(7R,6R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(Z)-trityloxyimino-acetylamino]-3-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester | 258497-39-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (7R,6R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(Z)-trityloxyimino-acetylamino]-3-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
• CAS: 258497-39-1
• 化学式: C₅₇H₅₂ClN₇O₇S₄
• 分子量: 1110.8
• InChiKey: LIZYZVQAUWLEKQ-DWNIFQPTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.98
• 重原子数：
  76.0
• 可旋转键数：
  19.0
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  187.43
• 氢给体数：
  3.0
• 氢受体数：
  15.0

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 (7R,6R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(Z)-trityloxyimino-acetylamino]-3-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 在 三乙基硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以85%的产率得到(7R,6R)-3-[4-(2-amino-ethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(Z)-hydroxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid bis-trifluoroacetic acid bis-trifluoroacetate
  参考文献：
  名称：

  Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio)cephems. Discovery of RWJ-333441 (MC-04,546)

  摘要：

  SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC-I mug/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED50=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl-total=0.39 L/h/kg). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00431-5
• 作为产物：
  描述：

  (3-tritylsulfanyl-pyridin-4-yl)-methanol 在 三乙基硅烷 、 氯化亚砜 、 sodium methylate 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 6.5h， 生成 (7R,6R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(Z)-trityloxyimino-acetylamino]-3-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  参考文献：
  名称：

  Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio)cephems. Discovery of RWJ-333441 (MC-04,546)

  摘要：

  SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC-I mug/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED50=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl-total=0.39 L/h/kg). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00431-5