Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate | 183482-89-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并环庚烷吡啶
• 英文名称: Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate
• CAS: 183482-89-5
• 化学式: C₂₂H₂₂BrClN₂O₂
• 分子量: 461.786
• InChiKey: FURYSQRMQHILDB-UHFFFAOYSA-N

物化性质

• 沸点：
  566.4±50.0 °C(Predicted)
• 密度：
  1.426±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate 在 N-甲基吗啉 、 盐酸 、 乙胺嗪 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 1-[4-(6-Bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidin-1-yl]-2-(1-oxidopyridin-1-ium-4-yl)ethanone
  参考文献：
  名称：

  Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity

  摘要：

  We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t(1/2) of 82 min. Compound 4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.

  DOI：

  10.1021/jm980013b
• 作为产物：
  描述：

  Ethyl 4-(6-amino-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate 在 氢溴酸 、 溴 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 0.75h， 生成 Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate 、 Ethyl 4-(6,9-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-2-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  BENZO(5,6)CYCLOHEPTA(1,2B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE

  摘要：

  公开号：

  EP0993460B1

文献信息

• COMPOUNDS USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0942906B1

  公开（公告）日：2004-11-03
• BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP1019398B1

  公开（公告）日：2004-09-15
• TRICYCLIC INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0929545B1

  公开（公告）日：2004-12-29
• BENZO(5,6)CYCLOHEPTA(1,2B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0993460B1

  公开（公告）日：2004-09-15
• Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide <i>N</i>-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity
  作者：F. George Njoroge、Bancha Vibulbhan、Patrick Pinto、W. Robert Bishop、Mathew S. Bryant、Amin A. Nomeir、C.-C. Lin、Ming Liu、Ronald J. Doll、V. Girijavallabhan、Ashit K. Ganguly

  DOI：10.1021/jm980013b

  日期：1998.5.1

  We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t(1/2) of 82 min. Compound 4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.