4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic acid dimethylamide | 299396-99-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic acid dimethylamide
• 英文别名: 4-[2-(1-hydroxyethyl)pyrimidin-4-yl]-N,N-dimethylpiperazine-1-sulfonamide
• CAS: 299396-99-9
• 化学式: C₁₂H₂₁N₅O₃S
• 分子量: 315.396
• InChiKey: CALZSMZYNXWGJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  98.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  乙酸乙烯酯 、 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic acid dimethylamide 在 Lipase P₃₀ 作用下， 以 乙二醇二甲醚 为溶剂， 反应 336.0h， 以43%的产率得到[(1R)-1-[4-[4-(dimethylsulfamoyl)piperazin-1-yl]pyrimidin-2-yl]ethyl] acetate
  参考文献：
  名称：

  Sorbitol Dehydrogenase Inhibitors (SDIs):  A New Potent, Enantiomeric SDI, 4-[2-1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic Acid Dimethylamide

  摘要：

  We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure-activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10x more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.

  DOI：

  10.1021/jm0102001
• 作为产物：
  描述：

  4-[2-(羟甲基)嘧啶-4-基]-N,N-二甲基哌嗪-1-磺酰胺 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic acid dimethylamide
  参考文献：
  名称：

  Sorbitol Dehydrogenase Inhibitors (SDIs):  A New Potent, Enantiomeric SDI, 4-[2-1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic Acid Dimethylamide

  摘要：

  We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure-activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10x more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.

  DOI：

  10.1021/jm0102001

文献信息

• Compounds for treating and preventing diabetic complications
  申请人：Pfizer Inc.

  公开号：US06294538B1

  公开（公告）日：2001-09-25

  This invention is directed to sorbitol dehydrogenase inhibitory compounds of the formula I, wherein R is as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds and methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy and diabetic cardiomyopathy by administering such compounds to a mammal suffering from diabetes and therefore at risk for developing such complications. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an aldose reductase inhibitor and to methods of treating or preventing diabetic complications therewith. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an NHE-1 inhibitor and to methods of treating cardiomyopathy and other heart-related problems therewith. This invention is also directed to certain intermediates used in the synthesis of the compounds of formula I and to processes for preparing those intermediates.

  这项发明涉及式I的山梨醇脱氢酶抑制化合物，其中R如规范中所定义。这项发明还涉及含有这些化合物的药物组合物，以及通过向患有糖尿病且因此有发生这些并发症风险的哺乳动物施用这些化合物来治疗或预防糖尿病并发症，特别是糖尿病神经病变、糖尿病肾病和糖尿病心肌病。这项发明还涉及含有本发明式I化合物与醛糖还原酶抑制剂的组合物的药物组合物，以及用于治疗或预防糖尿病并发症的方法。这项发明还涉及含有本发明式I化合物与NHE-1抑制剂的组合物的药物组合物，以及用于治疗心肌病和其他心脏相关问题的方法。这项发明还涉及用于合成式I化合物的某些中间体以及制备这些中间体的方法。
• JP2000297075A
  申请人：——

  公开号：JP2000297075A

  公开（公告）日：2000-10-24
• US6294538B1
  申请人：——

  公开号：US6294538B1

  公开（公告）日：2001-09-25
• Sorbitol Dehydrogenase Inhibitors (SDIs):  A New Potent, Enantiomeric SDI, 4-[2-1<i>R</i>-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic Acid Dimethylamide
  作者：Banavara L. Mylari、Peter J. Oates、David A. Beebe、Nathaniel S. Brackett、James B. Coutcher、Michael S. Dina、William J. Zembrowski

  DOI：10.1021/jm0102001

  日期：2001.8.1

  We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure-activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10x more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.