SE437024B - PROCEDURE FOR THE PREPARATION OF SPIRO-HYDANTO COMPOUNDS - Google Patents

Description

7711053-4 2, U.S. Pat. No. 3,281,383 indeed that certain aldose reduction inhibitors, such as 1,3-dioxo-1H-benzyl, e] -isoquinoline-2 (3H) -acetic acid and certain related derivatives thereof are useful for these purposes, including those of these particular compounds which are not known to be hypoglycemic in nature. These particular aldose reductase inhibitors all work by inhibiting the activity of the enzyme aldose reductase that is responsible for regulating the reduction of aldoses (such as glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, undesirable accumulations of galactitis in the lens of galactosemic individuals and of sorbitol in the lens, peripheral nervous system and kidney of various diabetic individuals are prevented or reduced. Consequently, these compounds are of definite value as aldose reductase inhibitors for the control of certain chronic diabetic complications, incl. those of an ocular nature, since it is already known that the presence of polyols in the lens of the eye inevitably leads to cataract formation with concomitant turbidity of the lens.

U.S. Pat. No. 3,532,744 discloses the preparation of certain spiro- (imidazolidine) -2,4-diones which are useful as intermediates in the manufacture of antibiotics. However, this patent does not disclose any compound of the present invention.

In connection with the invention, it has now been unexpectedly found that various spiro-hydantoin compounds are extremely valuable in use in therapy as aldose reductate inhibitors for the control of certain chronic diabetic complications in a host individual to whom they are administered. The new method of treatment comprises treating a dietetic host for the prevention or alleviation of diabetes-associated, chronic ocular complications by administering to said host an effective amount of a compound of any of the formulas 7711053-4 3 and the base salts thereof with pharmacologically acceptable cations; wherein W is - (CH 2) n -, X is hydrogen and X 1 is hydrogen, hydroxy, fluorine, chlorine, lower alkyl or lower alkoxy (each having 1-4 carbon atoms), or wherein X and X 1 are each chlorine, lower alkyl or lower alkoxy or wherein X and X 1 together are -OCH 2 (CH 2) n O-; Y is oxygen or sulfur, Z is W, Y f? . or Q, wherein Q is -§- or -§-; and n is 0 or 1. These compounds are all active aldose reductase inhibitors and are therefore capable of markedly reducing or inhibiting sorbitol accumulation in the lens or peripheral nerves of various diabetic individuals.

In particular, the invention relates to the novel compounds of formula I which are disubstituted (neither X nor X 1 is hydrogen) and to those compounds of formula I which are monosubstituted (X is hydrogen), wherein Z is (CH 2) n and n is 0 and X 1 has a meaning other than hydrogen, 4-chloro and 5-butyl; Z is (CH 2) n and n is 1 and X 1 is non-hydrogen, 5-methoxy, 6-methoxy or 5-butoxy; Z is oxygen and X1 has a meaning other than hydrogen, chlorine, 6-bromo, 8-chloro, 6-methyl and 6-ethyl, Z is sulfur and X1 has a meaning other than hydrogen. Furthermore, the compounds of formula I wherein Z is Q as well as all compounds of formula II and III are new.

The novel compounds of formula I thus comprise epirohydantoin compounds of the formula and base salts thereof with pharmacologically acceptable cations, wherein X is hydrogen and X 2 is fluorine, hydroxy or 6 '- (lower alkoxy); or X and X 2 are each lower alkori or wherein X and X 2 together represent 0OCH 2 (CH 2) n ~ 0; and n is 0 or 1. The novel compounds of formula I also comprise spirohydantoins of formula 7711053-4 and base salts thereof with pharmacologically acceptable cations, wherein X is hydrogen and X 3 is fluorine, chlorine or bromine; or wherein X and X 3 are each chlorine or wherein X and X 3 together form -OCH 2 (CH 2) n -O-; and n is 0 or 1.

The novel compounds of formula I further comprise spirohydanteins of formula -v and base salts thereof with pharmacologically acceptable cations, wherein 1 d hydrogen and X 4 are fluorine, hydroxy or lower alkoxy; or wherein X and X 4 are each chlorine or lower alkoxy or wherein X and X 4 together are -OCH 2 (CH 2) n -O-; Y is oxygen or sulfur and n is 0 or 1.

The novel compounds of formula I also comprise spirohydantoin compounds of formula H fi> - ïfg, / wa and the base salts thereof with pharmacologically acceptable cations, wherein x is wheat and X5 is fluer, chlorine, bromine or lower eloxy; or X and X5 are each chlorine or lower alkoxy or wherein X and X5 together are -OCH2 (CH2) nO-; Q is -§- or 9 and n is 0 or 1.

O -S- II O. ._. l .............._._._._.._._....___....._., ._- 7711053-4 Av Of particular interest in this context are such typical and particularly suitable compounds as spiro- [imidazolidine-4,1'-indan] -2,5-dione, 6-fluoro-spiro- [chroman-4,4'-imidazolidine] ~ 2 ', 5'-dione. 6-chloro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, 1,7-dichloro-spiro- [chroman-4,4'-imidazolidine] -2', 5'-dione, 6,8-dichloro-spiro- [chroman-4,4'- -thiochroman] -2 °, 5'-dione and 6 ', 7'-dichloro-spiro- [imidazolidine-4,4' ~ ~ thiochroman] -2,5-dione. These particular compounds exhibit high activity in aldose reductase inhibitory activity in addition to being extremely effective in lowering sorbitol levels in the hip nerve and lens of diabetic individuals and gulactitol levels in the lens of galactosemic individuals to a remarkably high degree. The particularly suitable 6-fluorine and 6,8-dichloro derivatives are, as mentioned, new compounds.

The invention further relates to a process for the preparation of the novel compounds (namely those of formulas III-VII), wherein a corresponding carbonyl ring compound, such as the corresponding 1-indanone, 1-tetralone, 4-chroman, thiochroman-4-one, thioindan-3- on-1,1-dioxide and 4-oxothiochioroman-2,2-dioxide with the respective formulas: oxo x3 o 1 (WI "so I \;., / 2 'w X2 X4 .X5 lo v x7 p: <6 X8 wherein w, x, ix2, X3, X4, X5, X6, X7, X8, Y and Q are all of the given meaning, are condensed with an alkali metal cyanide (such as sodium cyanide or potassium cyanide) and ammonium carbonate to give the desired the spirohydantoin end product of the above formulas.

This particular reaction is normally carried out in the presence of a reaction-inert, polar organic solvent medium in which both the reactants and the penanders are mutually miscible. Particularly suitable reagents in this context include cyclic ethers such as di-oxane and tetrahydrofuran, lower alkylene glycols such as ethylene glycol and trimethylglycol, water-miscible lower alkanols such as methanol, ethanol and isopropanol, as well as N, N-di ( lower alkyl) -lower alkanamides such as N, N-dimethylformamide, N, N-diethylformamide and N, N-dimethyllacetamide, etc. The reaction is generally carried out at a temperature of about 20-12000 for a period of from about two hours to about four days. Although the amounts of reactant and treatment agent used in the reaction may vary to some extent, it is particularly convenient to use at least a slight molar excess of the alkali metal cyanide relative to the carbonyl ring compound starting material to achieve maximum yield. After completion of the reaction, the desired product is easily isolated in a conventional manner, such as by first diluting the reaction mixture with water (boiling, if necessary) and then cooling the resulting aqueous solution to room temperature, after which it is acidified to form the particular spiro. the hydantoin compound in the form of an easily recoverable falining. Compounds wherein Q in formula VII is -S- or -S- can be prepared from corresponding compounds of formula VI, wherein Y is sulfur, by simply oxidizing the latter class of compounds according to standard technology generally known to those skilled in the art. Thus, for example, the use of sodium periodate in this context leads to the formation of the oxosulfur compounds, while peroxyacids, such as peracetic acid, perbenzoic acid and m-chloroperoxybenzoic acid, etc., are suitably used to form the corresponding dioxose sulfur compounds. On the other hand, it is usually most convenient to prepare certain compounds having a ring substituent which is hydroxy (X2 or X6) by first preparing the corresponding alkoxy compounds, wherein X2 or X6 is lower alkoxy (as defined above), and then completely easily transferring the latter compounds to the desired hydroxy compounds by cleaving the ether moiety in a conventional manner.

The starting compounds required for the preparation of the spirohydantoin compounds are essentially known compounds and can either be readily obtained commercially, such as 1-indanone and 6-chloro-4-chromane, etc., or else they can be readily synthesized by those skilled in the art. man by using conventional chemical reagents and using conventional organic synthesis methods. Thus, for example, 6-fluoro-4-chromanone can be obtained by condensation of 6- (p-fluorophenoxy) propionic acid in the presence of polyphosphoric acid, while 6,7-dichlorotio- 'W fl vr fl f * * _. The chroman ~ 4 ~ one is obtained by condensation of B- (2,4 ~ dichlorophenylthio) -propionic acid in presence of concentrated sulfuric acid. In both cases, the starting organic acid is derived primarily from a commercially available compound. The chemical bases used as reactants according to the invention for the preparation of said pharmaceutically acceptable base salts are those which form non-toxic salts with various acids described herein. spiro-hydantoin compounds, such as 6-fluoro-spiro- [[chroman-4,4 '-imidazolidine] -2', 5'-dione. These particular non-toxic base salts are of such a nature that their cations can be said to be substantially non-toxic in nature over a wide dosage range. Examples of such cations include those of sodium, potassium, calcium and magnesium, etc. These salts can be readily prepared by treating said spirohydantoin compounds with an aqueous solution of the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by mixing lower alkanol solutions of said acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the manner indicated above. In both cases, stoichiometric quantities must be used to ensure complete reaction and maximum yields intended for the desired end product.

As noted above, all spirohydantoin compounds of the invention are well suited for therapeutic use as aldose reductase inhibitors for the control of chronic diabetic complications due to their ability to reduce lens sorbitol levels in diabetic individuals to a statistically significant level. Thus, 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, a typical, particularly suitable compound, has been found to provide consistent control (ie, inhibition) of the occurrence of sorbitol levels in diabetic rats significantly significantly during oral administration at dosage levels of 0.75-20 mg / kg, without showing any significant signs of toxic side effects.

The other compounds of the invention give similar results. All of the compounds described herein can be administered orally or parenterally as needed, without causing any significant, inappropriate pharmacological side effects to the individual to whom they are administered in said manner. These compounds are normally administered at a rate of about 0.1 mg per day and kg of body weight, although variations in necessity occur with respect to the weight and condition of the liberated individual and the mode of administration chosen.

In connection with the use of the spirohydantoin compounds of the invention for the treatment of diabetic individuals, it should be noted that these compounds may be administered either separately or in combination with pharmaceutically acceptable carriers according to either of the two methods indicated and that such administration may be performed both with single and multiple doses. The present compounds can be administered in a number of different dosage forms, i.e. that they can be combined with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, trocas, hard candies, powders, sprays, aqueous suspensions, injectable solutions, tinctures and mixtures, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Furthermore, such oral compositions may conveniently be sweetened and / or flavored by various means of the type commonly used for such purposes. The therapeutically useful compounds of the invention are present in such dosage forms in a concentration of about 0.5-90% by weight, based on the whole composition, i.e. in an amount sufficient to provide the desired unit dose.

For oral administration, tablets containing various excipients such as sodium citrate, potassium citrate and calcium phosphate may be used in conjunction with various disintegrants such as starch, preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binders such as polyvinylpyrrolidone. sucrose, gelatin and acacia. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, are often added for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard, filled gelatin capsules; Particularly suitable materials in this context include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or tinctures and mixtures are desired for oral administration, the essential active component therein may be combined with various sweetening or flavoring agents, coloring agents and optionally emulsifiers and / or suspending agents together with such diluents as water, ethanol, propylene glycol, glycerol and different combinations thereof.

For parenteral administration, solutions of these particular spirohydantoins in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble alkali metal or alkaline earth metal salts of the kind mentioned. Such aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonically with a sufficient amount of sodium chloride or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this context, sterile aqueous media can be used which can be easily obtained according to standard techniques. It is also possible to administer said spirohydantoin compounds topically via a suitable ophthalmic solution adapted for the present purpose, which solution can be applied dropwise to the eye.

The activity of the present compounds as agents for the control of chronic diabetic complications is determined by their ability to meet the requirements determined by the following standard biological and / or pharmacological tests: (1) measurement of their ability to inhibit the enzyme activity of isolated aldose reductase, (2) measurement of their ability to reduce or inhibit sorbitol accumulation in the hip nerve in acutely stretozotocinized (ie, diabetic) rats, (3) measurement of their ability to reverse already elevated sorbitol levels in the hip nerve and lens of streptozotocin-induced chronic diabetic rats, (4) their ability to prevent or inhibit galtitol formation in the lens of acute galactosemic rats and (5) their ability to delay cataract formation and reduce the extent of lens opacity in chronic galactosemic rats.

The invention is further illustrated by the following preparations and examples, in which the stated temperatures refer to degrees Celsius.

Preparation - A mixture of 3.5 g (0.019 mol) of B- (p-fluorophenoxy) -propionic acid [Finger et al., Journal of the American Chemical Society, vol. 81, p. 94 (1959)] and 40 g of polyphosphoric acid were heated for 10 minutes on a steam bath and poured into 300 ml of ice water. The resulting aqueous mixture was extracted with 3 separate portions of ethyl acetate and the combined organic layers were washed successively with dilute sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After elimination of the desiccant by filtration and the solvent evaporated to give a residue. , which was recrystallized from ethanol to give 2.93 g (93%) of pure 6-fluoro-4-chromanone, m.p.

C9H7FO2.0.25 H2O: Calculated: C 63.34 H 4.43 Found: C 63.24 H 4.15 - __ .......... ~ ........ ........__......_____._._...___.._- _ - I 7711053-4 io Pregaration B.

A solution of 12.5 g (0.07 mol) of 3,4-dichlorobenzene thiol (supplied by Aldrich Chemical Company, Inc., Milwaukee, Wisconsin) in 35 ml of 2N sodium hydroxide solution and 5 ml of ethanol was added to an ice-cold solution consisting of of 7.6 g (0.07 mol) of B-chloropropionic acid (Aldrich) and 8.6 g (0.07 mol) of sodium carbonate monohydrate, dissolved in 50 ml of water. The resulting reaction mixture was heated on a steam bath for two hours, cooled to room temperature (about 250) and extracted with ethyl acetate to eliminate any impurities.

The recovered aqueous portion was poured into 300 ml of ice-cold 3N hydrochloric acid and the precipitated solids were collected by suction filtration.

After washing this material with water, air drying to constant weight and recrystallization from ethyl acetate / n-hexane, 11.4 g (65% yield) of B- (3,4-dichlorophenylthio) -propionic acid with melting point were obtained; 70-72 °.

C 9 H 4 Cl 2 S: Calculated: C 43.04 H 3.21 Found: C 43.13 H 3.25 A solution of said product in concentrated sulfuric acid was prepared by adding 5.0 g (0.02 mol) of B- ( 3,4-Dichlorophenylthio) -propionic acid to 50 ml of ice-cold concentrated sulfuric acid with constant stirring throughout the addition step. The resulting solution was stirred for 20 minutes at 0 ° C and finally for 20 minutes at room temperature. At this point, the entire reaction mixture was poured into 300 ml of ice water and the precipitated solids were collected by suction filtration, washed with water and air dried to constant weight. Recrystallization from ethanol gave 2.5 g (54%) of pure 6.7 Dichlorothiochroman-4-one, m.p. 134-136 °.

CqH6Cl2OS: Calculated: C 46.37 H 2.60 Found: C 46.34 H 2.45 Preoaration C. 3 ', 4'-dihydro-spiro- [imidazolidine-4,1' (2'H) -naphthalene] -2,5- -dione was prepared according to Chemical Abstracts, åä, p. 65767 (1941), starting from 1-indanone and other readily available materials. The product obtained was identical in every respect to the previously described compound. 7711053-4 11 Example: A mixture of 2.5 g (0.1 mol) of 6-methoxy-1-indanone (Aldrich), 1.5 g (0.23 mol) of potassium cyanide and 6.7 g (0.07 mol) of ammonium carbonate in 20 ml of ethanol was immersed in a stainless steel bomb and heated for 20 hours at 1100. After cooling to room temperature (about 250), the contents of the bomb were diluted with 100 ml of water and acidified. to pH 2.0 with 6N hydrochloric acid. The precipitated product was collected by suction filtration and recrystallized from ethanol to give 0.49 g (14%) of pure 6'-methoxy-spiro [imidazolidine »4,1'-indane] -2,5-dione, m.p. 192-194 °.

Cl 2 H 12 N 2 O 3: Calculated: C 62.06 H 5.21 N 12.06 Found: C 61.94 H 5.26 N 12.01 Example Å; The experiment of Example 1 was repeated. but with the exception that 6-fluoro-1-indanone [Chemical Abstracts, vol. 55, p. 25873a (1961)] was used as starting material instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 6'-fluoro-spiro- [imidazolidine-4,1'-indane] -2,5-dione, m.p. 255-257 °. The yield of the pure product was 4.6% of the theoretical value. Cl1H19FN2O2: Calculated; C 60.00 H 4.12 N 12.72 Found: C 59.86 H 4.33 N 12.49 Example 1 The experiment of Example 1 was repeated, but with the exception that 5,6-dimethoxy-1-indanone [Koo , Journal of the American Chemical Society, vol. 75, p. 1891 (1953)] was used as a starting material instead of b-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 5 ', 6'-dimethoxy-spiro- - [imidazolidine * 4,1'-indane] -2,5-dione, m.p. 246-2480. The yield of pure product was 48% of the theoretical value. ° 13 “14N2 ° 4 * Calculated: C 59.53 H 5.38 N 10.68 Found: C 59.26 H 5.49 N § 10.54; emQgl, 4.

The experiment of Example 1 was repeated. but with the exception that 5,5-methylenedioxy-1-indanone [Perkin and Robinson, Journal of the Chemical Society, vol. 91, p. 1084 (1907)] was used as starting point 7? 11Ü53 ~ 4 _; :: fi :: er see: above. In this case, the final product was É '; -methylenedioxy-spiro- [imidazolidine-4,1'-inden] -2,5-dione with a melting point of 248-250 °. The yield of pure product was 29% of the theoretical value.

C12 ”10N2 ° 4” Calculated: C 58.53 H 4.09 N ll, 38 Found: C 58.44 H 4.14 N 11.25 §zsn2el_ši The experiment according to example 1 was repeated, but with the exception that 6 -methoxytiochroman-4-one [Chemical Abstracts, vol. 53. p. 7616 (1959)] was used as starting material instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was obtained 6 '-methoxy-spiro- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 170-1720. The yield of pure product was 41% of the theoretical value. cl2nl2N2o¿s = Calculated: c 54.53 H 4.58 N 10.61 space »c 54.64 H 4.67 N 10.66 Example Q; The experiment of Example 1 was repeated, but with the exception that 6-chlorothiochroman-4-one was used as starting material [Chemical Ahatracts, vol. 55, p. 123970 (1961)) in the stable of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 6'-chloro-spiro- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 244-2460. The yield of pure product was 53% of the theoretical value.

C11H9ClN2O2S: Calculated: C 49.16 H 3.38 N 10.43 Found: C 49.23 H 3.40 N 10.39 Example gel 7 The experiment according to Example 1 was repeated, but with the exception that 6-bromothiochroman was used. 4-one [Arndt, Chemical Reports, vol. 58, p. 1612 (1925)] as a starting material instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 6'-bromo-spiro- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 234-2360. The yield of pure product was 56% of the theoretical value.

P11H9BrN2O2S: Calculated: C 42.18 H 2.90 N 8.95 Found: C 41.98 H 2.92 N 8.95 ____._._...__ _., 7711053-4 13 šägvnpel Ü_ The experiment according to Example 1 was repeated, except that 6,7-dichlorothiochroman-4-one (prepared according to Preparation A) was used as starting material instead of 6-methoxy-lindanone, using the same molar proportions as above. In this particular case, the final product was 6 ', 7'-dichloro-spiro- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 298-300 °. The yield of pure product was 49% of the theoretical value. c H.c12N2o, s = ll C a Calculated: C 43.58 H 2.66 N 9.24 Found: Ü 43.77 H 2.85 N 9.38 Example 9- The experiment according to example 1 was repeated, but with the except that 6-fluorothiochroman-4-one [Chemical Abstracts, vol. 70, p. 47335x (1969)] was used as starting material instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 6-fluoro-spira- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 200-2020. The yield of pure product was 60% of the theoretical value._ Cl1H9FN2O2S: Calculated: c 52.37 H 3.60 N 11.11 Found: C 52.36 H 3.73 N 11.05 Example_LQ; The experiment of Example 1 was repeated, but with the exception that 8-chlorothiochroman-4-one was used as starting material [Chemical Abstracts, vol. 53, P. 71610 (1959)] instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 8'-chloro-spiro- [imidazolidine-4,4'-thiochroman] -2,5-dione, m.p. 265-267 °. The yield of pure product was 66% of the theoretical value. Cl1H9c1N2o2s = Calculated: C 49.16 H 3.38 N 10.43 Found: C 49.32 H 3.50 N 10.38 Ezsm2el_lll The experiment of Example 1 was repeated, but with the exception that 7-chlorothiochroman was used as starting material. 4-one [Chemical Abstractn, vol. 52, p. L1044b (l958)] instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the resulting product was 7-chloro-spiro- [imiaazoline-4,4'-chlorochroman] -Q, 5-dione, m.p. 235-2370. The yield of pure product was 67 ß 7711053 * 4 14 of the theoretical value.

C 11 H 9 ClN 2 O 3 S: Calculation: C 49.16 H}, 38 N 10.43 Found: C 49.32 H 3.36 N 10.03 βxamp, l2_ The experiment of Example 1 was repeated, but with the exception that 7- methoxy-1-tetralone (Aldrich) as the starting material instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was 3 ', 4'-dinydro-7'-motoxy-spiro- [imidazolidine-4,1' (2'H) -naphthalene]-2,5-dione, m.p. 227-2290. The yield of pure product was 59% of the theoretical value.

Cl 3 H 11 N 2 O 3: Calculated: C 63.40 H 5.73 N 11.38 Found: C 63.19 H 5.68 N 11.30 Example gel 1a; The experiment of Example 1 was repeated, but with the exception of using 6,7-dimethoxytetralone [Howell and Taylor, Journal of the Chemical Society, p. 1248 (1958)] instead of 6-methoxy-1-indanone, using the same molar proportions as above. In this case, the final product was obtained 3 ', 4'-dihydro-6', 7'-dimethoxy-spiro- [imidazolyl] -4,1 '(zu) -naphthalene] -2,5-ion with melting point 238- 24 ° °. Yield: of pure product was 49% of the theoretical value.

C14 "1eN2 ° 4 * Calculated: C 60.86 H 5.84 N 10.14 Found: C 60.94 H 6.04 N 10.46 Example gel * A solution of 1.18 g (0.005 mol) 6 ' -methoxy-spiro-fimidazolidine-4,1 '-indane] ~ 2,5-dione (prepared according to Example 2) in 10 ml of methylene chloride was cooled to -650 and then added dropwise with a solution of 1.44 ml (0.055 mol) of boron tribromide, dissolved in 10 ml of methylene chloride, with continuous stirring of the whole mixture in a nitrogen atmosphere. The resulting mixture was allowed to warm to room temperature (approximately 250) after removal of the cooling bath, after which this temperature was maintained for seven hours.

Then, 30 ml of water was added dropwise to the mixture, and the separated organic layer was collected and dried over anhydrous magnesium sulfate. After elimination of the organic solvent (ie methylene chloride) by evaporation under reduced pressure, a residue was finally obtained, which was then recrystallized from ethanol for e .-- fl- s fl n fl ”. formation of 240 mg (2%) of pure 6'-hydroxy-spiro- [imidazolidine-4,1'- ~ 1na fl n] ~ 2, s-aina with a melting point of 253-255 °. % l% nWQf Calculated: C 60.54 H 4.62 N 12.84 runner: c 60.29 H 4.66 N 12.93 ExemQel_15.

A mixture of 5.0 g (0.033 mol) of 4-chroman (Aldrich), 2.8 g (1.043 mol) of potassium oyanide and 8.26 g (0.086 mol) of powdered ammonium carbon in 40 ml of ethanol was dropped on a bomb. of stainless steel and heated for 24 hours in an oil bath at a temperature of 600. The reaction mixture was diluted with 300 ml of water, boiled for 15 minutes, cooled to room temperature and acidified with 6N hydrochloric acid. The precipitated product was collected by suction filtration and recrystallized from ethanol to give 2.5 g (35%) of pure spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, m.p. 238 ° (literature melting point 236-2420 according to the West German explanatory document 1,135,915).

C 11 H 11 NO 3: Calculated: C 64.38 H 5.40 N 6.83 Found: C 64.18 d 5.38 N 6.83 Example gel 1-6. A The experiment of Example 15 was repeated, but with the exception of using 6-methoxy-4-chromanone (British Patent Specification 1,024. U45) as starting material instead of 4-chromanone, using the same molar proportions as above. In this case, the final product was 6-methoxy-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, m.p. 170 DEG-172 DEG C. The yield of pure product was 32% of theory. ethical value.

Cl 2 H 12 N 2 O 42 Calculated: C 58.06 H 4.87 N 11.29 Found: C 58.04 H 4.98 N 11.17 Exemnel eel; The experiment of Example 15 was repeated, except that 6-fluoro-4-chromanone (prepared according to Preparation B) was used as starting material instead of 4-chromanone, using the same molar proportions as above. In this particular case, the final product was 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, m.p. 239-241 °. The yield of pure product was 36% of the theoretical value.

C11H9FN2O3: Calculated: C 55.93 H 3.84 N 11.86 Found: C 55.54 H 3.88 N 12.12 7711DJ3-4 16 Example The experiment according to Example 15 was repeated, but with the exception that used 6,7-dichloro-4-chromanone (DT-OS 1,928,027) as starting material instead of 4-chromanone, using the same molar proportions as above. In this case, the final product was 6,7-dichloro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, m.p. 263-2650. The yield of pure product was 8% of the theoretical value.

Cl1H8Cl2N2O3: Calculated: C 46.02 H 2.81 N 9.76 Found: C 45.83 H 2.94 N 9.65 Example 19.

The experiment of Example 15 was repeated, but with the exception of using 6,8-dichloro-4-chromanone [Huckle et al, Journal of Medicinal Chemistry, vol. 12, p. 277 (1969)] as starting material instead of 4-chromanone, using the same molar proportions as above.

In this case, the final product was 6,8-dichloro-spiro- [chroman--4,4'-imidazolidine] -2 ', 5'-dione, m.p. 234-2350. The yield of pure product was 20% of the theoretical value.

C H-Cl NQO3: II Ö 2 Calculated: C 46.02 H 2.81 N 9.76 Found = c 45.81 H 2.74 N 9.69 Example 20.

A mixture of 4.57 g (0.025 mol) of 6-chloro-4-chromanone (Aldrich), 2.8 g (0.043 mol) of potassium cyanide and 9.6 h (0.1 mol) of powdered ammonium carbonate in 62.5 ml of 50% ethanol was heated for 48 hours at 600. The reaction mixture was cooled to room temperature (about 250), diluted with 300 ml of water and acidified with 6N hydrochloric acid. The precipitated solids were collected by suction filtration and recrystallized from ethanol to give 5.1 g (81%) of pure 6-chloro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5' ~ dion with melting point 268-2700 (literature melting point 267-270 ° according to DT-As 1,135,915). C 19 H 21 N 2 O 3: Calculated: C 52.29 H 3.59 N 11.09 Found: C 52.15 H 3.73 N 10.99. .., _._.._... ._........... u .., ..., .., 7711053-4 ëæ2n22l_3ll The experiment according to Example 20 was repeated, but with the exception - taken that 8-chloro-4-chromanone was used [Chemical Abstracts, vol. 34, P-4'35d (l940)] instead of 6-chloro-4-chromanone, using the same molar proportions as above. In this case, the final product was obtained 8-chloro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione with Melting Purple: zii-egsf "(literature point 231-235 ° enzagt nT -ls 1,135,915).

The yield of pure product was 34% of the theoretical value.

Cl1H9ClN2O3: Calculated: U 52.29 H 3.59 N 11.09 Found: C 52.11 H 3.74 N 11.12 Example ÄåL The experiment according to Example 20 was repeated, but with the exception that 6 ~ bromo-4 was used. -chromanone [Gilman et al. Journal of the Ameri ~ can Chemical Society, vol. 73, p. 4205 (l95l)] instead of 6-chloro-4-chromanone, using the same molar proportions as above. In this fail, e-bromo-spiro- [chroman-w, Au-imidazolidine] -2 ', 5'-dione with a melting point of 266-2680 (literature melting point 264-2.59 ° according to DT-As 1,135 .915). The yield of pure product was 15 a of the theoretical value.

Example 23 A solution of 1.09 g (0.005 mol) of spiro- [chroman-4,4'-imidazolidine] 2 ', 5'-dione (prepared according to Example 20) and 10 mg of ferric chloride in 6 ml of dry dimethylformamide was cooled to 4040 ° and added dropwise and with constant stirring to a solution of 355 g of chlorine gas, dissolved in 4 ml of dry dimethylformamide. The resulting reaction mixture was maintained at -400 for 30 minutes with stirring, after which the temperature was raised to room temperature (about 250). After 2.5 hours at this temperature, the mixture was poured into 250 ml of ice water to form a crystalline precipitate, which was collected by suction filtration and air dried to constant weight. Recrystallization of the latter material from 6 ml of glacial acetic acid gave 0.31 g (25%) of pure 6-chloro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione, which in each respect was identical to the product of Example 25.

Example 24.

A mixture of 252 mg (0.001 mol) of 6'-fluoro-spiro- [imidazolidine-4,4 '-thiochroman] -2,5-dione (prepared according to Example 12) in 10 ml of methylene chloride was stirred together with 50 mg of 40 mg. % aqueous solution of totrabutylammonium hydroxide and 224 mg (0.01 mol) of sodium periodate in 5 ml of water at room temperature (approximately 250) for one hour. The precipitated solids were collected by suction filtration and then recrystallized from 3 ml of ethanol to give 60 mg (22%) of pure 6'-fluoro-spiro- [imidazolidine-4,4'-thiochroman] - 2,5-dione-1 'oxide with melting point 289-291 °.

C 11 H 9 FN 2 O 3 S: Calculated: C 49.25 H 3.33 N 10.44 Found: C 49.27 ß 3.35 N 10.35 Example 25- A suspension of 0.595 g (0.00236 mol) of 6'-fluoro-spiro - - [imidazolidine-4,4'-thiochroman [-2,5-dione (prepared according to Example 12) in 50 ml of chloroform in a 250 ml three-necked round bottom flask was added for one hour with 1.00 g (0.00579 mol) -chloroperoxybenzoic acid in small portions. The resulting slurry was stirred for 36 hours at room temperature (about 25 °) and diluted with 500 ml of ethyl acetate. The resulting yellow layer was washed with 4 x 50 mL of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the solvent removed to give 0.50 g (74.5%) of crude 6'-fluoro-spiro- [imidazolidine-4 , 4'-thiochroman] -2,5-dione-1 ', 1'-dioxide in the form of a white crystalline residue. Recrystallization from ethanol / ethyl acetate / n-hexane gave the pure material (m.p. 179-1800, dec.) As a first fraction of fine white crystals (yield 0.295 g). Two further recrystallizations from ethanol / ethyl acetate raised the melting point of the analytical sample to 184-186 ° (dec.).

C11H9FN2O4S.0.5CH3COOC2H5! Calculated: C 47.55 H 3.99 N 8.53 runner; C 47.54, H 3.93 N 8.56 Example 26.

The experiment of Example 25 was repeated, except that 0.234 g (0.001 mol) of spiro- [imidazolidine-4,4'- -thiochroman] -2,5-dione (prepared according to Example 7) and 0.426 g (0.00247 mol) of m-chloroperbenzoic acid to give 0.20 g (75%) of pure spiro- [imidazolidine-4,4 '-thiochroman] -2,5-dione-1', 1'-dioxide. Recrystallization from methanol / ethanol / n-hexane gave the analytical sample (m.p. 28 ° ~ 2 ° C).

C1HH10N2O4S = Calculated: C 49.61 H 3.78 N 10.52 Found: C 49.82 H 3.85 N 10.19 'gm »~ - - .v -« »7711053-4 19 Exemcelg1¿ A mixture of 1.0 g (0.00549 mol) of thioindan-3-one-1,1-dioxide [Regitz, Chemical Reports, vol. 98, p. 36 (1965)], 0.613 g (0.0094 mol) of potassium cyanide and 21.9 g (0.021 mol) of ammonium carbonate in 14 ml of 50% ethanol were immersed in a 50 ml reaction flask and heated for 48 hours at 600 ml. nitrogen atmosphere. The reaction mixture was diluted with 70 ml of water, a trace of solid was removed by filtration and the filtrate was acidified with 6N hydrochloric acid. The precipitated product was taken up by filtration, redissolved in 4N potassium hydroxide solution and acidified again with 6N hydrochloric acid. The acidified solution, containing the product, was saturated with sodium chloride and extracted with 6 x 150 ml of fresh ethyl acetate, after which the formed organic layers were combined and dried over anhydrous magnesium sulfate. After elimination of the drying agent by filtration and evaporation of the organic solvent under reduced pressure, 0.50 g (36%) of pure spiro- [imidezolidin-3, partition) after two recrystallizations from ethanol / ethyl acetate / n-hexane.

Clo fl NQOAS: Calculated: C 47.61 H 3.20 N 11.11 Found: C 47.77 H 3.28 N 10.85 §¿§mpel ÅQ_ A mixture of 2.75 g (0.0l562 mol) 6 , 8-dimethyl-4-chromanone [Chemical Ah tracts, vol. 58, p. 13900c (1964)], 3.5 g (0.053b mol) of potassium cyenide and 10.5 g (1.09 mol) of ammonium carbonate in 60 ml of 50% ethanol were immersed in a 125 ml reaction flask and heated 48 hours in an oil bath at 65 ° under a nitrogen atmosphere. The reaction mixture was cooled to room temperature (about 25 °) and filtered and the filtrate formed was extracted with 50 ml of diethyl ether. The water layer formed was collected and acidified to pH 2.0 with 3N hydrochloric acid (cooling was necessary). The cloudy mixture was extracted with 3 x 200 ml of ethyl acetate and the combined organic layers were re-extracted with 3 x 50 ml of 4N sodium hydroxide solution in water. The combined basic aqueous layers were acidified again to pH 2.0 with 3N hydrochloric acid in the indicated manner and then quenched with sodium chloride before extraction with 3 x 200 ml of fresh ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was eliminated from the filtrate by evaporation under reduced pressure to give 2.50 g (65%) of 6,8-dimethyl-spiro- [chroman-4,4 '-imidazole din [»2', 5 ' ~ dion with melting point 185-1900 (decomposition). Två om- ....__......_._.._......__. = _.___ ^ _-__- - ¿_¿ ~ -; ._ '/ Crystallizations from water-dilute ethanol gave analytically pure material (m.p. 188-1890). clmMx-zzoj: I ueraknat: o a3,4o H 5.73 N 11.38 Found: C 63.05 H 3.69 N 11.35 ilxzamlpcl 29.

The sodium salt of 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione is prepared by dissolving this compound in water, containing an equivalent amount in moles of sodium nitroxide, and then lyophilizing the mixture. . In this way, the desired alkali metal salt of the hydantoin is obtained in the form of an amorphous powder, which can be easily dissolved in water.

In the same manner, the potassium and lithium salts can be prepared, as well as the alkali metal salts of all other spirohydantoin compounds described in Examples 1-21 and 23-35.

Example 30.

The potassium salt of 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -3 ', 5'-dione is prepared by dissolving said compound in water, containing an equivalent amount in moles of calcium hydroxide, and then lyophilizing the mixture. . The corresponding magnesium salt is also prepared on this side, as is the case with all other alkaline earth metal salts of not only this particular compound, but also of the epirohydantoins described in Examples 1-21 and 23-35.

Example 31.

A dry solid pharmaceutical composition is prepared by mixing the following materials in the following weight proportions: o-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione 5C sodium citrate Alginic acid 10 Polyvinylpyrrolidone 10 Magnesium stearate 5 After careful mixing of the dried composition, tablets thereof are prepared, each tablet being of such a size that it contains 200 mg of the active component. Other tablets are prepared in a similar manner, containing 25, 50 and 100 mg of active cumin component, by simply selecting the correct amount of hydanone compound in each case. n- fl »» nuu-a -... Nl ... am 7711053-4 21 Example gel šåà A dry, solid pharmaceutical composition is prepared by combining the following materials in the specified weight proportions: 6 ~ chloro-spiro- [chroman ~ 4,4'-imidazolidine] -2 ', 5'-dione 50 Calcium carbonate 20 Polyethylene glycol, average molecular weight 4000 30 The dried mixture is stirred thoroughly to obtain a powdered product which is completely uniform in every respect. Soft elastic and hard, filled gelatin capsules containing this pharmaceutical composition are prepared, using a sufficient amount in each case to provide each capsule with 250 mg of the active ingredient.

Example 33.

The following spirohydantoin compounds of Preparation C and Examples 1-22 and 24-28 were tested for their ability to reduce or inhibit aldose reductase enzyme activity by a method of S. Hayman et al., Journal of Biological Chemistry, Vol. 240, p. 877 (1905), modified according to U.S. Pat. No. 3,821,383.

In each case, the substrate used consisted of partially purified aldose reductase enzyme obtained from calf lentils. The results obtained with each compound are expressed in% inhibition of enzyme activity with respect to the different levels of concentration tested: .- aq 771ïÛE »3- ~ â 22% inhibitory Compound 10o-4M 10o-5M: Lo-6M 10o-7M Product of prep . 72 34 13 7 Product of ex. 1 97 61 17 1 Product of ex. 2 74 12 22 -1 Product of ex. 3 90 81 35 9 Product of ex. 4 92 67 25 3 Product of ex. 5 76 60 18 7 Product of ex. 6 79 87 71 30 Product of ex. 7 32 - - - Product of ex. 8 67 84 76 69 Product of ex. 9 81 77 66 38 Product of ex. 10 60 - - - Product of ex. ll 70 - - - Product of ex. 12 54 - 23 - Product of ex. 13 82 26 8 16 Product of ex. 14 93 31 ll -30 Product of ex. 15 73 64 -9 -16 Product of ex. 16 100 92 35 7 Product of ex. 17 84 58 52 3 Product of ex. 18 59 96 91 84 Product of ex. 19 85 90 78 81 Product of ex. 20 73 81 77 64 Product of ex. 21 87 85 52 6 Product of ex. 22 74 - - - Product of ex 24 87 80 64 16 Product of ex. 25 85 74 74 28 Product of ex. Å6 94 69 31 2 Product of ex. 27 81 54 22 4 Product of ex. Example 71 The following spirohydantoin compounds from Preparation C and Examples 1-4, 5-6, 8-13, 14-20, 21 and 24-27 were tested with off. looking at their ability to reduce or inhibit accumulation in the hip nerves of streptozotocinated (ie, diabetic) rats according to a procedure essentially described in U.S. Pat. No. 3,82l. In the present study, the amount of sorbitol accumulated in the hip nerves was measured 27 hours after induction of diabetes.

The compounds were administered orally at the indicated dosage levels 4, 8 and 24 hours after administration of streptozotocin. The results obtained are given in the following summary as% inhibition produced by the test compound compared to the case where no compound was administered (ie the untreated animal with sorbitol levels normally rising from about 50-100 mM / g tissue up to as high as 400 mM / g tissue during the 27-hour test period). % inhibition Förenins 0.75 1.5 2.5 5.0 10 ma / ke Product of prep. C - - - 3 40 Product of ex. 1 - - - 6 54 Product of ex. 2 - - - 45 - Product of ex. 3 - - - 33 49 Product of ex. 4 - - - 9 - Product of ex. 5 - ~ - - 26 - Product of ex. 6 - - 55 - - Product of ex. 8 - - - 59 - Product of ex. 9 13 45 74 ~ - - Product of ex. 10 - 5 - ~ _- _ * Product of ex. ll - 26 - - - Product of ex. 12 - - - 25 44 Product of ex. l3 - - - - 3 Product of ex. 14 - - - - 15 Product of ex. 15 - - 34 58 77 Product of ex. 16 - - 24 - - Product of ex. 17 45 72 - - - 7711055-4 24 Product of ex. 18 - «64 ~ - - - Product of ex. 19 82 - - - - Product of ex. 20 64 84 - - - Product of ex. 21 - 30 - _- - Product of ex. 24 - 35 - - _- Product of ex. 25 - - 47 68 - Product of ex. 26 28 - 12 - - Product of ex. Example 5 6-Fluoro-spira- [chroman-4,4'-imidazolidine] -2 ', 5'-dione (the product of Example 22) was tested for its ability to reverse already elevated sorbitol levels in streptozotocin-induced diabetic rats for two weeks (ie, chronic condition) by administering said compound to the animals for a period of seven days. In this examination, the sorbitol determinations were performed in both the hip nerve and the lens. Streptozotocin was first administered to the animals at 65 mg / k intravenously. The animals then remained untreated for two weeks.

After this period, a control group of eight rats (control group I) was killed for baseline sorbitol determinations, while the other two groups of seven animals each received 6-fluoro-spiro- [chroman-4,4'-imidazolidine] ~ - 2 ', 5'-dione at 2.5 mg / kg twice a day or water only (control group II). After seven days, the dishes were sacrificed (three hours after dosing) and it was found that while the hip nerve sorbitol levels in the control group (control group II) had risen slightly above baseline values and the lens sorbitol values had stabilized, there were significant reductions in sorbitol levels in both hip nerves (68 %) and the lens (71%) in the treated group (ie such animals as obtained from the test compound) were obtained.

The ability of 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5'-dione to prevent or inhibit galactitol formation in acute galactosomal rats was determined by administering said compound to the animals via the diet during seven days. In this study, normal male rats were first divided into groups of six animals each, which were fed a 30 ”galactose diet together with the compound at three different dosage levels. One group of animals received 6-fluoro-spiro- [chroman--4,4'-imidazolidine] -2 ', 5'-dione in an amount of 10 mg / kg and another group 20 mg / kg. A control group of nine animals received a 30% galactose diet, but no compound. After the seven-day period, the lenses for galactitol determination were removed and it was found that while the polyol group had risen from substantially undetectable levels in control amounts to a value well above 30 μmol / g, In addition to galactose, the rats that received the test compound in the diet showed a very pronounced inhibition of the galactitol values at the two higher dosage levels, mfinligcn '12 f., at 20 mg / kg or 40 7 »at 10 Ing / kg.

Example 1L¿ To determine the effect of 6-fluoro-spiro- [chroman-4,4'- -imidazolidine] -2 ', 5'-dione on cataract formation in galactosemia, the dishes were fed a 30% diet with and without the addition of this compound for 29 days and examination of the eyes was routinely performed approximately twice a week throughout the period. The test animals obtained the test compound mixed in the feed at concentration levels sufficient to give approximate doses of 10 and 20 mg / kg. Control animals received only the galactose diet, i.e. without the association. After 8-14 days, it was found that lenticular opacities had developed in 90% of the eyes of the control animals compared to no opacity in the animals receiving the test compound at a dose of 10 or 20 mg / kg. After 17 days, it was found that 100% of the eyes of the control animals had opacities, while only 6% of the eyes of the rats receiving the test compound were affected in this respect. The equivalent for rats receiving the test compound at a dose of 20 mg / kg was 0%. This delay in cataract formation continued in all treated groups until the 22nd day, at which lenticular point capacitances could be observed in the animals receiving the test compound at a dose of 10 mg / kg. However, in the rats receiving the test compound at a dose of 20 mg / kg, a significant delay in cataract formation was observed on the 29th day, as evidenced by the fact that only 37% of the eyes of the animals in the treated group showed lentucular opacities.

Example 33.

The efficacy of 6-fluoro-spiro- [chroman-4,4'-imidazolidine] -2 ', 5' -dione in delaying cataract development in rats is further illustrated by the method described in Example 37 by careful consideration. to the extent of the lenticular opacities. In this study, the percentage of lens surfaces was monitored during the 29-day period and the results obtained were used as an index of the severity of the condition. It was then observed that after 17 days, 75% of the control lenses showed an infested area that was never less than 10%. On the other hand, the corresponding values were 6 resp. 0% fed rats that received the test compound at a dose of 10 and 20 mg / kg. In fact, the severity of the lens capacities was always lower in the treated groups than in the control group, incl. the values obtained, ...._ .. «_ - - * '-» more -. «_ The 29th day.

Claims (17)

A method of analogy for the preparation of a compound having the formula HN _____ ïåp l NH A //, ... IO and its base salts with pharmacologically acceptable cations, wherein A is X SO 2 IV X 2 V X 3 X 5 X 7, wherein X is hydrogen and X 2 is fluorine, hydroxy or 6 '- (lower alkoxy); or X and X 2, respectively, each represent lower alkoxy, and taken together represent -OCH 2 (CH 2) n O-r wherein n is 0 or 1, X! is hydrogen and X4 is 7'-lower alkoxy and X3 and X4 each represent lower alkoxy or X5 is hydrogen and X6 is fluorine, chlorine, bromine or lower alkoxy; or X5 and X6 each represent chlorine or lower alkyl, X7 represents hydrogen and X8 represents hydrogen or fluorine, Y represents oxygen or sulfur, Q represents -S- ~ II O e - - «-> - ^ wwn..s- = fsw-.ftvs ~ n: 7711053-4 (H- or - - provided that X and X6 are alkyl only if Y is oxygen Ö 10730 I 'and that X3 is hydrogen and X6 is chlorine or bromine only if Y is sulfur characterized in reacting a corresponding carbonyl ring compound having the formula: OA wherein A is as defined above, reacting with an alkali metal cyanide and ammonium carbonate and, when required, oxidizing a spirohydantoin product, wherein Y is sulfur, to a product in which Y is converted to Q to form a compound, in which A has the formula VIII and that, when required, a spiro-hydantoin product prepared according to any of the above steps is converted to a pharmacologically acceptable base salt hence. 2. A process according to claim 1, characterized in that the reaction is carried out in a reaction-inert solvent, e.g. a cyclic ether, at a temperature in the range of 20-120 ° C. 3. A process according to claim 1 or 2, characterized in that the prepared spiro-hydantoin compound has the form 1 4. A process according to claim 1 or 2, characterized in that the prepared spirohydantoin compound has the formula 7711053-4 A8 x - 0 NH X2 wherein X is hydrogen and X2 is fluorine. 5. A process according to claim 1 or 2, characterized in that the spirohydantoin compound prepared is HN CH O 3 6. A process according to claim 1 or 2, characterized in that the prepared spirohydantoin compound has the formula 7. A process according to claim 6, characterized in that X 5 is hydrogen, X 6 is fluorine and Y is oxygen. 8. A process according to claim 6, characterized in that X 5 is hydrogen, X 6 is lower alkoxy and Y is oxygen. 9. A method according to claim 6, characterized in -._..... í., .___._.__..__... ~ ~ - - --- ~ »- 7711053--4: H hence, that X5 is hydrogen, X6 is fluorine and Y is sulfur. 10. lO. Process according to Claim 6, characterized in that X 5 is hydrogen, X 6 is lower alkoxy and Y is sulfur. 11. ll. Process according to claim 6, characterized in that X5 and X6 are each chlorine and Y is oxygen. 12. A process according to claim 6, characterized in that X and X are each chlorine and Y is sulfur. 13. A process according to any one of claims 1 and 2, characterized in that the prepared spiro-hydantoin compound is 6-fluoro-spiro- / chroman-4,4-imidazolidine / -2 ', 5'-dione. Process according to either of Claims 1 and 2, characterized in that the spirohydantoin compound prepared is 6,7-dichloro-spiro- / chroman-4,4'-imidazolidine / -2 ', 5'- dion. Process according to either of Claims 1 and 2, characterized in that the spiro-hydantoin compound prepared is 6,8-dichloro-spiro- / chroman-4,4'-imidazolidine / -2 ', 5'- dion. 16. A process according to any one of claims 1 and 2, characterized in that the spiro-hydantoin compound prepared is 6'-fluoro-spiro- / imidazolidine-4,4'-thiochroman / -2,5-dione. Process according to either of Claims 1 and 2, characterized in that the spiro-hydantoin compound prepared is 6 ', 7'-dichloro-spiro- / imidazolidine-4,4'-thiochroman / -2,5- dion.