benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate | 145574-15-8

• 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: benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate
• 英文别名: benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate；Benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate；benzyl (1S,5R)-6-[(3,4-dimethoxyphenyl)methyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate
• CAS: 145574-15-8
• 化学式: C₂₂H₂₄N₂O₅
• 分子量: 396.443
• InChiKey: ROVQOWHXQWMMTI-XLIONFOSSA-N

物化性质

• 沸点：
  594.1±50.0 °C(Predicted)
• 密度：
  1.285±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  68.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate 在 palladium on activated charcoal 4-二甲氨基吡啶 、 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 、 水 、 乙腈 为溶剂， 反应 6.0h， 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：

  benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate 在 吡啶 、 sodium tetrahydroborate 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo<3.2.0>heptane-2-carboxylate
  参考文献：
  名称：

  用于合成疫苗设计和优化的病毒体模拟表位方法：潜在疟疾疫苗候选者的合成，构象和免疫识别。

  摘要：

  DOI：

  10.1002/anie.200250348

文献信息

• Compositions of bicyclic .beta.-lactams and uses thereof
  申请人：Hoffmann-La Roche Inc.

  公开号：US05698577A1

  公开（公告）日：1997-12-16

  There are described pharmaceutical compositions comprising (a) compounds of the formula ##STR1## in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, 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 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 (b) a therapeutically effective amount of a .beta.-lactam antibiotics or their pharmaceutically compatible salts; and a pharmaceutically compatible carrier and pharmaceutically compatible salts of these compounds. The combination is useful in the control or prevention of illnesses caused by .beta.-lactamase forming pathogens.

  描述了一种制药组合物，包括(a)式中的化合物##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Q-X-Y-（a）的一般式残基，其中Q表示一个3-6环的环，该环可以选择性地包含氮，硫和/或氧，并且可以与融合环连接，X表示直接键或具有最多6个由碳，氮，氧和/或硫组成的线性“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表示--CO--，--CS--，--CONH--和（当X不含硫或羰基作为末端组分时）--SO.sub.2--的一种基团; R.sup.1表示氢，卤素，氨基甲酰氧，低烷酰氧或式--S--Het的基团，其中Het表示一个含有氮，硫和/或氧的5-或6-环杂芳基团，R.sup.2表示磺酰基--SO.sub.3H，R.sup.3表示氢或R.sup.1和R.sup.3共同表示式.dbd.CH--R.sup.a（c）的基团，其中R.sup.a表示以下基团之一--COR.sup.b（c.sup.1）--CH.sub.2--OCOR.sup.c（c.sup.2）--CH.sub.2--NR.sup.dR.sup.e（c.sup.3）--CH.sub.2--S--Het（c.sup.4），其中R.sup.b表示低烷氧基或氨基，R.sup.c表示低烷基，苯基或氨基，R.sup.d和R.sup.e各自独立地表示氢或低烷基，或R.sup.d和R.sup.e与它们连接的N原子一起表示5-或6-环N-杂环，该杂环可以选择性地包含进一步的氮，氧或硫原子，Het表示一个含有氮，硫和/或氧的5-或6-环杂芳基团;（b）β-内酰胺类抗生素或其药学兼容盐的治疗有效量;以及药学兼容载体和这些化合物的药学兼容盐。该组合物在控制或预防由β-内酰胺酶形成的病原体引起的疾病方面很有用。
• Compositions of tricyclic .beta.-lactams and uses thereof
  申请人：Hoffmann-La Roche Inc.

  公开号：US05712268A1

  公开（公告）日：1998-01-27

  There are described pharmaceutical compositions comprising (a) compounds of the formula ##STR1## in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, 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 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.sub.3 represents hydrogen, or their pharmaceutically compatible salts; and (b) a therapeutically effective amount of a .beta.-lactam antibiotic or their pharmaceutically compatible salts; and a pharmaceutically acceptable carrier. The combination is useful in the control or prevention of illnesses caused by .beta.-lactamase forming pathogens.

  描述了一种含有以下化合物（a）的制药组合物：##STR1## 其中，R表示较低的烷氧羰基，较低的烷氧羰基氨基，α-或β-氨基酸的酰基残基或Q--X--Y--（a）一般公式的残基，其中Q表示一个3至6个成员的环，该环可选地含有氮，硫和/或氧，并且可选地与融合的环相结合，X表示直接键或由碳，氮，氧和/或硫组成的最多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，而Y代表--CO--，--CS--，--CONH--和（其中X不包含硫或羰基作为末端组分）--SO.sub.2--中的一种基团;并且其中R.sup.1和R.sup.2一起表示以下式子的基团：##STR2## 其中A表示氢或可用于头孢菌素类抗生素的3位，而R.sub.3表示氢，或其药学上相容的盐;以及（b）β-内酰胺抗生素或其药学上相容的盐的治疗有效量;和药学上可接受的载体。该组合物在控制或预防由β-内酰胺酶形成病原体引起的疾病中有用。
• Bicyclic and tricyclic &bgr;-lactams
  申请人：Hoffmann-La Roche Inc.

  公开号：US06566355B1

  公开（公告）日：2003-05-20

  There are described compounds of the formula in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, the acyl residue of an &agr;- or &bgr;-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, sulfur 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 sulfur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulfur, and Y represents one of the groups —CO—, —CS—, —CONH— and (where X contains neither sulfur nor carbonyl as a terminal component) —SO2—; and in which R1 and R2 together signify a group of the formula wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R3 represents hydrogen, and pharmaceutically compatible salts of these compounds. The products have &bgr;-lactamase inhibiting properties. They are useful in combination with &bgr;-lactam antibiotics in the control of &bgr;-lactamase forming pathogens.

  描述了一种化合物的公式，其中R表示较低的烷氧羰基，较低的烷氧羰基氨基，α-或β-氨基酸的酰基残基或一般公式Q-X-Y-的残基（a），其中Q表示可选地含有氮，硫和/或氧的3-至6-成员环，可选地与融合环连接，X表示直接键或最多由碳，氮，氧和/或硫组成的长达6个原子的线性“间隔物”，其中最多可以有2个氮原子和1个氧或硫原子，而Y代表其中一组- CO-，-CS-，-CONH-和（当X不包含硫或羰基作为末端组分时）-SO2-；其中R1和R2一起表示公式的一个基团，其中A表示氢或可用于头孢菌素类抗生素的3位，而R3表示氢，并且这些化合物的药物兼容盐。这些产品具有β-内酰胺酶抑制性能。它们在与β-内酰胺类抗生素结合使用时对β-内酰胺酶形成病原体的控制中很有用。
• 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.
• A Virosome-Mimotope Approach to Synthetic Vaccine Design and Optimization: Synthesis, Conformation, and Immune Recognition of a Potential Malaria-Vaccine Candidate
  作者：Bernhard Pfeiffer、Elisabetta Peduzzi、Kerstin Moehle、Rinaldo Zurbriggen、Reinhard Glück、Gerd Pluschke、John A. Robinson

  DOI：10.1002/anie.200250348

  日期：2003.5.30