(3aS,4R,8R,8aS)-5,7-dibenzyl-4,8-bis[(4-methoxyphenyl)methyl]-2,2-dimethyl-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | 207129-57-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (3aS,4R,8R,8aS)-5,7-dibenzyl-4,8-bis[(4-methoxyphenyl)methyl]-2,2-dimethyl-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
• CAS: 207129-57-5
• 化学式: C₃₈H₄₂N₂O₅
• 分子量: 606.762
• InChiKey: XSUPGIKVAQIBIM-NWJWHWDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  45
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  60.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3aS,4R,8R,8aS)-5,7-dibenzyl-4,8-bis[(4-methoxyphenyl)methyl]-2,2-dimethyl-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one 在 盐酸 、 三溴化硼 、 caesium carbonate 、 对甲苯磺酸 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 、 丙酮 为溶剂， 反应 2.5h， 生成 (4R,5S,6S,7R)-1,3-Dibenzyl-5,6-dihydroxy-4,7-bis-[4-(2-hydroxy-ethoxy)-benzyl]-[1,3]diazepan-2-one
  参考文献：
  名称：

  环状脲作为HIV蛋白酶抑制剂的合成和评估：P1 / P1'残基的修饰。

  摘要：

  制备了两个在P1 / P1'残基处修饰的环状脲，并评估了其对HIV蛋白酶的抑制作用和全细胞抗病毒活性。相对于先导化合物DMP323和DMP 450，化合物8b，10（3-和4-吡啶基甲基类似物）和6b（4-甲氧基类似物）显示出显着的抗病毒活性改善。

  DOI：

  10.1016/s0960-894x(98)00119-x
• 作为产物：
  描述：

  (4S,5S)-4,5-bis[(1R)-1-azido-2-(4-methoxyphenyl)ethyl]-2,2-dimethyl-1,3-dioxolane 在 lithium aluminium tetrahydride 、 sodium hydride 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 2.91h， 生成 (3aS,4R,8R,8aS)-5,7-dibenzyl-4,8-bis[(4-methoxyphenyl)methyl]-2,2-dimethyl-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n

文献信息

• Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors
  作者：David A. Nugiel、Kim Jacobs、Tabitha Worley、Mona Patel、Robert F. Kaltenbach、Dayton T. Meyer、Prabhakar K. Jadhav、George V. De Lucca、Thomas E. Smyser、Ronald M. Klabe、Lee T. Bacheler、Marlene M. Rayner、Steven P. Seitz

  DOI：10.1021/jm960083n

  日期：1996.1.1

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.
• The synthesis and evaluation of cyclic ureas as HIV protease inhibitors: Modifications of the P1/P1′ residues
  作者：Mona Patel、Lee T. Bacheler、Marlene M. Rayner、Beverly C. Cordova、Ronald M. Klabe、Susan Erickson-Viitanen、Steven P. Seitz

  DOI：10.1016/s0960-894x(98)00119-x

  日期：1998.4

  Two series of cyclic ureas modified at the P1/P1' residue were prepared and evaluated for HIV protease inhibition and whole cell antiviral activity. Compounds 8b, 10 (3- and 4-pyridylmethyl analogs) and 6b (4-methoxy analog) showed significant improvement in antiviral activity relative to lead compounds DMP323 and DMP 450.

  制备了两个在P1 / P1'残基处修饰的环状脲，并评估了其对HIV蛋白酶的抑制作用和全细胞抗病毒活性。相对于先导化合物DMP323和DMP 450，化合物8b，10（3-和4-吡啶基甲基类似物）和6b（4-甲氧基类似物）显示出显着的抗病毒活性改善。