Propan-2-yl 6-methyl-2-methylsulfanyl-4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate | 125734-89-6

• 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: Propan-2-yl 6-methyl-2-methylsulfanyl-4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate
• CAS: 125734-89-6
• 化学式: C₁₆H₁₉N₃O₄S
• 分子量: 349.411
• InChiKey: YUORQZNVVXGLHT-UHFFFAOYSA-N

物化性质

• 沸点：
  474.5±55.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  122
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Propan-2-yl 6-methyl-2-methylsulfanyl-4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate 在 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 mineral oil 为溶剂， 反应 5.0h， 生成 5-isopropyl 1-methyl 4-methyl-2-(methylamino)-6-(3-nitrophenyl)pyrimidine-1,5(6H)-dicarboxylate
  参考文献：
  名称：

  Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

  摘要：

  The L-type calcium channel (LTCC) Ca(v)1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through Ca(v)1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca(v)1.3 antagonist selective over Ca(v)1.2 is essential because Ca(v)1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of Ca(v)1.3 relative to Ca(v)1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of Ca(v)1.3 and Ca(v)1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for Ca(v)1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for Ca(v)1.3 over Ca(v)1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in Ca(v)1.3 and Ca(v)1.2 LTCCs are very similar. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.054
• 作为产物：
  描述：

  2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid,1-methylethyl ester 、 2-甲基-2-疏基硫酸脲 在 sodium acetate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 Propan-2-yl 6-methyl-2-methylsulfanyl-4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate
  参考文献：
  名称：

  Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines

  摘要：

  2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.

  DOI：

  10.1021/jm00167a035

文献信息

• Tunable Carbon−Carbon and Carbon−Sulfur Cross-Coupling of Boronic Acids with 3,4-Dihydropyrimidine-2-thiones
  作者：Alenka Lengar、C. Oliver Kappe

  DOI：10.1021/ol036496h

  日期：2004.3.1

  Direct microwave-assisted Pd(0)-catalyzed/Cu(I)-mediated carbon-carbon cross-coupling of 3,4-dihydropyrimidine-2-thiones and boronic acids under Liebeskind-Srogl conditions leads to 2-aryl-1,4-dihydropyrimidines in moderate to high yield. In contrast, Cu(II)-mediated reaction of the same substrates leads to carbon-sulfur cross-coupling. [reaction: see text]

  Liebeskind-Srogl条件下3,4-二氢嘧啶-2-硫酮与硼酸的直接微波辅助Pd（0）催化/ Cu（I）介导的碳-碳交叉偶联导致2-芳基-1,4 -二氢嘧啶，中等至高产率。相反，相同底物的Cu（II）介导的反应导致碳-硫交叉偶联。[反应：看文字]
• Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines
  作者：Karnail S. Atwal、George C. Rovnyak、Joseph Schwartz、Suzanne Moreland、Anders Hedberg、Jack Z. Gougoutas、Mary F. Malley、David M. Floyd

  DOI：10.1021/jm00167a035

  日期：1990.5

  2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.
• Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics
  作者：Soosung Kang、Garry Cooper、Sara Fernandez Dunne、Chi-Hao Luan、D. James Surmeier、Richard B. Silverman

  DOI：10.1016/j.bmc.2013.04.054

  日期：2013.7

  The L-type calcium channel (LTCC) Ca(v)1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through Ca(v)1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca(v)1.3 antagonist selective over Ca(v)1.2 is essential because Ca(v)1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of Ca(v)1.3 relative to Ca(v)1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of Ca(v)1.3 and Ca(v)1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for Ca(v)1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for Ca(v)1.3 over Ca(v)1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in Ca(v)1.3 and Ca(v)1.2 LTCCs are very similar. (C) 2013 Elsevier Ltd. All rights reserved.