Preparation and formulation of thieno[2,3-b]thiophene-2-sulfonamides as antiglaucoma drugs

Abstract

The title compds. [I; R = H, C1-6 alkyl; R1, R2 = H, OH, (substituted) C1-6 alkyl, alkylcarbonyl; R1R2N = 5- to 7-membered heterocyclyl; A = (substituted) C1-8 alkylene], useful in treating ocular hypertension/glaucoma (no data), were prepd. 3-Thiophenecarboxaldehyde ethylene ketal in THF at -74.degree. was treated successively with BuLi, S, and BrCH2CO2Me, followed by stirring 24 h at room temp., to give Me [[3-(2-dioxolanyl)-2-thienyl]thio]acetate. The latter was deketalized with acetone/tosic acid, followed by cyclization with 1,5-diazabicyclo[4..3..0]non-5-ene in MeOH, to give Me thieno[2,3-b]thiophene-2-carboxylate, which was converted in 7 steps to 5-[(isobutylamino)methyl]thieno[2,3-b]thiophene-2-sulfonamide.HCl (II). Ocular drops were prepd. contg. II 1, NaH2PO4.2H2O 9.38, NaHPO4.12H2O 28.48, benzalkonium chloride 0.10 mg, and H2O to 1.0 mL.