3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-4',5',6,6a,8,9a-hexahydrospiro[furo[3,2-f][1,3,5,2,4]-trioxadisilocine-9,3'-pyrazole]-8-yl)pyrimidine-2,4(1H,3H)-dione | 1202651-75-9

• 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: 3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-4',5',6,6a,8,9a-hexahydrospiro[furo[3,2-f][1,3,5,2,4]-trioxadisilocine-9,3'-pyrazole]-8-yl)pyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-[(6'aR,8'R,9'aS)-2',2',4',4'-tetra(propan-2-yl)spiro[3,4-dihydropyrazole-5,9'-6,6a,8,9a-tetrahydrofuro[3,2-f][1,3,5,2,4]trioxadisilocine]-8'-yl]-3-benzoylpyrimidine-2,4-dione
• CAS: 1202651-75-9
• 化学式: C₃₀H₄₄N₄O₇Si₂
• 分子量: 628.873
• InChiKey: VOJPOGDKFPGZAY-JNDKSWASSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.15
• 重原子数：
  43
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  119
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-4',5',6,6a,8,9a-hexahydrospiro[furo[3,2-f][1,3,5,2,4]-trioxadisilocine-9,3'-pyrazole]-8-yl)pyrimidine-2,4(1H,3H)-dione 在 二苯甲酮 作用下， 以 乙腈 、 苯 为溶剂， 生成 3-benzoyl-1-((6a'R,8'R,9a'S)-2',2',4',4'-tetraisopropylhexahydrospiro[cyclopropane-1,9'-furo[3,2-f][1,3,5,2,4]-trioxadisilocine]-8'-yl)pyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Cyclopropyl polymerase inhibitors

  摘要：

  公开号：

  EP2141172B1
• 作为产物：
  描述：

  重氮甲烷 、 3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione 以 乙醚 为溶剂， 反应 48.0h， 以85%的产率得到3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-4',5',6,6a,8,9a-hexahydrospiro[furo[3,2-f][1,3,5,2,4]-trioxadisilocine-9,3'-pyrazole]-8-yl)pyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  2′-Deoxy-2′-spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclo-propylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 of 7.3 mu M measured in the Huh7-Rep cell line and no associated cytotoxicity (CC50 > 98.4 mu M). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated, The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.

  DOI：

  10.1021/jm101050a

文献信息

• 2′-Deoxy-2′-spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Tim H. M. Jonckers、Tse-I Lin、Christophe Buyck、Sophie Lachau-Durand、Koen Vandyck、Steven Van Hoof、Leen A. M. Vandekerckhove、Lili Hu、Jan Martin Berke、Leen Vijgen、Lieve L. A. Dillen、Maxwell D. Cummings、Herman de Kock、Magnus Nilsson、Christian Sund、Christina Rydegård、Bertil Samuelsson、Åsa Rosenquist、Gregory Fanning、Kristof Van Emelen、Kenneth Simmen、Pierre Raboisson

  DOI：10.1021/jm101050a

  日期：2010.11.25

  The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclo-propylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 of 7.3 mu M measured in the Huh7-Rep cell line and no associated cytotoxicity (CC50 > 98.4 mu M). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated, The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.
• Cyclopropyl polymerase inhibitors
  申请人：Janssen Products, L.P.

  公开号：EP2141172B1

  公开（公告）日：2012-10-24