5′-Substituted Thalidomide Analogs as Modulators of TNF-α

• Published in: Archiv der Pharmazie (Weinheim) 1998-01, Vol.331 (1), p.7-12
• Main Authors: Teubert, Uwe, Zwingenberger, Kai, Wnendt, Stephan, Eger, Kurt
• Format: Article
• Language: English
• Subjects: 5′-substituted analogs; AIDS/HIV; Biological and medical sciences; Humans; Immunomodulators; In Vitro Techniques; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology; TNF-α; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0365-6233; 1521-4184
• 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‐α, 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.