Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperidine-1-carboxylate | 183482-82-8

• 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),4,6,12,14-hexaen-2-yl)piperidine-1-carboxylate
• CAS: 183482-82-8
• 化学式: C₂₂H₂₄BrClN₂O₂
• 分子量: 463.802
• InChiKey: DHXSZFYNOYGEDU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 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),4,6,12,14-hexaen-2-yl)piperidine-1-carboxylate 在 palladium diacetate 氢氧化钾 、 硫酸 、 四丁基氟化铵 、 四丁基溴化铵 、 碘 、 sodium carbonate 、 silver sulfate 、 potassium nitrate 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 (+)-4-(9-bromo-4-chloro-3,6,7,12-tetrahydro-1-methylpyrido[2',3':4,5]cyclohepta[2,1-e]indol-12-yl)-1-piperidine
  参考文献：
  名称：

  探索溴在（+）-4- [2- [4- [8-氯-3,10-二溴-6,11-二氢-5H-苯并[5,6]]环庚的C（10）上的作用[ 1,2-b]吡啶基-11（R）-基）-1-哌啶基] -2-氧代乙基] -1-哌啶甲酰胺（Sch-66336）：法呢基蛋白转移酶的吲哚环庚啶吡啶抑制剂的发现。

  摘要：

  10-溴苯并环庚啶基法呢基转移酶抑制剂（FTI）Sch-66336（1）目前正在临床评估中，用于治疗人类癌症。在形成1的结构活性关系发展过程中，发现10-溴苯并环庚啶基FTI比没有10-Br取代基的类似化合物更有效。认为这种效力增强部分是由于构象刚度的增加，因为10-溴取代基可能会限制轴向方向上附加的C（11）哌啶基取代基的构象。基于这一原理，设计了一种新颖有效的FTI，以吲哚环庚庚啶Sch-207758 [（+）-10a]为代表。尽管结构和热力学结果表明，熵在构象约束和溶剂化作用下对（+）-10a增强效力中起着关键作用，但结果还表明（+）-10a中的吲哚环庚庚啶部分提供与（+）-10a增强的疏水相互作用。通过添加吲哚基团的蛋白质。该报告详细介绍了（+）-10a的X射线结构，热力学和药代动力学概况，以及吲哚环庚庚啶FTI的合成及其在生化和生物学分析中的作用。

  DOI：

  10.1021/jm010463v
• 作为产物：
  描述：

  Ethyl 4-(13-chloro-6-nitro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperidine-1-carboxylate 在 氢溴酸 、 溴 、 铁粉 、 calcium chloride 、 sodium nitrite 作用下， 以 乙醇 、 水 为溶剂， 反应 17.0h， 生成 Ethyl 4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperidine-1-carboxylate
  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

文献信息

• TRICYCLIC ANTITUMOR COMPOUNDS BEING FARNESYL PROTEIN TRANSFERASE INHIBITORS
  申请人：SCHERING CORPORATION

  公开号：EP0929544B1

  公开（公告）日：2004-11-10
• Exploring the Role of Bromine at C(10) of (+)-4-[2-[4-(8-Chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(<i>R</i>)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336):  The Discovery of Indolocycloheptapyridine Inhibitors of Farnesyl Protein Transferase
  作者：Arthur G. Taveras、Cynthia Aki、Jianping Chao、Ronald J. Doll、Tarik Lalwani、Viyyoor Girijavallabhan、Corey L. Strickland、William T. Windsor、Patricia Weber、Frank Hollinger、Mark Snow、Robert Patton、Paul Kirschmeier、Linda James、Ming Liu、Amin Nomeir

  DOI：10.1021/jm010463v

  日期：2002.8.1

  hydrophobic interactions with the protein through the addition of the indole group. This report details the X-ray structure and the thermodynamic and pharmacokinetic profiles of (+)-10a, as well as the synthesis of indolocycloheptapyridine FTIs and their potencies in biochemical and biological assays.

  10-溴苯并环庚啶基法呢基转移酶抑制剂（FTI）Sch-66336（1）目前正在临床评估中，用于治疗人类癌症。在形成1的结构活性关系发展过程中，发现10-溴苯并环庚啶基FTI比没有10-Br取代基的类似化合物更有效。认为这种效力增强部分是由于构象刚度的增加，因为10-溴取代基可能会限制轴向方向上附加的C（11）哌啶基取代基的构象。基于这一原理，设计了一种新颖有效的FTI，以吲哚环庚庚啶Sch-207758 [（+）-10a]为代表。尽管结构和热力学结果表明，熵在构象约束和溶剂化作用下对（+）-10a增强效力中起着关键作用，但结果还表明（+）-10a中的吲哚环庚庚啶部分提供与（+）-10a增强的疏水相互作用。通过添加吲哚基团的蛋白质。该报告详细介绍了（+）-10a的X射线结构，热力学和药代动力学概况，以及吲哚环庚庚啶FTI的合成及其在生化和生物学分析中的作用。
• 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.