One mesoionic 4,4'-propylene-bis-oxazol-5-imine (5), two 2,2'-m-phenylene-bis-imidazol-4-imines (9a,b), five 4,4'-benzene-bis-(and tris)-thiazol-2-amines (13a,b, 14a-c) and 14 3,3'-benzene-bis-(and tris)-1,2,4-thiadiazolimines (18a-o) were synthesized and assayed for their antiplatelet and anticoagulant activities. The most potent compound was the tris-thiadiazole derivative 18m which inhibited the aggregation of platelets induced by collagen at a concentration of 10 mumol/L by 50 percent (Born-test). No anticoagulant effects (Quick-test) were observed up to 400 mumol/L. In the thiazolamine series combined antiplatelet and anticoagulant activities were seen.
Nine 4,4'-bis- and four 4,4'-tris-N-nitroso syndrome imines were synthesized. The sydnone imine moiety is connected either by aromatic 1,3-phenylene or 1,3,5-benzene or aliphatic methylene or propylene bridges. Compared to the corresponding sydnone imines the collagen induced platelet aggregation inhibiting activity is increased by several orders of magnitude by the nitroso derivatives. The most potent compound bears a hexyl substituent in 3-position (1d: IC50 = 0.05 mumol/L). These data show that aromatic bridges (1d, 2d) are more favourable than aliphatic ones (4b). This indicates the mutual influence of the nitroso-imino moieties via the aromatic bridges. In the series of 3,3'-bis-nitrososydnone imines (13 compounds) mostly additive effects of the nitroso groups are seen. The activities range from IC50 = 0.2 mumol/L (5i; 1,3-xylene bridge) to IC50 = 8 mumol/L (5b; trimethylene bridge). The differences suggest different affinities to the platelet membrane.
The synthesis of ten tris-sydnone imine derivatives, unknown up to now, is described. All compounds are alkyl or arylalkyl substituted in 3-position of the sydnone imine. The most powerful agent was the 3-propyl derivative 6c. It inhibits the aggregation of human platelets induced by collagen in a concentration of 1 mumol/L half maximally. Its N-ethoxycarbonyl derivative 7c, which was designed as a prodrug, showed only small antithrombotic effects in rats. The reason for this low degree of activity is discussed.
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New NO-Donors with Antithrombotic and Vasodilating Activities. Part 5. Oligonitroso Sydnone Imines.-Bis-and tris-N-nitroso sydnone imines are synthesized using previously reported methods.The sydnone imine moiety is connected by aliphatic or aromatic bridges via C-4 (→ (I), (II)) or N-3 ( . fwdarw. (III)). The influence of chain length in the side chain on antithrombotic effects is studied and hexyl substituents show the best results. -(REHSE, K.; SCHLEIFER, K.-J.; MARTENS, A.; KAEMPFE, M.; Arch.
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