2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid | 920509-35-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid
• 英文别名: 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid；2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylic acid
• CAS: 920509-35-9
• 化学式: C₁₇H₁₃Cl₂N₅O₆
• 分子量: 454.226
• InChiKey: CJGUAIIQEIRSNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  150
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 在 盐酸 、 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 生成 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione
  参考文献：
  名称：

  [EN] MODULATORS OF THR-β AND METHODS OF USE THEREOF
  [FR] MODULATEURS DE THR-β ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  公开号：

  WO2020227549A8
• 作为产物：
  描述：

  2,6-二氯-4-氨基苯酚 在 盐酸 、 sodium nitrate 、 copper(l) iodide 、 sodium acetate 、 potassium carbonate 、 溶剂黄146 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 122.0h， 生成 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid
  参考文献：
  名称：

  Discovery of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β Agonist in Clinical Trials for the Treatment of Dyslipidemia

  摘要：

  The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor beta (THR-beta) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor alpha (THR-alpha). A pyridazinone series has been identified that is significantly more THR-beta selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-beta over THR-alpha in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

  DOI：

  10.1021/jm4019299

文献信息

• [EN] THYROID HORMONE RECEPTOR AGONISTS<br/>[FR] AGONISTES DU RÉCEPTEUR DES HORMONES THYROÏDIENNES
  申请人：INVENTISBIO SHANGHAI LTD

  公开号：WO2020073974A1

  公开（公告）日：2020-04-16

  Provided herein are novel thyroid hormone receptor (TR) agonists, e. g., having Formula I, II, or III. Also provided are methods of preparing the novel TR agonists and method of using the novel TR agonists for treating diseases or disorder modulated by TR agonists, such as NAFLD, NASH, diabetes, hyperlipidemia and/or hypercholesterolemia.

  本文提供了新型甲状腺激素受体（TR）激动剂，例如具有公式I、II或III的激动剂。还提供了制备新型TR激动剂的方法以及利用新型TR激动剂治疗由TR激动剂调节的疾病或紊乱的方法，例如NAFLD、NASH、糖尿病、高脂血症和/或高胆固醇血症。
• THYROID HORMONE ANALOGS
  申请人：Haynes Nancy-Ellen

  公开号：US20090005383A1

  公开（公告）日：2009-01-01

  Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes and other related disorders and diseases, and may be useful for other diseases such as NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and other disorders and diseases related thereto.

  本文提供了公式（I）的化合物，以及其药学上可接受的盐，其中取代基如说明书所披露的那样。这些化合物和含有它们的药物组合物对于治疗肥胖症、高脂血症、高胆固醇血症和糖尿病以及其他相关疾病和疾病非常有用，并且可能对于其他疾病，如NASH，动脉粥样硬化，心血管疾病，甲状腺功能减退症，甲状腺癌和其他相关的疾病和疾病也有用。
• Thyroid hormone analogs
  申请人：Haynes Nancy-Ellen

  公开号：US20070032494A1

  公开（公告）日：2007-02-08

  Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes and other related disorders and diseases, and may be useful for other diseases such as NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and other disorders and diseases related thereto.

  本文提供的化合物公式(I)及其药学上可接受的盐，其中取代基如规范中所述。这些化合物及其含有的药物组成物，可用于治疗肥胖症、高脂血症、高胆固醇血症、糖尿病和其他相关疾病，也可能对NASH、动脉粥样硬化、心血管疾病、甲状腺功能减退症、甲状腺癌和其他相关疾病有用。
• 1,2,4-TRIAZINE-3,5-DIONE COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
  申请人：KPC Pharmaceuticals, Inc.

  公开号：EP4083024A1

  公开（公告）日：2022-11-02

  The present invention provides a 1,2,4-triazine-3,5-dione compound, a preparation method therefor, and an application thereof. The 1,2,4-triazine-3,5-dione compound having a structure represented by formula (I) provided by present invention has a selective agonistic effect on THRβ, and the activity, selectivity, and metabolic stability thereof have significant advantages over disclosed compounds, and can function as a therapeutic and/or preventive drug for thyroid hormone receptor related diseases, comprising, but not limited to, obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, liver steatosis, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism, and thyroid cancer.

  本发明提供了一种1,2,4-三嗪-3,5-二酮化合物、其制备方法和应用。本发明提供的具有式(I)所表示结构的1,2,4-三嗪-3,5-二酮化合物具有对THRβ的选择性激动作用，并且其活性、选择性和代谢稳定性具有明显优势，可作为治疗和/或预防甲状腺激素受体相关疾病的药物，包括但不限于肥胖症、糖尿病、高胆固醇血症、高脂血症、高甘油三酯血症、肝脂肪变性、非酒精性脂肪肝病、非酒精性脂肪性肝炎、家族性高胆固醇血症、脂质代谢异常、动脉硬化、甲状腺功能减退症和甲状腺癌等。
• [EN] SALT FORM AND CRYSTAL FORM OF 1,2,4-TRIAZINE-3,5-DIONE COMPOUND, AND PREPARATION METHOD THEREFOR<br/>[FR] FORME SALINE ET FORME CRISTALLINE DE COMPOSÉ DE 1,2,4-TRIAZINE-3,5-DIONE ET LEUR PROCÉDÉ DE PRÉPARATION<br/>[ZH] 一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法
  申请人：KPC PHARMACEUTICALS INC

  公开号：WO2022194073A1

  公开（公告）日：2022-09-22

  本发明公开了一种1，2，4-三嗪-3，5-二酮类(式I)化合物的盐型、晶型及其制备方法，其在治疗和或药物制备中的用途，所述的用途是治疗与甲状腺激素受体相关的疾病。