4-(6,7-Dimethoxy-quinazolin-4-yl)-piperazine-1-carboxylic acid 4-nitro-phenyl ester | 205259-68-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperazine-1-carboxylic acid 4-nitro-phenyl ester
• 英文别名: (4-nitrophenyl) 4-(6,7-dimethoxyquinazolin-4-yl)piperazine-1-carboxylate
• CAS: 205259-68-3
• 化学式: C₂₁H₂₁N₅O₆
• 分子量: 439.428
• InChiKey: BBZNQHDXQDIMEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  123
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-氯苯乙胺 、 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperazine-1-carboxylic acid 4-nitro-phenyl ester 以 N-甲基吡咯烷酮 为溶剂， 反应 4.5h， 以70%的产率得到N-[2-(4-Chlorophenyl)ethyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide
  参考文献：
  名称：

  Potent and Selective Inhibitors of PDGF Receptor Phosphorylation. 2. Synthesis, Structure Activity Relationship, Improvement of Aqueous Solubility, and Biological Effects of 4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline Derivatives

  摘要：

  4-[4-(N-Substituted(thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.

  DOI：

  10.1021/jm0201114
• 作为产物：
  描述：

  对硝基苯基氯甲酸酯 、 6,7-二甲氧基-4-哌嗪-1-基-喹唑啉 在 三乙胺 作用下， 以 氯仿 为溶剂， 以75%的产率得到4-(6,7-Dimethoxy-quinazolin-4-yl)-piperazine-1-carboxylic acid 4-nitro-phenyl ester
  参考文献：
  名称：

  Potent and Selective Inhibitors of PDGF Receptor Phosphorylation. 2. Synthesis, Structure Activity Relationship, Improvement of Aqueous Solubility, and Biological Effects of 4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline Derivatives

  摘要：

  4-[4-(N-Substituted(thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.

  DOI：

  10.1021/jm0201114

文献信息

• Potent and Selective Inhibitors of PDGF Receptor Phosphorylation. 2. Synthesis, Structure Activity Relationship, Improvement of Aqueous Solubility, and Biological Effects of 4-[4-(<i>N</i>-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline Derivatives
  作者：Kenji Matsuno、Takao Nakajima、Michio Ichimura、Neill A. Giese、Jin-Chen Yu、Nathalie A. Lokker、Junko Ushiki、Shin-ichi Ide、Shoji Oda、Yuji Nomoto

  DOI：10.1021/jm0201114

  日期：2002.9.1

  4-[4-(N-Substituted(thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.