[1-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperidin-4-yl]-morpholin-4-yl-methanone | 108297-13-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: [1-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperidin-4-yl]-morpholin-4-yl-methanone
• 英文别名: [1-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-morpholin-4-ylmethanone
• CAS: 108297-13-8
• 化学式: C₂₀H₂₇N₅O₄
• 分子量: 401.465
• InChiKey: WWHOAVVMDSXQOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-哌啶甲酸 在 3 A molecular sieve 、 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 甲苯 为溶剂， 反应 29.0h， 生成 [1-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperidin-4-yl]-morpholin-4-yl-methanone
  参考文献：
  名称：

  2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents

  摘要：

  A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.

  DOI：

  10.1021/jm00389a007

文献信息

• Piperidinoquinazolines and a process for the preparation thereof
  申请人：ORION-YHTYMÄ OY

  公开号：EP0034471A1

  公开（公告）日：1981-08-26

  Novel substituted 2-piperidino-4-amino-6,7-dimethoxy-quinazolines having the formula wherein R is an alkyl containing 1 to 5 carbons, a cycloalkyl containing 3 to 7 carbons, benzyl, an alkoxy containing 1 to 5 carbons, benzyloxy, or a group -NR1R2, wherein R1 or R2 is hydrogen or a chained alkyl containing 4 to 5 carbons or wherein R1 and R2, together with the nitrogen atom, form a cyclic amino group containing 3 to 7 carbons, which amino group may be substituted by one or two lower-alkyl groups, or their pharmaceutically acceptable salts.

  新型取代的 2-哌啶基-4-氨基-6,7-二甲氧基喹唑啉，其式如下 其中 R 是含 1 至 5 个碳原子的烷基、含 3 至 7 个碳原子的环烷基、苄基、含 1 至 5 个碳原子的烷氧基、苄氧基或基团-NR1R2，其中 R1 或 R2 是氢或含 4 至 5 个碳原子的链状烷基，或 R1 和 R2 与氮原子一起形成含 3 至 7 个碳原子的环状氨基，该氨基可被一个或两个低级烷基取代，或它们的药学上可接受的盐。
• 2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents
  作者：Valerie A. Alabaster、Simon F. Campbell、John C. Danilewicz、Colin W. Greengrass、Rhona M. Plews

  DOI：10.1021/jm00389a007

  日期：1987.6

  A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.