HK1010367B - Substituted imidazolidin-2,4-dione derivatives as immunomodulators - Google Patents

Description

The invention relates to substituted imidazolidin-2,4-dione compounds, their manufacturing processes and their use in medicinal products.

The overproduction of the cytotoxin tumor necrosis factor-α (TNF-α) plays a central role in the pathogenesis of a wide range of serious diseases, including multiple sclerosis, graft-versus-host syndrome, transplant rejection, aphthesic stomatitis, erythema nodosum leprosum, Boeck's disease, rheumatoid arthritis and a number of other diseases associated with inflammatory events. A known treatment approach for these diseases is the general suppression of TNF-α release by immunosuppressive modulators such as dexamethasone.

However, in diseases with leukocyte-dominated postcapillary venola vasculitis, such as aphthal stomatitis, cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcers in Behçet's disease, a focused intervention is preferable to avoid the disadvantages of general immunosuppression.

The pathogenic factors in these diseases are endogenous mediators that act on the endothelium and circulating leukocytes. Local release of TNF-α and other cytokines leads to a focal increase in the adhesion of the endothelium to the leukocytes, which contributes significantly to vasculitis formation [M. Clauss et al. in: Tumor Necrosis Factors, Ed: B. Beutler, Raven New York 1992, p. 49-64]. Substances that can suppress endothelial change by a focal intervention without blocking the specific cellular immune response may be superior to general immunosuppressants such as dexamethasone and open up new therapeutic possibilities.

The class of hydantoin compounds to which the compounds of the invention belong has been extensively studied in the past and a large number of derivatives have been synthesized, for example, for use in cosmetic articles, as insecticides or herbicides or as the basis for epoxy resins.

In the pharmaceutical field, hydantoin compounds are known to have anticonvulsant, anti-inflammatory [J. Med. Chem. 8, 239, (1965); Pharmaceutical Research/Drug Res. 27 (II), 1942 (1977); Pharmacy 38, 341, (1983); J. Med. Chem. 28, 601, (1985) ] and antitumor effects [J. Med. Chem. 18, 846, (1975), Pharmaceutical Research/Drug Res. 34 (I), 663, (1984) ] effects.

The purpose of the invention was to develop new stable immunomodulators which did not lead to general immunosuppression and which were to have an anti-vascular effect.

It has now been found that certain substituted imidazolidin-2,4-dione compounds satisfy the requirements for the substances to be developed. These compounds belonging to the class of hydantoins are characterized by a strong immunomodulatory effect. They suppress the release of TNF-α without at the same time leading to a general blockade of the cellular immune system. The compounds of the invention also exhibit an antivascular effect which is not due exclusively to the inhibition of TNF-α release.

The invention is therefore based on substituted imidazolidin-2,4-dione compounds of formula I. where R1 means C1-6-alkyl or C3-6-cycloalkyl,R2 means C1-6-alkyl, phenyl, - ((CH2) 1-3-phenyl or - ((CH2)1-4-COOR5 means orR1 and R2 together - ((CH2) 4-6-, - ((CH2) 2-O- ((CH2) 2) 2-, or means,R3 H,C1-5-alkyl or -(CH2)1-4-COOR5 means,R4 a heteroaromatic group of the formulas is,R5 is a C1-3 alkyl,R6H means a C1-4 alkyl, phenyl or benzyl andR7H means a C1-4 alkyl or trifluoromethyl.

The preferred substituted imidazolidin-2,4-dione compounds are in formula I, where R1 C1-4-alkyl or C3-4-cycloalkyl means,R2 C3-6-alkyl, phenyl, - ((CH2)1-2-phenyl or - ((CH2)1-2-COOR5 means, orR1 and R2 together - ((CH2) 5- or means,R3 H, C1-4-alkyl or -(CH2)1-2-COOR5 means,R4 a heteroaromatic group of the formulas is,R5 is C1-3 alkyl,R6 means H or phenyl andR7H means methyl, tert-butyl or trifluoromethyl.

In particular, compounds of formula I are preferred where R1 is ethyl or cyclobutyl, R2 is phenyl or R1 and R2 together mean -CH2) 5.

Other particularly preferred compounds of formula I are those in which R3 is H, C1-3-alkyl or -CH2-COOR5 and R5 means ethyl.

In addition, compounds of formula I are particularly preferred where R4 is a heteroaromatic of pyridin-4-yl, pyridin-3-yl, thiazol-2-yl, 3-methyl-isoxazol-5-yl or 5-methyl-isoxazol-3-yl, and in particular compounds of formula I where R4 is the heteroaromatic of thiazol-2-yl.

The further subject of the invention is a method for the production of a substituted imidazolidin-2,4-dione compound of formula I, in which the R1 C1-6-alkyl or C3-6-cycloalkyl means,R2 C1-6-alkyl, phenyl, - ((CH2) 1-3-phenyl or - ((CH2)1-4-COOR5 means orR1 and R2 together- ((CH2) 4-6-, - ((CH2) 2-O- ((CH2) 2- or means,R3 H,C1-5-alkyl or -(CH2)1-4-COOR5 means,R4 a heteroaromatic group of the formulas R5 is C1-3-alkyl,R6H means C1-4-alkyl, phenyl or benzyl andR7H means C1-4-alkyl or trifluoromethyl, the process being characterised by converting to an amine of formula II Other R4-NH2 Other 1,1-Carbonyldiimidazole or carbonic acid diphenylester and then with a compound of formula III in which R8 H or C1-3 alkyl is present, converted to a compound of formula I where R3 H means, which is deprotonated if desired and then with a compound of formula IV Other X-C1-5-alkyl Other or a compound of formula V Other The following substances are to be classified as: Other where X stands for Cl, Br or I, to a compound of formula I where R3 stands for C1-5 alkyl or -(CH2)1-4-COOR5.

The conversion of an amine of formula II to 1,1'-carbonyldiimidazole or to a carbonic acid diphenyl ester is carried out in a well-known way [Angew Chem., 73, 66 (1961) ]. The subsequent reaction with an amino acid ester of formula III to a compound of formula I in which R3H is preferably carried out in aprotic solvents such as ethers, such as diethyl ether or tetrahydrofuran, or in aromatic hydrocarbons, such as toluene, chlorobenzene or 1,2-dichlorobenzene, at temperatures between 20°C and 180°C. In this conversion, in addition to the compound of formula I, in which R3H is the corresponding urine derivative of formula VI, the corresponding urine derivative of formula VI can also be carried out. A compound of formula VI in which R8 is H can be converted by reaction with thionyl chloride to a compound of formula I in which R3 is H. A compound of formula VI in which R8 is C1-3 alkyl is either alkaline-dipulated prior to cycling to a compound of formula I in which R3 is H or directly converted to a compound of formula I in which R3 is H by heating with hydrochloric acid.

To produce a compound of formula I, where R3 means C1-5-alkyl or -(CH2)1-4-COOR5, a compound of formula I, where R3 is H, is deprotonated preferably with sodium hydride in dimethylformamide or tetrahydrofuran.

The amino acid ester of formula III required to produce a compound of formula I can be produced by esterification of the corresponding amino acid, for example by solutions of hydrochloric acid in the corresponding alcohol or by heating with the corresponding alcohol under acid catalysis, for example sulphuric or phosphoric acid.

Another way to obtain a compound of formula III is to convert an amino acid ester of formula VII with benzaldehyde to a compound of formula VIII which is deprotonated with a base, preferably lithium diisopropylamide, in ethers or hydrocarbons, such as diethyl ether, tetrahydrofuran or benzene, to a compound of formula IX, Other X-R1 Other The benzylid group is then cleaved by the action of acids.

The compounds of the invention are toxicologically harmless and therefore suitable as pharmaceutical active substances, and accordingly the invention also concerns the use of a substituted imidazolidin-2,4-dione compound of formula I as an active substance in medicinal products, preferably as immunomodulators or in medicinal products with an anti-vascular effect.

In addition to at least one substituted Imidazolidin-2,4-dione compound of formula I, the invention's active substance is a carrier, filler, solvent, diluent, colour and/ or binding agent. The choice of excipients and the amounts to be used depend on whether the product is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically. For oral application, preparations in the form of tablets, chewable tablets, dragons, capsules, granules, drops, juices or syrups, which are suitable for parental use, to be used in inhalation and injecting, are recommended, as well as solutions that are easily reconstituted or re-exposed in the form of powder or powder, which can be used in a dry or dry form.

The dose to be administered to the patient will vary depending on the patient' s weight, type of application, indication and severity of the disease, and usually 1 to 150 mg/ kg of at least one substituted imidazolidin-2,4-dione compound of formula I.

Examples

The stationary phase for column chromatography was silica gel 60 (0.040 - 0.0063 mm) from E. Merck, Darmstadt.

The dilution media mixing ratios for the chromatographic methods are always given in volume/volume.

Race separation was carried out on a Chiracel OD column of Daicel Chemical Industries, LTD.

The term "smelting point" means the melting point, e.g. example, RT room temperature and d. Th of the theory

Manufacture of compounds of the invention Example 1A

The following substances are to be classified in the same heading as the active substance: Stage one: 2-Amino-pentanoic acid ethyl esters

A suspension of 11.72 g DL-norvaline in 90 ml of ethanol was added to 3.6 ml of concentrated sulphuric acid and boiled for eight days in a return flow. A clear solution was formed from which ethanol was removed after cooling with distillate. The residue was absorbed in 200 ml of distilled water and a pH between 10 and 12 was set by adding potassium carbonate.

Stage two: 2- (benzylide-amino) -pentansanoic acid ethyl esters

A solution of 11.90 g of the stage 1 product in 150 ml of diethyl ether was successively mixed with 8.3 ml of benzaldehyde, 23 ml of triethylamine and 7.0 g of anhydrous magnesium sulphate. The mixture was stirred at room temperature for 24 hours, then filtered and washed with diethyl ether. After distillation of the solvent, 18.40 g of 2-benzylideneamino) pentanoic acid ethyl ester (96% by weight) was obtained in the form of a yellowish viscous mass.

Stage three: 2-Amino-2-propyl pentanoic acid ethyl ester

After cooling to -78°C, a solution of 18.31 g of the stage 2 product was added to 80 ml of tetrahydrofuran. The entire solution was stirred for 30 minutes and then a solution of 8.8 ml of 1-iodinepram in 4084 ml of tetrahydrofuran was added by dripping. The solution was stirred for 16 hours, increasing the temperature slowly to 20°C. The solvents were dried. The remaining residual orange oil was obtained in 1 500 ml of nitric acid. The solution was then mixed with a solution of 2-ethyl etheric acid (ethyl ether) at a pH of between 10 and 12 degrees. The product was then mixed with a dilute solution of 2-ethyl etheric acid (ethyl ether) and a dilute solution of 2-ethyl etheric acid (ethyl ether) at a pH of between 10 and 12 degrees.

Stage four: The following substances are to be classified in the same heading as the product:

A solution of 5.40 g 2-aminothiazol in 150 ml of tetrahydrofuran was mixed with 8.75 g 1.1'-carbonyl-di-imidazole at 20°C and stirred for 30 minutes. Then, within 20 minutes, a bath temperature of 55 to 60°C was reached and a solution of 9.80 g of the stage 3 product was dripped into 30 ml of tetrahydrofuran. A clear red-brown solution was obtained after stirring for 60 hours at 55°C to 60°C. After removal of the solvent, the residue was cleaned with a silica gel column of ethyl ether.

Stage five: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

10.03 g of the stage 4 product were dissolved by stirring in 200 ml of semi-concentrated baking soda at 20°C. Then a pH of 4 was adjusted with concentrated hydrochloric acid and extracted three times with 50 ml of dichloromethane. The extracts were washed once with a saturated sodium chloride solution and dried over sodium sulphate. After distillation of the solvent, 8.48 g of 2-propyl-2-(3-thiazol-2-yl-ureaedo) pentanoic acid (93% d. Th.) were obtained in the form of white crystals (at a temperature of 154°C to 155°C).

Stage 6: The following substances are to be classified in the same heading as the active substance:

8.28 g of the product of stage 5 were added to 20 ml of thionyl chloride. The mixture was stirred for 18 hours at 20°C. Ice was added for decomposition, an alkaline pH was adjusted with potassium carbonate and extracted three times with 20 ml of dichloromethane each. After washing the extracts with saturated sodium chloride solution and drying over sodium sulphate, the solvent of the distillate was removed. The resulting residue was cleaned with acetic acid ethyl ester using a silica column. 5,50 g of 5,5-dipropyl-3-thiazol-2-yl-imidazolidin-2,4-dione (71 d. Th) were obtained in white crystalline form (SMP - 128°C).

Example 1B

The following substances are to be classified in the same heading as the active substance:

1,71 g 2-propyl-2- ((3-thiazol-2-yl-ureido) pentanoic acid ethyl ester (product from example 1A, step 4) was added to 30 ml of 30% hydrochloric acid. The mixture was boiled for three hours under reflux. After cooling, an alkaline pH was determined with potassium carbonate, extracted three times with acetic acid ethyl ester, washed twice with saturated saline and dried with sodium sulphate. The product obtained by subsequent distillation of the solvent was cleaned with acetic acid from a raw silica saw. 0,62 g 5.5-dipropyl-3-thiazol-2-imidazolid-2-dione was obtained (42% d. Th.)

Example 2

The following substances are to be classified in the same category as the active substance: Stage one: 1-Amino-1-cyclohexanecarbonate ethyl ester

Under the conditions described in example 1A stage 1, 100 g of 1-amino-1-cyclohexanecarbonic acid, hydrochloride, 500 ml ethanol and 20 ml concentrated sulphuric acid were obtained after purification of the raw product by a silica gel column with acetic acid ethyl ester/methanol = 5/1 75,5 g 1-amino-1-cyclohexanecarbonic acid ethyl ester (80 % d. th.) in the form of a slightly yellow oil.

Stage two: The following substances are to be classified in the same category as the active substance:

44,4 g of 2-aminothiazole, 71,9 g of 1,1'-carbonyl-dimidazole and 73,7 g of the stage 1 product were converted according to the conditions described in example 1A, stage 4. The resulting mixture was purified by means of a silica gel column with acetic acid ethyl ester. 71,8 g of 3-thiazole-2-yl-1,3-diaza-spiro[4.5]decan-2,4-dione (66 % d. Th.) was obtained in the form of white crystals (Sms. 213 - 215°C).

Example 3

The following substances are to be classified in the same category as the active substance:

5,05 g of the product from example 2 stage 2 were dissolved in 20 ml of dimethylformamide. Then 1,10 g of sodium hydride (50% suspension in mineral oil) were added at 20 °C per serving, stirred for one hour, and 4 ml of 1-iodopropane were added. It was stirred for another three hours. Then, diluted with 100 ml of distilled water, extracted three times with 30 ml of acetic acid ethyl ester, washed with saturated sodium chloride solution and dried over sodium sulphate. After removal of the destillation, the residue was obtained by means of a silica crystal column with acetic acid ester/n-hexan = 8/5t. 3,95 g of 1-Propyl-2-Pethyl-Escanzazole-C-14.3-diethyl-diethyl-diethyl-diethyl-diethyl (PET) were obtained in white form (63,7 °C) (-135 °C).

Example 4

The following substances are to be classified in the same heading as the active substance: Stage one: 2-Amino-2-phenyl butyric acid ethyl ester

After three extractions with acetic acid ethyl ester, drying of the extracts with sodium sulphate and distillation of the solvent, the solvent was cleaned with acetic acid ethyl ester via a silica column. 6.93 g of 2-amino-2-phenyl butyl ester (62% d. th.) was obtained in the form of an oil gel.

Level 2 The following substances are to be classified in the same heading as the active substance:

2,12 g of 2-aminothiazole, 3,26 g of 1,1'-carbonyl dimidazole and 4,16 g of the stage 1 product were converted under the conditions described in example 1A, stage 4. After purification of the raw mixture by a silica gel column with acetic acid ethyl ester, 3,90 g of 5-ethyl-5-phenyl-3-thiazol-2-yl-imidazolidine-2,4-dione (68 d. th.) were obtained in the form of white crystals (at 150-152°C).

Example 5 (+) and (-) -5-ethyl-5-phenyl-3-thiazol-2-yl-imidazolidine-2,4-dione

The two enantiomers were obtained by separation of the racemate from example 4 on a chiral HPLC column (fluid medium: n-hexane/2-propanol = 1/1; stationary phase: cellulose-tris-3,5-dimethylphenylcarbamate).

Example 6

The following substances are to be classified in the same heading as the active substance:

In a nitrogen atmosphere and excluding moisture, 2.30 g 2-amino-5-methyl-1,3,4-thiadiazole were dissolved at room temperature in 40 ml of dry tetrahydrofuran. Then 3.24 g 1.1'-carbonyldiimidazole were added. It was stirred at 50°C for 30 minutes. To obtain the suspension, a solution of 4.15 g 2-amino-2-phenylbutyric acid ethyl ester (product from example 3, step 1) was dripped into 10 ml of dry tetrahydrofuran and stirred for 20 hours at 50°C. After the removal of the solvent, the residue of ethanol was decarboxylated. 3.94 g 5-ethyl-35-methyl[1.3.4]-2-amino-2-thiadiazole) - 5-phenylcrystalline-2-dione (54-pphenyl-2-dione-2-dione-2-) was obtained in white crystalline form.

Examples 7 - 28

The compounds in Table 1 were produced from the corresponding starting compounds under the conditions described in Examples 1-6.

By separating the racemates from examples 17, 18 and 28 under the conditions described in example 5, the enantiomers summarized in Table 2 in the form of viscous oils were obtained. $\frac{\text{RT}}{\text{D}}$ methanol was used as solvent. Other Tabelle 2:

29	(+)-5-Ethyl-3-(5-methylisoxazol-3-yl)-5-phenylimidazolidin-2,4-dion	+ 36,2°
30	(-)-5-Ethyl-3-(5-methylisoxazol-3-yl)-5-phenylimidazolidin-2,4-dion	- 36,4°
31	(+)-3-(5-tert-Butyl [1.3.4]thiadiazol-2-yl)-5-ethyl-5-phenyl-imidazolidin-2,4-dion	+ 26,0°
32	(-)-3-(5-tert-Butyl [1.3.4]thiadiazol-2-yl)-5-ethyl-5-phenyl-imidazolidin-2,4-dion	- 26,1°
33	(+)-5-Ethyl-3-(3-methylisoxazol-5-yl)-5-phenylimidazolidin-2,4-dion	+ 18,5°
34	(-)-5-Ethyl-3-(3-methylisoxazol-5-yl)-5-phenylimidazolidin-2,4-dion	- 18,2°

Pharmaceutical studies

The release of TNF-α can be studied in vitro in human peripheral blood mononuclear cells (T cells, B cells and monocytes) after stimulation with lipopolysaccharide (LPS) (see below, section 1).

In addition to LPS stimulation, TNF-α release can also be induced by stimulation of human mononuclear cells of the peripheral blood with T cell specific monoclonal antibodies to activation antigens (antiCD2/ antiCD28) or bacterial superantigen Toxic Shock Syndrome Toxin-1 (TSST-1).In addition to TNF-α release, these stimulations also lead to interleukin-2 (IL-2) formation, among other things.Compounds that result in general immunosuppression inhibit both TNF-α and IL-2 release.Compounds that do not result in blocking cell immune response, but should inhibit LNF-α release in TNF-α cells, should only inhibit TNF-α release after induced IL-2 release.

Effect on TNF-α release (in vitro)

The inhibitory effect of the compounds of the invention on the release of TNF-α was tested in an in vitro test with mononuclear cells.

The cell culture medium used was RPMI 1640 medium with 2 mM glutamate (Life Technologies, Eggenstein) supplemented with 10% foetal calf serum (Life Technologies), 50 μg/ml streptomycin (Sigma, Deisenhofen), 50 IU/ml penicillin (Sigma) and 100 μM mercaptoethanol (Merck, intestine). The mononuclear cells were then collected in 15 ml cell culture medium and in 1 ml incubator in a 24-Loch sterile tablet (A1A) used as a control.The test solutions were incubated for one hour in the CO2 incubator (5% CO2, 90% humidity) and then, with the exception of the controls, 2.5 μg LPS (from E. coli 0127:B8; Sigma, Deisenhofen) were added as stimulants. The incubation of the solutions was continued for 20 hours. The concentration of TNF-Bo in the cell cultures of the solutions was determined following the incubation with TSA-B (Mα-Mα-Mα) inhibitors. The measured levels of the inhibitors were calculated using the test measures and the ELNF-Bo test measures were calculated using the inhibitor release of the controls.A regression line was used to calculate the concentrations leading to a 50% inhibition of TNF-α release (IC50 values).

All compounds used showed a marked inhibitory effect on LPS-stimulated release of TNF-α. The results are shown in Table 3 below. Tabelle 3:

Wirkung auf die LPS-stimulierte TNF-α Freisetzung (Mittelwert und Standardabweichung)
1	83 ± 8
2	66 ± 18	31
3	80 ± 12
4	90 ± 3	8
5 (+)-Isomer	93 ± 6	4
5 (-)-Isomer	74 ± 16	10
6	74 ± 19
8	48 ± 14
10	76 ± 9	9
11	70 ± 16
13	73 ± 13	24
14	74 ± 6
15	78 ± 14
16	69 ± 8
18	65 ± 29
19	92 ± 4	<1
20	87 ± 3	5
22	80 ± 7
23	68 ± 6
24	89 ± 4
25	49 ± 13
26	71 ± 8
27	73 ± 20
29	87 ± 4	7
30	61 ± 6
31	68 ± 11
33	92 ± 4	6

Effect on cellular immune system (in vitro)

In the in vitro test series described below, mononuclear cells with different stimulation were used to investigate the effect of the compounds of the invention on cellular immune response.

Compounds of the invention were examined for their effects on TNF-α and IL-2 release. The trials were performed according to the conditions described in 1. The stimulants were varied for each test series. Either monoclonal antibodies antiCD2/anti-CD28, superantigen TSST-1 or LPS were used as stimulants.

The following endpoints of the stimulants were adjusted: The following are the most commonly used anti-CD2 antibodies: antiCD2/antiCD28:100 ng/ml AICD2.M1; 100 ng/ml AICD2.M2 (monoclonal antibodies, both directed against CD2, origin: German Cancer Research Centre, Prof. Dr. Meuer, Heidelberg); The test chemical is used to determine the concentration of the active substance in the test chemical.

The compounds of the invention were used at concentrations (see Table 4, column 2) that produced a 60-90% inhibition of LPS-induced TNF-α release.

In the anti-CD2/anti-CD28 antibody mixture or TSST-1 superantigen stimulated test approaches, IL-2 concentration was determined in cell culture residues after the end of the trial with ELISAs (Boehringer-Mannheim).

The compounds of the invention used did not produce a general immunosuppressive effect because, unlike dexamethasone, they induced only a relatively small inhibition of IL-2 release.

The results are summarised in Table 4:

3. Antisculite effect in the animal model

For the in vivo characterisation of the anti-vascular effects of compounds of the invention of formula I, a two-stage model, originally based on the local Shwartzman reaction, was used (Exp. Toxic. Pathol., 47, 167, (1995)). This animal model demonstrates an inhibition of endothelial permeability, which is not only due to the inhibition of TNF-α release. In addition to the quantified parameter of endothelial permeability, the substantial reduction or absence of tissue destruction characteristic of the Shwartzman reaction can be qualitatively detected.

Male NMRI mice were dorsally dehaired under short-term anaesthesia. 100 μg lipopolysaccharide (Salmonella typhosa; Sigma, Deisenhofen) or, as a control, saline was injected intradermally into both sides at symmetrical sites. 24 hours later, 1 ml/kg was applied via the Evans Blue tail vein (Merck, Darmstadt) followed by a subcutaneous injection of recombinant, murine TNF-α (133 ng) under the two LPS sensitive skin sections. Four hours after the TNF-α injection, euthanasia was performed and the affected areas were treated to a defined extent. The Evans Blue was injected into the skin by photometric extraction at a temperature of 18 to 60 °C at 623 nm.

The compounds of the invention were suspended in an aqueous 1% carboxylmethylcellulose solution and administered intraperitoneally or orally. The compounds of the invention were administered 10 minutes before the LPS or TNF-α and 30 minutes before the stimuli. A further administration of the compounds of the invention was carried out during the preparation phase 8 hours after the LPS injection. The dosages ranged from 5 to 400 mg/kg. Control animals were also treated with NaCl instead of LPS.

Table 5 shows maximum inhibition effects in % in LPS-prepared animals treated with compounds of the invention compared to NaCl-prepared animals treated with compounds of the invention, the percentages being averages of ≥ 10 animals per group.

The compounds of the invention exhibit an anti-vascular effect which has been quantified by the inhibition of endothelial permeability. Other Tabelle 5:

Inhibition der Endothelpermeabilität (Evans Blau Extraktion)
2	3 x 50	67 %
4	3 x 100	48 %
5 (+)-Isomer	3 x 50	38 %
5 (-)-Isomer	3 x 100	58 %

Claims (12)

1. Substituted 2,4-imidazolidinedione compounds of the formula I in which

   R¹ means C_1-6 alkyl or C_3-6 cycloalkyl,

   R² means C_1-6 alkyl, phenyl, -(CH₂)_1-3-phenyl or -(CH₂)_1-4-COOR⁵

   or

   R¹ and R² together mean -(CH₂)_4-6- , -(CH₂)₂-O-(CH₂)₂- or

   R³ means H, C_1-5 alkyl or -(CH₂)_1-4-COOR⁵,

   R⁴ is a heteroaromatic selected from the group of the formulae

   R⁵ denotes C_1-3 alkyl,

   R⁶ means H, C_1-4 alkyl, phenyl or benzyl and

   R⁷ means H, C_1-4 alkyl or trifluoromethyl.
2. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 1, characterised in that

   R¹ means C_1-4 alkyl or C_3-4 cycloalkyl,

   R² C_3-6 alkyl, phenyl, (CH₂)_1-2-phenyl or -(CH₂)_1-2-COOR⁵, or

   R¹ and R² together mean -(CH₂)₅- or

   R³ means H, C_1-4 alkyl or -(CH₂)_1-2-COOR⁵,

   R⁴ is a heteroaromatic selected from the group of the formulae

   R⁵ denotes C_1-3 alkyl,

   R⁶ means H or phenyl and

   R⁷ means H, methyl, tert.-butyl or trifluoromethyl.
3. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 1 or 2, characterised in that

   R¹ means ethyl or cyclobutyl,

   R² is phenyl or

   R¹ and R² together mean -(CH₂)₅-.
4. Substituted 2,4-imidazolidinedione compounds of the formula I according to one of claims 1 to 3, characterised in that

   R¹ and R² together mean -(CH₂)₅-.
5. Substituted 2,4-imidazolidinedione compounds of the formula I according to one of claims 1 to 4, characterised in that

   R³ means H, C_1-3 alkyl or -CH₂-COOR⁵ and

   R⁵ is ethyl.
6. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 5, characterised in that

   R³ means H.
7. Substituted 2,4-imidazolidinedione compounds of the formula I according to one of claims 1 to 6, characterised in that

   R⁴ means pyridin-4-yl, pyridin-3-yl, thiazol-2-yl, 3-methylisoxazol-5-yl or 5-methylisoxazol-3-yl.
8. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 7, characterised in that

   R⁴ is thiazol-2-yl.
9. Process for the production of a substituted 2,4-imidazolidinedione compound of the formula I according to claim 1 characterised in that 1,1'-carbonyldiimidazole or diphenyl carbonate are added to an amine of the formula II         R⁴-NH₂ and then reacted with a compound of the formula III in which R⁸ denotes H or C_1-3 alkyl to yield a compound of the formula I in which R³ means H, which compound is then, if desired, deprotonated and then reacted with a compound of the formula IV         X-C_1-5 alkyl or a compound of the formula V         X- (CH₂)_1-4-COOR⁵ in which X means Cl, Br or I, to yield a compound of the formula I in which R³ means C_1-5 alkyl or -(CH₂)_1-4-COOR⁵.
10. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 1 for use as an active ingredient in a pharmaceutical preparation.
11. Substituted 2,4-imidazolidinedione compounds of the formula I according to claim 1 for use according to claim 10, characterised in that the pharmaceutical preparation is an immunomodulator.
12. Substituted 2,4-imidazolidinedione compounds of the formula I accdrding to claim 1 for use according to claim 10, characterised in that the pharmaceutical preparation has an antivasculitic action.