1-{4-[3,5-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl}-ethanol

• 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: 1-{4-[3,5-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl}-ethanol
• 英文别名: 1-{4-[4-(4-phenyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-[1,3,5]triazin-2-yl}-ethanol；1-[4-[(3S,5R)-3,5-dimethyl-4-(4-phenyl-1,3,5-triazin-2-yl)piperazin-1-yl]-1,3,5-triazin-2-yl]ethanol
• 化学式: C₂₀H₂₄N₈O
• 分子量: 392.464
• InChiKey: HSFMIPIHXPWRRO-YIONKMFJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2,6-dimethylpiperazine 在 palladium on activated charcoal 盐酸 、 ammonium formate 、 三溴化硼 、 碳酸氢钠 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 8.5h， 生成 1-{4-[3,5-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl}-ethanol
  参考文献：
  名称：

  Design and synthesis of a novel family of triazine-based inhibitors of sorbitol dehydrogenase with oral activity: 1-?4-[3R,5S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl?-(R) ethanol

  摘要：

  Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10 mg/kg. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00490-5

文献信息

• Novel triazine compounds useful as sorbitol dehydrogenase inhibitors
  申请人：——

  公开号：US20030004166A1

  公开（公告）日：2003-01-02

  This invention is directed to sorbitol dehydrogenase inhibitory compounds of formula I 1 wherein R 1 , R 2 and R 3 are as defined in the specification. This invention is also directed to pharmaceutical compositions containing these compounds which inhibit sorbitol dehydrogenase and to methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, diabetic cardiomyopathy and foot ulcers, 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 the present invention with a second pharmaceutical agent, including an aldose reductase inhibitor, a sodium hydrogen ion exchange (NHE-1) inhibitor, a glycogen phosphorylase inhibitor (GPI), a selective serotonin reuptake inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, an angiotensin converting enzyme inhibitor, a thiazolidinedione antidiabetic agent, an angiotensin 11 receptor antagonist, a &ggr;-aminobutyric acid (GABA) agonist, a phosphodiesterase type 5 inhibitor, an adenosine agonist, and a CETP inhibitor and to methods of using these combination compositions.

  这项发明涉及到化合物的抑制山梨醇脱氢酶的公式I1，其中R1、R2和R3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，其抑制山梨醇脱氢酶，并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的方法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、糖尿病微血管病、糖尿病大血管病、糖尿病心肌病和足部溃疡。这项发明还涉及含有本发明公式I的化合物与第二药物剂的组合的药物组合物，包括醛糖还原酶抑制剂、钠氢离子交换（NHE-1）抑制剂、糖原磷酸化酶抑制剂（GPI）、选择性5-羟色胺再摄取抑制剂、3-羟基-3-甲基戊二酸辅酶A还原酶抑制剂、血管紧张素转换酶抑制剂、噻唑烷二酮抗糖尿病药物、血管紧张素II受体拮抗剂、γ-氨基丁酸（GABA）激动剂、磷酸二酯酶5抑制剂、腺苷激动剂和CETP抑制剂，以及使用这些组合组合物的方法。
• Triazine compounds useful as sorbitol dehydrogenase inhibitors
  申请人：Pfizer Products Inc.

  公开号：EP1247809A2

  公开（公告）日：2002-10-09

  This invention is directed to sorbitol dehydrogenase inhibitory compounds of formula I wherein R1, R2 and R3 are as defined in the specification. This invention is also directed to pharmaceutical compositions containing these compounds which inhibit sorbitol dehydrogenase and to methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, diabetic cardiomyopathy and foot ulcers, 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 the present invention with a second pharmaceutical agent, including an aldose reductase inhibitor, a sodium hydrogen ion exchange (NHE-1) inhibitor, a glycogen phosphorylase inhibitor (GPI), a selective serotonin reuptake inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, an angiotensin converting enzyme inhibitor, a thiazolidinedione antidiabetic agent, an angiotensin II receptor antagonist, a γ-aminobutyric acid (GABA) agonist, a phosphodiesterase type 5 inhibitor, an adenosine agonist, and a CETP inhibitor and to methods of using these combination compositions.

  本发明涉及式 I 的山梨醇脱氢酶抑制性化合物 其中 R1、R2 和 R3 如说明书中所定义。本发明还涉及含有这些抑制山梨醇脱氢酶的化合物的药物组合物，以及通过向患有糖尿病并因此有可能患上此类并发症的哺乳动物施用此类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、糖尿病微血管病变、糖尿病大血管病变、糖尿病心肌病和足部溃疡的方法。本发明还涉及药物组合物，该组合物包含本发明式 I 化合物与第二种药物制剂的组合，第二种药物制剂包括醛糖还原酶抑制剂、氢离子交换钠（NHE-1）抑制剂、糖原磷酸化酶抑制剂（GPI）、选择性 5-羟色胺再摄取抑制剂、3-羟基-3-甲基-2-巯基乙醇抑制剂、3-羟基-3-甲基-2-巯基乙醇抑制剂、3-羟基-3-甲基-2-巯基乙醇抑制剂、3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂、血管紧张素转换酶抑制剂、噻唑烷二酮类抗糖尿病剂、血管紧张素 II 受体拮抗剂、γ-氨基丁酸（GABA）激动剂、5 型磷酸二酯酶抑制剂、腺苷激动剂和 CETP 抑制剂，以及使用这些组合物的方法。
• US6894047B2
  申请人：——

  公开号：US6894047B2

  公开（公告）日：2005-05-17
• Design and synthesis of a novel family of triazine-based inhibitors of sorbitol dehydrogenase with oral activity: 1-?4-[3R,5S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl?-(R) ethanol
  作者：B Mylari

  DOI：10.1016/s0968-0896(03)00490-5

  日期：2003.9.15

  Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10 mg/kg. (C) 2003 Elsevier Ltd. All rights reserved.