tert-butyl 5-methyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: tert-butyl 5-methyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-1-carboxylate
• 英文别名: Tert-butyl 5-methyl-2,4-dioxo-3-[[4-(3-piperidin-1-ylpropoxy)phenyl]methyl]pyrimidine-1-carboxylate；tert-butyl 5-methyl-2,4-dioxo-3-[[4-(3-piperidin-1-ylpropoxy)phenyl]methyl]pyrimidine-1-carboxylate
• 化学式: C₂₅H₃₅N₃O₅
• 分子量: 457.57
• InChiKey: PLPHKSRHAHHVJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  79.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 5-methyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-1-carboxylate 在 氨 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以25.55%的产率得到5-methyl-3-({4-[3-(piperidin-1-yl)propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione
  参考文献：
  名称：

  Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs

  摘要：

  The histamine H-3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH(3)R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH(3)R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH(3)R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH(3)Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH(3)R (pK(i) (hH(3)R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pK(i); (hH(3)R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.011
• 作为产物：
  描述：

  1-哌啶丙醇 在 氯化亚砜 、 potassium carbonate 、 potassium iodide 作用下， 以 丙酮 、 甲苯 为溶剂， 反应 54.0h， 生成 tert-butyl 5-methyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-1-carboxylate
  参考文献：
  名称：

  Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs

  摘要：

  The histamine H-3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH(3)R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH(3)R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH(3)R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH(3)Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH(3)R (pK(i) (hH(3)R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pK(i); (hH(3)R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.011

文献信息

• Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs
  作者：Luca Lipani、Dalibor Odadzic、Lilia Weizel、Johannes-Stephan Schwed、Bassem Sadek、Holger Stark

  DOI：10.1016/j.ejmech.2014.09.011

  日期：2014.10

  The histamine H-3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH(3)R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH(3)R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH(3)R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH(3)Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH(3)R (pK(i) (hH(3)R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pK(i); (hH(3)R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively. (C) 2014 Elsevier Masson SAS. All rights reserved.