(6R,7R)-7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-(Z)-trityloxyimino-acetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester | 331780-41-7

• 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: (6R,7R)-7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-(Z)-trityloxyimino-acetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester
• CAS: 331780-41-7
• 化学式: C₃₄H₃₁ClN₆O₅S₂
• 分子量: 703.242
• InChiKey: JDQWLDBASLCGPW-JKCCFDMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.03
• 重原子数：
  48.0
• 可旋转键数：
  9.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  149.1
• 氢给体数：
  2.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  (6R,7R)-7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-(Z)-trityloxyimino-acetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester 在 三乙基硅烷 、 碳酸氢钠 、 三苯基膦 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 (6R,7R)-3-[2-(2-Amino-ethylsulfanylmethyl)-pyridin-3-ylsulfanyl]-7-{2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-[(Z)-hydroxyimino]-acetylamino}-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  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：

  7-氨基-3-氯-3-头孢环-4-羧酸 在 三氟化硼乙醚 、 氯磷酸二苯酯 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 (6R,7R)-7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-(Z)-trityloxyimino-acetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl 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