6-(indole-2-sulfonyl)-2H-pyridazin-3-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 6-(indole-2-sulfonyl)-2H-pyridazin-3-one
• 英文别名: 6-(1H-indole-2-sulfonyl)-2,3-dihydropyridazin-3-one；3-(1H-indol-2-ylsulfonyl)-1H-pyridazin-6-one
• 化学式: C₁₂H₉N₃O₃S
• 分子量: 275.288
• InChiKey: HXNAGYMCTAINEA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  99.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6-(indole-2-sulfenyl)-3-methoxypyridazine 在 盐酸 、 间氯过氧苯甲酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 6-(indole-2-sulfonyl)-2H-pyridazin-3-one
  参考文献：
  名称：

  A Highly Selective, Non-Hydantoin, Non-Carboxylic Acid Inhibitor of Aldose Reductase with Potent Oral Activity in Diabetic Rat Models:  6-(5-Chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one

  摘要：

  We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED90 values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).

  DOI：

  10.1021/jm034065z
• 作为试剂：
  描述：

  6-(indole-2-sulfonyl)-3-methoxypyridazine 、 盐酸 在 水 、 6-(indole-2-sulfonyl)-2H-pyridazin-3-one 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 6-(indole-2-sulfonyl)-2H-pyridazin-3-one
  参考文献：
  名称：

  Pyridazinone aldose reductase inhibitors

  摘要：

  本发明涉及新型吡啶二酮化合物，包括这些化合物的制药组合物以及使用这些化合物和组合物的方法，以抑制醛固酮还原酶，降低山梨醇水平，从而降低果糖水平，并/或治疗或预防哺乳动物的糖尿病并发症，如糖尿病神经病变，糖尿病视网膜病变，糖尿病肾病，糖尿病心肌病，糖尿病微血管病和糖尿病大血管病。本发明还涉及为未患糖尿病的受试者提供心脏保护的方法。本发明还涉及制药组合物和工具包，其中包括本发明的醛固酮还原酶抑制剂（ARI）和山梨醇脱氢酶抑制剂的组合物，以及使用这些组合物或工具包来治疗或预防哺乳动物的上述糖尿病并发症的方法。本发明还涉及与本发明的ARI的其他组合物，包括与腺苷受体激动剂的组合物；NHE-1抑制剂；肝醇磷酸化酶抑制剂；选择性5-羟色胺再摄取抑制剂；GABA激动剂；降压药物；3-羟基-3-甲基谷氨酸共价酶A还原酶抑制剂；磷酸二酯酶-5抑制剂；以及降糖药物的组合物。

  公开号：

  US07572910B2

文献信息

• [EN] PYRIDAZINONE ALDOSE REDUCTASE INHIBITORS<br/>[FR] INHIBITEURS PYRIDAZINONE D'ALDOSE RÉDUCTASE
  申请人：PFIZER PROD INC

  公开号：WO2002079198A1

  公开（公告）日：2002-10-10

  The present invention relates to novel pyridazinone compounds, pharmaceutical compositions comprising those compounds and to methods of using such compounds and compositions to inhibit aldose reductase, lower sorbitol levels and, thus, lower fructose levels, and/or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to methods of affording cardioprotection to subjects not suffering from diabetes. This invention also relates to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI) of this invention and a sorbitol dehydrogenase inhibitor and to methods of using such compositions or kits to treat or prevent the above diabetic complications in mammals. This invention also relates to other combinations with the ARIs of this invention, including combinations with adenosine agonists; NHE-1 inhibitors; glycogen phosphorylase inhibitors; selective serotonin reuptake inhibitors; GABA agonists; antihypertensive agents; 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibitors; phosphodiesterase-5 inhibitors; and to glucose lowering agents.

  本发明涉及新型吡啶二酮化合物、包含这些化合物的制药组合物以及使用这些化合物和组合物的方法，以抑制醛糖还原酶、降低山梨醇水平，从而降低果糖水平，并/或治疗或预防哺乳动物的糖尿病并发症，如糖尿病神经病、糖尿病视网膜病、糖尿病肾病、糖尿病心肌病、糖尿病微血管病和糖尿病大血管病。本发明还涉及为非糖尿病患者提供心脏保护的方法。本发明还涉及包含本发明的醛糖还原酶抑制剂（ARI）和山梨醇脱氢酶抑制剂的组合物和工具箱，以及使用这些组合物或工具箱治疗或预防哺乳动物的上述糖尿病并发症的方法。本发明还涉及其他与本发明的ARI结合的组合物，包括与腺苷酸激动剂的组合物；NHE-1抑制剂；糖原磷酸化酶抑制剂；选择性5-羟色胺再摄取抑制剂；GABA激动剂；降压药物；3-羟基-3-甲基谷氨酰辅酶A还原酶抑制剂；磷酸二酯酶-5抑制剂；以及降血糖药物。
• [EN] COMBINATIONS OF ALDOSE REDUCTASE INHIBITORS AND CYCLOOXYGENASE-2 INHIBITORS<br/>[FR] COMBINAISONS D'INHIBITEURS D'ALDOSE REDUCTASE ET INHIBITEURS DE CYCLO-OXYGENASE 2
  申请人：PFIZER PROD INC

  公开号：WO2002087584A1

  公开（公告）日：2002-11-07

  This invention relates to pharmaceutical compositions and kits comprising pyridazinone compounds and cyclooxygenase-2 inhibitors, therapeutic methods of treatment or prevention of certain complications arising from diabetes mellitus in mammals and therapeutic methods of treatment or prevention of cardiac tissue ischemia in mammals.

  本发明涉及含有吡啶并咪唑酮化合物和环氧合酶-2抑制剂的药物组合物和套装，以及治疗或预防哺乳动物糖尿病引起的某些并发症和心脏组织缺血的治疗方法。
• Therapies relating to combinations of aldose reductase inhibitors and cyclooxygenase-2
  申请人：Pfizer Inc

  公开号：US20040198740A1

  公开（公告）日：2004-10-07

  This invention relates to pharmaceutical compositions and kits comprising pyridazinone compounds and cyclooxygenase-2 inhibitors, therapeutic methods of treatment or prevention of certain complications arising from diabetes mellitus in mammals and therapeutic methods of treatment or prevention of cardiac tissue ischemia in mammals.

  本发明涉及药物组合物和工具包，包括吡啶并咪唑酮化合物和环氧合酶-2抑制剂，用于治疗或预防哺乳动物糖尿病引起的某些并发症的治疗方法和用于治疗或预防哺乳动物心脏组织缺血的治疗方法。
• THERAPIES RELATING TO COMBINATIONS OF ALDOSE REDUCTASE INHIBITORS AND CYCLOOXYGENASE-2 INHIBITORS
  申请人：Mylari L. Banavara

  公开号：US20050004124A1

  公开（公告）日：2005-01-06

  This invention relates to pharmaceutical compositions and kits comprising pyridazinone compounds and cyclooxygenase-2 inhibitors, therapeutic methods of treatment or prevention of certain complications arising from diabetes mellitus in mammals and therapeutic methods of treatment or prevention of cardiac tissue ischemia in mammals.

  本发明涉及含有吡啶并咪唑酮化合物和环氧合酶-2抑制剂的药物组合物和工具包，以及哺乳动物糖尿病引起的某些并发症的治疗或预防方法和哺乳动物心脏组织缺血的治疗或预防方法。
• A Novel Series of Non-Carboxylic Acid, Non-Hydantoin Inhibitors of Aldose Reductase with Potent Oral Activity in Diabetic Rat Models:  6-(5-Chloro-3-methylbenzofuran-2-sulfonyl)-2<i>H</i>-pyridazin-3-one and Congeners
  作者：Banavara L. Mylari、Sandra J. Armento、David A. Beebe、Edward L. Conn、James B. Coutcher、Michael S. Dina、Melissa T. O'Gorman、Michael C. Linhares、William H. Martin、Peter J. Oates、David A. Tess、Gregory J. Withbroe、William J. Zembrowski

  DOI：10.1021/jm050462t

  日期：2005.10.1

  Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 81, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t(1/2) (26 +/- 3 h).