The synthesis of 8,10,12-triazaprostaglandin analogues: 1,2,4-triazolidine-3,5-dione derivatives

Abstract

In the search for active, more selective prostaglandin analogues, the synthesis of 8,10,12-tri-azaprostaglandin analogues has been achieved from readily available 4-methyl-1,2,4-triazolidine-3,5-dione. The general approach involved introduction of the α- and ω-side-chain as entire units by step-wise N-alkylation. The problems encountered with this approach of competing N-and O-mono-and di-alkylation were overcome, eventually, such that judicious choice of the initial mono-N-alkylation step enabled the synthesis of analogues incorporating wide variations in the α- and ω-side-chain. Important structural modifications included introduction of unsaturation into the α-side-chain at the 5,6- position and of methyl groups into the ω-side-chain at the 15- and 16-position as exemplified by the synthesis of 1-[(Z)-6-carboxyhex-2-enyl]-2-(3-hydroxy-3,4-dimethyloctyl)-4-methyl-1,2,4-tri-azolidine-3,5-dione (19). The stable triazaprostaglandin analogues were synthesized as racemic compounds but, nevertheless, compound (19) possessed bronchodilator activity of a similar order to that of the natural prostaglandins PGE₁ and PGE₂.