N-propyl thalidomide | 54946-22-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: N-propyl thalidomide
• 英文别名: 1H-Isoindole-1,3(2H)-dione, 2-(2,6-dioxo-1-propyl-3-piperidinyl)-；2-(2,6-dioxo-1-propylpiperidin-3-yl)isoindole-1,3-dione
• CAS: 54946-22-4
• 化学式: C₁₆H₁₆N₂O₄
• 分子量: 300.314
• InChiKey: LYIKHGOXEXNKEV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  74.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  正丙胺 、 N-酞酰基-DL-谷氨酸酐 反应 8.0h， 以60%的产率得到N-propyl thalidomide
  参考文献：
  名称：

  摘要：

  Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties.Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion.Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100degreesC. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well.Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.

  DOI：

  10.1023/a:1013643013244

文献信息

• ——
  作者：Colleen Goosen、Timothy J. Laing、Jeanetta du Plessis、Theunis C. Goosen、Tharaknath B. Rao、Gordon L. Flynn

  DOI：10.1023/a:1019866730266

  日期：——

  Purpose. To determine whether the N-alkyl analogs of the thalidomide are active and stable, their stabilities in buffer and their abilities to inhibit tumor necrosis factor alpha (TNF-alpha) in vitro in human peripheral blood mononuclear cell cultures were investigated.Methods. TNF-alpha concentrations were determined with the aid of ELISA kits. Chemical stabilities of the compounds were determined in three phosphate buffer solutions (pH 6, 6.4, and 7.4) at 25 and 32degreesC by high-pressure liquid chromatography, and half-lives were calculated.Results. The addition of N-alkyl groups to the glutarimide ring of the thalidomide molecule had little effect on the ability such compounds have to inhibit TNF-alpha production. There was no statistical difference between the activity of thalidomide and its N-alkyl analogs at a 95% confidence level. Like thalidomide, the N-alkyl analogs in this series inhibit an average of 60% of the TNF-alpha synthesis in lipopolysaccharide-stimulated peripheral blood mononuclear cell cultures. Thalidomide and its N-alkyl analogs are hydrolyzed at very similar rates, with half-lives ranging from 25 to 35 h at 32degreesC at pH 6.4 and an average rate constant of 2.35 x 10(-2)/h.Conclusions. Alkylating thalidomide had little effect on its ability to inhibit the production of TNF-alpha in these cell cultures. All of the compounds tested seem to have some, perhaps comparable, therapeutic potential.
• ——
  作者：Colleen Goosen、Timothy J. Laing、Jeanetta du Plessis、Theunis C. Goosen、Gordon L. Flynn

  DOI：10.1023/a:1013643013244

  日期：——

  Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties.Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion.Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100degreesC. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well.Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.