4-[(3-chloro-4-methoxybenzyl)amino]-1-(1,2,3,6-tetrahydro-1-pyridinyl)-6-phthalazine carbonitrile

• 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: 4-[(3-chloro-4-methoxybenzyl)amino]-1-(1,2,3,6-tetrahydro-1-pyridinyl)-6-phthalazine carbonitrile
• 英文别名: 4-(3-Chloro-4-methoxy-benzylamino)-1-(3,6-dihydro-2H-pyridin-1-yl)-phthalazine-6-carbonitrile; hydrochloride；4-[(3-chloro-4-methoxyphenyl)methylamino]-1-(3,6-dihydro-2H-pyridin-1-yl)phthalazine-6-carbonitrile
• 化学式: C₂₂H₂₀ClN₅O
• 分子量: 405.887
• InChiKey: MOBLCRUCOTWZAS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  74.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1,2,3,6-四氢吡啶 、 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine 在 N-甲基吡咯烷酮 、 N,N-二异丙基乙胺 作用下， 反应 4.5h， 以55%的产率得到4-[(3-chloro-4-methoxybenzyl)amino]-1-(1,2,3,6-tetrahydro-1-pyridinyl)-6-phthalazine carbonitrile
  参考文献：
  名称：

  4-(3-Chloro-4-methoxybenzyl)aminophthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

  摘要：

  We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2 alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 mu g/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

  DOI：

  10.1021/jm9905054

文献信息

• 4-(3-Chloro-4-methoxybenzyl)aminophthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5
  作者：Nobuhisa Watanabe、Hideyuki Adachi、Yasutaka Takase、Hirofumi Ozaki、Masayuki Matsukura、Kazuki Miyazaki、Keiji Ishibashi、Hiroki Ishihara、Kohtarou Kodama、Mayu Nishino、Motoharu Kakiki、Yasuhiro Kabasawa

  DOI：10.1021/jm9905054

  日期：2000.6.1

  We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2 alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 mu g/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.