New polycyclic pyrimidine derivatives with antiplatelet in vitro activity:Synthesis and pharmacological screening

The preparation and the pharmacological screening of novel anti-aggregatory /antiphlogistic polycyclic pyrimidine derivatives are described. The compou nds were developed starting from bioactive 2-aminobenzopyranopyrimidine der ivatives in order to assess the importance of the benzopyrano[4,3-d]pyrimid ine structure and the role of an amino basic moiety in position 2. Antiplat elet activity was assessed in vitro against ADP and arachidonic acid-induce d aggregation in guinea-pig plasma. Anti-inflammatory analgesic/antipyretic activities were studied in rat paw oedema, mouse writhing test and E coli- induced rat fever. Ulcerogenic and gastroprotective effects were also inves tigated in vivo on rat gastric mucosa. Among the tested compounds, the 5-su bstituted benzopyranopyrimidine derivatives 3d and 4d proved to be the most active antiplatelet agents as potent as acetylsalicylic acid against arach idonic acid-stimulated aggregation. Furthermore the 2-methylthio derivative 4d was endowed with greater efficacy against ADP aggregation suggesting th at additional non-TXA(2) dependent mechanisms are involved in its biologica l activity. Orally administered at 100 mg kg(-1) in rats this latter compou nd displayed antiphlogistic acitivity comparable to indomethacin (10 mg kg( -1)) coupled with an unusual gastroprotective effect on ethanol-induced ulc ers. In conclusion, these findings indicate that the 5-pyrrolidino-2-methyl thiobenzopyrano[4d] fulfils the chemical requirements to exhibit antiplatel et activity associated with gastroprotective effect. (C) 2001 Elsevier Scie nce Ltd. All rights reserved.