HRP960564A2 - Quinoxaline compounds, pharmaceutical preparations containing them and a process for the preparation thereof - Google Patents

Description

The invention relates to new derivatives of 3-amino-quinoxalin-2-one of the general formula I, their salts, tautomeric forms and N-oxides, to pharmaceutical preparations containing these compounds, and their preparation processes.

In the last 10 years, many publications and patent specifications have been published in the field of CNS. The area of N-methyl-D-aspartate receptor antagonists has become particularly interesting. Among others, WO 9400124 and the references cited therein describe quinoxaline-2,3-dione derivatives with this effect.

N-substituted quinoxaline diones are described for example in: WO 9113878 (Novo Nordisk), WO 9308188 (Sumitomo), WO 9320077 (Yamanouchi); tricyclic quinoxaline derivatives in: J. Med. Chem. 35 (1992) 3319-3324 (Eli Lilly), WO 9409000 (Wamer-Lambert), WO 9306103 (Novo Nordisk), US 5196421 (1993) Eli Lilly, US 5153196 (1992) Eli Lilly;

Tetracyclic quinoxaline derivatives in: WO 9502601 (Rhone-Poulenc Rorer SA), WO 2 9502602 (Rhone-Poulenc Rorer SA). The synthesis of 3-amino-quinoxalin-2-one derivatives is described in Tetrahedron Letters 23 No. 33, p. 3357-60, without mentioning the technique.

The partial hydrolysis (J. Am. Chem. Soc. 68 (1946) 1035) of 2,3-diamino-quinoxaline was carried out by various methods of synthesis. We surprisingly found that quinoxaline derivatives of the general formula I show significant activity on the glycine binding site of the NMDA-receptor, and therefore can have a significant neuroprotective effect, which can play a therapeutic role in the treatment of Alzheimer's disease, seizures, epilepsy, in AIDS-dementia and in the treatment of Parkinson's disease .

The meaning of the substituents in the general formula I is as follows:

Z1 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl ;

Y1 means hydrogen or an optionally substituted amino group, or

Y1 and Z1 together form a -CO-O-group, where

Y2 and Z2 together mean a valence bond, iii

Y1 and Y2 together mean a valence bond, and at the same time

Z2 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl ;

X1 and X2 together mean =O or =S, or

X1 means hydrogen, groups -NHR4 or -WR5, and at the same time

X2 means hydrogen, or

X2 and X3 together form a valence bond,

X3 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl group,

R1 and R2 mean hydrogen, halogen, C1-4 alkyl, trifluoromethyl, cyano, mercapto or sulfonylamido group,

R3 means hydrogen or a nitro group,

R4 means hydrogen or a hydroxyl group,

R5 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl group,

W stands for oxygen or sulphur,

provided that

a) if at least one of the substituents R1, R2 and R3 is different from hydrogen, or

b) if Z1 and Z2 mean hydrogen, i

- R1 means 6-chloro, R3 means hydrogen

- R 2 has a different meaning than 7-chloro, or

- R1 means 6-methyl, R3 means hydrogen,

- R2 has a different meaning than 7-methyl.

Compounds of general formulas IA, IB, IC, ID, IE, IF, IG, their salts, tautomeric forms and N-oxides form smaller groups of compounds of general formula I.

Compounds of general formula I can be prepared in the following ways:

a) for the preparation of compounds of the general formula IA - where the meanings of R1, R2 and R3 and W are given earlier - some 1,2-diaminobenzene of the general formula II reacts with carboalkoxyformimidate derivatives of the general formula III - where the meanings of R1, R2 and R3 and W mentioned above, R 6 means hydrogen, R 7 means C 1-2 alkyl; or the compounds of the general formula IF, where the meanings for R1, R2, R3 are given earlier, are hydrolyzed in an acidic medium;

b) for the preparation of compounds of the general formula IB - where the meanings for R1, R2 and R3, and W are given earlier, Z2 means hydrogen and Z1 means C1-4 alkyl, C7-9 phenylalkyl, or an optionally substituted phenyl group - some 1,2 -diaminobenzene of the general formula II reacts with a compound of the general formula IV - where the meanings for R1, R2, R3, R7 and W are given above, H1g means halogen, R8 means C1-4 alkyl, C7.9 phenylalkyl, or an optionally substituted phenyl group, R7 means a C1-2 alkyl group;

c) for the preparation of compounds of the general formula IB - where the meanings of R1, R2, R3, W and Z1 are given earlier, Z2 means a C2.14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl group - compounds of general formulas IB containing a hydrogen atom in the Z2 position react with acylating compounds of the general formula Z2-L - where Z2 means a C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl group, and L means a leaving group;

d) for the preparation of compounds of the general formula IC - where the meanings of R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II where the meanings of R1, R2, R3 are given earlier is cyanomethylated, and then the intermediate product thus obtained ring closure of general formulas VI using hydroxylamine;

e) for the preparation of compounds of the general formula ID, where the meanings of R1, R2, R3 are given earlier, compounds of the general formula IC, where the meanings of R1, R2, R3 are given earlier, are acylated using formic acid derivatives, and then they are closed into a ring or react with dialkylcarbonate;

f) for the preparation of compounds of the general formula IE, where the meanings for R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II, where the meanings for R1, R2, R3 are given earlier, react with dihalogen glyoxime;

g) for the preparation of compounds of the general formula IF, where the meanings for R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II reacts with diiminoester of oxalic acid of the general formula VII, where the meanings for R1, R2, R3 are given earlier ;

h) for the preparation of compounds of the general formula IB containing sulfur in the W position, where the meanings for R1, R2, R3, Z1 and Z2 are given earlier, a compound of the general formula IB containing oxygen in the W position or a compound of the general formula IF, where the meanings are for R1, R2 and R3 mentioned earlier, is reacted with reagents suitable for the introduction of sulfur, or the compound of the general formula IB containing sulfur in the W position is prepared by means of a selective transformation from the corresponding derivative of 2,3-dichloroquinoxaline or 2,3-dithioquinoxaline substituted with R1, R2, R3;

i) for the preparation of compounds of the general formula IG, where the meanings of R1, R2, R3, Z1, X1, X2, X3 are given above, and the meaning of A is an optionally substituted amino group, compounds of the general formula IA are N-animated, where the meanings are for R1, R2 and R3 mentioned earlier, and W is an oxygen atom, and as desired in the thus obtained compounds of the general formula I, the substituents R1, R2 and R3 and X3 are transformed in a manner known per se into other substituents R1, R2, R3 and X3, and/or into their N-oxides, and/or salts, and/or are released from their salts.

In particular, the preparation of compounds of the general formula IA can be carried out by the method described in Tetrahedron Lett., 23 No. 33, p. 3357-60 or J.C.S., 96(1947).

For the preparation of compounds of the general formula IB containing an alkyl, phenylalkyl or optionally substituted phenyl group in the Z1 position, the reaction preferably takes place in a polar solvent, preferably in a lower alcohol, in dimethylformamide or in dimethylsulfoxide, or in a non-polar solvent such as tetrahydrofuran, between 0 °C and boiling points, preferably between 20 and 80 °C.

Compounds of the general formula IB containing acyl, alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted by a phenylsulfonyl group in the Z1 and/or Z2 position, can be prepared first of all by reacting the compounds of the general formula IB, which contain a hydrogen atom in the Z1 and/or Z2 position, with some acylating reagent, optionally in the presence of a proton acceptor. It is advantageous to use acid anhydride as an acylating reagent, and to carry out the reaction without a proton acceptor.

According to the invention, it is advantageous to carry out procedure e) using methyl chloroformate as a derivative of formic acid. Acylation is carried out under mild conditions and a basic catalyst is used to close the ring. It is advantageous to carry out the reaction of compounds of the general formula IC and dialkyl carbonates in a weakly basic environment.

It is advantageous to carry out the reaction of compounds of general formula II and dihalogen glyoxime /(Chem. Ber., 85 3 5 (1952)/ in a two-phase system, in the presence of a proton acceptor /(J. Het. Chem., 26 (1989) 1415/).

According to the literature J. Org. Chem. 21 (1956) 470, compounds of general formula IB containing sulfur in the W position can be synthesized from the corresponding substituted quinoxaline 2,3-diones, preferably in an excess of ammonia or a primary amine, optionally in the presence of a solvent.

Compounds of general formula IA can be converted to toluenesulfonic acid salts of compounds of general formula IG using O-tosyl hydroxylamine in the presence of NaH in a medium containing DMF. The free base can be released by using sodium carbonate in an aqueous medium.

Compounds of formula I where one of R1, R2 and R3 is a nitro group can also be prepared by using a starting material containing hydrogen in the appropriate position and introducing the nitro group into the molecule using a mild nitrating agent such as ccH2SO4+KNO3 at 0 °C, Ac2O +Cu(NO3)2, NO+2BF4 and, if necessary, by removing the acid protective group.

If necessary, a halogen atom can also be introduced by using a halogenating agent, for example an elemental halogen, a perhalide and a halogen transfer catalyst, for example FeCI3, AICI3, ZnCI2, and the like.

Description of biological test methods

3H-Dichlorokynurenic Acid (DCK) Binding Assay [3H]DCK (10 nM) binding was assayed by the method described by T. Canton et al (J. Pharm. Pfarmacol. 44 (1992) 812-816). After removal of the cerebellum and cerebellum from the whole brain of a 150-200 g male rat (Sprague-Dawley), membrane preparation was performed by homogenization and repeated centrifugation. It was incubated for 30 minutes at 4 °C in 50 mM HEPES/KOH buffer (pH=7.5), in the presence and absence of the test substance. Radioactive ligand bound to the membrane was separated by a filtration method (Whatman GF&B). The bound radioactivity was measured with a liquid scintillation spectrophotometer. Nonspecific binding was determined in the presence of 1 mM glycine. The binding percentage was determined using the following formula:

[1-{ (B1-NSP)/(Bt-NSP)}]X100

where is

B1 binding measured in the presence of the test substance

Bt total binding measured in the absence of test substance

NSP non-specific binding.

Table 1 contains the tested substances and their concentrations that cause 50% binding (IC50 value).

Table I

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The compounds of the general formula I or their salts can be used in therapy as pharmaceutical preparations containing an active ingredient and an inert solid or liquid organic or inorganic additive. Preparations are produced according to known methods.

The preparations are made in forms suitable for oral or parenteral administration, for example tablets, coated tablets, capsules or their versions with extended action ("retard"). These preparations may contain suitable solid diluents or carriers, a sterile aqueous solvent or a non-toxic non-aqueous solvent. For this purpose, substances can be added to oral preparations to sweeten or achieve other flavors.

Tablets suitable for oral administration may contain lactose, sodium citrate, calcium carbonate as carrier substances, and substances that promote decomposition (for example, starch, alginic acid), lubricants (for example, talc, sodium lauryl sulfate, magnesium stearate). Carrier substances in capsules can be lactose or polyethylene glycol. Aqueous suspensions may contain agents for the formation of emulsions or suspensions. Diluents for suspensions in organic solvents can be ethanol, glycerin, chloroform, and the like.

Preparations suitable for parenteral administration are solutions or suspensions of the active ingredients in some suitable media (eg almond oil, sesame oil, polypropylene glycol or water).

The content of active ingredients in pharmaceutical preparations can vary within wide ranges, and can be between 0.005-99%.

The daily dose of the active ingredient can vary within a wide range and depends on the severity of the condition, age, body weight of the patient, the form of the preparation and the effectiveness of the given active ingredient. In the case of oral administration, the daily dose of the active ingredient is generally 0.5-20 mg/kg in a single administration or in multiple daily administrations. The above data are of informative significance, and they can be deviated from by higher or lower values, depending on the given case and the doctor's instructions.

Further details of the invention are given in the following non-limiting examples.

Examples

Example 1.

Method of preparing a substance of the general formula IA containing an oxygen atom in the W position.

10 mmol of the 1,2-diaminobenzene derivative of the general formula II is suspended or dissolved in 15-20 cm3 of solvent depending on the starting substance (use of methanol, ethanol, dimethylformamide, DMSO, water or their mixture is suitable), and treated with 12 mmol ( 1.40 g) ethyl carboethoxyformimidate. The reaction mixture is stored at 25-30 °C for 8-48 hours. The precipitated substance of general formula IA is filtered, washed with methanol and dried. Table II contains the yields and melting points of the thus obtained compounds.

Table II

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Example 2.

Introduction of the nitro group

The product from example 1 or 4 is dissolved in concentrated sulfuric acid and treated with 1-1.2 equivalents of KNO3 at a temperature of 0 to 5 °C. The end point of the reaction is determined by TLC for a sample taken from the mixture. In case of a complete reaction, the reaction mixture is poured onto ice, which is 5-15 times more than the sulfuric acid used as a solvent, and the precipitated substance is filtered.

The physical data for the thus obtained substance are identical to the data from examples 6 and 7 listed in table 1.

Example 3.

The products from examples 1 and 4 can also be nitrated by treating their anhydrous "sulfolane" suspension with nitronium tetrafluoroborate at a temperature of a maximum of 20°C. The processing of the obtained products and their physical properties are identical to those of example 2.

Example 4.

Treatment of compounds of the general formula IF (J. Am. Chem. Soc. 68 (1946) 1035) with a 2.5-5 M aqueous solution of hydrochloric acid for a short time at 100-120°C results in compounds IA. Isomers can be separated, for example, by vacuum chromatography. Table III shows a summary of the physical data and utilization of the prepared compounds.

Table III

[image] * Isomeric ratios were determined by NMR

In the case of separate isomers, the identification of the regio-isomers was performed using 13C NMR. 13C spectra of uncoupled interlaced bonds and coupled protons for both pure isomers were performed, and to identify the long-range 13C-1H coupling constants, a series of selective INEPT measurements were performed. With the knowledge of 13C-1H coupling constants with far-reaching effect, the chemical shifts of carbon atoms in different positions of both isomers in the aromatic ring without heteroatoms were identified and compared with two hydrogen atoms. It is known that the effect of the amide and imino groups on the chemical shift affecting the aromatic carbon atoms is characteristically different (E. Pretsch, J. Seibl, W. Simon, T. Clerc: Tabellen zur Strukturaufklärung organischer Verbindung mit spectroskopischen Methoden, Springer, Berlin, 1981.)- On the carbon atom in the ipso and ortho position in relation to the amide group, a smaller deviation is expected than on the carbon atoms that are in the same position in relation to the imino group. Two sets of signals were assigned to the isomers listed in Table IV, by comparing the measured values for those carbon atoms in the two compounds. In the case of other unseparated isomeric mixtures, the isomers were assigned according to the chemical shifts of these characteristic signs. The isomer ratio was determined according to the intensities of these signals.

Table IV

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Example 5

Preparation of compounds of the general formula IC

Preparation and transformation of compounds of general formula VI

0.1 M derivative of 1,2-diaminobenzene of general formula II is dissolved/suspended in 20 cm3 of methanol and 8.75 cm3 of 36% hydrochloric acid solution is added. The mixture is then cooled to below 10°C and added drop by drop. per drop with constant stirring 1.05 M potassium cyanide. The pH value of the reaction mixture is adjusted to 6.5, and 8.90 g of 35% formaldehyde is added drop by drop at 40 °C over 20 to 35 minutes. It is cooled to 0°C after 2 hours and the precipitated material is separated from the aqueous alcoholic mother by either filtration or extraction after dilution with water.

The thus obtained raw material of the general formula VI is boiled without any purification in a 60% aqueous alcoholic solution of 0.2 M hydroxylamine base for 3 to 5 hours, until the evolution of ammonia stops. After clarification, the solution is cooled, left to stand in the refrigerator, and the precipitated crystals are filtered. Table V contains melting points and yields.

Table V

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Example 6.

Preparation of compounds of the general formula ID

10 mmol of compound IC is dissolved in 15 to 20 cm3 of acetone and 11 mmol of triethylamine is added, and the reaction mixture is treated with 10.5 mmol of methyl chloroformate at between 0 and 25°C. After removal of triethylamine hydrochloride compounds, compounds of the general formula ID crystallize. Utilization and physical data are summarized in Table VI.

Table VI

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Example 7.

Preparation of compounds of the general formula IE

5 mmol of substituted 1,2-diaminobenzene of general formula II and 5.2 mmol of dichloroglyoxime are suspended in 25 cm of dichloromethane, then 50 mmol of Na2CO3 dissolved in 25 cm3 of distilled water are added drop by drop, and the mixture is vigorously stirred for 1 hour. (The reaction is monitored by TLC). The precipitated substance is filtered, washed with water and dichloromethane, and purified by chromatography if necessary. Table VII contains data on the obtained compounds.

Table VII

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Example 8.

Preparation of compounds of the general formula IB containing an oxygen atom in the W position

a) 8 mmol of substituted 1,2-diaminobenzene of general formula II is dissolved in 12 cm3 of THF. Keeping the temperature of the mixture at ≈10°C, 10 mmol of imidoyl chloride of the general formula IV is added. After standing at room temperature for 1 hour, the precipitated substance is filtered, washed with ethanol and, if necessary, purified by chromatography.

Table VIII

[image] *Isomeric ratios were determined by 13C NMR.

**HCl salt

b) The preparation of nitro compounds of general formula IB containing an oxygen atom in position W can be carried out according to examples 2 or 3.

Table IX

[image] *The isomeric ratios were determined by NMR

Example 9.

Preparation of compounds of the general formula IB containing an oxygen atom in the W position

a) 1 mmol of acid anhydride is added to 0.35 mmol of the product from example 1, i.e. 8. The mixture is boiled while the reaction takes place, then evaporated and the product is recrystallized from ethanol.

Table X

[image] *The isomeric ratios were determined by NMR.

b) The compounds prepared according to examples 1 and 2 are dissolved in acetone, and are acylated in the presence of a proton acceptor using the equivalent of + 10% acid halide at room temperature. The obtained substance is recrystallized after dilution with water or evaporation in a vacuum.

Table XI

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Example 10

Preparation of substances of the general formula IF

0.1 mol of 1,2-diaminobenzene derivative is dissolved in 3 to 10 times methanol (ethanol, DMSO), and 1.15 dimethyl ester of oxalic acid diimide and 3 to 5 mmol of p-toluenesulfonic acid are added as a catalyst. The reaction mixture is left to stand at room temperature for 5 to 20 hours, the precipitated substance is filtered and washed with alcohol. The following table contains the substances prepared in this way. For other starting materials see Chem. Ber. 97 (1964) 1599.

Table XII

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Example 11.

Preparation of compounds of the general formula IB containing a sulfur atom in the W position

10 cm3 of ethanol saturated with ammonia is added to 0.5 g of 6-trifluoromethyl-7-chloro-2,3-quinoxaline-dithione. The reaction mixture is kept in a closed container for 5 days at room temperature. It is purified by pressure vacuum chromatography /J. Org. Chem. 44 (1979) 4963; MKL 40 (1985) 366/.

Table XIII

[image] * Isomeric ratios were determined by NMR.

Example 12.

Preparation of compounds of the general formula IG

a) 0.4 g (1.5 mmol) of O-tosyl-acetoxy-hydroxamate is added to 2 cm of 60% perchloric acid, stirred at room temperature for 20 minutes, poured onto ice, then extracted with 2x1 cm3 of dichloromethane. The thus obtained solution, which contains approximately 0.2 g (1.1 mmol) of O-tosyl-hydroxylamine, is added to a suspension of 1 mmol of the 3-amino-quinoxalin-2-one derivative and 50 mg (1.25 mmol) of sodium hydride (60% dispersion in mineral oil) in 5 cm3 DMF, stir at room temperature for 2 hours, and then process. The base is released from the tosylate salt by treatment with an aqueous solution of sodium carbonate.

Table XIV

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b) Compounds of the general formula IA - where W denotes an oxygen atom - react with alkyl halides in DMF in the presence of K2CO3.

Table XV

[image] Example 13.

Preparation of compounds of general formula IB, where W=O and Z1=OH;

Z2-H

4.6 mmol of 1,2-diaminobenzene of general formula II is dissolved in 10 cm3 of ethanol. To this is added 4.6 mmol (0.7 g) of chloro-oximino-ethyl-acetate. After dissolution, 4.6 mmol of NaHCO3 dissolved in 5 cm3 of distilled water is added drop by drop with constant stirring. After standing overnight, the precipitated substance is filtered, washed with water and cleaned if necessary.

Table XVI contains data on the obtained compounds.

Table XVI

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Example 14.

Compounds of the general formula ID containing an oxo group in position 4 can be prepared according to example 6.

Table XVII contains data on the obtained compounds.

Table XVII

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Claims (6)

1. Compounds of the general formula I, and their salts, tautomeric forms and N-oxides, characterized by the fact that in the formula: Z1 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl ; Y1 means hydrogen or an optionally substituted amino group, or Y1 and Z1 together form a -CO-O-group, where Y2 and Z2 together mean a valence bond, iii Y1 and Y2 together mean a valence bond, and at the same time Z2 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl ; X1 and X2 together mean =O or =S, or X1 means hydrogen, groups -NHR4 or -WR5, and at the same time X2 means hydrogen, or X2 and X3 together form a valence bond, X3 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl group, R1 and R2 mean hydrogen, halogen, C1-4 alkyl, trifluoromethyl, cyano, mercapto or sulfonylamido group, R3 means hydrogen or a nitro group, R4 means hydrogen or a hydroxyl group, R5 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl group, W stands for oxygen or sulphur, provided that a) if at least one of the substituents R1, R2 and R3 is different from hydrogen, or b) if Z1 and Z2 mean hydrogen, i - R1 means 6-chloro, R3 means hydrogen - R 2 has a different meaning than 7-chloro, or - R1 means 6-methyl, R3 means hydrogen, - R2 has a different meaning than 7-methyl. 2. Compounds of the general formulas IA, IB, IC, ID, IE, IF, IG, their salts, tautomeric forms and N-oxides, indicated by the fact that the meanings of R1, R2, R3, Z1 X1, X2, X3 are specified in the request 1, W represents sulfur or oxygen, and A represents an optionally substituted amino group. 3. Compounds according to claim 1, characterized in that they are: 3-amino-6,7-dichloro-8-nitro-quinoxalin-2-one 3-amino-6-trifluoromethyl-7-chloro-8-nitro-quinoxalin-2-one 3-acetylamido-6,7-dichloro-8-nitro-quinoxalin-2-one 3-lauroylamido-6,7-dichloro-8-nitro-quinoxalin-2-one 3-methylsulfonylamido-6-trifluoromethyl-7-chloro-8-nitro-quinoxalin-2-one. 4. Process for the preparation of compounds of the general formula I, characterized in that a) for the preparation of compounds of the general formula IA - where the meanings of R1, R2 and R3 and W are given earlier - some 1,2-diaminobenzene of the general formula II reacts with carboalkoxyformimidate derivatives of the general formula III - where the meanings of R1, R2 and R3 and W mentioned above, R 6 means hydrogen, R 7 means C 1-2 alkyl; or the compounds of the general formula IF, where the meanings for R1, R2, R3 are given earlier, are hydrolyzed in an acidic medium; b) for the preparation of compounds of the general formula IB - where the meanings for R1, R2 and R3, and W are given earlier, Z2 means hydrogen and Z1 means C1-4 alkyl, C7-9 phenylalkyl, or an optionally substituted phenyl group - some 1,2 -diaminobenzene of the general formula II reacts with a compound of the general formula IV - where the meanings for R1, R2, R3, R7 and W are given above, H1g means halogen, R8 means C1-4 alkyl, C7.9 phenylalkyl, or an optionally substituted phenyl group, R7 means a C1-2 alkyl group; c) for the preparation of compounds of the general formula IB - where the meanings of R1, R2, R3, W and Z1 are given earlier, Z2 means a C2-14 acyl, C14 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl group - compounds of the general formula IBs containing a hydrogen atom in position Z react with acylating compounds of the general formula Z2-L - where Z2 denotes a C2-14 acyl, C1 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl group, and L means a leaving group; d) for the preparation of compounds of the general formula IC - where the meanings of R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II where the meanings of R, R, R3 are given earlier is cyanomethylated, and then the thus obtained intermediate product ring closure of general formulas VI using hydroxylamine; e) for the preparation of compounds of the general formula ID, where the meanings of R1, R2, R3 are given earlier, compounds of the general formula IC, where the meanings of R1, R2, R3 are given earlier, are acylated using formic acid derivatives, and then they are closed in a ring or react with dialkylcarbonate; f) for the preparation of compounds of the general formula IE, where the meanings for R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II, where the meanings for R1, R2, R3 are given earlier, react with dihalogenated glyoxime; g) for the preparation of compounds of the general formula IF, where the meanings of R1, R2, R3 are given earlier, some 1,2-diaminobenzene of the general formula II reacts with the diiminoester of oxalic acid of the general formula VII, where the meanings of R1, R2, R3 are given earlier ; h) for the preparation of compounds of the general formula IB containing sulfur in the W position, where the meanings for R1, R2, R3, Z1 and Z2 are given earlier, a compound of the general formula IB containing oxygen in the W position or a compound of the general formula IF, where the meanings are for R1, R2 and R3 mentioned earlier, is reacted with reagents suitable for the introduction of sulfur, or the compound of the general formula IB containing sulfur in the W position is prepared by means of a selective transformation from the corresponding derivative of 2,3-dichloroquinoxaline or 2,3-dithioquinoxaline substituted with R1, R2, R3; i) for the preparation of compounds of the general formula IG, where the meanings of R1, R2, R3, Z1, X1, X2, X3 are given earlier, and the meaning of A is an optionally substituted amino group, compounds of the general formula IA are N-animated, where the meanings are for R1, R2 and R3 mentioned earlier, and W is an oxygen atom, and as desired in the thus obtained compounds of the general formula I, the substituents R1, R2 and R3 and X3 are transformed in a manner known per se into other substituents R1, R2, R3 and X3, and/or into their N-oxides, and/or salts, and/or are released from their salts. 5. Z1 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenyl- sulfonyl group; Y1 means hydrogen or an optionally substituted amino group, or Y1 and Z1 together form a -CO-O-group, where Y2 and Z2 together mean a valence bond, iii Y1 and Y2 together mean a valence bond, and at the same time Z2 means hydrogen, hydroxy, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulfonyl, trifluoromethylsulfonyl, optionally substituted benzoyl, optionally substituted phenylsulfonyl ; X1 and X2 together mean =O or =S, or X1 means hydrogen, groups -NHR4 or -WR5, and at the same time X2 means hydrogen, or X2 and X3 together form a valence bond, X3 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl group, R1 and R2 mean hydrogen, halogen, C1-4 alkyl, trifluoromethyl, cyano, mercapto or sulfonylamido group, R3 means hydrogen or a nitro group, R4 means hydrogen or a hydroxyl group, R5 means hydrogen, C1-4 alkyl, C7-9 phenylalkyl group, W stands for oxygen or sulphur, provided that a) if at least one of the substituents R1, R2 and R3 is different from hydrogen, or b) if Z1 and Z2 mean hydrogen, i - R1 means 6-chloro, R3 means hydrogen - R 2 has a different meaning than 7-chloro, or - R1 means 6-methyl, R3 means hydrogen, - R2 has a different meaning than 7-methyl. 6. Pharmaceutical preparations according to claim 5, characterized by the fact that as an active ingredient they contain one or more compounds, their tautomeric forms, salts and/or N-oxides: 3-amino-6,7-dichloro-8-nitro-quinoxalin-2-one 3-amino-6-trifluoromethyl-7-chloro-8-nitro-quinoxalin-2-one 3-acetylamido-6,7-dichloro-8-nitro-quinoxalin-2-one 3-lauroylamido-6,7-dichloro-8-nitro-quinoxalin-2-one 3-methylsulfonylamido-6-trifluoromethyl-7-chloro-8-nitro-quinoxalin-2-one.