3,3-dimethyl-1-[1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]pyrrolidine-2,5-dione

• 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: 3,3-dimethyl-1-[1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]pyrrolidine-2,5-dione
• 英文别名: 3,3-Dimethyl-1-[1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]pyrrolidine-2,5-dione
• 化学式: C₁₄H₂₃N₃O₃
• 分子量: 281.355
• InChiKey: MBQRMICWVBSKDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  60.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,2-二甲基琥珀酸 在 二氧化碳 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 25.5h， 生成 3,3-dimethyl-1-[1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]pyrrolidine-2,5-dione
  参考文献：
  名称：

  New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones

  摘要：

  The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyland 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl) propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl-or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl) propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N, N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES = 74.8 mg/kg, ED50 scPTZ = 51.6 mg/kg, ED50 6 Hz = 16.8 mg/kg) which showed TD50 = 213.3 mg/kg in the chimney test that yielded satisfying protective indexes (PI MES = 2.85, PI scPTZ = 4.13, PI 6 Hz = 12.70) at time point of 0.5 h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.12.027

文献信息

• New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones
  作者：Krzysztof Kamiński、Mirosław Zagaja、Anna Rapacz、Jarogniew J. Łuszczki、Marta Andres-Mach、Michał Abram、Jolanta Obniska

  DOI：10.1016/j.bmc.2015.12.027

  日期：2016.2

  The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyland 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl) propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl-or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl) propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N, N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES = 74.8 mg/kg, ED50 scPTZ = 51.6 mg/kg, ED50 6 Hz = 16.8 mg/kg) which showed TD50 = 213.3 mg/kg in the chimney test that yielded satisfying protective indexes (PI MES = 2.85, PI scPTZ = 4.13, PI 6 Hz = 12.70) at time point of 0.5 h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice. (c) 2015 Elsevier Ltd. All rights reserved.