t-butyl 7α-methoxy-3-methyl-3-cephem-4-carboxylate 1,1-dioxide | 95671-89-9

• 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 7α-methoxy-3-methyl-3-cephem-4-carboxylate 1,1-dioxide
• 英文别名: (6R,7S)-7-methoxy-3-methyl-5,5,8-trioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester；tert-butyl (6R,7S)-7-methoxy-3-methyl-5,5,8-trioxo-5λ6-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 95671-89-9
• 化学式: C₁₃H₁₉NO₆S
• 分子量: 317.363
• InChiKey: OBNGIXNPNKMQKJ-GXSJLCMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  98.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  t-butyl 7α-methoxy-3-methyl-3-cephem-4-carboxylate 1,1-dioxide 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 苯 为溶剂， 以85%的产率得到tert-butyl 3-bromomethyl-7α-methoxy-3-cephem-4-carboxylate 1,1-dioxide
  参考文献：
  名称：

  New biological properties of tert-butyl cephalosporanate sulfones

  摘要：

  tert-Butyl cephalosporanate I,l-dioxides variously substituted in positions 7 and 3 were obtained from 7-aminodeacetoxycephalosporanic acid (7-ADCA) and 7-aminocephalosporanic acid (7 ACA). It was found that the cephalosporins containing Aspirin and Diclofenac in a prodrug form in their 3-acyloxymethyl moiety release them after hydrolytic splitting of the beta-lactam ring. They also demonstrated high efficacy as elastase inhibitors. Two of them stimulated the biosynthesis of nitric oxide in RAW 264.7 macrophages cells. The same effect observed in tumor and normal cells in the presence of cephalosporins was accompanied by cytotoxic effect in vitro. (C) Elsevier, Paris.

  DOI：

  10.1016/s0223-5234(99)80027-0
• 作为产物：
  描述：

  7-氨基-3-甲基-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-甲酸 在 sodium tungstate 、 亚硝酸异丙酯 、 三氟化硼乙醚 、 双氧水 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 53.0h， 生成 t-butyl 7α-methoxy-3-methyl-3-cephem-4-carboxylate 1,1-dioxide
  参考文献：
  名称：

  Synthesis and evaluation of dual action cephalosporins as elastase inhibitors

  摘要：

  tert-Butyl 7 alpha-chloro- and 7 alpha-methoxycephalosporanate 1,1-dioxides containing Aspirin and Diclofenac in their 3-acyloxymethyl moiety were synthesized. These dual action cephalosporins have been found to be potent elastase inhibitors and stimulators of NO biosynthesis in macrophages. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(97)00104-2

文献信息

• 4-SUBSTITUTED CEPHEM DERIVATIVES AS ELASTASE INHIBITORS
  申请人：——

  公开号：US20010011085A1

  公开（公告）日：2001-08-02

  The present invention relates to cephem-derivatives and to a process for their preparation, having proper substituents at C-2 position, i.e. heterocyclylthio or acyloxy group. They are potent protease inhibitors, in particular human leucocyte elastase (HLE) inhibitors. These inhibitors can be synthesised by way of a substitution reaction starting from known cephem compounds having a 2-position a suitable leaving group.

  本发明涉及头孢烯衍生物及其制备方法，该衍生物在C-2位具有适当的取代基，即杂环硫基或酰氧基。它们是强效的蛋白酶抑制剂，特别是人白细胞弹性蛋白酶（HLE）抑制剂。这些抑制剂可以通过从已知的头孢烯化合物开始，通过取代反应合成，该化合物在2位具有合适的离去基团。
• Cephem Sulfones as Inactivators of Human Leukocyte Elastase. 5. 7.alpha.-Methoxy- and 7.alpha.-Chloro-1,1-dioxocephem 4-Ketones
  作者：Marco Alpegiani、Pierluigi Bissolino、Riccardo Corigli、Stefano Del Nero、Ettore Perrone、Vincenzo Rizzo、Nereo Sacchi、Giuseppe Cassinelli、Giovanni Franceschi、Antonio Baici

  DOI：10.1021/jm00049a020

  日期：1994.11

  as inhibitors of human leukocyte elastase (HLE) have been extended to the new class of cephem 4-ketones. tert-Butyl and phenyl ketones were prepared from 4-carboxycephem derivatives, at either the sulfide or sulfone oxidation level, by chemoselective Grignard reaction. Obtained products were functionalized with heterocyclothio and acyloxy substituents at C-3', C-2, or both positions. tert-Butyl ketones

  作为人类白细胞弹性蛋白酶（HLE）抑制剂的头孢砜的研究已经扩展到新的头孢4-酮类。叔丁基和苯基酮是通过化学选择性的格氏反应从4-羧甲基苯丙氨酸衍生物以硫化物或砜的氧化水平制备的。将获得的产物在C-3'，C-2或两个位置上用杂环硫基和酰氧基取代基官能化。通常，在抑制酶方面，7α-氯乙苯系列的叔丁基酮至少与相应的酯一样有效，但是水解稳定性的改善仅是很小的。另一方面，7α-甲氧基头孢酮系列的叔丁基酮将强大的生化活性与可接受的水解稳定性结合在一起，从而超过了先前报道的酯，硫酯和酰胺。特别是，在C-3'或C-2处具有杂环硫基的叔丁基酮的活性至少与相应的叔丁基酯同等，但在生理缓冲液（pH 7.4，37摄氏度）中则稳定了一个数量级。在C-2处引入酰氧基提供了迄今为止报道的头孢烯类最有效的HLE抑制剂，其抑制参数通常超出了我们标准方案的测定范围（二级速率常数kon> 2,000,000 M-1 s-1； Ki稳态<2
• Synthesis and evaluation of new elastase inhibitors. I. 1,1-Dioxocephem-4-thiolesters
  作者：M Alpegiani、A Baici、P Bissolino、P Carminati、G Cassinelli、S Del Nero、G Franceschi、P Orezzi、E Perrone、V Rizzo、N Sacchi

  DOI：10.1016/0223-5234(92)90019-w

  日期：1992.12

  Several 7alpha-chloro and 7alpha-methoxy cephalosporin thiolester sulphones variously substituted at the C-3' position were synthesized from 7-amino-3-deacetoxycephalosporanic acid (7-ADCA). The compounds are time-dependent inhibitors of human leukocyte elastase (HLE) with effective K(i) ranging from micro- to nanomolar values, and second order rate constant reaching 10(6) M-1s-1; they also inhibit porcine pancreatic elastase with similar, though not identical efficiency. Compared to the corresponding cephem esters, the thiolesters of the 7-Cl series inhibit HLE up to 10 times as fast. Complete enzyme inactivation is achieved when a leaving group at C-3' (OAc or S-Het) is present, at the expense however of stability towards hydrolytic beta-lactam cleavage. In the 7-OMe series the thiolester compounds are far more stable and retain good efficiency for irreversible enzyme inhibition, superior to that displayed by the corresponding ester compounds. Three representative compounds (including one ester and two thiolesters) are shown to be effective inhibitors of HLE in the presence of insoluble elastin.
• Alpegiani, Marco; Bissolino, Pierluigi; Borghi, Daniela, Heterocycles, 1993, vol. 36, # 8, p. 1747 - 1762
  作者：Alpegiani, Marco、Bissolino, Pierluigi、Borghi, Daniela、Sbraletta, Pietro、Tonani, Roberto、Perrone, Ettore

  DOI：——

  日期：——
• Synthesis and human leukocyte elastase inhibitory activity of novel 2-spiro(2′,2′-diphenylcyclopropane) cephalosporin sulfones
  作者：Andhe V. Narender Reddy、Charles Y. Fiakpui、David P. Czajkowski、Paul Spevak、Jadwiga Kaleta、Ronald G. Micetich、Samarendra N. Maiti

  DOI：10.1007/bf02256809

  日期：1998.11