1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]pyrimidin-2-yl}ethyl butyrate | 400785-93-5

• 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-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]pyrimidin-2-yl}ethyl butyrate
• 英文别名: [(1R)-1-[4-[(3S)-4-[4-(methoxymethyl)-6-methylpyrimidin-2-yl]-3-methylpiperazin-1-yl]pyrimidin-2-yl]ethyl] butanoate
• CAS: 400785-93-5
• 化学式: C₂₂H₃₂N₆O₃
• 分子量: 428.534
• InChiKey: GSDXJTXISYMTHL-DLBZAZTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  93.6
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]pyrimidin-2-yl}ethyl butyrate 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以31%的产率得到1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol
  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
• 作为产物：
  描述：

  (S)-1-苄基-3-甲基哌嗪 在 10percent Pd/C 盐酸 、 甲酸铵 、 三乙胺 作用下， 以 甲醇 、 异丙醇 、 正丁醇 为溶剂， 反应 23.5h， 生成 1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-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

• 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.