A new synthesis of sulfonamides by aminolysis of p-nitrophenylsulfonates
yielding potent and selective adenosine A2B receptor antagonists
J Med Chem, 49 (14):
4384-91 (July 2006)Yan, Luo Bertarelli, Daniela C G Hayallah, Alaa M Meyer, Heiko Klotz,
Karl-Norbert Muller, Christa E In Vitro Research Support, Non-U.S.
Gov't United States Journal of medicinal chemistry J Med Chem. 2006
Jul 13;49(14):4384-91..Abstract
1-Propyl- and 1,3-dimethyl-8-p-sulfophenylxanthine (PSB-1115 and SPT)
were used as starting compounds for the development of adenosine
A(2B) 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 A(2B)
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 K(i) value of 3.6 nM for the human A(2B)
receptor combined with high selectivity versus the other human adenosine
receptor subtypes (575-fold versus A(1), 134-fold versus A(2A), and
>278-fold versus A(3)).