(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazol[5,1-b][1,3]oxazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2. 0]hept-2-ene-2-carboxylic acid sodium salt | 623931-96-4

• 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: (5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazol[5,1-b][1,3]oxazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2. 0]hept-2-ene-2-carboxylic acid sodium salt
• 英文别名: sodium;(5R,6Z)-6-(7,10-dioxa-2,3-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,5-trien-4-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
• CAS: 623931-96-4
• 化学式: C₁₅H₁₀N₃O₅S*Na
• 分子量: 367.317
• InChiKey: NRUCVQIWTLYXSP-LJYDOUJQSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -3.11
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  125
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-nitrobenzyl (5R)-6-[(acetyloxy)(7,8-dihydro-5H-pyrano[4,3]pyrazolo[5,1-b][1,3]oxazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 在 锌 、 sodium hydroxide 作用下， 以 四氢呋喃 、 phosphate buffer 、 乙腈 为溶剂， 反应 2.0h， 以25%的产率得到(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazol[5,1-b][1,3]oxazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2. 0]hept-2-ene-2-carboxylic acid sodium salt
  参考文献：
  名称：

  5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of β-lactamases

  摘要：

  beta-Lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging beta-lactamases. Bacterial production of diverse beta-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5, 5] [5, 6] and [5, 5, 5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum beta-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC beta-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.006

文献信息

• [EN] HETEROTRICYCLYL 6-ALKYLIDENE-PENEMS AS BetaEpsilonTauAlpha-LACTAMASE INHIBITORS<br/>[FR] DERIVES D'HETEROTRICYCLYL 6-ALKYLIDENE-PENEMES EN TANT QU'INHIBITEURS DE BETA-LACTAMASE
  申请人：WYETH CORP

  公开号：WO2003093280A1

  公开（公告）日：2003-11-13

  The present invention provides a compound of formula I, pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof.

  本发明提供了一种I式化合物，药物组合物以及其用于治疗患有细菌感染或疾病的患者的用途。
• 5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of β-lactamases
  作者：Aranapakam M. Venkatesan、Atul Agarwal、Takao Abe、Hideki Ushirogochi、Mihira Ado、Takasaki Tsuyoshi、Osvaldo Dos Santos、Zhong Li、Gerry Francisco、Yang I. Lin

  DOI：10.1016/j.bmc.2007.11.006

  日期：2008.2.15

  beta-Lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging beta-lactamases. Bacterial production of diverse beta-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5, 5] [5, 6] and [5, 5, 5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum beta-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC beta-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature. (c) 2007 Elsevier Ltd. All rights reserved.