Novel spiro-oxazolidindiones

#This invention relates to novel spiro-oxazolidindiones useful in the treatment of certain chronic complications arising from diabetes mellitus, such as diabetic cataracts and neuropathy, to intermediates for the preparation thereof, to pharmaceutical compositions containing such compounds and to a method of using these compounds.

#In the past various attempts have been made to obtain novel, more effective oral anti-diabetic agents. Generally these efforts have involved synthesis of new organic compounds, particularly sulfonyl ureas, and determination of their ability to substantially lower blood sugar levels when administered orally. However, little is known about the effect of organic compounds in preventing or alleviating chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 discloses aldose reductase inhibitors like 1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and derivatives thereof to be useful for the treatment of these conditions. Such aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, of peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, such compounds are of therapeutic value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those of an ocular nature, since it is known in the art that the presence of polyols in the lens of the eye leads to cataract formation, with a concommitant loss of lens clarity.

#The present invention relates to novel aldose reductase inhibitors useful as therapeutic agents for preventing or alleviating chronic diabetic complications. Specifically, the compounds of the present invention are novel spiro-oxazolidindiones of the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of oxygen and sulfur; n is 1 or 2; R is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, benzyl and monosubstituted benzyl, wherein said substituent is selected from the group consisting of chloro, bromo, fluoro, hydroxy, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; and R.sub.1, R.sub.2 and R.sub.3 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms, phenyl and monosubstituted phenyl, wherein said substituent is selected from the group consisting of chloro, bromo, fluoro, hydroxy, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms.

#The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples.

#A mixture of 6-chloro-4H-2,3-dihydrobenzopyran-4-one (20.0 g, 0.11 mol, Aldrich), trimethylsilyl cyanide (13.0 g, 0.13 mol, Silar), and zinc iodide (0.2 g in Alfa) in 50 ml ether was stirred for 18 hours. The solution was decolorized with charcoal (Darco), filtered, and evaporated in vacuo to an orange oil which on addition of pentane gave crystalline 6-chloro-4-cyano-4-trimethylsilyloxy-4H-2,3-dihydrobenzopyran, 26.4 g (84%), m.p. 67.degree.-69.degree. C.

#A saturated solution of 6-chloro-4-cyano-4-trimethylsilyloxy-4H-2,3-dihydrobenzopyran (273.0 g, 0.97 mol) in 2.0 l of ethanol was cooled to 0.degree. C. and perfused with dry hydrogen chloride for 40 minutes. A slight exotherm occurred while the mixture became homogeneous. After 16 hours at 4.degree. C. the volatiles were removed in vacuo yielding a semi-solid residue. Trituration with 800 ml diethyl ether followed by filtration afforded a solid which was partitioned between 3.8 l of chloroform and 500 ml saturated sodium bicarbonate. The organic layer was washed with an additional 500 ml saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo to solid ethyl 6-chloro-4-hydroxy-4H-2,3-dihydrobenzopyran-4-carboximidate, 193.0 g (78%). Trituration with ether afforded material of mp 124.degree.-126.degree. C.