methyl (1R,2S,5S)-3-[(2S)-2-amino-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | 864907-89-1

• 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: methyl (1R,2S,5S)-3-[(2S)-2-amino-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
• CAS: 864907-89-1
• 化学式: C₁₈H₃₀N₂O₃
• 分子量: 322.448
• InChiKey: VTROASVVPDEGAE-XDQVBPFNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (1R,2S,5S)-3-[(2S)-2-amino-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 在 二氯乙酸 、 lithium hydroxide 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 73.0h， 生成 (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  参考文献：
  名称：

  实用高效的含β-季中心氨基酸衍生物的方法：在丙型肝炎病毒NS3丝氨酸蛋白酶抑制剂的合成中的应用

  摘要：

  利用非对映选择性Strecker反应，已经开发出一种实用而有效的合成含β-季中心氨基酸衍生物的途径。该方法用于制备> 100 g的β-甲基环己基甘氨酸衍生物21。在P3位置掺入一些受阻氨基酸衍生物会产生有效的HCV NS3丝氨酸蛋白酶抑制剂。

  DOI：

  10.1016/j.tetlet.2007.07.002
• 作为产物：
  描述：

  1-甲基环己烷-1-甲醛 在 palladium on activated charcoal 盐酸 、 sodium hydroxide 、 氢气 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 189.0h， 生成 methyl (1R,2S,5S)-3-[(2S)-2-amino-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
  参考文献：
  名称：

  实用高效的含β-季中心氨基酸衍生物的方法：在丙型肝炎病毒NS3丝氨酸蛋白酶抑制剂的合成中的应用

  摘要：

  利用非对映选择性Strecker反应，已经开发出一种实用而有效的合成含β-季中心氨基酸衍生物的途径。该方法用于制备> 100 g的β-甲基环己基甘氨酸衍生物21。在P3位置掺入一些受阻氨基酸衍生物会产生有效的HCV NS3丝氨酸蛋白酶抑制剂。

  DOI：

  10.1016/j.tetlet.2007.07.002

文献信息

• Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
  作者：Kevin X. Chen、Bancha Vibulbhan、Weiying Yang、Latha G. Nair、Xiao Tong、Kuo-Chi Cheng、F. George Njoroge

  DOI：10.1016/j.bmcl.2008.12.111

  日期：2009.2

  Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl- sultam cappings were selected for further SAR development. Modi. cation at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall pro. le in potency and PK profile: excellent K-i* of 5.3 nM and activity in replicon (EC90) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 mu Mh. (C) 2009 Elsevier Ltd. All rights reserved.
• Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease
  作者：Kevin X. Chen、Latha Nair、Bancha Vibulbhan、Weiying Yang、Ashok Arasappan、Stephane L. Bogen、Srikanth Venkatraman、Frank Bennett、Weidong Pan、Melissa L. Blackman、Angela I. Padilla、Andrew Prongay、Kuo-Chi Cheng、Xiao Tong、Neng-Yang Shih、F. George Njoroge

  DOI：10.1021/jm801238q

  日期：2009.3.12

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
• Novel compounds as inhibitors of hepatitis C virus NS3 serine protease
  申请人：Arasappan Ashok

  公开号：US20070142300A1

  公开（公告）日：2007-06-21

  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.
• US7186747B2
  申请人：——

  公开号：US7186747B2

  公开（公告）日：2007-03-06
• US7425576B2
  申请人：——

  公开号：US7425576B2

  公开（公告）日：2008-09-16