(1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 3-aminocrotonate | 250330-30-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 3-aminocrotonate
• 英文别名: methyl (2R,3S)-3-[(E)-3-aminobut-2-enoyl]oxy-2-[(3,5-dinitrobenzoyl)amino]butanoate
• CAS: 250330-30-4
• 化学式: C₁₆H₁₈N₄O₉
• 分子量: 410.34
• InChiKey: CQHFUHFYOGVAEE-YGDBTEFTSA-N

物化性质

• 沸点：
  633.1±55.0 °C(Predicted)
• 密度：
  1.413±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  199
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  1-硝基乙酮 、 邻三氟甲基苯甲醛 、 (1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 3-aminocrotonate 以 乙醇 为溶剂， 反应 17.0h， 以12%的产率得到(1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate
  参考文献：
  名称：

  The design of (−)-(S)-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)Pyridine-5-carboxylate: A cardioselective positive inotropic derivative of bay K 8644

  摘要：

  The title compound, (-)-(S)-9, is a novel cardioselective calcium channel modulator that exhibits a calcium channel agonist effect on heart, a weak calcium channel antagonist effect on smooth muscle, and releases nitric oxide in vitro. (-)-(S)-9 is a useful lead-compound for the design of positive inotropic agents to treat congestive heart failure, and to study the structure-function relationship of calcium channel modulation. (C) 1999 Elsevier Science Ltd. Ail rights reserved.

  DOI：

  10.1016/s0960-894x(99)00445-x
• 作为产物：
  描述：

  (1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl acetoacetate 在 氨 、 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 4.0h， 以55%的产率得到(1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 3-aminocrotonate
  参考文献：
  名称：

  The design of (−)-(S)-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)Pyridine-5-carboxylate: A cardioselective positive inotropic derivative of bay K 8644

  摘要：

  The title compound, (-)-(S)-9, is a novel cardioselective calcium channel modulator that exhibits a calcium channel agonist effect on heart, a weak calcium channel antagonist effect on smooth muscle, and releases nitric oxide in vitro. (-)-(S)-9 is a useful lead-compound for the design of positive inotropic agents to treat congestive heart failure, and to study the structure-function relationship of calcium channel modulation. (C) 1999 Elsevier Science Ltd. Ail rights reserved.

  DOI：

  10.1016/s0960-894x(99)00445-x

文献信息

• Syntheses, Calcium Channel Agonist−Antagonist Modulation Activities, and Nitric Oxide Release Studies of Nitrooxyalkyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate Racemates, Enantiomers, and Diastereomers
  作者：Rudong Shan、Carlos Velazquez、Edward E. Knaus

  DOI：10.1021/jm030333h

  日期：2004.1.1

  A novel group of hybrid calcium channel (CC) modulators was prepared where the isopropyl ester moiety of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxyla te (PN 202-791) was replaced by a variety of nitric oxide (*NO) donor nitrooxyalkyl ester substituents. Enantiomers, or diastereomers, having the (R)-configuration at the C-4 position of the 1,4-dihydropyridine

  制备了一组新的杂化钙通道（CC）调节剂，其中异丙基1,4-二氢-2,6-二甲基-3-硝基-4-（2,1,3-苯并恶二唑-4-基）的异丙基酯部分吡啶5-羧基（PN 202-791）被各种一氧化氮（* NO）供体硝基氧基烷基酯取代基取代。在1,4-二氢吡啶环（1,4-DHP）的C-4位具有（R）构型的对映异构体或非对映异构体对豚鼠回肠纵向平滑肌（GPILSM）表现出更有效的体外CC拮抗剂活性），而不是具有（4S）-构型的化合物。硝基氧烷基化合物均未对GPILSM表现出禁忌的CC激动剂作用，该作用会引起平滑肌收缩。结构活性研究表明，对映异构体在1的C-4位置具有（S）-构型 在1,4-DHP环的C-4位置具有（4S）构型的4-DHP环或非对映异构体与（1R-）-1-甲基-2-硝基氧乙基酯取代基一起显示出最有效的豚鼠左心房（GPLA）的心脏CC激动剂（正性肌力）活性。这类化合物在体外释放* NO，
• Syntheses, Calcium Channel Agonist−Antagonist Modulation Activities, Nitric Oxide Release, and Voltage-Clamp Studies of 2-Nitrooxyethyl 1,4-Dihydro- 2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate Enantiomers
  作者：Rudong Shan、Susan E. Howlett、Edward E. Knaus

  DOI：10.1021/jm010394k

  日期：2002.2.1

  The novel (-)-(S)-2 and (+)-(R)-3 enantiomers of 2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate were synthesized for evaluation as calcium channel modulators. Determination of their in vitro calcium-channel-modulating activities using guinea pig left atria (GPLA) and ileum longitudinal smooth muscle (GPILSM) showed that the (-)-(S)-2 enantiomer acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the (+)(R)-3 enantiomer exhibited calcium channel antagonist activity on both GPLA and GPILSM. The 2-nitrooxyethyl racemate is a nitric oxide ((NO)-N-.) donor that released 2.7% (NO)-N-., relative to the reference drug glyceryl trinitrate (5.3% (NO)-N-. release/ONO2 moiety), in the presence of N-acetylcysteamine. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that both enantiomers inhibit calcium current but that the (-)-(S)-2 enantiomer is a weaker antagonist than the (+)-(R)-3 enantiomer. These results indicate that replacement of the methyl ester substituent of (-)-(S)-methyl 1,4-dihydro-2,6-dimetyl-3-nitro4-(2-trifluoromethylphenyl)pyridine-5-carboxylate [(-)-(S)-1] by the 2-nitrooxyethyl ester (NO)-N-. donor substituent present in (-)-(S)-2 provides a useful drug design concept to abolish the contraindicated calcium channel agonist effect of (-)-(S)-1 on vascular smooth muscle. The novel (-)-(S)-2 enantiomer is a useful lead compound for drug discovery targeted toward the treatment of congestive heart failure, and it provides a useful probe to study the structure-function relationships of calcium channels.