N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(3(S)-tetrahydrothiofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide | 150406-28-3

• 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: N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(3(S)-tetrahydrothiofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
• 英文别名: N-tert-butyl-2-(2(R)-hydroxy-4-phenyl-3(S)-{[N-(2-quinolylcarbonyl)-2(S)-(3(S)-tetrahydrothiofuranyl)glycinyl]amino}butyl)decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide；(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3S)-2-hydroxy-4-phenyl-3-[(2S)-2-(quinolin-2-ylformamido)-2-[(3S)-thiolan-3-yl]acetamido]butyl]-decahydroisoquinoline-3-carboxamide；N-[(1S)-2-[[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]amino]-2-oxo-1-[(3S)-thiolan-3-yl]ethyl]quinoline-2-carboxamide
• CAS: 150406-28-3
• 化学式: C₄₀H₅₃N₅O₄S
• 分子量: 699.958
• InChiKey: ZOMNPGWFMCUJBM-DRNYJLRZSA-N

物化性质

• 沸点：
  977.8±65.0 °C(predicted)
• 密度：
  1.202±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  50
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  149
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(3(S)-tetrahydrothiofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide 在 四氧化锇 、 N-甲基吗啉氧化物 作用下， 以 水 、 丙酮 为溶剂， 反应 24.0h， 以10.4 mg的产率得到N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(3(S)-dioxotetrahydrothiofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006
• 作为产物：
  描述：

  [(2R,3R)-3-(苯基甲基)环氧乙烷-2-基]甲醇 在 palladium on activated charcoal titanium(IV) isopropylate 、 叠氮基三甲基硅烷 、 氢气 、 sodium methylate 、 2-乙酰氧基异丁酰氯 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 异丙醇 、 苯 为溶剂， 反应 35.25h， 生成 N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(3(S)-tetrahydrothiofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006

文献信息

• Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands
  作者：Arun K. Ghosh、Wayne J. Thompson、M. Katharine Holloway、Sean P. McKee、Tien T. Duong、Hee Yoon Lee、Peter M. Munson、Anthony M. Smith、Jenny M. Wai、Paul L. Darke、Joan A. Zugay、Emilio A. Emini、William A. Schleif、Joel R. Huff、Paul S. Anderson

  DOI：10.1021/jm00068a006

  日期：1993.8.1

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.