N-[(3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-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'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-ylidene]hydroxylamine | 1037210-75-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-[(3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-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'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-ylidene]hydroxylamine
• CAS: 1037210-75-5
• 化学式: C₂₈H₄₄N₂O₂
• 分子量: 440.67
• InChiKey: CDHLHLMZNHWKLM-FPVLXLKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  32
• 可旋转键数：
  0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  53.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  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 palladium 10% on activated carbon 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 3.0h， 生成 N-[(3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-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'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-ylidene]hydroxylamine
  参考文献：
  名称：

  WO2008/83248

  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.