O-[1-(phenylsulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethyl carbamate | 1346434-61-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: O-[1-(phenylsulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethyl carbamate
• 英文别名: O-[1-(phenylsulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethylcarbamate
• CAS: 1346434-61-4
• 化学式: C₂₆H₃₄ClN₅O₅S
• 分子量: 564.105
• InChiKey: KNZMQFJGPCJZEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.02
• 重原子数：
  38.0
• 可旋转键数：
  15.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  132.75
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  O-[1-(phenylsulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethyl carbamate 在 吡啶 、 potassium tert-butylate 、 溶剂黄146 、 三甲基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.25h， 生成
  参考文献：
  名称：

  Macromolecular Prodrug That Provides the Irinotecan (CPT-11) Active-Metabolite SN-38 with Ultralong Half-Life, Low C_max , and Low Glucuronide Formation

  摘要：

  We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

  DOI：

  10.1021/jm401644v
• 作为产物：
  描述：

  4-氨基-N,N-二乙基苯甲酰胺 在 三甲基氯硅烷 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 生成 O-[1-(phenylsulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethyl carbamate
  参考文献：
  名称：

  [EN] HYDROGELS WITH BIODEGRADABLE CROSSLINKING
  [FR] HYDROGELS À RÉTICULATION BIODÉGRADABLE

  摘要：

  描述了在适当的pH和温度条件下通过交联化合物裂解的水凝胶。这些水凝胶可用于传递各种药剂，如药物。该发明提供了在暴露于生理条件下会非酶催化降解为较小可溶性组分的水凝胶，以及制备它们的方法。这些水凝胶是由在生理条件下发生消除反应的交联剂制备而成，从而将交联剂从水凝胶的骨架中裂解出来。该发明还涉及交联剂本身以及形成该发明的水凝胶的中间体。根据该发明的方法制备的可生物降解水凝胶可用于各种领域，包括生物医学工程、吸收材料以及作为药物传递的载体。

  公开号：

  WO2013036847A1

文献信息

• [EN] CONTROLLED RELEASE FROM MACROMOLECULAR CONJUGATES<br/>[FR] LIBÉRATION CONTRÔLÉE À PARTIR DE CONJUGUÉS MACROMOLÉCULAIRES
  申请人：PROLYNX LLC

  公开号：WO2011140393A1

  公开（公告）日：2011-11-10

  The invention relates to conjugates of macromolecular carriers and drugs comprising linkers that release the drug or a prodrug through rate-controlled beta-elimination, and methods of making and using the conjugates.

  这项发明涉及大分子载体和药物的共轭物，包括释放药物或前药的连接剂，通过速率控制的β-消除释放药物，以及制备和使用这些共轭物的方法。
• [EN] SULFONE LINKERS<br/>[FR] COUPLEURS AU SULFONE
  申请人：PROLYNX LLC

  公开号：WO2013036857A1

  公开（公告）日：2013-03-14

  Sulfone linkers which couple drugs to carriers of various types are described. These linkers permit the release of the drug over time in a controlled manner. The release occurs through beta-elimination, and does not require enzymatic cleavage. Products of the linkers with both drugs and macromolecules and methods of using them are described as well.

  研究描述了将药物与各种载体耦合的砜键连接剂。这些连接剂允许药物以受控方式随时间释放。释放是通过β-消除而发生的，并不需要酶解。还描述了连接剂与药物和大分子的产物以及它们的使用方法。
• β-Eliminative Releasable Linkers Adapted for Bioconjugation of Macromolecules to Phenols
  作者：Eric L. Schneider、Louise Robinson、Ralph Reid、Gary W. Ashley、Daniel V. Santi

  DOI：10.1021/bc4002882

  日期：2013.12.18

  We recently reported a chemical approach for half-life extension that utilizes sets of releasable linkers to attach drugs to macromolecules via a cleavable carbamate group (Santi et al., Proc. Nat. Acad. Sci. U.S.A. 2012, 109, 6211-6216). The linkers undergo a beta-elimination cleavage to release the free, native amine-containing drug. A limitation of the technology is the requirement for an amino group on the drug in order to form the carbamate bond, since most small molecules do not have an amine functional group. Here, we describe an approach to adapt these same beta-elimination carbamate linkers so they can be used to connect other acidic heteroatoms, in particular, phenolic hydroxyl groups. The approach utilizes a methylene adaptor to connect the drug to the carbamate nitrogen, and an electron-withdrawing group attached to carbamate nitrogen to stabilize the system against a pH-independent spontaneous cleavage. Carbamate cleavage is driven by beta-elimination to give a carboxylated aryl amino Mannich base which rapidly collapses to give the free drug, an aryl amine, and formaldehyde.