New antithrombotic 1-phthalazinamines with serotonin antagonistic properties

We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1, 2, 4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7 c) was the most potent compound, having an IC(50) of 8 microM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8 a) had an IC(50) of 2 microM. In vivo potencies were highly significant. N-[5-(1H-1, 2, 4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT(2A) receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.