(1R,2S)-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)-1-methylethyl β-aminocrotonate | 166733-04-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (1R,2S)-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)-1-methylethyl β-aminocrotonate
• 英文别名: methyl (2S,3R)-3-[(E)-3-aminobut-2-enoyl]oxy-2-[(4-methylphenyl)sulfonylamino]butanoate
• CAS: 166733-04-6
• 化学式: C₁₆H₂₂N₂O₆S
• 分子量: 370.426
• InChiKey: RHPUDANBQPPAFU-QSKJXDJHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  吡啶-2-甲醛 、 1-硝基乙酮 、 (1R,2S)-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)-1-methylethyl β-aminocrotonate 以 乙醇 为溶剂， 反应 17.0h， 以22.3%的产率得到(1R,2S)-1-methyl-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylate
  参考文献：
  名称：

  Syntheses, Calcium Channel Agonist-Antagonist Modulation Activities, and Voltage-Clamp Studies of Isopropyl 1,4-Dihydro-2,6-dimethyl-3-nitro- 4-pyridinylpyridine-5-carboxylate Racemates and Enantiomers

  摘要：

  A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/-)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity an both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (I-Ca), that (+)-12A increased slightly I-Ca; and that (+/-)-12 inhibited I-Ca but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited I-Ca at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

  DOI：

  10.1021/jm00015a007
• 作为产物：
  描述：

  Tos-Thr-OMe 在 4-二甲氨基吡啶 、 氨 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 6.0h， 生成 (1R,2S)-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)-1-methylethyl β-aminocrotonate
  参考文献：
  名称：

  Syntheses, Calcium Channel Agonist-Antagonist Modulation Activities, and Voltage-Clamp Studies of Isopropyl 1,4-Dihydro-2,6-dimethyl-3-nitro- 4-pyridinylpyridine-5-carboxylate Racemates and Enantiomers

  摘要：

  A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/-)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity an both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (I-Ca), that (+)-12A increased slightly I-Ca; and that (+/-)-12 inhibited I-Ca but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited I-Ca at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

  DOI：

  10.1021/jm00015a007