benzyl (2S,3R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bR)-3,6,11',12'b-tetramethyl-3'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,9'-4a,5,6,6a,6b,7,8,10,12,12a-decahydro-4H-naphtho[2,1-a]azulene]-4-carboxylate | 1055981-20-8

• 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 (2S,3R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bR)-3,6,11',12'b-tetramethyl-3'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,9'-4a,5,6,6a,6b,7,8,10,12,12a-decahydro-4H-naphtho[2,1-a]azulene]-4-carboxylate
• CAS: 1055981-20-8
• 化学式: C₃₆H₄₇NO₄
• 分子量: 557.773
• InChiKey: ASBZSIPSEXHGGI-PTKIWVSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  41
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  benzyl (2S,3R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bR)-3,6,11',12'b-tetramethyl-3'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,9'-4a,5,6,6a,6b,7,8,10,12,12a-decahydro-4H-naphtho[2,1-a]azulene]-4-carboxylate 在 盐酸羟胺 、 sodium acetate 、 吡啶 、 对甲苯磺酰氯 、 盐酸 作用下， 以 乙醇 、 甲醇 、 水 、 甲苯 为溶剂， 反应 20.0h， 以61%的产率得到benzyl (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]nonadeca-3,17-diene]-4-carboxylate
  参考文献：
  名称：

  Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

  摘要：

  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.

  DOI：

  10.1021/jm900305z
• 作为产物：
  描述：

  benzyl (2S,3R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bS)-2'-formyl-3,6,11',12'b-tetramethyl-3'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,9'-4a,5,6,6a,6b,7,8,10,12,12a-decahydro-4H-naphtho[2,1-a]azulene]-4-carboxylate 在 Wilkinson's catalyst 作用下， 以 甲苯 为溶剂， 反应 0.5h， 以64%的产率得到benzyl (2S,3R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bR)-3,6,11',12'b-tetramethyl-3'-oxospiro[3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine-2,9'-4a,5,6,6a,6b,7,8,10,12,12a-decahydro-4H-naphtho[2,1-a]azulene]-4-carboxylate
  参考文献：
  名称：

  Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

  摘要：

  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.

  DOI：

  10.1021/jm900305z

文献信息

• CYCLOPAMINE LACTAM ANALOGS AND METHODS OF USE THEREOF
  申请人：Infinity Discovery, Inc.

  公开号：EP2134719B1

  公开（公告）日：2013-07-17
• US7964590B2
  申请人：——

  公开号：US7964590B2

  公开（公告）日：2011-06-21
• US8293760B2
  申请人：——

  公开号：US8293760B2

  公开（公告）日：2012-10-23
• US8431566B2
  申请人：——

  公开号：US8431566B2

  公开（公告）日：2013-04-30
• [EN] CYCLOPAMINE LACTAM ANALOGS AND METHODS OF USE THEREOF<br/>[FR] ANALOGUES DE CYCLOPAMINE LACTAME ET PROCÉDÉS D'UTILISATION DE CEUX-CI
  申请人：INFINITY PHARMACEUTICALS INC

  公开号：WO2008109829A1

  公开（公告）日：2008-09-12

  [EN] The present invention relates to steroidal alkaloids useful in the treatment of hedgehog pathway related disorders, particularly cancers.
  [FR] L'invention concerne des alcaloïdes stéroïdes utiles dans le traitement de troubles associés à la voie hedgehog, notamment des cancers.