Zenarestat

Originator

FK 366 ,Fujisawa Pharmaceutical

Uses

Treatment of diabetic neuropathy (aldose reductase inhibitor).

Manufacturing Process

To a solution of 4-bromo-2-fluorobenzylamine and triethylamine in chloroform was added dropwise a solution of 4-chloro-2-nitrobenzoyl chloride in chloroform at 0°C with stirring and the mixture was stirred at the same temperature for 1 h. The reaction mixture was washed in turn with diluted aqueous hydrochloric acid and water, and then dried. Evaporation of the solvent followed by recrystallization from diethyl ether gave N-(4-bromo-2- fluorobenzyl)-4-chloro-2-nitrobenzamide.
A mixture of N-(4-bromo-2-fluorobenzyl)-4-chloro-2-nitrobenzamide and iron (1.45 g) in acetic acid (66 ml) was stirred at 100°C for 30 min. After cooling, iron was filtered off. The filtrate was evaporated to give a residue, which was made alkaline with aqueous 1 N sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide.
2-Amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide and N,N'- carbonyldiimidazole were dissolved in dioxane (50 ml). The solution was evaporated to give a residue, which was stirred at 150°C for 30 min. After cooling, the precipitates were collected by filtration and washed with ethanol to give 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4- dioxoquinazoline; melting point >280°C.
To a suspension of 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro- 2,4-dioxoquinazoline in N,N-dimethylformamide was added sodium hydride (60% in mineral oil) with stirring at 0°C and the mixture was stirred for 15 min at the same temperature. To this mixture was added ethyl bromoacetate and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated to give a residue. Thus obtained product was purified by recrystallization from isopropyl ether to give 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4- dioxoquinazolin-1-yl]acetic acid melting point 223°-224°C.

Therapeutic Function

Aldose reductase inhibitor