Carbonic anhydrase inhibitors. Synthesis of topically effective intraocular pressure lowering agents derived from 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide

Reaction of the acyl chlorides of phthalimido-glycine or phthalimido-beta-a lanine with 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded after hydrazin olysis and deprotection of the phthalimido group the corresponding 5-(omega -aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamides. Reaction of 5-(be ta-aminoethylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide with sulfonyl hal ides or acyl halides afforded a series of compounds possessing beta-alky/la rylsulfonyl/carbonylamidoethylcarboxamido moieties in the 5 position of the thiadiazole-2-sulfonamide ring. The new derivatives were efficient inhibit ors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) a nd IV (membrane-bound form), but especially against CA II and CA IV (in nan omolar range), the two isozymes known to play an important role in aqueous humor secretion within the ciliary processes of the eye. Some of the synthe sized inhibitors possessed good water solubility (as hydrochlorides or sodi um salts) and were applied as 2% solutions directly into the eye of normote nsive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP ) lowering was observed for many of them for prolonged periods of 1-2 h, an d the active drug was detected in eye tissues and fluids indicating that th e antiglaucoma effect is due to CA inhibition within the eye.