1-(4-chlorobenzoyl)-4-(3-pyridinylacetyl)piperazine

• 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: 1-(4-chlorobenzoyl)-4-(3-pyridinylacetyl)piperazine
• 英文别名: 1-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-2-pyridin-3-yl-ethanone；1-[4-(4-chlorobenzoyl)piperazin-1-yl]-2-pyridin-3-ylethanone
• 化学式: C₁₈H₁₈ClN₃O₂
• 分子量: 343.813
• InChiKey: AQIKNWJBMPQSJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  53.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-(2-pyridin-3-ylacetyl)piperazine-1-carboxylic acid tert-butyl ester 在 硫酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 1.5h， 生成 1-(4-chlorobenzoyl)-4-(3-pyridinylacetyl)piperazine
  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

• Inhibitors of Farnesyl Protein Transferase. 4-Amido, 4-Carbamoyl, and 4-Carboxamido Derivatives of 1-(8-Chloro-6,11-dihydro-5<i>H</i>-benzo[5,6]- cyclohepta[1,2-<i>b</i>]pyridin-11-yl)piperazine and 1-(3-Bromo-8-chloro-6,11- dihydro-5<i>H</i>-benzo[5,6]cyclohepta[1,2-<i>b</i>]pyridin-11-yl)piperazine
  作者：Alan K. Mallams、Randall R. Rossman、Ronald J. Doll、Viyyoor M. Girijavallabhan、Ashit K. Ganguly、Joanne Petrin、Lynn Wang、Robert Patton、W. Robert Bishop、Donna M. Carr、Paul Kirschmeier、Joseph J. Catino、Matthew S. Bryant、Kwang-Jong Chen、Walter A. Korfmacher、Cymbelene Nardo、Shiyong Wang、Amin A. Nomeir、Chin-Chung Lin、Zujun Li、Jianping Chen、Suining Lee、Janet Dell、Philip Lipari、Michael Malkowski、Bodan Yaremko、Ivan King、Ming Liu

  DOI：10.1021/jm970462w

  日期：1998.3.1

  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.