Novel spiro-furanohydantoin derivatives useful as aldose reductase inhibitors and as therapeutic agents for the treatment of chronic diabetic complications are disclosed. The compounds include 2-methyl-spiro-[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione, 2-fluoro-spiro-[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione, 2-chloro-spiro-[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione, 2-bromo-spiro-[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione and spiro-[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione.

BACKGROUND OF THE INVENTION 
This invention relates to novel spiro-furanohydantoin derivatives useful in 
the treatment of certain chronic complications arising from diabetes 
mellitus, such as diabetic cataracts and neuropathy, to pharmaceutical 
compositions containing such compounds and to a method of using these 
compounds. Although many oral antidiabetic agents, such as the sulfonyl 
ureas, effectively lower blood sugar levels, the prevention or alleviation 
of the chronic complications of diabetes, such as diabetic cataracts, 
neuropathy, retinopathy and nephropathy has proved harder to achieve. 
According to U.S. Pat. No. 3,821,383, aldose reductase inhibitors such as 
1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and its derivatives 
are useful in this regard. Spiro-thienohydantoin derivatives are also 
aldose reductase inhibitors according to U.S. application Ser. No. 
870,542. Such compounds inhibit the enzymatic reduction of aldoses, such 
as glucose and galactose, to the corresponding polyols, such as sorbitol 
and galactitol, thus preventing or reducing the harmful and unwanted 
accumulations of polyols in the lens and retina of the diabetically 
cataractous eye, the diabetically neuropathic peripheral nerve and the 
diabetically nephropathic kidney. 
SUMMARY OF THE INVENTION 
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-furanohydantoin derivatives of the formula 
##STR1## 
and the metal salts thereof with pharmaceutically acceptable cations, 
wherein R is hydrogen, methyl, fluoro, chloro or bromo. 
The present invention further comprises a novel method for the treatment of 
a diabetic host to prevent or alleviate diabetes-associated complications, 
such as cataracts, neuropathy, nephropathy or retinopathy, which method 
comprises administering to the host an effective amount of a compound of 
formula I. Further disclosed is a pharmaceutically-acceptable carrier and 
a compound of formula I in an amount effective to prevent or alleviate 
diabetes-associated complications, such as cataracts, neuropathy, 
nephropathy or retinopathy. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of the present invention are readily prepared from an 
appropriate ketone of the formula 
##STR2## 
wherein R is as previously defined. A ketone of formula II is condensed 
with an alkali metal cyanide, such as sodium cyanide or potassium cyanide, 
and ammonium carbonate to form the desired spiro-furanohydantoin of 
formula I. The reaction is normally conducted in the presence of a 
reaction-inert polar organic solvent in which both the reactants and 
reagents are mutually miscible. Preferred organic solvents include, but 
are not limited to, cyclic ethers such as dioxane and tetrahydrofuran, 
lower alkylene glycols such as ethylene glycol and trimethylene glycol, 
water-miscible lower alkanols such as methanol, ethanol and isopropanol, 
and N,N-di(lower alkyl) lower alkanoamides such as N,N-dimethyl formamide, 
N,N-diethyl formamide and N,N-dimethyl acetamide. In general, the reaction 
is conducted at a temperature between about 50.degree. C. and about 
150.degree. C., perferably about 90.degree. C. to 130.degree. C., for a 
period of about 2 hours to about 4 days, depending on the temperature 
employed. Although the amount of reactants and reagents employed in the 
reaction can vary to some extent, it is preferable to employ at least a 
slight molar excess of the alkali metal cyanide reagent with respect to 
the ketone starting material in order to achieve maximum yield. Upon 
completion of the reaction, the desired product is readily isolated in a 
conventional manner, for example by first diluting the reaction mixture 
with water and then cooling the resultant aqueous solution to room 
temperature, followed by acidification to afford the desired 
spiro-furanohydantoin compound in the form of a readily-recoverable 
precipitate. 
The starting materials of formula II are readily prepared from the 
appropriate precursor according to the procedures described in Bull. Soc. 
Chim. Fr., 1967, 2796. 
Pharmaceutically acceptable metal salts can be readily prepared from 
compounds of formula I by conventional methods. Thus, these salts may be 
prepared by treating the spiro-furanohydantoins with an aqueous solution 
of the desired pharmaceutically acceptable metallic hydroxide or other 
metallic base and evaporating the resulting solution to dryness, 
preferably under reduced pressure. Alternatively, a lower alkanoic 
solution of the spiro-furanohydantoin may be mixed with an alkoxide of the 
desired metal and subsequently evaporating the solution to dryness. The 
pharmaceutically acceptable metallic hydroxides, bases and alkoxides 
include those with cations that form metal salts with the acidic compounds 
of formula I and that are non-toxic at the dosages administered to a 
subject in need of treatment. Suitable cations for this purpose include, 
but are not limited to, potassium, sodium, ammonium, calcium and 
magnesium. 
The novel spiro-furanohydantoins of this invention are useful as aldose 
reductase inhibitors, and as such are of therapeutic value in the 
treatment of chronic complications of diabetes, such as cataracts, 
retinopathy, nephropathy and neuropathy. As used in the claims and 
specification hereof, treatment is meant to include both prevention or 
alleviation of such conditions. The compounds may be administered to a 
subject in need of treatment by a variety of conventional routes of 
administration, including orally and parenterally. In general, these 
compounds will be administered at dosages between 1 and 250 mg per kg body 
weight of the subject to be treated per day. However, some variation in 
dosage will necessarily occur depending on the condition of the subject 
being treated and the physician will, in any event, determine the 
appropriate dose for the individual subject. 
The compounds may be administered alone or in combination with 
pharmaceutically acceptable carriers, in either single or multiple doses. 
Suitable pharmaceutical carriers include inert solid diluents or fillers, 
sterile aqueous solutions and various nontoxic organic solvents. The 
pharmaceutical compositions formed by combining the spiro-furanohydantoin 
and the pharmaceutically acceptable carrier are then readily administered 
in a variety of dosage forms such as tablets, powders, lozenges, syrups, 
injectable solutions and the like. These pharmaceutical compositions can, 
if desired, contain additional ingredients such as flavorings, binders, 
excipients and the like. Thus, for purposes of oral administration, 
tablets containing various excipients such as sodium citrate, calcium 
carbonate and calcium phosphate may be employed along with various 
disintegrants such as starch and preferably potato or tapioca starch, 
alginic acid and certain complex silicates, together with binding agents 
such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, 
lubricating agents such as magnesium stearate, sodium lauryl sulfate and 
talc are often useful for tableting purposes. Solid compositions of a 
similar type may also be employed as fillers in soft and hard-filled 
gelatin capsules; preferred materials for this include lactose or milk 
sugar and high molecular weight polyethylene glycols. When aqueous 
suspensions or elixirs are desired for oral administration, the essential 
active ingredient therein may be combined with various sweetening or 
flavoring agents, coloring matter or dyes, and if desired emulsifying or 
suspending agents, together with diluents such as water, ethanol, 
propylene glycol, glycerin and combinations thereof. 
For parenteral administration, solutions of the spiro-furanohydantoins in 
sesame or peanut oil or in aqueous propylene glycol may be employed, as 
well as sterile aqueous solutions of the corresponding water-soluble 
pharmaceutically acceptable metal salts previously described. Such aqueous 
solutions should be suitably buffered if necessary and the liquid diluent 
first rendered isotonic with sufficient saline or glucose. These 
particular aqueous solutions are especially suitable for intravenous, 
intramuscular, subcutaneous and intraperitoneal injection purposes. In 
this connection, the sterile aqueous media employed are all readily 
obtainable by standard techniques well known to those skilled in the art. 
Additionally, it is also possible to administer the spiro-furanohydantoin 
compounds topically, by use of an appropriate opthalmic solution, which 
may then be administered dropwise to the eye. 
The activity of the compounds of the present invention as agents for the 
control of chronic diabetic complications may be determined by a number of 
standard biological or pharmacological tests. Suitable tests include (1) 
measuring their ability to inhibit the enzyme activity of isolated aldose 
reductase and (2) measuring their ability to reduce or inhibit sorbitol 
accumulation in the sciatic nerve of acutely streptozotocinized (i.e., 
diabetic) rats.

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. 
EXAMPLE 1 
Spiro[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione 
A mixture of 2.7 g of cyclohexa(b)furan-4-one (Bull. Soc. Chim. Fr., 1967, 
2796), 1.95 g of potassium cyanide and 9.6 g of powdered ammonium 
carbonate were heated with 40 ml of 95% aqueous ethanol at 
110.degree.-120.degree. C. in a steel bomb for 16 hours. The reaction 
mixture was cooled, diluted with 200 ml of water, and acidified with 12 N 
hydrochloric acid. The precipitated product was isolated by filtration and 
recrystallized from ethanol to give 1.73 g of 
spiro[cyclohexa(b)furan-4,4'-imidazolidine]-2', 5'-dione, mp 
245.degree.-248.degree. C. 
Analysis: Calcd for C.sub.10 H.sub.10 N.sub.2 O.sub.3 : C, 58.24%; H, 
4.89%; N, 13.59%. Found: C, 58.31%; H, 4.93%; N, 13.82%. 
EXAMPLE 2 
2-methyl-spiro[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione 
The procedure described in Example 1 was repeated using 
2-methyl-cyclohexa(b)furan-4-one (Bull. Soc. Chim. Fr., 1967, 2796) as 
starting material. 
2-methyl-spiro[cyclohexa(b)furan-4,4'-imidazolidine]-2',5'-dione was 
obtained in 40% yield, mp 234.degree.-236.degree.. 
Analysis: Calcd for C.sub.11 H.sub.12 N.sub.2 O.sub.3 : C, 59.99%; H, 
5.49%; N, 12.72%. Found: C, 59.77%; H, 5.44%; N, 12.80%. 
EXAMPLE 3 
The spiro-furanohydantoins of Examples 1 and 2 were tested for their 
ability to reduce or inhibit aldose reductase enzyme activity, following 
the procedure described in U.S. Pat. No. 3,821,383 and based on the 
procedure on Hayman et. al., Journal of Biological Chemistry, 240, 877 
(1965). The substrate employed was partially purified aldose reductase 
enzyme obtained from calf lens. The results obtained are expressed as the 
compound concentration that gives 50 percent inhibition of enzyme 
activity. 
______________________________________ 
Compound of 50% Inhibitory Concentration 
______________________________________ 
Example 1 10.sup.-4 M 
Example 2 10.sup.-4 M 
______________________________________ 
EXAMPLE 4 
The compounds of Examples 1 and 2 were tested for their ability to reduce 
or inhibit sorbitol accumulation in the sciatic nerve of 
streptozotocinized (i.e., diabetic) rats by the procedure essentially 
described in U.S. Pat. No. 3,821,383. In the present study, the amount of 
sorbitol accumulation in the sciatic nerves was measured 27 hours after 
induction of diabetes. The compounds were administered orally at the dose 
levels indicated at 4, 8 and 24 hours following the administration of 
streptozotocin. The results obtained in this manner are presented as the 
percent inhibition (%) obtained at a 25 mg/kg dose compared to the 
untreated animal standard (i.e., the untreated animal where sorbitol 
levels normally rise from approximately 50-100 mM/g. tissue to as high as 
400 mM/g. tissue in the 27-hour test period): 
______________________________________ 
Compound of Percent Inhibition at 25 mg/kg 
______________________________________ 
Example 1 46% 
Example 2 2% 
______________________________________