Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4 H-[1,2,4]oxadiazolo[3,4- c][1,4]benzoxazin-1-one NS2028

Abstract

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2 H-benzo[ b][1,4]oxazin-3(4 H)-one oxime ( 6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4 H-[1,2,4]oxadiazolo[3,4- c][1,4]benzoxazine-1-thione ( 3a) in 83% yield. Alternatively reacting NS2028 1a with P 2S 5 (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b– d with P 2S 5 gave the carbamothioates 3b– d in 64–91% yields. Although quite stable, the carbamothioates 3a– d could be thermally isomerized in the presence of Cu (10 mol %) to afford the thiocarbamates 4a– d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a– d with P 2S 5 (0.5 equiv) affords the carbamodithioates 5a– d in 72–89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization.