(6R,7S)-3-(acetoxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 95570-59-5

• 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: (6R,7S)-3-(acetoxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
• 英文别名: 3-Acetoxymethyl-7alpha-methoxy-3-cephem-4-carboxylic acid；(6R,7S)-3-(acetyloxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
• CAS: 95570-59-5
• 化学式: C₁₁H₁₃NO₆S
• 分子量: 287.293
• InChiKey: VBHGLWPMGRSASA-WCBMZHEXSA-N

物化性质

• 沸点：
  535.9±50.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (6R,7S)-3-(acetoxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 在 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 生成 tert-butyl 2-[[(6R,7S)-3-(acetyloxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbonyl]-methylamino]acetate
  参考文献：
  名称：

  Inhibition of human leukocyte elastase. 4. Selection of a substituted cephalosporin (L-658,758) as a topical aerosol

  摘要：

  Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases. The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical activity in an in vivo hamster lung hemorrhage model. While the most potent in vitro HLE inhibition had previously been obtained with lipophilic ester derivatives, it was found that the less active, but more polar and stable, amide derivatives were much more effective in vivo. The development of the structure-activity relations for optimization of these activities is discussed. These results led to the selection of 3-(acetoxymethyl)-2-[(2(S)-carboxypyrrolidino)carbonyl]-7alpha-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5,5-dioxide (3, L-658,758) as a selective, potent, time-dependent HLE inhibitor suitable for formulation as a topical aerosol drug for possible clinical use.

  DOI：

  10.1021/jm00099a002
• 作为产物：
  描述：

  7-苯乙酰氨基-3-氯甲基-4-头孢烷酸对甲氧基苄酯 在 吡啶 、 三异丙基硅烷 、 五氯化磷 、 硫酸 、 三氟乙酸 、 sodium iodide 、 sodium nitrite 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.67h， 生成 (6R,7S)-3-(acetoxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  参考文献：
  名称：

  立体化学改变的头孢菌素作为新德里金属-β-内酰胺酶的有效抑制剂

  摘要：

  由β-内酰胺酶，特别是金属-β-内酰胺酶引起的抗生素耐药性已成为全球公共卫生的主要威胁。新德里金属-β-内酰胺酶-1 (NDM-1) 是最重要的金属-β-内酰胺酶之一；细菌病原体中 NDM-1 的产生显着降低了 β-内酰胺类抗生素的功效，包括挽救生命的碳青霉烯类抗生素。在这里，我们已经证明了立体化学改变的头孢菌素作为针对 NDM-1 的有效抑制剂，以及 NDM 的突变体。对 20 多种头孢菌素类似物的结构和活性关系 (SAR) 研究表明，头孢菌素的立体化学和 7 位和 3' 位的取代基对抑制 NDM-1 的活性至关重要，最佳化合物1u的 IC为 500.13 μM。此外，已经获得了NDM-1和1u的晶体复合物，表明这种头孢菌素衍生物通过形成相对稳定的水解产物-NDM-1中间体来抑制酶活性。这项研究的发现可能为将头孢菌素（β-内酰胺酶的天然底物）转化为有效的 NDM-1 抑制剂以对抗抗生素耐药性铺平道路。

  DOI：

  10.1016/j.ejmech.2022.114174

文献信息

• [EN] INTERLEUKIN CONVERTING ENZYME AND APOPTOSIS<br/>[FR] ENZYME DE CONVERSION D'INTERLEUKINES ET APOPTOSE
  申请人：SMITHKLINE BEECHAM CORPORATION

  公开号：WO1997007805A1

  公开（公告）日：1997-03-06

  (EN) The present invention is to the novel compounds of Formula (I), their pharmaceutical compositions, and to the novel inhibition of ICE and ICE-like proteins for use in the treatment of apoptosis, and disease states caused by excessive or inappropriate cell death.(FR) L'invention concerne des composés nouveaux de formule (I), leurs compositions pharmaceutiques et une inhibition nouvelle de protéines de l'enzyme de conversion d'interleukines et de protéines analogues à l'enzyme de conversion d'interleukines destinées à être utilisées pour traiter l'apoptose et les états pathologiques causés par une mort cellulaire excessive ou inappropriée.

  该发明涉及化合物式(I)的新型化合物、它们的药物组合物以及用于治疗由过度或不适当的细胞死亡引起的凋亡和疾病状态的新型ICE和类ICE蛋白的抑制。
• Tetrazolyl derivatives of .beta.-lactams useful as elastase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US04699904A1

  公开（公告）日：1987-10-13

  Tetrazolyl derivatives of .beta.-lactams are found to be potent elastase inhibitors and thereby useful anti-inflammatory/antidegenerative agents.

  四唑衍生物的β-内酰胺被发现是有效的弹性蛋白酶抑制剂，因此是有用的抗炎/抗退化剂。
• Tetrazolyl derivatives of beta-lactams useful as elastase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US04845088A1

  公开（公告）日：1989-07-04

  Tetrazolyl derivatives of .beta.-lactams are found to be potent elastase inhibitors and thereby useful anti-inflammatory/antidegenerative agents.

  四唑基衍生物的β-内酰胺被发现是有效的弹性蛋白酶抑制剂，因此是有用的抗炎/抗退行性药物。
• Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides
  作者：Paul E. Finke、Bonnie M. Ashe、Wilson B. Knight、Alan L. Maycock、Manuel A. Navia、Shrenik K. Shah、Kevan R. Thompson、Dennis J. Underwood、Hazel Weston

  DOI：10.1021/jm00171a029

  日期：1990.9

  A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.
• Reactions of cephalosporin sulphones 1. Rearrangement of the β-lactam ring to a triazole derivative
  作者：Tamás E Gunda、László Tamás、Szabolcs Sályi

  DOI：10.1016/s0040-4039(98)00358-x

  日期：1998.5

  The 7 beta-amino-cephalosporin sulphones, generated in situ from the appropriate 7 beta-tBoc-amino derivative and diazotized in a one-pot reaction in aq. HClO4 - MeOH - NaNO2, rearrange exclusively to the triazoles 5 in a multistep reaction. (C) 1998 Elsevier Science Ltd. All rights reserved.