RO 481256 | 197702-36-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: RO 481256
• 英文别名: (1S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid
• CAS: 197702-36-6
• 化学式: C₁₁H₁₈N₄O₅S
• 分子量: 318.354
• InChiKey: RCBJACYFANFNGP-BDAKNGLRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-benzylpiperidin-4-ylcarbamic acid 2,5-dioxopyrrolidin-1-yl ester 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 生成 RO 481256
  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

• Process for the preparation of 2-(primary/secondary amino)hydrocarbyl)-carbamoyl-7-oxo-2,6-diaza-bicyclo [3.2.0.]heptane-6-sulfonic acid derivatives
  申请人：Desarbe Eric

  公开号：US20100305315A1

  公开（公告）日：2010-12-02

  A process for the production of a compound of formula (I) wherein A LINKER B represents a linker moiety of formula (V): A [G1-G2*-G3] B ; wherein A and B indicate the orientation of the group of formula (V) in formula (I); G1, G2 and G3 have specific meanings described herein and may be present or absent, with the proviso that at least one of G1 or G3 is present; which linker group may furthermore optionally contain one or more groups of formula (VI); and/or other substituents; and R1 represents hydrogen or a C 1 -C 4 -alkyl group; R2 represents hydrogen or a C 1 -C 4 -alkyl group; R3 independently at each occurrence, represents hydrogen or a C 1 -C 4 -alkyl group; x is 0 or 1; y is 0 or 1; z independently at each occurrence, is 0 or 1; and (—) represents a single bond between a primary, secondary or tertiary carbon atom of the moiety A LINKER B and the adjacent nitrogen atom; in which process (A) a compound of formula (II) is reacted with a compound of formula (III) wherein Pr represents an amino protecting group selected from t-butyloxy carbonyl (t-Boc), 1-methyl-1-(4-biphenylyl)ethyloxy carbonyl (Bpoc), 1-(1-adamantyl)-1-methylethyloxy carbonyl (Adpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyloxy carbonyl (t-Bumeoc), 1-adamantyloxy carbonyl (Adoc), p-methoxybenzyloxy carbonyl (Moz), o,p-dimethoxybenzyloxy carbonyl, A LINKER B has the same meaning as in formula (I) with the exception that one or more of the optional groups of formula (VII) may be replaced by a group of formula (VII) and R1; R2; R3; x; y; z and (—), at each occurrence, have the same meaning as in formula (I) and Pr is as defined above; in a dipolar aprotic solvent in the presence of a base to obtain a compound of formula (IV) wherein Pr; A LINKER B ; R1; R2; R3; x; y; z; and (—), at each occurrence, have the same meaning as in formula (III); which compound is then (B) deprotected by reaction with formic acid or a mixture of formic acid or acetic acid with hydrochloric acid or hydrobromic acid, to give the compound of formula (I) as well as the compounds of the aforementioned formula (IV).
• 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.