3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole | 680611-18-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole
• 英文别名: 3-(2,4-dimethoxyphenyl)-7-trifluoromethyl-1H-indazole；3-(2,4-methoxyphenyl)-7-trifluoromethyl-1H-indazole；3-(2,4-methoxyphenyl)-7-trifluoromethyl-lH-indazole；3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-2H-indazole
• CAS: 680611-18-1；875795-86-1
• 化学式: C₁₆H₁₃F₃N₂O₂
• 分子量: 322.287
• InChiKey: XUKSJOBSGNPSNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  47.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole 在 三溴化硼 、 sodium hydride 作用下， 以 二氯甲烷 、 环己烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 9.0h， 生成 2-[1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol
  参考文献：
  名称：

  Development of a Selective Modulator of Aryl Hydrocarbon (Ah) Receptor Activity that Exhibits Anti-Inflammatory Properties

  摘要：

  The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAAI) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAAI gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.

  DOI：

  10.1021/tx100045h
• 作为产物：
  描述：

  magnesium,1,3-dimethoxybenzene-6-ide,bromide 在 吡啶 、 肼 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole
  参考文献：
  名称：

  Development of a Selective Modulator of Aryl Hydrocarbon (Ah) Receptor Activity that Exhibits Anti-Inflammatory Properties

  摘要：

  The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAAI) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAAI gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.

  DOI：

  10.1021/tx100045h

文献信息

• [EN] METHOD OF TREATING RHEUMATOID ARTHRITIS USING NF-kB INHIBITORS<br/>[FR] METHODE PERMETTANT DE TRAITER L'ARTHRITE RHUMATOIDE A L'AIDE D'INHIBITEURS DE NF-KB
  申请人：WYETH CORP

  公开号：WO2005039583A1

  公开（公告）日：2005-05-06

  The present invention concerns a method of treating rheumatoid arthritis by diagnosing that a person is in need of treatment for rheumatoid arthritis and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER-α, estrogen receptor ER-β, or both ER-α and ER- β estrogen receptors with a substantial absence of creatine kinase stimulation. In certain embodiments, the administration is with a substantial absence of uterotropic activity.

  本发明涉及一种治疗类风湿性关节炎的方法，通过诊断一个人需要治疗类风湿性关节炎，并且通过与雌激素受体ER-α、雌激素受体ER-β或ER-α和ER-β雌激素受体中的一个相互作用来给予调节NF-kB转录因子的配体的治疗有效量，且在很大程度上缺乏肌酸激酶的刺激。在某些实施例中，给药在很大程度上缺乏子宫营养活性。
• Methods of treating rheumatoid arthritis using NF-kB inhibitors
  申请人：Harnish Carl Douglas

  公开号：US20050113405A1

  公开（公告）日：2005-05-26

  The present invention concerns a method of treating rheumatoid arthritis by diagnosing that a person is in need of treatment for rheumatoid arthritis and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER-α, estrogen receptor ER-β, or both ER-α and ER-β estrogen receptors with a substantial absence of creatine kinase stimulation. In certain embodiments, the administration is with a substantial absence of uterotropic activity.

  本发明涉及一种治疗类风湿性关节炎的方法，通过诊断一个人需要治疗类风湿性关节炎，并且通过与雌激素受体ER-α、雌激素受体ER-β或ER-α和ER-β雌激素受体中的一个相互作用来给予调节NF-kB转录因子的配体的治疗有效量，且在很大程度上缺乏肌酸激酶的刺激。在某些实施例中，给药时很大程度上缺乏子宫营养活性。
• [EN] USE OF ESTROGEN RECEPTOR LIGANDS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE<br/>[FR] UTILISATION DE LIGANDS DE RECEPTEUR D'OESTROGENE POUR LE TRAITEMENT D'UNE MALADIE INTESTINALE INFLAMMATOIRE
  申请人：WYETH CORP

  公开号：WO2005039581A1

  公开（公告）日：2005-05-06

  The present invention concerns a method of treating inflammatory bowel disease by diagnosing that a person is in need of treatment for inflammatory bowel disease and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER-α, estrogen receptor ER-β, or both ER-α and ER-β estrogen receptors with a substantial absence of creatine kinase stimulation. In certain preferred embodiments, the administration is substantially without uterotropic activity.

  本发明涉及一种治疗炎症性肠病的方法，通过诊断一个人需要治疗炎症性肠病，并且通过与雌激素受体ER-α、雌激素受体ER-β或ER-α和ER-β雌激素受体中的任一相互作用来给予调节NF-kB转录因子的配体的治疗有效量，且在很大程度上缺乏肌酸激酶刺激。在某些优选实施方式中，给药基本上没有子宫营养活性。
• Method of treating or preventing myocardial ischemia-reperfusion injury using NF-kB inhibitors
  申请人：Chadwick Cyril Christopher

  公开号：US20060111421A1

  公开（公告）日：2006-05-25

  The present invention concerns a method of treatment or prevention of myocardial ischemia-reperfusion injury by diagnosing that a person is in need of treatment or prevention of myocardial ischemia-reperfusion injury and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER-α, estrogen receptor ER-β, or both ER-α and ER-β estrogen receptors with a substantial absence of creatine kinase stimulation. In certain preferred embodiments, the administration is substantially without uterotropic activity.

  本发明涉及一种治疗或预防心肌缺血再灌注损伤的方法，通过诊断一个人需要治疗或预防心肌缺血再灌注损伤，并通过与雌激素受体ER-α、雌激素受体ER-β或ER-α和ER-β雌激素受体中的一个或两个相互作用来给予调节NF-kB转录因子的配体的治疗有效量，其中刺激肌酸激酶的作用显著缺乏。在某些优选实施例中，给药基本上不具有子宫营养活性。
• [EN] METHODS OF TREATING ATHEROSCLEROSIS USING NF-kB INHIBITORS<br/>[FR] METHODES DE TRAITEMENT DE L'ATHEROSCLEROSE FAISANT APPEL A DES INHIBITEURS DE NF-KB
  申请人：WYETH CORP

  公开号：WO2005039582A1

  公开（公告）日：2005-05-06

  The present invention concerns a method of treating atherosclerosis by diagnosing that a person is in need of treatment for atherosclerosis and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER-α, estrogen receptor ER-β, or both ER-α and ER-β estrogen receptors with a substantial absence of creatine kinase stimulation. In certain preferred embodiments, the administration is substantially without uterotropic activity.

  本发明涉及一种治疗动脉粥样硬化的方法，通过诊断一个人需要接受动脉粥样硬化治疗，并通过与雌激素受体ER-α、雌激素受体ER-β或ER-α和ER-β雌激素受体中的一个相互作用来给予调节NF-kB转录因子的配体的治疗有效量，且在很大程度上缺乏肌酸激酶刺激。在某些优选实施例中，给药基本上不具有子宫营养活性。