(+/-)-(2R,4R,5R,1'S)-5-(1'-acetylamino-3'-methylbutyl)-1-benzyl-4-formylpyrrolidine-2-carboxylic acid tert-butyl ester

• 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: (+/-)-(2R,4R,5R,1'S)-5-(1'-acetylamino-3'-methylbutyl)-1-benzyl-4-formylpyrrolidine-2-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (2R,4R,5R)-5-[(1S)-1-acetamido-3-methylbutyl]-1-benzyl-4-formylpyrrolidine-2-carboxylate
• 化学式: C₂₄H₃₆N₂O₄
• 分子量: 416.561
• InChiKey: JIJBDWUHMJHPAL-FNAHDJPLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  75.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (+/-)-(2R,4R,5R,1'S)-5-(1'-acetylamino-3'-methylbutyl)-1-benzyl-4-formylpyrrolidine-2-carboxylic acid tert-butyl ester 在 palladium on activated charcoal 草酰氯 、 甲酸铵 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 (2S,4S,5S)-5-((R)-1-Acetylamino-3-methyl-butyl)-4-propionyl-pyrrolidine-2-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Structure-Based Characterization and Optimization of Novel Hydrophobic Binding Interactions in a Series of Pyrrolidine Influenza Neuraminidase Inhibitors

  摘要：

  The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.

  DOI：

  10.1021/jm049276y
• 作为产物：
  描述：

  (+/-)-(2R,4R,5R,1'S)-5-(1'-acetylamino-3'-methylbutyl)-1-benzyl-4-hydroxymethylpyrrolidine-2-carboxylic acid tert-butyl ester 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以70%的产率得到(+/-)-(2R,4R,5R,1'S)-5-(1'-acetylamino-3'-methylbutyl)-1-benzyl-4-formylpyrrolidine-2-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Structure-Based Characterization and Optimization of Novel Hydrophobic Binding Interactions in a Series of Pyrrolidine Influenza Neuraminidase Inhibitors

  摘要：

  The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.

  DOI：

  10.1021/jm049276y

文献信息

• Inhibitors of neuraminidases
  申请人：——

  公开号：US20040097471A1

  公开（公告）日：2004-05-20

  Disclosed are compounds of the formula: 1 which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

  本发明涉及以下式子的化合物：1，该化合物对于抑制疾病引起微生物的神经氨酸酶，特别是流感神经氨酸酶非常有用。本发明还涉及预防和治疗由具有神经氨酸酶的微生物引起的疾病的组合物和方法，以及用于制备这些化合物和合成中间体的过程。
• PYRROLIDINES AS INHIBITORS OF NEURAMINIDASES
  申请人：ABBOTT LABORATORIES

  公开号：EP1315698A1

  公开（公告）日：2003-06-04
• PYRROLIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF NEURAMINIDASES
  申请人：Abbott Laboratories

  公开号：EP1358154A2

  公开（公告）日：2003-11-05
• US6455571B1
  申请人：——

  公开号：US6455571B1

  公开（公告）日：2002-09-24
• US6831096B2
  申请人：——

  公开号：US6831096B2

  公开（公告）日：2004-12-14