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A number of 1,4-benzothiazine-2-acetic acid derivatives (1, 2 and 3) and their bioisosteres (15b, 16, 18 and 20b) were synthesized and evaluated in vitro for the ability to inhibit aldose reductase (AR) in porcine lens. The compounds which exhibited potent activity in vitro were also assayed in vivo for inhibitory activity against sorbitol accumulation in the erythrocytes, sciatic nerve and lens of streptozotocin-diabetic rats. The 4-(substituted benzothiazol-2-ylmethyl)-1,4-benzothiazine-2-acetic acid derivatives (2 and 3) showed more potent AR inhibitory activity than did the 4-(4-bromo-2-fluorobenzyl)-1,4-benzothiazine-2-acetic acid derivatives (1). 4-(4,5,7-Tri-fluorobenzothiazol-2-ylmethyl)-3,4-dihydro-3- oxo-2H-1,4-benzothiazine-2-acetic acid (2q, SPR-210) showed not only a potent AR-inhibitory activity in vitro (IC50 9.5 x 10(-9) M) but also a significant reduction in sorbitol accumulation in rat sciatic nerve (ID50 0.1 mg/kg) and lens (ID50 9.8 mg/kg). Optical resolution of the racemic SPR-210 was achieved by means of a diastereomer salt method using (-)-brucine. The biological activities of both enantiomers, (+)- and (-)-SPR-210, were comparable to that of the racemate.

chemical and pharmaceutical bulletin/chemical and pharmaceutical bulletin

Novel and Potent Aldose Reductase Inhibitors: 4-Benzyl- and 4-(Benzothiazol-2-ylmethyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetic Acid Derivatives.