(3S,4S)-<1-(3,4-dimethoxybenzyl)-2-oxo-4-<(R)-2-oxo-1,3-dioxololan-3-yl>azetidin-3-yl>carbamic acid benzyl ester | 214837-07-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (3S,4S)-<1-(3,4-dimethoxybenzyl)-2-oxo-4-<(R)-2-oxo-1,3-dioxololan-3-yl>azetidin-3-yl>carbamic acid benzyl ester
• 英文别名: Benzyl (2S,3S)-1-(3,4-dimethoxybenzyl)-2-[(R)-2-oxo-1,3-dioxolan-4-yl]-4-oxo-3-azetidinecarbamate；Benzyl (2S,3S)-1-(3,4-dimethoxybenzyl)-2-[(R)-2-oxo-1,3-dioxolan-4-yl]-4-oxo-3-azetidine carbamate；benzyl N-[(3S,4S)-1-[(3,4-dimethoxyphenyl)methyl]-2-oxo-4-[(4R)-2-oxo-1,3-dioxolan-4-yl]azetidin-3-yl]carbamate
• CAS: 214837-07-7
• 化学式: C₂₃H₂₄N₂O₈
• 分子量: 456.452
• InChiKey: MNLPJEXZDOVOFV-SLFFLAALSA-N

物化性质

• 沸点：
  734.7±60.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3S,4S)-<1-(3,4-dimethoxybenzyl)-2-oxo-4-<(R)-2-oxo-1,3-dioxololan-3-yl>azetidin-3-yl>carbamic acid benzyl ester 在 palladium on activated charcoal 吡啶 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 dipotassium peroxodisulfate 、 三氧化硫 N,N-二甲基甲酰胺络合物 、 四丁基溴化铵 、 水 、 氢气 、 碳酸氢钠 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 13.0h， 生成 (1S,5R)-7-oxo-2,6-diazabicyclo<3.2.0>heptane-6-sulfonic acid
  参考文献：
  名称：

  Structure-Based Design of β-Lactamase Inhibitors. 1. Synthesis and Evaluation of Bridged Monobactams

  摘要：

  Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking access of water to the enzyme-inhibitor ester bond. Bridged monobactams are selective class C beta-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 mu M) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.

  DOI：

  10.1021/jm980023c
• 作为产物：
  描述：

  [(2S,3S)-2-((R)-1,2-Dihydroxy-ethyl)-1-(3,4-dimethoxy-benzyl)-4-oxo-azetidin-3-yl]-carbamic acid benzyl ester 、 N,N'-羰基二咪唑 在 四氢呋喃 、 盐酸 、 水 、 氯化钠 、 magnesium sulfate 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以were obtained without further purification 220.3 g (yield: 96%) of pure product的产率得到(3S,4S)-<1-(3,4-dimethoxybenzyl)-2-oxo-4-<(R)-2-oxo-1,3-dioxololan-3-yl>azetidin-3-yl>carbamic acid benzyl ester
  参考文献：
  名称：

  .beta.-lactam compounds

  摘要：

  本文披露了公式##STR1##的化合物，其中Z，A和R如本文所述，并且这些化合物的药学相容性良好，容易水解的酯和盐也被披露。这些化合物具有β-内酰胺酶抑制作用，并且与β-内酰胺类抗生素联合使用可以控制β-内酰胺酶形成的病原体。它们还具有自身的抗菌活性，因此可以自己用于控制或治疗传染性疾病。

  公开号：

  US05494666A1

文献信息

• .beta.-lactam compounds
  申请人：Hoffmann-La Roche Inc.

  公开号：US05464617A1

  公开（公告）日：1995-11-07

  Compounds of the formula ##STR1## where Z, A, and R are as disclosed herein and pharmaceutically compatible, readily hydrolyzable esters and salts of these compounds are disclosed. The compounds have .beta.-lactamase inhibiting properties and are useful in the control of .beta.-lactamase-forming pathogens in combination with .beta.-lactam antibiotics. They also exhibit antibacterial activity of their own and can accordingly be used themselves in the control or treatment of infectious diseases.

  这些化合物的分子式为##STR1##其中Z、A和R如本文所披露的，这些化合物的药用兼容、易水解的酯和盐也被披露。这些化合物具有β-内酰胺酶抑制特性，并可与β-内酰胺类抗生素结合使用，用于控制β-内酰胺酶形成的病原体。它们还表现出自身的抗菌活性，因此可以单独用于控制或治疗传染病。
• Structure-Based Design of β-Lactamase Inhibitors. 1. Synthesis and Evaluation of Bridged Monobactams
  作者：Ingrid Heinze-Krauss、Peter Angehrn、Robert L. Charnas、Klaus Gubernator、Eva-Maria Gutknecht、Christian Hubschwerlen、Malgosia Kania、Christian Oefner、Malcolm G. P. Page、Satoshi Sogabe、Jean-Luc Specklin、Fritz Winkler

  DOI：10.1021/jm980023c

  日期：1998.10.1

  Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking access of water to the enzyme-inhibitor ester bond. Bridged monobactams are selective class C beta-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 mu M) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.