A New Synthesis of Sulfonamides by Aminolysis of P-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A2B Receptor Antagonists

J Med Chem. 2006 Jul 13;49(14):4384-91. doi: 10.1021/jm060277v.

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)).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Arylsulfonates / chemistry*
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • In Vitro Techniques
  • Radioligand Assay
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Xanthines / chemical synthesis*
  • Xanthines / chemistry
  • Xanthines / pharmacology

Substances

  • 8-(4-(4-benzylpiperazide-1-sulfonyl)phenyl)-1-propylxanthine
  • Adenosine A2 Receptor Antagonists
  • Arylsulfonates
  • Recombinant Proteins
  • Sulfonamides
  • Xanthines