Web Release Date: June 13,
A New Synthesis of Sulfonamides by Aminolysis of p-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A2B Receptor Antagonists
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Pharmaceutical Institute, Pharmaceutical Chemistry Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany, Faculty of Pharmacy, Assiut University, Egypt, and Institute of Pharmacology and Toxicology, University of Würzburg, D-97078 Würzburg, Germany
Received March 13, 2006
Abstract:
1-Propyl- and 1,3-dimethyl-8-p-sulfophenylxanthine (PSB-1115 and SPT) were used as starting compounds for the development of adenosine A2B receptor antagonists with a sulfonamide structure. Since standard reactions for sulfonamide formation failed or resulted in very low yields, we developed a new method for the preparation of sulfonamides. p-Nitrophenoxide was used as a suitable leaving group with well balanced stability-reactivity properties. A large variety of amines, including aniline, benzylamine, phenethylamine, propylamine, butylamine, 2-hydroxyethylamine, aminoacetic acid, and N-benzylpiperazine reacted with p-nitrophenoxysulfonylphenylxanthine derivatives yielding the desired sulfonamides in satisfying to very good yields. The obtained sulfonamides were much more potent at A2B receptors than the parent sulfonates. The most active compound of the present series was 8-[4-(4-benzylpiperazide-1-sulfonyl)phenyl]-1-propylxanthine (11, PSB-601) exhibiting a Ki value of 3.6 nM for the human A2B receptor combined with high selectivity versus the other human adenosine receptor subtypes (575-fold versus A1, 134-fold versus A2A, and >278-fold versus A3).
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