benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate | 145574-13-6

• 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: benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate
• 英文别名: benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate；benzyl (1S,4S,5S)-4-hydroxy-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate；benzyl (1S,4S,5S)-6-[(3,4-dimethoxyphenyl)methyl]-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate
• CAS: 145574-13-6
• 化学式: C₂₂H₂₄N₂O₆
• 分子量: 412.442
• InChiKey: TYEWWTLJSBGBGE-DBVUQKKJSA-N

物化性质

• 沸点：
  636.3±55.0 °C(Predicted)
• 密度：
  1.350±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  88.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate 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 、 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 8.0h， 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 在 四丁基溴化铵 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate
  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

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。
• Bicyclic and tricyclic .beta.-lactams
  申请人：Hoffmann-La Roche Inc.

  公开号：US05510343A1

  公开（公告）日：1996-04-23

  There are described compounds of the formula ##STR1## in which R signifies lower alkoxycarbonyl, lower alkoxycarbonylamino, the acyl residue of an .alpha.- or .beta.-amino acid or a residue of the general formula Q--X--Y-- (a) wherein Q signifies a 3- to 6-membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a fused ring, X signifies a direct bond or a linear "spacer" with up to 6 atoms consisting of carbon, nitrogen, oxygen and/or sulphur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, and Y represents one of the groups --CO--, --CS--, --CONH-- and (where X contains neither sulphur nor carbonyl as a terminal component) --SO.sub.2 --; and in which R.sup.1 signifies hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula --S--Het, wherein Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and R.sup.2 represents the sulpho group --SO.sub.3 H or R.sup.1 and R.sup.2 together signify a group of the formula ##STR2## wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R.sup.3 represents hydrogen or R.sup.1 and R.sup.3 together represent a group of the formula .dbd.CH--R.sup.a (c) wherein R.sup.a signifies one of the groups --COR.sup.b (c.sup.1) --CH.sub.2 --OCOR.sup.c (c.sup.2) --CH.sub.2 --NR.sup.d R.sup.e (c.sup.3) --CH.sub.2 --S--Het (c.sup.4) in which R.sup.b represents lower alkoxy or amino, R.sup.c represents lower alkyl, phenyl or amino, R.sup.d and R.sup.e each independently represent hydrogen or lower alkyl or R.sup.d and R.sup.e together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen, oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and pharmaceutically compatible salts of these compounds. The products have .beta.-lactamase inhibiting properties. They are useful in combination with .beta.-lactam antibiotics in the control of .beta.-lactamase forming pathogens.

  该文描述了以下式子的化合物：##STR1## 其中R表示低烷氧羰基，低烷氧羰基氨基，α-或β-氨基酸的酰基残基或一般式Q-X-Y-的残基(a)，其中Q表示含有氮、硫和/或氧的3-至6-环，可以与融合环相结合，X表示直接键或由碳、氮、氧和/或硫组成的长达6个原子的线性“间隔物”，其中最多有2个原子可以是氮原子，1个原子可以是氧或硫，Y代表--CO--、--CS--、--CONH--和（当X不含硫或羰基作为末端组分时）--SO.sub.2--中的一种基团；其中R.sup.1表示氢、卤素、氨基甲酸酯氧、低烷酰氧或公式--S--Het的基团，其中Het表示含有氮、硫和/或氧的5-或6-成员杂环芳基基团，R.sup.2表示磺酰基--SO.sub.3H或R.sup.1和R.sup.2在一起表示公式##STR2##其中A表示氢或可用于头孢菌素类抗生素的3位的残基，R.sup.3表示氢或R.sup.1和R.sup.3在一起表示公式.dbd.CH--R