Design, synthesis and antihistaminic (H 1) activity of some condensed 3-aminopyrimidin-4(3 H)-ones

Anovel series of condensed 3-amino-2-(substituted)methylpyrimidin-4(3 H)-ones is reported with potential H 1 receptor antagonistic activity. The IC 50 values for 23 compounds were found to be in the micromolar range. Five lead compounds ( 10c, e, g, r and t), when evaluated by the in vivo method were found to protect guinea-pigs from the histamine induced asphyxia and antagonized histamine in a competitive and reversible manner. With a pA 2 value of 8.7 and protection time of 9.5 min (in vivo test), compound 10g was the most active amongst these five compounds. The isosteric replacement of the side chain -NH- in series 1, by oxygen and -NHSO 2- functions, was undertaken to investigate the role of two amino functions in the receptor binding. This isosteric replacement with -O- does not affect the antihistaminic activity and the sedative potential of the series. Preliminary molecular modelling studies indicate that the compounds with -NHSO 2- in the side chain exhibit a closer fit with temelastine than their -O- isosteres.