benzyl (3aS,6S,6aR)-4-{[cis-2,3-dimethylcyclopropyl]-cis-carbonyl}-6-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate | 214337-06-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl (3aS,6S,6aR)-4-{[cis-2,3-dimethylcyclopropyl]-cis-carbonyl}-6-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate
• CAS: 214337-06-1
• 化学式: C₂₁H₂₆N₂O₄
• 分子量: 370.448
• InChiKey: UOZDCCIXXAQPLF-WHKCWQGWSA-N

物化性质

• 沸点：
  527.8±50.0 °C(Predicted)
• 密度：
  1.233±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.67
• 重原子数：
  27.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  66.92
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  benzyl (3aS,6S,6aR)-4-{[cis-2,3-dimethylcyclopropyl]-cis-carbonyl}-6-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate 在 palladium on activated charcoal 氢气 作用下， 以 水 、 异丙醇 为溶剂， 反应 2.0h， 生成 (3S,3aR,6aS)-1-[(cis-2,3-dimethylcyclopropyl)-cis-carbonyl]-3-methylhexahydropyrrolo[3,2-b]pyrrol-2(1H)-one
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5‘-trans-Lactams (5-Oxo-hexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability

  摘要：

  A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K-i) against the viral enzyme. The. SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.

  DOI：

  10.1021/jm030810w
• 作为产物：
  描述：

  (3S,3aR,6aS)-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester 在 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 2.33h， 生成 benzyl (3aS,6S,6aR)-4-{[cis-2,3-dimethylcyclopropyl]-cis-carbonyl}-6-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5‘-trans-Lactams (5-Oxo-hexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability

  摘要：

  A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K-i) against the viral enzyme. The. SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.

  DOI：

  10.1021/jm030810w

文献信息

• Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability
  作者：Alan D Borthwick、Anne M Exall、Terry M Haley、Deborah L Jackson、Andrew M Mason、Gordon G Weingarten

  DOI：10.1016/s0960-894x(02)00294-9

  日期：2002.7

  Mechanism-based inhibitors of HCMV protease, which Lire stable to human plasma (greater than or equal to20h) and have single-figure potency in the muM range against HCMV protease, have been developed based on the dansylprohne alpha-methyl pyrrolidine-5,5-translactam nucleus. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Design and Synthesis of Pyrrolidine-5,5‘-<i>trans-</i>Lactams (5-Oxo-hexahydropyrrolo[3,2-<i>b</i>]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability
  作者：Alan D. Borthwick、Dave E. Davies、Peter F. Ertl、Anne M. Exall、Terry M. Haley、Graham J. Hart、Deborah L. Jackson、Nigel R. Parry、Angela Patikis、Naimisha Trivedi、Gordon G. Weingarten、James M. Woolven

  DOI：10.1021/jm030810w

  日期：2003.10.1

  A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K-i) against the viral enzyme. The. SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.