Synthesis of Imidazo[4,5-c][1,2,6]thiadiazine 2-Oxides from Hydrolytes of Xanthines and Determination of Their Vasodilating Activity

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Novel 1,3,6,7-tetrahydro-7-oxoimidazo[4,5-c][1,2,6]thiadiazine 2-oxide derivatives (2a-q) were synthesized by the reaction of imidazole derivatives (1), obtained by alkaline hydrolysis of 1,3,7-trisubstituted xanthines (3), with SOCl_2 in 42-93% yields. Chlorination of 2 with SO_2Cl_2 gave the 5-chloro derivatives (10a, d, i-q), though in low yields. The reaction of 2 with benzoyl chloride derivatives (14) gave 3,7-dihydro-6H-purin-6-one derivatives (15a-d).Among 2 and 10,compounds having the phenoxyalkyl group at the l-position exhibited potent vasodilating activity on the mesenteric artery of spontaneously hypertensive rats. In particular, ED_<50> values of the order of 10^<-7> M were obtained with those having a 1-[6-(4-chlorophenoxy)hexyl]-6-propyl (2o), 6-hexyl-1-[6-(4-methoxyphenoxy)hexyl] (2p), 1-[6-(4-chlorophenoxy)hexyl]-6-hexyl (2q), 5-chloro-1-[6-(4-chlorophenoxy)hexyl]-6-methyl (101), 5-chloro-1-[4-(4-methoxyphenoxy)-butyl]-6-propyl (10m), 5-chloro-1-[6-(4-methoxyphenoxy)hexyl]-6-propyl (10n), or 5-chloro-1-[6-(4-chlorophenoxy)hexyl]-6-propyl (10o) substituent.
公益社団法人日本薬学会の論文
1988-03-25