(Z)-tert-butyl 2-(((1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethylidene)amino)oxy)-2-methylpropanoate | 1229937-12-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (Z)-tert-butyl 2-(((1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethylidene)amino)oxy)-2-methylpropanoate
• 英文别名: (Z)-2-(((1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid tert-butyl ester；tert-butyl 2-[({(1Z)-1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethylidene}amino)oxy]-2-methylpropanoate；tert-butyl 2-[(Z)-[2-(2,5-dioxopyrrolidin-1-yl)oxy-1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoethylidene]amino]oxy-2-methylpropanoate
• CAS: 1229937-12-5
• 化学式: C₂₂H₃₀N₄O₉S
• 分子量: 526.568
• InChiKey: QPNYFMRIFMTNPR-MYYYXRDXSA-N

物化性质

• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  191
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (Z)-tert-butyl 2-(((1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethylidene)amino)oxy)-2-methylpropanoate 在 盐酸 、 4-二甲氨基吡啶 、 三氧化硫 N,N-二甲基甲酰胺络合物 、 palladium on activated charcoal 、 氢气 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 0.5h， 生成 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((3-((1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl)ureido)methyl)-4-oxo-1-sulfoazetidin-3-yl)-amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid
  参考文献：
  名称：

  能够合成Monobactam 1以便早期开发的过程

  摘要：

  的有效方法合成单酰胺菌素1从中间体2，3和4被开发。该方法最初能够提供500克1进行探索性毒性研究，并进一步改进以促进千克规模的活性药物成分的生产，并提高了质量和产量。该方法的重点包括利用1,1'-羰基二咪唑构建具有良好选择性的尿素接头，氧化裂解以去除2,4-二甲氧基苄基保护基，两种活化方法形成酰胺键，高产率的反应引入N-磺酸部分，并进行整体脱保护以除去所有保护基。通过将浓缩的底物添加到抗溶剂中以部分纯化获得可过滤的无定形固体，开发了在途中分离中间体的实用程序。Amberchrom CG161M树脂不仅用作“树脂捕获释放”工具以去除大量的水，而且还作为一种有效的提纯方法1。最后，过程中分离1五水合物（1·5H 2 O）从酸性水溶液中结晶固体，基于两性离子结晶的方法显影。

  DOI：

  10.1021/acs.oprd.9b00374
• 作为产物：
  描述：

  N-羟基丁二酰亚胺 、 (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid 在 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 以85%的产率得到(Z)-tert-butyl 2-(((1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethylidene)amino)oxy)-2-methylpropanoate
  参考文献：
  名称：

  能够合成Monobactam 1以便早期开发的过程

  摘要：

  的有效方法合成单酰胺菌素1从中间体2，3和4被开发。该方法最初能够提供500克1进行探索性毒性研究，并进一步改进以促进千克规模的活性药物成分的生产，并提高了质量和产量。该方法的重点包括利用1,1'-羰基二咪唑构建具有良好选择性的尿素接头，氧化裂解以去除2,4-二甲氧基苄基保护基，两种活化方法形成酰胺键，高产率的反应引入N-磺酸部分，并进行整体脱保护以除去所有保护基。通过将浓缩的底物添加到抗溶剂中以部分纯化获得可过滤的无定形固体，开发了在途中分离中间体的实用程序。Amberchrom CG161M树脂不仅用作“树脂捕获释放”工具以去除大量的水，而且还作为一种有效的提纯方法1。最后，过程中分离1五水合物（1·5H 2 O）从酸性水溶液中结晶固体，基于两性离子结晶的方法显影。

  DOI：

  10.1021/acs.oprd.9b00374

文献信息

• MONOCARBAMS
  申请人：Brickner Steven Joseph

  公开号：US20100160281A1

  公开（公告）日：2010-06-24

  The invention relates to compounds of formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 as defined herein. The invention also relates to pharmaceutical compositions and methods of treating bacterial infections using compounds of formula (I).

  这项发明涉及式(I)的化合物： 其中R1，R2，R3，R4，R5和R6如本文所定义。该发明还涉及使用式(I)的化合物治疗细菌感染的药物组合物和方法。
• [EN] MONOBACTAMS<br/>[FR] MONOBACTAMES
  申请人：PFIZER

  公开号：WO2012073138A1

  公开（公告）日：2012-06-07

  The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.

  本发明涉及一类新的单环内酰胺衍生物及其用于治疗细菌感染的用途。
• Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity
  作者：Matthew F. Brown、Mark J. Mitton-Fry、Joel T. Arcari、Rose Barham、Jeffrey Casavant、Brian S. Gerstenberger、Seungil Han、Joel R. Hardink、Thomas M. Harris、Thuy Hoang、Michael D. Huband、Manjinder S. Lall、M. Megan Lemmon、Chao Li、Jian Lin、Sandra P. McCurdy、Eric McElroy、Craig McPherson、Eric S. Marr、John P. Mueller、Lisa Mullins、Antonia A. Nikitenko、Mark C. Noe、Joseph Penzien、Mark S. Plummer、Brandon P. Schuff、Veerabahu Shanmugasundaram、Jeremy T. Starr、Jianmin Sun、Andrew Tomaras、Jennifer A. Young、Richard P. Zaniewski

  DOI：10.1021/jm400560z

  日期：2013.7.11

  Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monohactam analogues with in vitro, antibacterial activity against clinically relevant Grain-negative species including Pseuedomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with,compound 17 demonstrate low clearance and low plasma protein binding. In addition evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
• SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of <i>Pseudomonas aeruginosa</i> PBP3
  作者：Kerry E. Murphy-Benenato、Brian Dangel、Hajnalka E. Davis、Thomas F. Durand-Réville、Andrew D. Ferguson、Ning Gao、Haris Jahić、John P. Mueller、Erika L. Manyak、Olga Quiroga、Michael Rooney、Li Sha、Mark Sylvester、Frank Wu、Mark Zambrowski、Shannon X. Zhao

  DOI：10.1021/acsmedchemlett.5b00026

  日期：2015.5.14

  A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-beta-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.
• Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria
  作者：Jeremy Starr、Matthew F. Brown、Lisa Aschenbrenner、Nicole Caspers、Ye Che、Brian S. Gerstenberger、Michael Huband、John D. Knafels、M. Megan Lemmon、Chao Li、Sandra P. McCurdy、Eric McElroy、Mark R. Rauckhorst、Andrew P. Tomaras、Jennifer A. Young、Richard P. Zaniewski、Veerabahu Shanmugasundaram、Seungil Han

  DOI：10.1021/jm500219c

  日期：2014.5.8

  Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drugtarget interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and beta-lactam core structures. Results from drug sensitivity studies with beta-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.