N-(4-chlorophenyl)-4-phenylphthalazin-1-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-(4-chlorophenyl)-4-phenylphthalazin-1-amine
• 化学式: C₂₀H₁₄ClN₃
• 分子量: 331.804
• InChiKey: AAUGIQYXZOLAEN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1,4-二氯酞嗪 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 乙醇 、 水 、 异丙醇 、 甲苯 为溶剂， 反应 1.0h， 生成 N-(4-chlorophenyl)-4-phenylphthalazin-1-amine
  参考文献：
  名称：

  Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model

  摘要：

  Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50=3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.026

文献信息

• PYRIDAZINE AND PHTHALAZINE DERIVATIVES, PROCESS OF THEIR PREPARATION AND THEIR USE AS ANTICONVULSANTS
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0975605A1

  公开（公告）日：2000-02-02
• US6207666B1
  申请人：——

  公开号：US6207666B1

  公开（公告）日：2001-03-27
• [EN] PYRIDAZINE AND PHTHALAZINE DERIVATIVES, PROCESS OF THEIR PREPARATION AND THEIR USE AS ANTICONVULSANTS<br/>[FR] DERIVES DE PYRIDAZINE ET DE PHTALAZINE, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION COMME ANTI-CONVULSIFS
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1998046574A1

  公开（公告）日：1998-10-22

  (EN) A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS) comprises administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof in which the ring system Q is pyridazinyl or phthalazinyl; the ring system P is phenyl or pyridyl; R1 is hydrogen, C1-6 alkyl, phenyl or C1-6 alkylphenyl; R2 is hydrogen or C1-6 alkyl; R3 is hydrogen or up to three substituents selected from halogen, CN, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, phenyl, phenoxy, phenylC1-4alkyl, benzyloxy, or benzoyl.(FR) L'invention concerne un procédé de traitement ou de prophylaxie des maladies ou troubles suivants: anxiété, manie, dépression, troubles paniques ou comportement agressif, troubles associés à une hémorragie sous-arachnoïdienne ou à un choc nerveux, effets associés au sevrage de substances donnant lieu à des abus telles que cocaïne, nicotine, alcool et benzodiazépines, troubles pouvant être traités ou prévenus avec des agents anti-convulsifs tels que épilepsie incluant l'épilepsie post-traumatique, maladie de Parkinson, psychose, migraine, ischémie cérébrale, maladie d'Alzheimer et autres maladies dégénératives telles que chorée de Huntington, schizophrénie, troubles obsessionnels-compulsifs, déficits neurologiques associés au SIDA, troubles du sommeil (incluant troubles du rythme circadien, insomnie et narcolepsie), tics (maladie de Gilles de la Tourette, par exemple), lésion traumatique du cerveau, acouphène, névralgie, en particulier névralgie faciale, douleur névropathique, douleur dentaire, douleur cancéreuse, activité nerveuse inappropriée causant des neurodysthésies dans des maladies telles que diabète, sclérose en plaques et maladie du motoneurone, ataxies, rigidité musculaire (hypertonie spastique), dysfonction temporo-mandibulaire et sclérose latérale amyotrophique. Ce procédé comprend l'administration à la personne souffrante en ayant besoin d'une quantité active ou prophylactique d'un composé de formule (I) ou d'un sel ou solvate acceptable pharmaceutiquement de ce composé. Dans la formule (I), le système cyclique Q représente pyridazinyle ou phtalazinyle, le système cyclique P représente phényle ou pyridyle, R1 représente hydrogène, alkyle C1-6, phényle ou alkyle C1-6 phényle, R2 représente hydrogène ou alkyle C1-6, R3 représente hydrogène ou jusqu'à trois substituants sélectionnés dans le groupe halogène, CN, trifluorométhyle, trifluorométhoxy, alkyle C1-6, alcoxy C1-6, alkyle C1-6 carbonyle, alcoxy C1-6 carbonyle, phényle, phénoxy, phénylalkyle C1-4, benzyloxy ou benzoyle.
• Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model
  作者：Maud Bollenbach、Claire Lugnier、Mélanie Kremer、Eric Salvat、Salim Megat、Frédéric Bihel、Jean-Jacques Bourguignon、Michel Barrot、Martine Schmitt

  DOI：10.1016/j.ejmech.2019.05.026

  日期：2019.9

  Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50=3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment. (C) 2019 Elsevier Masson SAS. All rights reserved.