4-Substituted-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase

#Close to 70% of kidney stones in man are composed partially or predominantly of calcium oxalate. There is no satisfactory drug therapy specific for the treatment of calcium oxalate renal lithiasis, nor for prophylactic use by patients prone to recurrent attacks of this disease.

#The most common treatment for renal lithiasis due to calcium oxalate consists of surgical removal of stones, control of the diet to restrict calcium or oxalate, and ingestion of large quantities of water to dilute the urine. Attempts at chemotherapy have included the administration of magnesium oxide, calcium carbimide, orthophosphate, cellulose phosphate, isocarboxazide, thiazide diuretics, allopurinol and succinimide. Limited success has been realized by these drug approaches. No drug which specifically inhibits the biosynthetic formation of oxalic acid has previously been developed for the treatment of renal lithiasis.

#The immediate metabolic precursor of the majority of the oxalate in the urine of a typical patient is glyoxylic acid. In turn its most important precursor is glycolic acid. The enzyme glycolate oxidase is able to carry out the oxidation of glycolic acid, through glyoxylic acid, to oxalic acid. Inhibition of this enzyme will, therefore, reduce the concentration of oxalic acid in the kidney and bladder, decreasing the probability that calcium oxalate crystallization will occur. Thus inhibitors of glycolate oxidase provide a specific approach to the prevention and treatment of calcium oxalate renal lithiasis.

#920 mg sodium (40 mmole) is dissolved in 45 ml ethanol and to the ice-bath cooled solution is added 4.66 g diethyl oxalate (31.9 mmole) and 4.17 g hydrocinnamonitrile (31.9 mmole). The mixture is stirred at room temperature for 1 hour, under reflux for 3 hours, and then allowed to stand at room temperature overnight. Evaporation, acidification of the residue, and extraction with methylene chloride affords ethyl 3-cyano-2-oxo-4-phenylbutanoate in 38% yield. The compound crystallizes from petroleum ether in colorless needles; m.p. 80.degree.-83.degree. C.

#462 mg ethyl 3-cyano-2-oxo-4-phenylbutanoate is added to ethanol saturated with hydrogen chloride (10 ml) and the mixture is allowed to stand at room temperature overnight. The solvent is evaporated and the residue dried at 0.05 Torr. Dry chloroform is added and the mixture heated under reflux for 3 hours. The chloroform is extracted with excess 2N sodium hydroxide solution, then the aqueous solution is acidified and extracted with chloroform to afford 43 mg (10%) of product; m.p. 140.degree.-142.degree. C.