benzyl (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-3-hydroxyimino-3',6',11,12b-tetramethylspiro[2,4,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydro-1H-naphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate | 1037210-78-8

• 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,12bS)-3-hydroxyimino-3',6',11,12b-tetramethylspiro[2,4,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydro-1H-naphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate
• CAS: 1037210-78-8
• 化学式: C₃₆H₅₀N₂O₄
• 分子量: 574.804
• InChiKey: WVUHFVWOMNZTMY-PTKIWVSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  42
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  5

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,12bS)-3-hydroxyimino-3',6',11,12b-tetramethylspiro[2,4,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydro-1H-naphtho[2,1-a]azulene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-carboxylate 在 吡啶 、 甲基磺酰氯 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 生成 [(1'S,2S,2'R,3R,3aS,6S,7aR,8'S,11'R,12'S)-2',3,6,17'-tetramethyl-5'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,15'-6-azatetracyclo[9.8.0.02,8.012,18]nonadec-17-ene]-4-yl] benzoate
  参考文献：
  名称：

  WO2008/109829

  摘要：

  公开号：
• 作为产物：
  描述：

  BisCBzcyclopamine 在 palladium hydroxide on carbon 、 palladium 10% on activated carbon 二(2,6-二甲基苯基)磷酸氢酯 、 盐酸羟胺 、 氢气 、 diethylzinc 、 sodium acetate 、 aluminum tri-tert-butoxide 、 三乙胺 、 丁酮 作用下， 以 四氢呋喃 、 吡啶 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 甲苯 为溶剂， -20.0~75.0 ℃ 、101.33 kPa 条件下， 反应 28.5h， 生成 benzyl (3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-3-hydroxyimino-3',6',11,12b-tetramethylspiro[2,4,4a,5,6,6a,6b,7,8,10,12,12a-dodecahydro-1H-naphtho[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：

  WO2008/109829

  摘要：

  公开号：

文献信息

• WO2008/83248
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.