4-amino-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)pyrimidin-2(1H)-one | 1202487-53-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-amino-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)pyrimidin-2(1H)-one
• 英文别名: 1-[(6aR,8R,9aS)-2,2,4,4-tetra(propan-2-yl)spiro[6,6a,8,9a-tetrahydrofuro[3,2-f][1,3,5,2,4]trioxadisilocine-9,1'-cyclopropane]-8-yl]-4-aminopyrimidin-2-one
• CAS: 1202487-53-3
• 化学式: C₂₃H₄₁N₃O₅Si₂
• 分子量: 495.767
• InChiKey: YZWAQBKAIPURLU-HMXCVIKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.46
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  95.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-amino-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)pyrimidin-2(1H)-one 在 吡啶 、 N-甲基咪唑 、 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (2S)-benzyl 2-((((4R,6R,7S)-4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-5-oxaspiro[2,4]heptan-6-yl)methoxy)((phenoxy)phosphorylamino)propanoate
  参考文献：
  名称：

  Cyclopropyl polymerase inhibitors

  摘要：

  公开号：

  EP2141172B1
• 作为产物：
  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 吡啶 、 二苯甲酮 、 氨 、 4-氯苯基二氯磷酸酯 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 、 苯 为溶剂， 反应 1.0h， 生成 4-amino-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)pyrimidin-2(1H)-one
  参考文献：
  名称：

  Cyclopropyl polymerase inhibitors

  摘要：

  公开号：

  EP2141172B1

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