1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine | 178309-12-1

• 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-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine
• 英文别名: (3-Chloro-4-methoxy-benzyl)-(4-chloro-7-nitro-phthalazin-1-yl)-amine；4-chloro-N-[(3-chloro-4-methoxyphenyl)methyl]-7-nitrophthalazin-1-amine
• CAS: 178309-12-1
• 化学式: C₁₆H₁₂Cl₂N₄O₃
• 分子量: 379.202
• InChiKey: SHCVFTMYELJHHC-UHFFFAOYSA-N

物化性质

• 沸点：
  622.1±50.0 °C(Predicted)
• 密度：
  1.517±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  92.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-羟基哌啶 、 1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine 在 N-甲基吡咯烷酮 、 N,N-二异丙基乙胺 作用下， 反应 4.5h， 生成 1-[4-(3-Chloro-4-methoxy-benzylamino)-6-nitro-phthalazin-1-yl]-piperidin-4-ol
  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
• 作为产物：
  描述：

  4-硝基邻苯二甲酰肼 在 i-PrEtN 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 反应 9.0h， 生成 1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine
  参考文献：
  名称：

  4-Benzylamino-1-chloro-6-substituted Phthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

  摘要：

  We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the B-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F-2 alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.

  DOI：

  10.1021/jm970815r

文献信息

• Fused pyridazine compounds
  申请人：Eisai Co., Ltd.

  公开号：US05849741A1

  公开（公告）日：1998-12-15

  A fused pyridazine compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof which exhibits an inhibitory activity against cyclic GMP phosphodiesterase (hereinafter referred to as "cGMP-PDE"). The compounds are useful as preventive and therapeutic agents for diseases for which a cGMP-PDE inhibiting action is efficacious, for example, ischemic heart diseases such as angina pectoris, myocardial infarct and chronic and acute cardiac failure, pulmonary hypertension, arteriosclerosis and bronchial asthma. ##STR1##

  以下是一种融合吡啶并嘧啶化合物，其化学式如下（I），或其药理学上可接受的盐，具有对环磷酸鸟苷磷酸二酯酶（以下简称“cGMP-PDE”）的抑制活性。这些化合物可用作预防和治疗剂，用于对于cGMP-PDE抑制活性有效的疾病，例如缺血性心脏病，如心绞痛，心肌梗死和慢性和急性心衰，肺动脉高压，动脉硬化和支气管哮喘。##STR1##
• FUSED PYRIDAZINE COMPOUND
  申请人：Eisai Co., Ltd.

  公开号：EP0722936A1

  公开（公告）日：1996-07-24

  A fused pyridazine compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof which exhibits an inhibitory activity against cyclic GMP phosphodiesterase (hereinafter referred to as "cGMP-PDE"). The compounds are useful as preventive and therapeutic agents for diseases for which a cGMP-PDE inhibiting action is efficacious, for example, ischemic heart diseases such as angina pectoris, myocardial infarct and chronic and acute cardiac failure, pulmonary hypertension, arteriosclerosis and bronchial asthma.

  由以下通式（I）代表的融合哒嗪化合物或其药理学上可接受的盐，对环 GMP 磷酸二酯酶（以下简称 "cGMP-PDE"）具有抑制活性。 这些化合物可作为 cGMP-PDE 抑制作用有效的疾病的预防和治疗药物，例如缺血性心脏病，如心绞痛、心肌梗塞、慢性和急性心力衰竭、肺动脉高压、动脉硬化和支气管哮喘。
• US5849741A
  申请人：——

  公开号：US5849741A

  公开（公告）日：1998-12-15
• US6218392B1
  申请人：——

  公开号：US6218392B1

  公开（公告）日：2001-04-17
• 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.