(4R,5R,6R)-4-Benzyl-6-phenethyl-5-(tetrahydro-pyran-2-yloxy)-1,3-bis-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylmethyl]-tetrahydro-pyrimidin-2-one | 210635-16-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: (4R,5R,6R)-4-Benzyl-6-phenethyl-5-(tetrahydro-pyran-2-yloxy)-1,3-bis-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylmethyl]-tetrahydro-pyrimidin-2-one
• 英文别名: (4R,5R,6R)-4-benzyl-5-(oxan-2-yloxy)-6-(2-phenylethyl)-1,3-bis[[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]methyl]-1,3-diazinan-2-one
• CAS: 210635-16-8
• 化学式: C₅₂H₇₀N₆O₅Si₂
• 分子量: 915.336
• InChiKey: JWQAMDSIPHWPAK-VFRKINNMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.97
• 重原子数：
  65
• 可旋转键数：
  21
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  96.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (4R,5R,6R)-4-Benzyl-6-phenethyl-5-(tetrahydro-pyran-2-yloxy)-1,3-bis-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylmethyl]-tetrahydro-pyrimidin-2-one 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以88%的产率得到(4R,5R,6R)-4-Benzyl-5-hydroxy-1,3-bis-(1H-indazol-5-ylmethyl)-6-phenethyl-tetrahydro-pyrimidin-2-one
  参考文献：
  名称：

  Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors

  摘要：

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.

  DOI：

  10.1021/jm9803626
• 作为产物：
  描述：

  Acetic acid (4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-[1,3]diazepan-5-yl ester 在 sodium hydroxide 、 potassium tert-butylate 、 氢溴酸 、 对甲苯磺酸 、 溶剂黄146 、 4,4'-二氨基二苯乙烯-2,2'-二磺酸 、 锌 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 9.33h， 生成 (4R,5R,6R)-4-Benzyl-6-phenethyl-5-(tetrahydro-pyran-2-yloxy)-1,3-bis-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylmethyl]-tetrahydro-pyrimidin-2-one
  参考文献：
  名称：

  Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors

  摘要：

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.

  DOI：

  10.1021/jm9803626

文献信息

• Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors
  作者：George V. De Lucca、Jing Liang、Indawati De Lucca

  DOI：10.1021/jm9803626

  日期：1999.1.1

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.