benzyl (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bR)-3',6',11,12b-tetramethyl-3-triethylsilyloxyspiro[1,2,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydronaphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate | 1055988-91-4

• 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 (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bR)-3',6',11,12b-tetramethyl-3-triethylsilyloxyspiro[1,2,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydronaphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate
• CAS: 1055988-91-4
• 化学式: C₄₂H₆₃NO₄Si
• 分子量: 674.052
• InChiKey: JLDGLCWOTUVZOK-YFCZMYIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.68
• 重原子数：
  48
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  benzyl (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bR)-3',6',11,12b-tetramethyl-3-triethylsilyloxyspiro[1,2,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydronaphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate 在 四丁基氟化铵 、 戴斯-马丁氧化剂 、 肼 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 1.5h， 生成 benzyl (1'S,2S,2'R,3R,3aS,6S,7aR,10'S,13'R,14'S)-2',3,6,19'-tetramethylspiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,17'-6,7-diazapentacyclo[11.8.0.02,10.05,9.014,20]henicosa-5(9),7,19-triene]-4-carboxylate
  参考文献：
  名称：

  WO2008/109184

  摘要：

  公开号：
• 作为产物：
  描述：

  环巴胺 在 palladium(II) hydroxide/carbon 、 palladium 10% on activated carbon 吡啶 、 4-二甲氨基吡啶 、 二(2,6-二甲基苯基)磷酸氢酯 、 氢气 、 diethylzinc 、 双(三甲基硅烷基)氨基钾 、 aluminum tri-tert-butoxide 、 三乙胺 、 丁酮 作用下， 以 四氢呋喃 、 吡啶 、 二氯甲烷 、 乙酸乙酯 、 甲苯 为溶剂， -74.0~75.0 ℃ 、101.33 kPa 条件下， 反应 29.5h， 生成 benzyl (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bR)-3',6',11,12b-tetramethyl-3-triethylsilyloxyspiro[1,2,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydronaphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate
  参考文献：
  名称：

  WO2008/109184

  摘要：

  公开号：

文献信息

• Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)
  作者：Martin R. Tremblay、André Lescarbeau、Michael J. Grogan、Eddy Tan、Grace Lin、Brian C. Austad、Lin-Chen Yu、Mark L. Behnke、Somarajan J. Nair、Margit Hagel、Kerry White、James Conley、Joseph D. Manna、Teresa M. Alvarez-Diez、Jennifer Hoyt、Caroline N. Woodward、Jens R. Sydor、Melissa Pink、John MacDougall、Matthew J. Campbell、Jill Cushing、Jeanne Ferguson、Michael S. Curtis、Karen McGovern、Margaret A. Read、Vito J. Palombella、Julian Adams、Alfredo C. Castro

  DOI：10.1021/jm900305z

  日期：2009.7.23

  Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or Solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.