New NO donors with antithrombotic and vasodilating activities, Part 28. N-(1-cyanoalkyl)-N-hydroxyureas

Nineteen N-(1-cyanoalkyl)-N-hydroxyureas comprising aliphatic (3a-i, 4a, b, and 5a) and aromatic (3j-n, 4c, 5b) compounds were prepared, fourteen of them for the first time, and tested for antithrombotic (p.o. administration to rats, 60 mg/kg) effects. The N-(1-cyanocyclohexyl)-N-hydroxy-N'-phenylurea (3j) was most potent and inhibited laser-induced (35 mW, 50 ms) thrombus formation in arterioles by 21% and that in venules by 15%. The compounds form nitric oxide in vitro by the addition of a Fe3(+)-porphyrin complex and an oxygen donor. Moreover, the most active compound 3j in vivo exhibits the highest NO formation in vitro. Furthermore, it was shown that the cyano group is essential for the desired activities and NO formation. These results suggest that the title compounds act as NO donors.