4-(2-{4-[(2S)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)-1-oxidopyridin-1-ium

• 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: 4-(2-{4-[(2S)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)-1-oxidopyridin-1-ium
• 英文别名: 1-[4-[(2S)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-(1-oxidopyridin-1-ium-4-yl)ethanone
• 化学式: C₂₆H₂₄Br₂ClN₃O₂
• 分子量: 605.756
• InChiKey: UZMOGBCVDQWRFX-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  58.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-<3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester 在 N-甲基吗啉 、 盐酸 、 乙胺嗪 、 二异丁基氢化铝 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 40.67h， 生成 4-(2-{4-[(2S)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)-1-oxidopyridin-1-ium
  参考文献：
  名称：

  (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336):  A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent

  摘要：

  We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

  DOI：

  10.1021/jm980462b

文献信息

• (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5<i>H</i>-benzo[5,6]cyclohepta[1,2-<i>b</i>]- pyridin-11(<i>R</i>)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336):  A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent
  作者：F. George Njoroge、Arthur G. Taveras、Joseph Kelly、Stacy Remiszewski、Alan K. Mallams、Ronald Wolin、Adriano Afonso、Alan B. Cooper、Dinananth F. Rane、Yi-Tsung Liu、Jesse Wong、Bancha Vibulbhan、Patrick Pinto、Jeffrey Deskus、Carmen S. Alvarez、Joycelyn del Rosario、Michael Connolly、James Wang、Jagdish Desai、Randall R. Rossman、W. Robert Bishop、Robert Patton、Lynn Wang、Paul Kirschmeier、Mathew S. Bryant、Amin A. Nomeir、C.-C. Lin、Ming Liu、Andrew T. McPhail、Ronald J. Doll、Viyyoor M. Girijavallabhan、Ashit K. Ganguly

  DOI：10.1021/jm980462b

  日期：1998.11.1

  We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.