thiocarbonic acid S-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-yl] ester O-tert-butyl ester | 258497-37-9

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: thiocarbonic acid S-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-yl] ester O-tert-butyl ester
• 英文别名: 4-[(2-N-tert-Butoxycarbonylaminoethylthio)methyl]-3-(tert-butoxycarbonylthio)pyridine；Tert-butyl [4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethylsulfanylmethyl]pyridin-3-yl]sulfanylformate
• CAS: 258497-37-9
• 化学式: C₁₈H₂₈N₂O₄S₂
• 分子量: 400.563
• InChiKey: JCGZVBUZZNYHLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  26
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  128
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  thiocarbonic acid S-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-yl] ester O-tert-butyl ester 在 sodium methylate 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 1.5h， 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
• 作为产物：
  描述：

  3-疏基吡啶-4-羧酸 在 三乙基硅烷 、 氯化亚砜 、 硼烷 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 thiocarbonic acid S-[4-(2-tert-butoxycarbonylaminoethylsulfanylmethyl)-pyridin-3-yl] ester O-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

文献信息

• 7-acylamino-3-heteroarylthio-3-cephem carboxylic acid antibiotics and prodrugs thereof
  申请人：Essential Therapeutics, Inc.

  公开号：US06723716B1

  公开（公告）日：2004-04-20

  The present invention relates to a cephem prodrug having formula III or formula IV: or a pharmaceutically acceptable salt thereof, wherein R′1 is selected from the group consisting of hydrogen and —C(O)CH(NH2)CH3 and R′2 is selected from the group consisting of hydrogen and an acyl group that is cleaved by an enzyme found in mammals, with the proviso that, when either R′1 or R′2 is hydrogen, the other is not. A, B, L, G, E, and J are each independently nitrogen or carbon such that the respective rings are selected from the group consisting of provided that the group —CH2—S—CH2CH2NHR′2 is attached only to a carbon atom of said heterocyclic group, and Q is selected from the group consisting of nitrogen and —CX, wherein X is selected from the group consisting of hydrogen and chlorine.

  本发明涉及具有III式或IV式的头孢菌素前药：或其药用可接受的盐，其中R′1选自由氢和—C(O)CH(NH2)CH3的群组，R′2选自由氢和在哺乳动物中发现的一种酶可水解的酰基团，但条件是当R′1或R′2中的一个是氢时，另一个不是。A、B、L、G、E和J分别独立地为氮或碳，使得相应的环被选自的群组选中，前提是群组—CH2—S— NHR′2仅连接到所述杂环基团的一个碳原子上，Q选自氮和—CX的群组，其中X选自氢和氯。
• Cephalosporin antibiotics
  申请人：Microcide Pharmaceuticals, Inc.

  公开号：US06030965A1

  公开（公告）日：2000-02-29

  The present invention includes novel compounds of formula where A, B, D, and E are selected from the group consisting of carbon, nitrogen and sulfur, R.sup.99 is selected from the group consisting of sulfur, SO, S0.sub.2, NH, N-alkyl, oxygen, C.dbd.C (cis or trans), and C.tbd.C, and R.sup.12 is NR.sup.13 R.sup.14, ##STR1## The invention also includes the pharmacologically acceptable salts which exhibit antibiotic activity against a wide spectrum of organisms including organisms which are resistant to .beta.-lactam antibiotics and are useful as antibacterial agents. The invention also relates to novel intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds.

  本发明包括以下式的新化合物，其中A、B、D和E选自碳、氮和硫组成的群体，R.sup.99选自硫、SO、SO.sub.2、NH、N-烷基、氧、C.dbd.C（顺式或反式）和C.tbd.C，R.sup.12为NR.sup.13 R.sup.14，本发明还包括表现出抗生素活性的药理学上可接受的盐，对包括对β-内酰胺抗生素具有抗性的广泛范围的生物体具有抗生素活性，并且可用作抗菌剂。本发明还涉及用于制备本发明新化合物的新中间体以及用于生产新化合物和中间化合物的新方法。
• 7-ACYLAMINO-3-HETEROARYLTHIO-3-CEPHEM CARBOXYLIC ACID ANTIBIOTICS AND PRODRUGS THEREOF
  申请人：Trine Pharmaceuticals, Inc.

  公开号：EP1222194B1

  公开（公告）日：2005-06-15
• US6030965A
  申请人：——

  公开号：US6030965A

  公开（公告）日：2000-02-29
• US6025352A
  申请人：——

  公开号：US6025352A

  公开（公告）日：2000-02-15