NEW NO-DONORS WITH ANTITHROMBOTIC AND VASODILATING ACTIVITIES, PART 17 - ARYLAZOMIDOXIMES AND 3-ARYLAZO-1,2,4-OXADIAZOL-5-ONES

Seven arylazoamidoximes (3), six phenoxycarbonyl derivatives (4), and six 1,2,4-oxadiazol-5-ones (5) have been prepared and their structure and purity etablished by spectroscopy and elemental analysis, In the E I mass spectra ready elimination of NO from the title amidoximes was o bserved. A new addition reaction of 3a with hydrochloric acid to 4-chl orophenylhydroazoamidoxime 7 is described. The compounds were tested f or nitric oxide dependent biological properties, i.e. platelet aggrega tion, antithrombotic effects, and decrease in blood pressure. In arter ioles of rats 5/19 compounds inhibited the formation of thrombi with a laser beam by greater than or equal to 20% 2 h after oral administrat ion of 60 mg/kg, Among these are three amidoximes (3a, 3e, 3f) one phe noxycarbonyl derivative (4a), and one oxadiazolone (5a). With the 4-ch lorophenylazoamidoxime 3c a long lasting (24 h) decrease of blood pres sure in spontaneously hypertensive rats was observed. Microsomal fract ions of rat liver oxidize arylazoamidoximes and generate nitric oxide (e.g. 3a and 3b). NO was measured by the oxyhemoglobin assay, The infl uence of SOD, pretreatment of the rats with dexamethasone, as well as kinetic parameters were determined. Type 3 compounds, therefore, are a new class of NO donors. Type 4 and 5 corn pounds function as their pr odrugs.