4-[2-[4-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-methyl-1-piperidinecarboxamide

• 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-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-methyl-1-piperidinecarboxamide
• 英文别名: 4-[2-[4-(6-bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperazin-1-yl]-2-oxoethyl]-N-methylpiperidine-1-carboxamide
• 化学式: C₂₇H₃₃BrClN₅O₂
• 分子量: 574.948
• InChiKey: XWCMUCOWDZOIAS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  36
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  68.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 在 N-甲基吗啉 、 硫酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 212.0h， 生成 4-[2-[4-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-methyl-1-piperidinecarboxamide
  参考文献：
  名称：

  Inhibitors of Farnesyl Protein Transferase. 4-Amido, 4-Carbamoyl, and 4-Carboxamido Derivatives of 1-(8-Chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-Bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine

  摘要：

  The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin -11-yl)piperazine to explore the SAR of of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

  DOI：

  10.1021/jm970462w

文献信息

• N-substituted urea inhibitors of farnesyl-protein transferase
  申请人：Schering Corporation

  公开号：US06358968B1

  公开（公告）日：2002-03-19

  Novel halo-N-substituted urea compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel halo-N-substituted urea compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammals such as a human.

  揭示了一种新型的卤代-N-取代脲化合物和药物组合物，它们是酶法尼基蛋白转移酶的抑制剂。还公开了一种抑制Ras功能从而抑制细胞异常生长的方法。该方法包括向生物系统施用这种新型的卤代-N-取代脲化合物。具体来说，该方法抑制了哺乳动物（如人类）中细胞的异常生长。
• Novel N-substituted urea inhibitors of farnesyl-protein transferase
  申请人：——

  公开号：US20020119981A1

  公开（公告）日：2002-08-29

  Novel halo-N-substituted urea compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel halo-N-substituted urea compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammals such as a human.

  本发明涉及一种新型的卤代-N-取代脲类化合物和制药组合物，它们是韦尼酰基蛋白转移酶的抑制剂。同时，本发明还公开了一种抑制Ras功能，从而抑制细胞异常生长的方法。该方法包括将新型的卤代-N-取代脲类化合物用于生物系统。特别地，该方法可抑制哺乳动物，如人类中细胞的异常生长。
• NOVEL N-SUBSTITUTED UREA INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0989979A1

  公开（公告）日：2000-04-05
• US6358968B1
  申请人：——

  公开号：US6358968B1

  公开（公告）日：2002-03-19
• US6699872B2
  申请人：——

  公开号：US6699872B2

  公开（公告）日：2004-03-02