1R-(4-{4-[2-(1R-butyryloxy-ethyl)pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}pyrimidin-2-yl)ethyl butyrate | 300551-74-0

• 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: 1R-(4-{4-[2-(1R-butyryloxy-ethyl)pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}pyrimidin-2-yl)ethyl butyrate
• 英文别名: [(1R)-1-[4-[(3R,5S)-4-[2-[(1R)-1-butanoyloxyethyl]pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethyl] butanoate
• CAS: 300551-74-0
• 化学式: C₂₆H₃₈N₆O₄
• 分子量: 498.626
• InChiKey: MFBZNMKLNAJURA-IYWMVGAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  111
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  1R-(4-{4-[2-(1R-butyryloxy-ethyl)pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}pyrimidin-2-yl)ethyl butyrate 在 manganese(IV) oxide 、 lithium hydroxide 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 9.0h， 生成 1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone
  参考文献：
  名称：

  山梨糖醇脱氢酶抑制剂CP-470,711的SAR和物种/立体选择性代谢。

  摘要：

  对CP-470,711立体异构体的SAR研究表明，大鼠体内发生了差向异构。进一步的代谢研究表明，在狗中没有发生差向异构化，并且在人类中没有期望的差向异构化。与化学合成过程中相同中心的酸/碱促进的差向异构化相反，提出了一种体内差向异构化的机制，涉及仲苄醇的氧化-还原途径。

  DOI：

  10.1016/s0960-894x(02)00208-1
• 作为产物：
  描述：

  (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate 在 10percent Pd/C 盐酸 、 甲酸铵 、 三乙胺 作用下， 以 甲醇 、 异丙醇 为溶剂， 反应 43.5h， 生成 1R-(4-{4-[2-(1R-butyryloxy-ethyl)pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}pyrimidin-2-yl)ethyl butyrate
  参考文献：
  名称：

  Orally-Effective, Long-Acting Sorbitol Dehydrogenase Inhibitors:  Synthesis, Structure−Activity Relationships, and in Vivo Evaluations of Novel Heterocycle-Substituted Piperazino-Pyrimidines

  摘要：

  Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for similar to17 h, when administered orally at a single dose of 2 mg/kg/day.

  DOI：

  10.1021/jm010440g

文献信息

• Sorbitol dehydrogenase inhibitors
  申请人：Pfizer Inc.

  公开号：US06414149B1

  公开（公告）日：2002-07-02

  This invention is directed to sorbitol dehydrogenase inhibitory compounds of the formula I, wherein R1, R2 and R3 are 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, diabetic microangiopathy, diabetic macroangiopathy 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.

  本发明涉及式I的山梨醇脱氢酶抑制化合物，其中R1、R2和R3如规范中定义。本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展这些并发症风险的哺乳动物投与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、糖尿病微血管病、糖尿病大血管病和糖尿病心肌病。本发明还涉及一种含有本发明式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。本发明还涉及一种含有本发明式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相关心脏问题的方法。本发明还涉及合成式I化合物的某些中间体以及制备这些中间体的方法。
• Orally-Effective, Long-Acting Sorbitol Dehydrogenase Inhibitors:  Synthesis, Structure−Activity Relationships, and in Vivo Evaluations of Novel Heterocycle-Substituted Piperazino-Pyrimidines
  作者：Margaret Y. Chu-Moyer、William E. Ballinger、David A. Beebe、Richard Berger、James B. Coutcher、Wesley W. Day、Jiancheng Li、Banavara L. Mylari、Peter J. Oates、R. Matthew Weekly

  DOI：10.1021/jm010440g

  日期：2002.1.1

  Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for similar to17 h, when administered orally at a single dose of 2 mg/kg/day.
• SAR and species/stereo-selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711
  作者：Margaret Y. Chu-Moyer、William E. Ballinger、David A. Beebe、James B. Coutcher、Wesley W. Day、Jiancheng Li、Peter J. Oates、R.Matthew Weekly

  DOI：10.1016/s0960-894x(02)00208-1

  日期：2002.6

  711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during

  对CP-470,711立体异构体的SAR研究表明，大鼠体内发生了差向异构。进一步的代谢研究表明，在狗中没有发生差向异构化，并且在人类中没有期望的差向异构化。与化学合成过程中相同中心的酸/碱促进的差向异构化相反，提出了一种体内差向异构化的机制，涉及仲苄醇的氧化-还原途径。