New NO‐Donors with Antithrombotic and Vasodilating Activities, II: 3‐Alkyl‐N‐nitroso‐5‐sydnone Imines

Abstract

Fifteen 3-alkyl-, four 3-cycloalkyl-N-nitroso-5-sydnone imines and five 3-alkyl-N-nitro-5-sydnone imines were synthesized and their ability to inhibit platelet aggregation induced by collagen (Born-test) was studied in vitro. Dependent on the chemical structure, the IC50-values for the inhibition of platelet aggregation were in the range of 0.2-140 mumol/L. It is suggested that this scale reflects different binding properties of the nitrosimines with respect to the platelet membrane. Highest activities were observed for the 3-hexyl (2f) and the 3-cyclohexyl (2p) derivative. Three nitrimines (3e, 3f, 3i) also showed IC50 values below 10 mumol/L. For the nitrosimines 2a, 2f, and 2m antithrombotic activity was demonstrated in vivo. They inhibited laser induced arterial thrombosis in anesthetized rats up to 70% two h after oral administration. In conscious renal-hypertensive dogs, the decrease in systolic blood pressure and left ventricular enddiastolic pressure suggests an antianginal activity of the compound 2a similar to that of molsidomine (M). The smoother onset and the longer duration of action of the new compound as compared to M could be a significant advantage of 2a in the therapy of angina pectoris.

Heterocycle Syntheses with Anionic N‐Heterocyclic Carbenes: Ring Transformations of Sydnone Imine Anions

“…1 H NMR (400 MHz, [D 6 ]DMSO): δ = 9.87 (s, 2 H, 6‐H), 8.17 (s, 1 H, 4‐H), 4.88 (tt, J H,H 1 = 11.3, J H,H 2 = 3.8 Hz, 1 H, 7‐H), 2.17–2.20 (m, 2 H, 8/8′‐H), 1.81–1.91 (m, 4 H, 8/8′‐H + 9/9′‐H), 1.62–1.65 (m, 1 H, 10‐H), 1.36–1.47 (m, 2 H, 9/9′‐H), 1.19–1.30 (m, 1 H, 10‐H) ppm. Spectroscopic data are in agreement with those reported in the literature …”

Nitric Oxide Donors: Chemical Activities and Biological Applications

“…Some of them also exhibit antithrombotic and blood pressure lowering abilities in vivo. 290,293 Nitrosimines are relatively stable when dissolved in aqueous buffers, kept cool, and protected from light. They release both NO and N 2 O, the latter is via a nitroxyl intermediate (HNO).…”

“…They are the N -nitrosation products of their corresponding imines. Several types of nitrosimines have been reported such as 1,3-disubstituted nitrosiminobenzimidazoles ( 22 ), 1,3,4-thiadiazole-2-nitrosimines ( 23 ), benzothiazole-2(3H)-nitrosimines ( 24 ), thiazole-2-nitrosimines ( 25 ), oligonitroso sydnonimines ( 26 ), 3-alkyl- N -nitroso-sydnonimines ( 27 ), − and 2 H -1,3,4-thiadiazine nitrosimines ( 28 ) (Figure ) . These nitrosimines have the ability to inhibit platelet aggregation in vitro.…”

Interaction of Viagra with the NO Donors Molsidomine and RE 2047 with Regard to Antithrombotic and Blood Pressure Lowering Activities

“…RE 2047 was synthesized as already described [2] . Molsidomine was a generous gift from Casella, Ger.…”

“…If the stimulation of GC occurs in smooth muscle cells of blood vessels, vasodilation and hence lowering of the blood pressure (b.p.) results [2] . The c-GMP is degraded to guanosine monophosphate which does not have the above effects of c-GMP.…”