Teubert U, Zwingenberger K, Wnendt S, Eger K
Universität Leipzig, Institut für Pharmazie, Germany.
Arch Pharm (Weinheim). 1998 Jan;331(1):7-12. doi: 10.1002/(sici)1521-4184(199801)331:1<7::aid-ardp7>3.0.co;2-n.
The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.
描述了5'-取代的沙利度胺类似物的合成。通过迈克尔反应制备合成目标化合物所需的氨基酸2。2与邻苯二甲酸酐缩合，然后与尿素反应，得到非对映异构体混合物4。此外，通过改进的方法将格鲁米特（5）溴化，所得化合物6经过几步与叠氮化钠、氢气和邻苯二甲酸酐反应，得到8。以类似的方式，6与叠氮化钠和各种邻苯二甲酸酐反应，得到9、10和11。使用刺激的外周血单核细胞（PBMC）对所有最终化合物进行体外测试，以检测它们对TNF-α释放的抑制活性。在沙利度胺分子的5'位带有额外芳基取代基的化合物比沙利度胺更具活性。化合物11能够在体外降低升高的IL-2水平。
