7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine | 1263187-63-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: 2-nitro-7-[(4-phenylmethoxyphenyl)methoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• CAS: 1263187-63-8
• 化学式: C₂₁H₂₁N₃O₅
• 分子量: 395.415
• InChiKey: AFYYMFBWQPYVNA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  91.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-(2-bromo-4-nitro-1H-imidazol-1-yl)-1-[(triisopropylsilyl)oxy]butan-2-ol 在 盐酸 、 sodium hydride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.42h， 生成 7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

  摘要：

  Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7 substituted 2-nitro-5,6-dihydroimidazo [2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

  DOI：

  10.1021/acs.jmedchem.7b00034

文献信息

• NITROIMIDAZOOXAZINE AND NITROIMIDAZOOXAZOLE ANALOGUES AND THEIR USES
  申请人：Thompson Andrew Mark

  公开号：US20110028466A1

  公开（公告）日：2011-02-03

  The current invention pertains to nitroimidazooxazine and nitroimidazooxazole analogues, their methods of preparation, and uses of the compounds as treatment for Mycobacterium tuberculosis , for use as anti-tubercular drugs, for use as anti-protozoal agents with unexpectedly high potency against Trypanosoma cruzi or Leishmania donovani , and for the treatment of other microbial infections.

  当前的发明涉及硝基咪唑噁啉和硝基咪唑噁唑类似物，它们的制备方法，以及将这些化合物用作治疗结核分枝杆菌、用作抗结核药物、用作对克氏锥虫或唐氏利什曼原虫具有意外高效的抗原虫药剂，以及用于治疗其他微生物感染的用途。
• [EN] NITROIMIDAZOOXAZINE AND NITROIMIDAZOOXAZOLE ANALOGUES AND THEIR USES<br/>[FR] ANALOGUES DE NITRO-IMIDAZO-OXAZINE ET DE NITRO-IMIDAZO-OXAZOLE ET LEURS UTILISATIONS
  申请人：GLOBAL ALLIANCE FOR TB DRUG DEV

  公开号：WO2011014776A1

  公开（公告）日：2011-02-03

  The current invention pertains to nitroimidazooxazine and nitroimidazooxazole analogues, their methods of preparation, and uses of the compounds as treatment for Mycobacterium tuberculosis, for use as anti-tubercular drugs, for use as anti-protozoal agents with unexpectedly high potency against Trypanosoma cruzi or Leishmania donovani, and for the treatment of other microbial infections.

  本发明涉及硝基咪唑氧杂环丙烷和硝基咪唑氧杂环咪唑类似物，它们的制备方法以及将这些化合物用作治疗结核分枝杆菌的药物，用作抗结核药物，用作抗原虫药物，对Trypanosoma cruzi或Leishmania donovani具有意外高效的药物，并用于治疗其他微生物感染。
• Development of (6<i>R</i>)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5<i>H</i>-imidazo[2,1-<i>b</i>][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis
  作者：Andrew M. Thompson、Patrick D. O’Connor、Andrew J. Marshall、Adrian Blaser、Vanessa Yardley、Louis Maes、Suman Gupta、Delphine Launay、Stephanie Braillard、Eric Chatelain、Baojie Wan、Scott G. Franzblau、Zhenkun Ma、Christopher B. Cooper、William A. Denny

  DOI：10.1021/acs.jmedchem.7b01581

  日期：2018.3.22

  Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo [2,1-1)] [1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
• NITROIMIDAZOOXAZINE ANALOGUES AND THEIR USES
  申请人：Global Alliance For Tb Drug Development

  公开号：EP2459570B1

  公开（公告）日：2014-12-24
• US8293734B2
  申请人：——

  公开号：US8293734B2

  公开（公告）日：2012-10-23