WO1997019934A1

WO1997019934A1 - Quinoxaline compounds, pharmaceutical preparations containing them and a process for the preparation thereof

Info

Publication number: WO1997019934A1
Application number: PCT/HU1996/000072
Authority: WO
Inventors: Imre Bata; Sándor BÁTORI; Judit Bence; Zsolt BÖCSKEI; Éva CSIKÓS; Sándor ERDO^'; Csaba GÖNCZI; István HERMECZ; Gergely HÉJA; Viktor Lakics; Csilla MAJLÁTH; Péter Molnár; Benjamin PODÁNYI; Imola Ritz; Csutor Andrea SÁNTÁNÉ; Szappanos Andrea SZO^'KÉNÉ; Györgyné SZVOBODA
Original assignee: Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
Priority date: 1995-11-30
Filing date: 1996-11-28
Publication date: 1997-06-05
Also published as: AU7705396A; ZA9610002B; HU9503422D0; HRP960564A2; YU63496A; HUT76302A

Abstract

The invention relates to compounds of general formula (I) and salts, tautomeric forms and N-oxides thereof in which formula: Z1 means hydrogen, hydroxy, C¿1-4? alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulphonyl, trifluoromethyl-sulphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group; Y?1¿ means hydrogen, or optionally substituted amino group, or Y?1 and Z1¿ form together a -CO-O- group, where Y?2 and Z2¿ mean together a valency bond, or Y?1 and Y2¿ mean together a valency bond, and at the same time Z2 means hydrogen, hydroxy, C¿1-4? alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC1-4 alkyl, C2-14 acyl, C1-4 alkylsulphonyl, trifluoromethyl-sulphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group; X?1 and X2¿ mean together =O, or =S, or X1 means hydrogen, -NHR?4 or -WR5¿ groups, and at the same time X2 means hydrogen, or X?2 and X3¿ together form a valency bond, X3 means hydrogen, C¿1-4? alkyl, C7-9 phenylalkyl, optionally substituted phenyl, R?1 and R2¿ mean hydrogen, halogen, C¿1-4? alkyl, trifluoromethyl, ciano, mercapto or sulphonylamido group, R?3¿ means hydrogen or nitro group, R4 means hydrogen or hydroxy group, R5 means hydrogen, C¿1-4? alkyl, C7-9 phenylalkyl group, W means oxygen or sulfur with the proviso, that a) if at least one of the substituents of R?1, R2 and R3¿ is different from hydrogen or b) if the meaning of Z?1 and Z2¿ is hydrogen and R1 means 6-chloro, R3 means hydrogen, R2 has a different meaning from 7-chloro, or R1 means 6-methyl, R3 means hydrogen, R2 has a different meaning from 7-methyl; compounds of general formula (I) show a significant activity at the glycine binding site of the NMDA-receptor, therefore they can be used as active ingredients of pharmaceutical compositions.

Description

QUINOXALINE COMPOUNDS , PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND A PROCESS FOR THE PREPARATION THEREOF

The invention relates to new 3-amιno-quιnoxaiιne-2-one derivatives of the general formula I their salts, tautomeπc forms and N-oxides, to pharmaceutical preparations containing these compounds and the process for the preparation of them

In the past 10 vears a lot of communications and patent specifications have been published in the CNS area Special interest brisked up in the area of N-methyl-D- ι aspartate receptor antagonists

.Among others WO 9400124 and references cited in it describe derivatives of quιnoxalιne-2,3-d_one with this effect

N-substituted quinoxaline diones are described eg in WO 91 13878 (Novo Nordisk),

WO 9308188 (Sumitomo), WO 9320077 (Yamanouchi), derivatives of tπcyclic quinoxaline in J Med Chem 1992, 35, 3319-3324 (Eh Lilly),

WO 9409000 (Warner-Lambert), WO 9306103 (Novo Nordisk), US 51964 1 ( 1993)

Eh Lilly, US 5 153 196 ( 1992) Ely Lilly, tetracyc c quinoxaline derivatives tn WO 9502601 (Rhone-Poulenc Rorer SA), WO 2

9502602 (Rhone-Poulenc Rorer SA)

The svnthesis of 3-amιno-quιnoxalme-2-one derivatives is described in Tetrahedron Letters 23 No 33 pp 3357-60 without mentioning the technic

Partial hydrolysis (J Am Chem Soc 68 1035, ( 1946)) of 2,3-dιamιno-quιnoxahne is earned out in a different synthesis way

Surprisingly we found that quinoxaline derivatives of the general formula I show a significant activity at the glycine binding site of the NMDA-receptor, therefore they mav have a significant neuro protective effect which may play a therapeutic role in the treatment of Alzheimer disease, stroke, epiiepsy, in AIDS dementia and in the treatment of Parkinson^'s disease The meaning of the substituents in the general formula I is as follows

Z' means hydrogen, hydroxy, Cι_ alkyl, C7. phenylalkyl, optionally substituted phenyl,

COOC 1.4 alkvl, C₂_ acyl, C_t- alkylsulphonyl, tπfluoromethyl-sulphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyi group, Y' means hydrogen, or optionally substituted amino group, or

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

Y² and Z² mean together a valency bond, or

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

Z² means hydrogen, hydroxy, C alkyl, C7-9 phenylalkyl, optionally substituted phenyl, COOC ₁.4 alkyl, C:.u acyl, C 1.4 alkylsulphonyl, tπfluoromethyl-sulphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group;

X¹ and X² mean together =O, or =S, or

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

X² means hydrogen, or X² and X^J together form a valency bond,

X^* means hydrogen, C 1.4 alkyl, C7-9 phenylalkyl, optionally substituted phenyl,

R^l and R² mean hydrogen, halogen, C1.4 alkyl, trifluoromethyl, ciano, mercapto or sulphonylamido group,

R³ means hydrogen or nitro group, R⁴ means hydrogen or hydroxy group,

R³ means hydrogen, Cι_ alkyl, C .0 phenylalkyl group,

W means oxygen or sulfur with the proviso, that a ) if at least one of the substituents of R¹, R² and R^J is different from hydrogen or b ) if the meaning of Z¹ and Z² is hydrogen and R¹ means 6-chloro, R^? means hydrogen R² has a different meaning from 7-chloro, or R¹ means 6-methyl, R^J means hydrogen, R² has a different meaning from 7-methyl

Compounds of the general formula IA, IB, IC, ID, IE, IF, IG, their salts, tautomeπc forms and N-oxides form smaller groups of the compounds of the general formula I Compounds of the general formula I can be prepared in the following ways:

a. ) for the preparation of compounds of the general formula I A - where the meanings of R¹. R^~, R^' and W are as given above - an 1,2-dιamιnobenzene of the general formula II is reacted with a carboalkoxyformimidate derivative of the general formula III - where the meanings of R^l. R^", R^" and W are as given above. R" means hydrogen, R⁷ means Cι_: alkyl, or compounds of the general formula IF, where R¹. R², R' have the meanings as given above are hydrolyzed in acidic medium,

b ) for the preparation of compounds of the general formula IB - where the meanings of R¹, R^:, R^J and W are as given above, Z² means hydrogen and Z' means Cι_* alkyl, -1.9 phenylalkyl, or optionally substituted phenyl group - an 1,2-dιamιnobenzene of the eneral formula II is reacted with a compound of the general formula IV - where the eanmgs of R¹, R², R³, R⁷ and W are as given above, Hlg means halogen, R* means C|. alkyl, C7.₉ phenylalkyl, or optionally substituted phenyl group, R means C|.₂ alkyl group;

c.) for the preparation of compounds of the general formula IB - where the meanings of R¹, R², R^J, W and Z¹ are as given above, Z² means C₂-u acyl, C1.4 alkylsulphonyl, tπfluoromethylsulphonyl, optionally substituted benzoyl, optionally substituted phenyisulphonyl group - compounds of the general formula IB containing hydrogen atom in place of Z² are reacted with acylating agents of the general formula Z² -L, where the meaning of Z" is

acyl, Cι_» alkylsulphonyl, tπflouromethylsulphonyl, optionally substituted benzoyl, optionally substituted phenyisulphonyl group and the meaning of L is a leaving group;

d.) for the preparation of compounds with the general formula IC, where the meanings of R^l, R², R^' are as given above, an 1,2-dιamιnobenzene of the general formula II, where the meanings of R¹, R^", R^" are as given above, is cianomethylated, then the intermediate of general formula VI thus obtained is ciosed into a ring with hydroxylamme; e ) for the preparation of compounds of the general formula ID. where the meanings of R¹, R² R^' are as given above, compounds of the general formula IC, where the meanings of R¹, R^", R' are as given above, are acylated with formic acid derivatives, then closed into a ring or reacted with dialkylcarbonate.

f ) for the preparation of compounds of the general formula IE, where the meanings of R¹. R^" R^' are as given above, an 1.2-dιamιnobenzene of general formula II. where the meanings of R¹, R^", R³ are as given above, is reacted with dihalogenic glyoxime.

g.) for the preparation of compounds of the general formula IF, where the meanings of R¹, R². R^J are as given above, an 1.2-dιamιnobenzene of general formula II is reacted with oxalic acid diiminoester of general formula VII, where the meanings of R¹. R², R' and R⁷ are as given above,

h.) for the preparation of compounds of the general formula IB containing a sulfur atom in place of W, where the meanings of R¹, R\ R³, Z^l and Zr are as given above, a compound of the general formula EB containing oxygen in place of W or a compound of the general formula EF, where the meanings of R¹, R², R³ are as given above, is reacted with reagents suitable for sulfur introduction, or the compound of the general formula IB containing a sulfur atom in place of W is prepared from an appropriate R^l, R². R' substituted 2.3-dιchloroquιnoxalιne or 2,3-dιthιoquιnoxalιne derivatives by selective transformation,

l ) for the preparation of compounds of the general formula IG, where the meanings of R¹, R², R^J, Z¹, X¹, X², X^J are as given above and the meaning of A is an optionally substituted amino group, compounds of the general formula I A, where the meanings of R¹, R², R³ are as given above, W is an oxygen atom, are N-animated and

if desired in the compounds of the general formula I thus obtained, substituents R¹. R^". R' and X³ are transformed in a manner known per se into other R¹, R², R' and X' substituents, and/or into their N-oxides, and/or salts, and/or are deliberated from their salts Advantageously the preparation of the compounds of the general formula I A can be carried out by a method described in Tetrahedron Lett 23 No 33, pp 3357-60 or J C S 96( 1947)

For the preparation of compounds of the general formula IB containing alkvl, phenvialkyl or optionally substituted phenyl group in place of Z' the reaction is advantageously earned out in a polar solvent, advantageously in lower alcohol, in dimethylformamide or in dimethylsulphoxide, or m an apolar solvent such as tetrahydrofuran, between 0°C and boiling point, advantageously between 20 and 80°C

Compounds of the general formula IB containing acyl, alkylsulphonyl, tπfluoromethylsulphonyl, optionally substituted phenyisulphonyl group in place of Z¹ and/or Z^" can be prepared advantageously by reacung the compound of general formula IB, containing hydrogen atom in place of Z¹ and/or Z^" with an acylating agent optionally in the presence of a proton acceptor It is advantageous to use acid anhydride as acylating agent and perform the reaction without a proton acceptor

According to the invention it is advantageous to perform procedure e ) by applying methyl chloroformate as a formic acid derivative The acylation is performed under mild conditions and a basic catalyst is applied for the ring closure It is advantageous to perform the reaction of compounds of the general formula IC and dialkylcarbonates in a weak basic medium

It is advantageous to perform the reaction of compounds of the general formula II and dihalogeno glyoximes /(Chem Ber 85 3 5,( 1952)/ in a biphasic system, in the presence of a proton acceptor /(J Het Chem 26 1415 ( 1989)/

Based on the literature of J Org Chem Vol 1 , pp 470. ( 1 56), compounds of the general formula IB containing a suifur atom in place of W can be synthesized from appropπately substituted quinoxaline 2,3-dιones. advantageously in excess of ammonia or a primary amine, optionally in the presence of a solvent Compounds of the general formula I A can be transformed into toluene sulfonic acid salts of compounds of the general formula IG with O-tosyl hydroxyiamine in the presence of NaH in a medium containing DMF. The free base can be deliberated by using sodium-carbonate in aqueous medium

Compounds of the formula I where one of R¹, R², R^J is a nitro group can also be prepared by using a starting material containing hydrogen at the appropnate place and introducing the nitro group into the molecule using a mild nitrating agent such as ccH₂SO + K O₃ at 0°C, Ac₂O+HNO_?, Ac₂O+Cu(NO_?)₂. NO%BF₄ and if necessary removing the acyl protecting group.

If necessary the halogen atom can also be introduced subsequently using a halogenating agent e.g.: elemental halogen, perhalogenides and halogen transferring catalysts e.g. FeCL, A1CL, ZnCL, etc.

Description of biological test methods

Η-dichlorokinurenic acid (DCK) binding assay

[^'H]DCK ( l OnM) binding was examined by the method of T Canton and his collaborators (J. Pharm. Pharmcol., 44 812-816. ( 1992) After removal of the cerebellum and the brain stem from the whole brain of 150-200 g male rats (Sprague- Dawley) a membrane preparation was made by homogenization and repeated centπfugation. Incubation was done for 30 minutes at 4°C in 50 mM HEPES/KOH buffer (pH=7 5) in the presence and absence of test substances. Radio ligand bound to the membrane was separated by filtration method ( Whatman GF&B) Bound radioactivity was measured by liquid scintillation spectrophotometer. Non-specific binding was determined in the presence of 1 m glycme. The percent of binding was determined by the following formula:

|l-{B,-NSP)/(B NSP)}]X100, where

Bj is the binding measured in the presence of the test substance B_t total binding measured in the absence of the test substance NSP non-specific binding

20

Table I contains the tested substances and their 50% binding causing concentration (IC5 value)

Table I.

-> ς

30

Compounds of the general formula I or their salts may be used in the therapy as pharmaceutical preparations containing the active ingredient and inert solid or liquid organic or inorganic excipients. Manufacturing of the preparations takes place according to known methods.

Preparations are made in forms suited for oral or parenteral application e tablet, coated tablet, capsule, or their retard versions. The preparations may contain appropriate solid diluting or earner substances, steπle aqueous solvent or non-toxic organic solvent. For such purpose sweetening and flavoring substances can be added to oral preparations.

Tablets suitable for oral application may contain lactose, sodium citrate, calcium carbonate as earner substances, and substances promoting disintegration (e g. starch, alginic acid), lubricants (e.g. talc, sodium laurylsulfate, magnesium stearate). Carrier substances of capsuies may be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying and suspending agents. Diluting agents of the organic solvent suspensions may be ethanol, glycerin, chloroform, etc.

Preparations suitable for parenteral application are solutions or suspensions of the active ingredient in an appropnate medium (e.g. hazelnut oil, sesame oil, polypropylene glycol or water).

The active ingredient content of the pharmaceutical preparations can change within wide ranges, it may be between 0.005-99%. The daily dose of the active ingredient can change within wide ranges and depends on the severity of the condition, age, body weight of the patient, form of the preparation and activity of the given active ingredient. In case of oral dosage, the daily active ingredient dose is generally 0.5-20 mg/kg in a single dose or in daily multiple doses. The above data is of informational character from which in a given case and depending on instructions of the physician it can be deviated up or down

Further details of the invention are given in the following examples without limiting it Examples

Example 1.

Method for the preparation of substances with the general formula I. A. containing an oxygen atom in place of W.

10 mmol 1 ,2-diamιnobenzene derivative of the general formula II are suspended or dissolved in 15-20 cm^" solvent depending on the starting material (use of methanol. ethanol, dimethylformamide, DMSO, water or mixture thereof is advantageous), and treated with 12 mmol ( 1 40 g) ethyl carboethoxyformimidate. The reaction mixture is keeped at 25-30°C for 8-48 hours. The precipitated substance of the general formula I A is filtered, washed with methanol and dried. Table II contains yieids and melting points of the compounds thus obtained.

Table II

Example 2

Introduction of the nitro group:

The product of example 1 resp. 4 is dissolved in concentrated sulfuric acid and treated with 1- 1 2 equivalent KNO₅ at a temperature of 0 to 5°C. The endpomt of the reaction is determined by TLC from the sample taken from the mixture. In case of complete reaction the reaction mixture is poured on ice 5- 1 5 fold of the volume of the sulfuric acid used as solvent and the precipitated substance is filtered.

Physical data of the substances thus obtained are identical with the data of examples 6 and 7 listed in Table I.

Example 3

The products of examples 1 and 4 may also be nitrated by treating their water free „Sulfolanιc" suspension with nitronium tetrafluoroborate at a temperature of max. 20°C. Processing of the obtained products and their physical data are identical with those of example 2.

Example 4

Treating compounds of the general formula IF (J Am. Chem. Soc. 68. 1035 ( 1946)) with 2.5-5 M aqueous hydrochloric acid for a short time at 100-120°C results compounds of I A. Isomers can be separated by e.g. flash vacuum chromatography Table III summarizes physical data and yields of the compounds prepared.

Table III

In case of separated isomers the identification of regio isomers was performed by C¹ ' NMR. Bread bound decoupled and proton coupled C¹ ' spectra of both pure isomers were made and for the identification of C^l3-Η coupling constants with long range effects selective INEPT measurement series were made. With the knowledge of the C^l3-^!H coupling constants with long range effects chemical shifts of carbon atoms in different positions of both isomers were identified in the heteroatom free aromatic ring and they were compared to the two hydrogen atoms. It is known that the effect of the amide and imino group on the chemical shift influencing effect of aromatic carbon atoms is characteristically different (E Pretsch, J Seibl. W Simon, T Clerc Tabellen zur Strukturaufklarung organischer Verbindungen mit spektroskopischen Methoden, Springer, Berlin ( 1981)). On carbon atoms in ipso and ortho position to the amide group a smaller deviation is expected than on carbon atoms having the same position to an imino group. The two sets of signals were matched with the isomers given in table

IV by comparing the vaiues measured for these carbon atoms in the two compounds In case of the other not separated isomeπc mixtures the isomers were matched based on chemical shifts of these characteristic signs. The ratio of the isomers was determined from the intensity of the signals. Table IV

Example 5

Preparation of compounds of the general formula IC

Preparation and transformation of compounds of the general formula VI

0.1 M 1 ,2-dιamιnobenzene deπvative of the general formula II is dissolved/suspended in 20 cm³ methanol and 8.75 cm³ 36% hydrochloπc acid solution are added to it. The solution thus formed is cooled to below 10°C and 1.05 M potassium cyanide are added to it dropwise while constantly stirring. The pH of the reaction mixture is adjusted to 6 5 and 8.90 g 35% formaldehyde solution are added to it dropwise at 40°C in 20 to 35 minutes. It is cooled to 0°C after 2 hours and the precipitated material is separated from the aqueous alcoholic mother liquor either by filtration or by extraction following an aqueous dilution.

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

Example 6

Preparation of compounds with the general formula ID

10 mmole IC compound are dissolved in 15 to 20 cm' acetone and 1 1 mmole triethylamine are added to it and the reaction mixture is treated with 10 5 mmole methyl chloroformate between 0 and 25°C After the removal of triethylamine hydrochloride compounds of the general formula ID are crystallized

Yields and physical data are summarized in table VI

15

20 Example 7

Preparation of compounds of the general formula IE

5 mmole substituted 1 ,2-dιamιnobenzene of the general formula II and 5 2 mmole dichloroglyoxime are suspended in 25 cm³ dichloromethane, then 50 mmole Na₃COι

-> <; dissolved in 25 cm^' distilled water are added to it dropwise, and the mixture is rigorously stirred for 1 hour (The reaction is followed by TLC) The precipitated substance is filtered, washed with water and dichloromethane and purified by chromatography if necessary Table VII contains data of the obtained compounds Table VII.

Example 8

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

a / 8 mmole substituted 1 ,2-dιamιnobenzene of the general formula II are dissolved in 12 cm^' THF By keeping the temperature of the mixture at ~10°C 10 mmol tmidovl chloride of general formula IV are added to it. After standing at room temperature for 1 day, the precipitated substance is filtered, washed with ethanol, puπfied by chromatography if necessary

Table VIII

* Isomeπc ratios were determined by ^1JCNMR ** HCL salt b < Preparation of nitro compounds of the general formula IB contaimnti tin oxvu«n atom in place of W can be carried out according to examples 2 or 3

Table IX

Example 9 Preparation of compounds of the general formula IB containing an oxygen atom in place of W

a / 1 mmol acid anhydnde is added to 0 35 mmole of the product of examples 1 resp 8 The mixture is boiled until reaction takes place, evaporated and the product is recrystallized from ethanol

Table X.

b / Compounds prepared according to examples I and 2 are dissolved in aceton. and acylated in the presence of a proton acceptor and with equivalent ^■+^• 10% acid halogenide at room temperature. The substance obtained after aqueous dilution or evaporation in vacuo is recrystallized.

Table XI.

Example 10 Preparation of substances of the general formula FF

0. 1 mol 1,2-dιamιnobenzene derivative is dissolved in 3 to 10 times methanol (ethanol DMSO) and 1.15 mol oxalic acid diimid dimethylester and 3 to 5 mmole p-toluene sulfonic acid are added to it as a catalyst. The reaction mixture is let stand at room temperature for 5 to 20 hours, the precipitated substance is filtered and washed with alcohol The following table contains substances thus prepared. For other starting material see Chem. Ber. 97 1599 ( 1964)

Table XII

Example 1 1

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

1 0 cm ^' abs. ethanol saturated with ammonia is added to 0 5 g 6-tπfluoromethvl-7- chloro-2,3-quιnoxaiιne-dιthιone The reaction mixture is kept in closed vessel for 5 days at room temperature. It is purified by "flash" vacuum chromatography . J Org Chem. 44, 4963 ( 1979), MKL 40, 366 ( 1985)/..

Table Xm

* Isomenc ratios were determined by NMR.

Example 12

Preparation of compounds of the general formula IG

a./ 0.4 g ( 1.5 mmole) O-tosyl-acetoxy-hydroxamate are added to 2 cm' 60% perchloric acid, mixed at room temperature for 20 minutes, poured on ice, then extracted with 2x 1 cm^' dichloromethane. The solution thus obtained, which contains approximately 0.2 g ( 1 1 mmole) O-tosyl-hydroxylamine is added to the suspension of 1 mmol 3- amιno-quιnoxalιne-2 one derivative and 50 mg ( 1.25 mmole) sodium hydride (60% dispersion in mineral oil) in 5 cm^' DMF, mixed at room temperature for 2 hours, then worked up. The base is released from the tosylate salt by aqueous sodium carbonate treatment. Table XIV

* Tosvlate salt ** monohydrate

b / Compounds of the general formula IA -where the meaning of W is an oxygen atom -are reacted with alkyl halogenides in DMF in the presence of K2CO,

Table XV

Example 13

Preparation of compounds of the general formula IB, where W=O and Z|=OH;

Z_.=H

4 6 mmole 1,2-dιamιnobenzene of the general formula II are dissolved in 10 cm^' ethanol. 4 6 mmole (0 7 g) chloro-oximino-ethyl-acetate are added to it After dissolution while constantly stirring 4 6 mmole NaHCO, dissolved in 5 cm' distilled water are added to it dropwise. After standing over night, the precipitated substance is filtered, washed with water and purified if necessary Table XVI contains data of the obtained compounds. Table XVI

Example 14 Compounds of the general formula ID containing an oxo-group in position 4 may be prepared according to example 6.

Table XVII contains data of the obtained compound

Table XVII

Claims

I ) Compounds of the general formula I and salts, tautomeπc forms and N-oxides thereof in which formula Z¹ means hydrogen, hydroxy. Cι_ alkyl, C₇->. phenylalkyl, optionally substituted phenyl,

COOC ι-4 alkyl, C .u acyl, C ι_₄ alkylsulphonyl. tπfluoromethyl-sulphonvl. optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group,

Y' means hydrogen, or optionally substituted amino group, or

Y' and Z¹ form together a -CO-O- group, where Y^: and Z^~ mean together a valency bond, or

Y' and Y² mean together a valency bond, and at the same time

Z² means hydrogen, hydroxy, C M alkyl, C7.9 phenylalkyl, optionally substituted phenyl, COOC M alkyl, C₂-i4 acyl, C 1. alkylsulphonyl, tnfluoromethyl-suiphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group; X¹ and X² mean together =0, or =S, or

X¹ means hydrogen, -NHR⁴ or -WR^S groups, and at the same time

X² means hydrogen, or

X² and X" together form a valency bond,

X³ means hydrogen, C alkyl, C7.9 phenylalkyl, optionally substituted phenyl, R¹ and R² mean hydrogen, halogen, G- alkyl, trifluoromethyl, ciano, mercapto or sulphonylamido group,

R^J means hydrogen or nitro group,

R⁴ means hydrogen or hydroxy group,

R^ means hydrogen, C alkyl, CT-Q phenylalkyl group, W means oxygen or sulfur with the proviso, that a.) if at least one of the substituents of R^l, R² and R³ is different from hydrogen or b.) if the meaning of Z¹ and Z² is hydrogen and R¹ means 6-chloro, R^' means hydrogen R¹ has a different meaning from 7-chloro, or

R' means 6-methyi, R^' means hydrogen. R^" has a different meaning from 7-methvl

2 ) Compounds of the general formula I A, IB, IC. ID. IE. IF. IG. their salts, tautomeπc forms and N-oxides, where the meaning of R¹. R², R^J, Z¹, X¹, X². X3 are given in claim I. W means a sulfur or an oxygen and the meaning of A is an optionally substituted amino group

3 ) Compounds according to claim 1 ) 3-amιno-6,7-dichloro-8-nιtro-quιnoxalιne-2-one 3-amιno-6-tπfluoromethyl-7-chloro-8-nιtro-quιnoxalιne-2-one 3-acetylamιdo-6,7-dιchloro-8-nιtro-quιnoxalιne-2-one 3-lauroylamιdo-6,7-dιchloro-8-nιtro-quιnoxahne-2-one

3-methylsulfonamιdo-6-tπfluoromethyl-7-chloro-8-nιtro-quιnoxalιne-2-one

4 ) Process for the preparation of compounds of the general formula I, characterized that a ) for the preparation of compounds of the general formula I A - where the meanings of R¹. R^", R^J and W are as given above - an 1.2-dιamιnobenzene of the general formula II is reacted with a carboalkoxyformimidate derivative of the general formula III - where the meanings of R¹, R², R³ and W are as given above, R⁶ means hvdrogen, R⁷ means Cι._: alkyl, or compounds of the general formula IF, where R¹, R², R' have the meaning:, a., given above are hydrolyzed in acidic medium.

b ) for the preparation of compounds of the general formula IB - where the meanings of R¹, R², R' and W are as given above, Z² means hydrogen and Z' means C alkyl, C₇. phenylalkyl, or optionally substituted phenyl group - an 1 ,2-dιamιnobenzene of the general formula II is reacted with a compound of the general formula IV - where the meanings of R^l, R², R^J, R and W are as given above, Hlg means halogen, R* means C₁.4 alkyl, C7.9 phenylalkyl, or optionally substituted phenyl group, R⁷ means C_l-2 alkyl group. ) for the preparation of compounds of the general formula IB - where the meanings of R¹, R^", R', W and Z¹ are as given above, Z² means C . acyl, C alkylsulphonyl, tπfluoromethylsulphonyl, optionally substituted benzoyl. optionally substituted phenyisulphonyl group - compounds of the general formula IB containing hydrogen atom in place of Z^" are reacted with acylating agents of the general formula Z² -L, where the meaning of Z^" is C -u acyl. C M alkylsulphonyl, tπflouromethvlsulphonyl, optionally substituted benzoyl, optionally substituted phenylsulphonvl group and the meaning of L is a leaving group,

d ) for the preparation of compounds with the general formula IC, where the meanings of R¹, R^", R³ are as given above, an 1.2-dιamιnobenzene of the general formula II, where the meanings of R , R^", R' are as given above, is cianomethylated, then the intermediate of general formula VI thus obtained is closed into a ring with hydroxyiamine,

e.) for the preparation of compounds of the general formula ID, where the meanings of R¹, R², R" are as given above, compounds of the general formula IC. where the meanings of R^l, R", R^J are as given above, are acylated with formic acid derivatives, then closed into a ring or reacted with dialkylcarbonate,

f ) for the preparation of compounds of the general formula IE, where the meanings of R¹, R², R^J are as given above, an 1 ,2-dιamιnobenzene of general formula II, where the meanings of R¹, R², R^J are as given above, is reacted with dihalogene glyoxime.

g.) for the preparation of compounds of the general formula IF, where the meanings of R¹, R^", R' are as given above, an 1,2-dιamιnobenzene of general formula II is reacted with oxalic acid dnminoester of general formula VII, where the meanings of R^l, R². R^J and R are as given above.

h ) for the preparation of compounds of the general formula IB containing a sulfur atom in place of W, where the meanings of R¹, R², R\ Z' and Z² are as given above, compound of the general formula IB containing oxygen in place of W or a compound of the general formula IF, where the meanings of R¹, R². R' are as given above, is reacted with reagents suitable for sulfur introduction, or the compound of the general formula IB containing a sulfur atom in place of W is prepared from an appropriate R¹.

R², R' substituted 2,3-dιchloroquιnoxaiιne or 2,3-dιthιoquιnoxalιne derivatives by selective transformation,

i ) for the preparation of compounds of the general formula IG, where the meanings of R¹, R². R\ Z¹, X¹, X², X³ are as given above and the meaning of A is an optionally substituted amino group, compounds of the general formula I A. where the meanings of R¹, R², R^J are as given above, W is an oxygen atom, are N-animated and

if desired in the compounds of the general formula I thus obtained, substituents R¹, R², R³ and X³ are transformed in a manner known per se into other R¹, R², R^"' and X⁵ substituents, and/or into their N-oxides, and/or salts, and/or are deliberated from their salts

5 ) Pharmaceutical preparations containing as active ingredient a compound of general formula I, wherein

Z¹ means hydrogen, hydroxy, C _M alkyl, C7-9 phenylalkyl, optionally substituted phenyl,

COOC ₁.4 alkyl, C -14 acyl, C 1- alkylsulphonyl. tπfluoromethyl-sulphonyl, optionally substituted benzoyl, optionally substituted phenyl-sulphonyl group,

Y¹ means hydrogen, or opuonally substituted ammo group, or

Y' and Z¹ form together a -CO-O- group, where

Y² and 7} mean together a valency bond, or

Y' and Y² mean together a valency bond, and at the same time Z² means hydrogen, hydroxy. C _M alkyl, C7-9 phenylalkyl, optionally substituted phenyl. COOC alkyl, C₂- acyl, C M alkylsulphonyl, tπfluoromethyl-suiphonyl, optionally substituted benzovl, optionally substituted phenyl-sulphonyl group,

X¹ and X² mean together =O, or =S, or

X¹ means hvdrogen. -NHR⁴ or -WR' groups, and at the same time X² means hydrogen, or

X² and X^' together form a valency bond,

X^' means hydrogen. C M alkyl, C7.9 phenyialkyl, optionally substituted phenvl,

R' and R² mean hydrogen, halogen. C_M alkyl, trifluoromethyl, ciano, mercapto or sulphonylamido group, means hydrogen or nitro group,

R⁴ means hydrogen or hydroxy group,

R' means hydrogen. C M alkyl, C7.9 phenylalkyl group,

W means oxygen or sulfur with the proviso, that a ) if at least one of the substituents of R¹, R² and R³ is different from hydrogen or b ) if the meaning of Z¹ and Z^" is hydrogen and R¹ means 6-chloro, R³ means hydrogen R² has a different meaning from 7-chloro, or R^l means 6-methyl, R^J means hydrogen, R² has a different meaning from 7-methyl

6 ) Pharmaceutical preparation according to claim 5 ) comprising as active ingredient one or more of the compounds, tautomeπc forms, salts and /or N-oxides thereof 3-amιno-6,7-dιchloro-8-nιtro-quιnoxalιne-2-one 3-amιno-6-trιfluoromethyl-7-chloro-8-nιtro-quιnoxalιne-2-one 3-acetylamιdo-6,7-dιchloro-8-nιtro-quιnoxalιne-2-one 3 -lauroyiamιdo-6, 7-dιchloro-8-n_tro-quιnoxalιne-2-one 3-methvlsulfonamιdo-6-tπfluoromethyl-7-chloro-8-nιtro-quιnoxalιne-2-one