以4.031 g的产率得到(6S)-2-nitro-6-(2-propynyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  Synthesis and Structure−activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side Chains

  摘要：

  Recently described biphenyl analogues Of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility.

  DOI：

  10.1021/jm901378u

文献信息

• BICYCLIC NITROIMIDAZOLE-SUBSTITUTED PHENYL OXAZOLIDINONES
  申请人：Ding Charles Z.

  公开号：US20090281088A1

  公开（公告）日：2009-11-12

  The current invention provides a series of bicyclic nitroimidazole-substituted phenyl oxazolidinones in which a bicyclic nitroimidazole pharmacophore is covalently bonded to a phenyl oxazolidinone, their pharmaceutical compositions, and the method of use of the compositions for prevention and treatment of bacterial infections. The bicyclic nitroimidazole-substituted phenyl oxazolidinones possess surprising antibacterial activity against wild-type and resistant strains of pathogens, and are therefore useful for the prevention, control and treatment of a number of human and veterinary bacterial infections caused by these pathogens, such as Mycobacterium tuberculosis.

  本发明提供了一系列双环硝基咪唑取代的苯基噁唑烷酮，其中双环硝基咪唑药效团与苯基噁唑烷酮共价键合，它们的制药组合物以及用于预防和治疗细菌感染的组合物的使用方法。这些双环硝基咪唑取代的苯基噁唑烷酮对野生型和耐药菌株具有惊人的抗菌活性，因此对于预防、控制和治疗由这些病原体引起的许多人类和兽医细菌感染是有用的，如结核分枝杆菌。
• Bicyclic nitroimidazole-substituted phenyl oxazolidinones
  申请人：Global Alliance for TB Drug Development

  公开号：US07666864B2

  公开（公告）日：2010-02-23

  The current invention provides a series of bicyclic nitroimidazole-substituted phenyl oxazolidinones in which a bicyclic nitroimidazole pharmacophore is covalently bonded to a phenyl oxazolidinone, their pharmaceutical compositions, and the method of use of the compositions for prevention and treatment of bacterial infections. The bicyclic nitroimidazole-substituted phenyl oxazolidinones possess surprising antibacterial activity against wild-type and resistant strains of pathogens, and are therefore useful for the prevention, control and treatment of a number of human and veterinary bacterial infections caused by these pathogens, such as Mycobacterium tuberculosis.

  本发明提供了一系列双环硝基咪唑取代的苯基噁唑烷酮，其中双环硝基咪唑药效团与苯基噁唑烷酮共价键合，它们的制药组合物以及用于预防和治疗细菌感染的组合物的使用方法。这些双环硝基咪唑取代的苯基噁唑烷酮对野生型和耐药菌株具有惊人的抗菌活性，因此对于预防、控制和治疗由这些病原体引起的多种人类和兽医细菌感染，如结核分枝杆菌等，非常有用。
• [EN] BICYCLIC NITROIMIDAZOLES COVALENTLY LINKED TO SUBSTITUTED PHENYL OXAZOLIDINONES<br/>[FR] NITROIMIDAZOLES BICYCLIQUES LIÉS PAR COVALENCE À DES PHÉNYLOXAZOLIDINONES SUBSTITUÉES
  申请人：GLOBAL ALLIANCE FOR TB DRUG DE

  公开号：WO2009120789A8

  公开（公告）日：2010-10-28
• BICYCLIC NITROIMIDAZOLES COVALENTLY LINKED TO SUBSTITUTED PHENYL OXAZOLIDINONES
  申请人：Global Alliance For Tb Drug Development

  公开号：EP2254892A1

  公开（公告）日：2010-12-01
• US7666864B2
  申请人：——

  公开号：US7666864B2

  公开（公告）日：2010-02-23