1,1-dimethylethyl [(16aS,17aR,17bS)-3(S)-[1,2-dioxo-2-(2-propenylamino)ethyl]octadecahydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13(S)-yl]carbamate

• 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: 1,1-dimethylethyl [(16aS,17aR,17bS)-3(S)-[1,2-dioxo-2-(2-propenylamino)ethyl]octadecahydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13(S)-yl]carbamate
• 英文别名: (13-allylaminooxalyl-18,18-dimethyl-2,15-dioxo-1,14-diaza-tricyclo[14.4.0.0^17,19]icos-3-yl)-carbamic acid tert-butyl ester；tert-butyl N-[(3S,13S,16S,17R,19S)-18,18-dimethyl-2,15-dioxo-13-[(prop-2-en-1-ylcarbamoyl)carbonyl]-1,14-diazatricyclo[14.4.0.0^{17,19}]icosan-3-yl]carbamate；tert-butyl N-[(3S,13S,16S,17R,19S)-18,18-dimethyl-2,15-dioxo-13-[2-oxo-2-(prop-2-enylamino)acetyl]-1,14-diazatricyclo[14.4.0.017,19]icosan-3-yl]carbamate
• 化学式: C₃₀H₄₈N₄O₆
• 分子量: 560.734
• InChiKey: KCGQQQFOEAVEDN-VUBDRERZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  40
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  134
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl [(16aS,17aR,17bS)-3(S)-[1,2-dioxo-2-(2-propenylamino)ethyl]octadecahydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13(S)-yl]carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 2-[(3S,13S,16S,17R,19S)-3-amino-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-13-yl]-2-oxo-N-prop-2-enylacetamide
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of P₁−P₃ Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease

  摘要：

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P-1-P-3 macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P-3 imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.

  DOI：

  10.1021/jm800940u
• 作为产物：
  描述：

  5-己烯醛 在 palladium on activated charcoal 、 Grubbs catalyst first generation N-甲基吗啉 、 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 lithium hydroxide 、 锂硼氢 、 氢气 、 乙酸酐 、 戴斯-马丁氧化剂 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 肼 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 60.0 ℃ 、413.7 kPa 条件下， 反应 51.5h， 生成 1,1-dimethylethyl [(16aS,17aR,17bS)-3(S)-[1,2-dioxo-2-(2-propenylamino)ethyl]octadecahydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13(S)-yl]carbamate
  参考文献：
  名称：

  闭环复分解在合成大环拟肽作为HCV NS3蛋白酶抑制剂中的应用。

  摘要：

  提出了一种有效的合成方法，用于制备可抑制HCV NS3的大环拟肽。大环核心是使用三肽二烯的闭环复分解（RCM）构建的。提出的方法允许在沿大环的重要位置引入杂原子。通过Passerini反应，对RCM产品中的甲酯部分进行了合成操作，以安装酮酰胺部分。

  DOI：

  10.1021/ol0711265

文献信息

• US7592419B2
  申请人：——

  公开号：US7592419B2

  公开（公告）日：2009-09-22
• [EN] MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS NS3 SERINE PROTEASE<br/>[FR] INHIBITEURS MACROCYCLIQUES DE LA SÉRINE PROTÉASE NS3 DU VIRUS DE L'HÉPATITE C
  申请人：SCHERING CORP

  公开号：WO2009058856A1

  公开（公告）日：2009-05-07

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
• Discovery and Structure−Activity Relationship of P₁−P₃ Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease
  作者：Srikanth Venkatraman、Francisco Velazquez、Wanli Wu、Melissa Blackman、Kevin X. Chen、Stephane Bogen、Latha Nair、Xiao Tong、Robert Chase、Andrea Hart、Sony Agrawal、John Pichardo、Andrew Prongay、Kuo-Chi Cheng、Viyyoor Girijavallabhan、John Piwinski、Neng-Yang Shih、F. George Njoroge

  DOI：10.1021/jm800940u

  日期：2009.1.22

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P-1-P-3 macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P-3 imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.
• Application of Ring-Closing Metathesis for the Synthesis of Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease
  作者：Francisco Velázquez、Srikanth Venkatraman、Wanli Wu、Melissa Blackman、Andrew Prongay、Viyyoor Girijavallabhan、Neng-Yang Shih、F. George Njoroge

  DOI：10.1021/ol0711265

  日期：2007.8.1

  An efficient synthetic approach for the preparation of macrocyclic peptidomimetics for inhibition of HCV NS3 is presented. The macrocyclic core is built using ring-closing metathesis (RCM) of a tripeptidic diene. The presented approach allows the introduction of heteroatoms in strategic places along the macrocyclic ring. The methyl ester moiety in the RCM products was synthetically manipulated to install

  提出了一种有效的合成方法，用于制备可抑制HCV NS3的大环拟肽。大环核心是使用三肽二烯的闭环复分解（RCM）构建的。提出的方法允许在沿大环的重要位置引入杂原子。通过Passerini反应，对RCM产品中的甲酯部分进行了合成操作，以安装酮酰胺部分。