(8-methoxycarbonyloxy-1,3-benzoxazine-2,4-dione-3-yl)acetyl chloride | 212777-29-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: (8-methoxycarbonyloxy-1,3-benzoxazine-2,4-dione-3-yl)acetyl chloride
• 英文别名: (8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazin-3-yl)-acetyl chloride；(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazin-3-yl)-acetyl-chlorid；[3-(2-chloro-2-oxoethyl)-2,4-dioxo-1,3-benzoxazin-8-yl] methyl carbonate
• CAS: 212777-29-2
• 化学式: C₁₂H₈ClNO₇
• 分子量: 313.651
• InChiKey: AFWXGZOONSBEBI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  99.2
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (8-methoxycarbonyloxy-1,3-benzoxazine-2,4-dione-3-yl)acetyl chloride 在 N-甲基吗啉 、 碳酸氢钠 、 三乙胺 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 4.0h， 生成 N-{[3,5-N',N''-bis-(8-methoxycarbonyloxy-1,3-benzoxazine-2,4-dione-3-yl)acetylamino]benzoyl}ampicillin
  参考文献：
  名称：

  Highly Antibacterial Active Aminoacyl Penicillin Conjugates with Acylated Bis-Catecholate Siderophores Based on Secondary Diamino Acids and Related Compounds

  摘要：

  New acylated bis-catecholates and 1,3-benzoxazine-2,4-dione derivatives based on secondary diamino acids (N-(aminoalkyl)glycines, N-aminopropyl-alanine, and N-aminopropyl-4-amino-valeric acid), on N-(aminoalkyl)aminomethyl benzoic acids, on N-(aminoalkyl)aminomethyl phenoxyacetic acids, or on 3,5-diaminobenzoic acid were synthesized as artificial siderophores. The corresponding diamino acids were obtained from the diamines and oxocarboxylic acids by catalytic hydrogenation. The acylated bis-catecholates and 1,3-benzoxazine-2,4-diones were coupled with ampicillin or amoxicillin to new siderophore aminoacylpenicillin conjugates. These conjugates exhibited very strong antibacterial activity in vitro against Gram-negative bacterial pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens. The ampicillin derivative 7b (HKI 9924154) and the corresponding amoxicillin derivative 8 (HKI 9924155) represent the most active compounds. The conjugates can use bacterial iron siderophore uptake routes to penetrate the Gram-negative outer membrane permeability barrier. This was demonstrated by assays with mutants deficient in components of the iron transport systems. New siderophore penicillin V conjugates with the siderophore component attached to the phenyl ring of penicillin V are inactive against these Gram-negative bacteria.

  DOI：

  10.1021/jm010546b
• 作为产物：
  描述：

  苯甲酸,二羟基- 在 sodium hydroxide 、 五氯化磷 、 碳酸氢钠 作用下， 以 四氢呋喃 、 四氯化碳 、 水 为溶剂， 反应 1.17h， 生成 (8-methoxycarbonyloxy-1,3-benzoxazine-2,4-dione-3-yl)acetyl chloride
  参考文献：
  名称：

  Wittmann; Scherlitz-Hofmann; Mollmann, Arzneimittel-Forschung/Drug Research, 2000, vol. 50, # 8, p. 752 - 757

  摘要：

  DOI：

文献信息

• Benzoxazinedione derivatives, method of producing them and uses thereof
  申请人：Gruenenthal GmbH

  公开号：US06013647A1

  公开（公告）日：2000-01-11

  This invention relates to new benzoxazinedione derivatives corresponding to the formula I: ##STR1## wherein R.sup.1 =H or carboxyalkyl, R.sup.2 =H, alkyl or phenyl, and R.sup.3 represents different acid groups derived from amino acids, dipeptides and hydrazones or conjugates thereof with active ingredients, e.g. antibiotics. The compounds may be present as free acids, in the form of their salts or as readily cleavable esters. The compounds according to the invention constitute heterocyclically protected catechol derivatives and are effective as siderophores against gram-negative bacterial strains, particularly against Pseudomonads and strains of E. coli and Salmonella. In the form of their conjugates with active ingredients, e.g. antibiotics (as "siderophore-antibiotic conjugates"), they can transport the latter into bacterial cells and can improve or extend the antibacterial effect thereof, sometimes even in relation to bacterial strains which are resistant to other .beta.-lactams. In addition, said compounds, as potential prodrug forms for iron chelating agents, are suitable for use against diseases which are caused by a disorder of the iron metabolism. The invention can be employed in pharmaceutical research and in the pharmaceutical industry, and in agriculture.

  该发明涉及与以下式I对应的新苯并噁唑二酮衍生物：##STR1## 其中R.sup.1=H或羧基烷基，R.sup.2=H、烷基或苯基，而R.sup.3代表源自氨基酸、二肽和醛腙或其与活性成分（如抗生素）的结合物的不同酸基。这些化合物可以以游离酸的形式存在，也可以以其盐的形式或易于水解的酯的形式存在。根据本发明的化合物构成了杂环保护的邻苯二酚衍生物，对革兰氏阴性细菌株，特别是对铜绿假单胞菌和大肠杆菌和沙门氏菌株具有有效作用。作为与活性成分（例如抗生素）结合物的形式（如“铁载体-抗生素结合物”），它们可以将后者运送到细菌细胞内，并可以改善或延长其抗菌作用，有时甚至相对于对其他β-内酰胺类抗生素具有耐药性的细菌株。此外，所述化合物作为铁螯合剂的潜在前药形式，适用于用于对抗由铁代谢紊乱引起的疾病。该发明可应用于制药研究、制药工业和农业中。
• Neue Benzoxazindionderivate, Verfahren zu ihrer Herstellung und ihre Verwendung
  申请人：Grünenthal GmbH

  公开号：EP0863139A1

  公开（公告）日：1998-09-09

  Die Erfindung betrifft neue Benzoxazindionderivate der allgemeinen Formel I, und deren Konjugate mit Wirkstoffen, z B. Antibiotika. Die erfindungsgemäßen Verbindungen stellen heterocyclisch geschützte Catecholderivate dar und sind bei gramnegativen Bakterienstämmen, insbesondere Pseudomonaden, E.coli- und Salmonella-Stämmen, als Siderophore wirksam. Sie können in Form ihrer Konjugate mit Wirkstoffen, z. B. Antibiotika (als "Siderophor-Antibiotikakonjugate") diese in Bakterienzellen einschleusen und deren antibakterielle Wirksamkeit verbessern bzw. erweitern, z. T. auch bei gegenüber anderen β-Laktamen resistenten Bakterienstämmen. Außerdem sind die genannten Verbindungen als potentielle Prodrugformen für Eisenchelatoren geeignet zur Verwendung bei Erkrankungen, die auf einer Störung des Eisenstoffwechsels beruhen. Die Anwendung der Erfindung kann in der pharmazeutischen Forschung, Industrie und Landwirtschaft erfolgen. Formel I: wobei R1 = H oder Carboxyalkyl, R2 = H, Alkyl oder Phenyl und R3 = verschiedene, von Aminosäuren, Dipeptiden und Hydrazonen abgeleitete Säuregruppen bzw. deren Konjugate mit Wirkstoffen, z. B. Antibiotika bedeuten. Die genannten Verbindungen können als freie Säuren, in Form ihrer Salze oder als leicht spaltbare Ester vorliegen.

  本发明涉及通式 I 的新苯并噁嗪二酮衍生物及其与活性物质（如抗生素）的共轭物。本发明的化合物是杂环保护的儿茶酚衍生物，在革兰氏阴性细菌菌株，特别是假单胞菌、大肠杆菌和沙门氏菌菌株中作为嗜苷酸盐有效。以它们与活性物质（如抗生素）共轭的形式（作为 "嗜苷酸盐-抗生素共轭物"），它们可以将这些活性物质引入细菌细胞，改善或增强其抗菌功效，在某些情况下，甚至可以改善对其他β-内酰胺类药物产生抗药性的细菌菌株的抗菌功效。此外，上述化合物还可作为铁螯合剂的潜在原药形式，用于治疗基于铁代谢紊乱的疾病。本发明可用于医药研究、工业和农业。 式 I： 其中 R1 = H 或羧烷基，R2 = H、烷基或苯基，R3 = 由氨基酸、二肽和酰肼或它们与活性物质（如抗生素）的共轭物衍生的各种酸基。上述化合物可以游离酸、盐或易裂解酯的形式存在。
• Benzoxazindionderivate, Verfahren zu ihrer Herstellung und ihre Verwendung
  申请人：Grünenthal GmbH

  公开号：EP0863139B1

  公开（公告）日：2001-03-28
• US6013647A
  申请人：——

  公开号：US6013647A

  公开（公告）日：2000-01-11
• Highly Antibacterial Active Aminoacyl Penicillin Conjugates with Acylated Bis-Catecholate Siderophores Based on Secondary Diamino Acids and Related Compounds
  作者：Lothar Heinisch、Steffen Wittmann、Thomas Stoiber、Albrecht Berg、Dorothe Ankel-Fuchs、Ute Möllmann

  DOI：10.1021/jm010546b

  日期：2002.7.1

  New acylated bis-catecholates and 1,3-benzoxazine-2,4-dione derivatives based on secondary diamino acids (N-(aminoalkyl)glycines, N-aminopropyl-alanine, and N-aminopropyl-4-amino-valeric acid), on N-(aminoalkyl)aminomethyl benzoic acids, on N-(aminoalkyl)aminomethyl phenoxyacetic acids, or on 3,5-diaminobenzoic acid were synthesized as artificial siderophores. The corresponding diamino acids were obtained from the diamines and oxocarboxylic acids by catalytic hydrogenation. The acylated bis-catecholates and 1,3-benzoxazine-2,4-diones were coupled with ampicillin or amoxicillin to new siderophore aminoacylpenicillin conjugates. These conjugates exhibited very strong antibacterial activity in vitro against Gram-negative bacterial pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens. The ampicillin derivative 7b (HKI 9924154) and the corresponding amoxicillin derivative 8 (HKI 9924155) represent the most active compounds. The conjugates can use bacterial iron siderophore uptake routes to penetrate the Gram-negative outer membrane permeability barrier. This was demonstrated by assays with mutants deficient in components of the iron transport systems. New siderophore penicillin V conjugates with the siderophore component attached to the phenyl ring of penicillin V are inactive against these Gram-negative bacteria.