t-butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate | 95570-83-5

• 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: t-butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate
• 英文别名: tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate；3-Acetoxymethyl-7-methoxy-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester；tert-butyl (6R,7S)-3-(acetyloxymethyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 95570-83-5
• 化学式: C₁₅H₂₁NO₆S
• 分子量: 343.401
• InChiKey: VGRZYXLVWWCRRJ-WCQYABFASA-N

物化性质

• 熔点：
  66-68 °C
• 沸点：
  495.8±45.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  t-butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate 在 吡啶 、 titanium(IV) isopropylate 、 氯化亚砜 、 碳酸氢钠 、 苯甲醚 、 间氯过氧苯甲酸 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 异丙醇 、 丙酮 为溶剂， 反应 21.0h， 生成 3-({[(6R,7S)-7-甲氧基-5,5-二羟基-8-羰基-2-(吡咯烷-1-基羰基)-5-硫杂-1-氮杂二环[4.2.0]辛-2-烯-3-基]甲基}硫烷基)-2-甲基-1,2-二氢-1,2,4-三嗪-5,6-二酮
  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：

  tert-butyl 3-(acetyloxymethyl)-7-diazo-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 在 N-溴代丁二酰亚胺(NBS) 、 ammonium acetate 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 t-butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate
  参考文献：
  名称：

  Inhibition of human leukocyte elastase. 1. Inhibition by C-7-substituted cephalosporin tert-butyl esters

  摘要：

  Time-dependent inhibitors of the enzyme human leukocyte elastase have been developed based on the cephem nucleus. A series of cephalosporin tert-butyl esters has been examined, and the activity of these compounds has been found to be very sensitive to C-7 substituents, with small, alpha-oriented, electron-withdrawing groups showing greatest activity. Additionally, the oxidation state of the sulfur atom has been found to play a role in potency, with sulfones showing considerably greater activity than the corresponding sulfides or beta-sulfoxides. The alpha-sulfoxides were inactive.

  DOI：

  10.1021/jm00171a028

文献信息

• 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.
• Inhibition de l'élastase leucocytaire humaine: inhibition par des céphalosporines sulfones substituées sur le C-2
  作者：W Hagmann

  DOI：10.1016/0223-5234(89)90027-5

  日期：1989.12
• Inhibition of human leukocyte elastase. 3. Synthesis and activity of 3'-substituted cephalosporins
  作者：Shrenik K. Shah、Karen A. Brause、Gilbert O. Chandler、Paul E. Finke、Bonnie M. Ashe、Hazel Weston、Wilson B. Knight、Alan L. Maycock、James B. Doherty

  DOI：10.1021/jm00171a030

  日期：1990.9

  Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate. A method was also developed to prepare a 3-vinylcephalosporin. Some of these compound were found to be potent time-dependent inhibitors of human leukocyte elastase (HLE). The HLE inhibitory activity was correlated with sigma 1 and it was concluded that the potency was determined by the electron-withdrawing ability as well as the size of the substituent. A mechanism for inhibition of HLE by cephalosporin sulfones is proposed.