[4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-2-methyl-piperazin-1-yl]-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone | 70918-27-3

• 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-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-2-methyl-piperazin-1-yl]-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone
• 英文别名: Methanone, [4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-methyl-1-piperazinyl](2,3-dihydro-1,4-benzodioxin-2-yl)-；[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-2-methylpiperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone
• CAS: 70918-27-3
• 化学式: C₂₄H₂₇N₅O₅
• 分子量: 465.509
• InChiKey: PZLDMJQEKRSBKQ-UHFFFAOYSA-N

物化性质

• 沸点：
  715.0±70.0 °C(Predicted)
• 密度：
  1.332±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-甲基哌嗪 以 二氯甲烷 、 正丁醇 为溶剂， 反应 19.0h， 生成 [4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-2-methyl-piperazin-1-yl]-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone
  参考文献：
  名称：

  2,4-Diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-Benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents

  摘要：

  A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.

  DOI：

  10.1021/jm00384a009

文献信息

• 2,4-Diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-Benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents
  作者：Simon F. Campbell、Michael J. Davey、J. David Hardstone、Brian N. Lewis、Michael J. Palmer

  DOI：10.1021/jm00384a009

  日期：1987.1

  A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.