FI59998B - FRUIT PROCEDURE FOR THERAPEUTIC USE OF THERAPEUTIC ANVAENDBARA 6- ELLER 7-CYAN-3-METHYLKINOXALIN-2-CARBOXAMIDE-1,4-DIOXIDE - Google Patents

Description

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1 4 1 'UTLÄGGN I NGSSKRIFT 377./ O

c <4s);: i: nr: ^; t! '7; 111Λ ^ ^ ^ (51) Kv.ik? /int.ct.3 c 07 D 241/52 SUOMI-FINLAND (21) PatanUlhtlcemu * - PitanUftafiknlnf 730017 (22) HakwnltpUvl —AMttknln | * da | 06.01.75 '' (23) Primary Cloud — GUtlghaodag 06.01.7 5 (41) Interpreters for Public - Bllvlt offantllg 08.07.75

Patent and Registry Administrators „...........,. .. ,,, B. . . . ^ ^, (44) Date of issue of Nikaviksipan a. - οτ n? fli

Patent and registration requirements' 'AntAkan utl.jd oeh utl.skrlftan publlcarad 5X' u 1 · 01 (32) (33) (31) Pyrdtty atuolkaus-Baglrd prtarltat ° T · 01.71 * USA (US) U31170 (71) Pfizer Inc ., 235 East U2nd Street, Nev York, NY, USA (72) James William McFarland, Old Lyme, Connecticut, USA (7M Ltd Kolster Ab (5M Method for Therapeutically Applicable 6- or 7 ~ Cyano-3 This invention relates to a process for the preparation of therapeutically useful 6-cyano-3-methylquinoxaline-2-carboxamide-1H-dioxide derivatives. This invention relates to a process for the preparation of therapeutically useful 6-methyl-quinoxaline-1,2-carboxamide-1,1-dioxide derivatives. - or 7-cyano-3-methylquinoxaline-2-carboxamine-1,1 + -dioxide derivatives, which have useful antibacterial properties and are also of value because of their activity as growth promoters in animals, and more specifically these quinoxaline-2-carboxamide derivatives. 1,1 + -dioxy di-derivatives having a cyano substituent ti in the fused benzene ring and the methyl group in C-3 and optionally substituents on the nitrogen atom of the carboxamide.

Quinoxaline-1,1 + dioxides are well known chemical compounds, some of which are reported to have antibacterial properties and / or some of which are reported to be useful as animal growth promoters. U.S. Patent No. 3,660,398 and British Patent No. 1,308,370 both disclose quinoxaline-2-carboxamide-1,10-dioxides and describe, in particular, a number of compounds having substituents of 5 "> 6, 7 ~ and 8 stations. However, neither of these patents discloses quinoxaline-2-carboxamide-1,4-dioxides having a cyano substituent on a fused benzene ring. Landquis and Stacey, Journal of the Chemical Society (London), 2822 (1953, 259998) describe the preparation of 6-cyano-2,3-dimethylquinoxaline-1,1-dioxide.

The present invention relates to a process for the preparation of therapeutically useful 6- or 7-cyano-3-methylquinoxaline-2-carboxamide-1,1-dioxide derivatives of the formula 0 0 f II 1 n ^ c-f TT n \ R2 1 CH3 O and their for the preparation of acid addition salts in which the cyano substituent is in the 6- or 7-position.

1.2

Preferred are compounds of formula I in which R and R each represent alkyl groups having 1 to 1 carbon atoms, and those in which R is hydrogen.

Among the preferred compounds prepared according to the invention, the following should be mentioned separately: 6 (7) -cyano-N, Ν-3-trimethylquinoxaline-2-carboxamide-1,1-dioxide, 6 (7) -cyano-3-methylquinoxaline-2-carboxamide-1 1,1 ± -dioxide, 6 (7) -cyano-N, 3-dimethylquinoxaline-2-carboxamide-1,1-dioxide, 6 (7) -cyano-N-ethyl-3-methylquinoxaline-2-carboxamide-1, 1 + dioxide and 6 (7) -cyano-N- (2- (N, N-dimethylamino) ethyl) -3-methylquinoxaline-2-carboxamide-1,1-dioxide.

The process according to the invention is characterized in that the formula NC M

The compound of formula xx> i o is reacted with (i) the formula 0 0 R1 H li /

CH C - CHpC - N III

With a compound of formula R 2 or an enamine thereof, wherein R 1 and R 2 are as defined above, or (ii) diketene and R 1 CH 3 <r? 3 59998 1.2.

wherein R and R are as defined above, and if desired, pharmaceutically acceptable salts are prepared from the resulting compounds.

The process for the preparation of quinoxaline-1, U-dioxides of the formula I is discussed in more detail below. In this process, 5-cyanobenzofurazan-1-oxide (II) is reacted with an acetoacetamide of formula III in the presence of a 1.2 basic catalyst, wherein R and R are as defined above. The reaction is normally carried out by contacting the reagents in a suitable solvent system at a temperature in the range of about 0 ° C to about 100 ° C, preferably about 20 ° C to about 60 ° C.

0 li, 2 N; C --- 0 n CH2 - C - NR R2 ln

sN. ^ / I

N CO - CH3

Suitable solvents are those which are capable of dissolving at least one of the reactants and which do not adversely affect either of the starting reagents or the final product. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dialkyl ethers of ethylene glycol, propylene glycol and diethylene glycol methylene, lower alkanols such as methanol, ethanol, such as methanol. lene chloride and 1,2-dichloroethane, tertiary amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone, acetonitrile and mixtures of these solvents.

The reaction time varies depending on several different factors, such as the reactivity and concentration of the reactant and the reaction temperature. As will be appreciated by those skilled in the art, the reaction occurs more rapidly at higher temperatures, resulting in shorter reaction times, while at lower temperatures the reaction time is slower and longer reaction times are required to obtain good product yields. Taking these factors fully into account when working at about 25 ° C, reaction times of several hours are typically used, e.g. from about 2 hours to about 2U per hour.

Many different basic catalysts can be used in this process, and examples of the bases used include ammonia, primary amines such as methylamine, ethylamine, butylamine, cyclohexylamine, aniline and benzylamine, secondary amines such as diethylamine, dimethylamine, morpholine, morpholine, , tertiary amines such as “59998 triethylaraine, N-methylmorpholine, Ν, Ν-dimethylaniline, pyridine and Quinoline, alkoxides such as sodium methoxide, sodium ethoxide and potassium ethoxide, hydroxides such as sodium, potassium and calcium hydroxide, such as and potassium hydride. The amount of alkaline catalyst used is not critical, and amounts as low as about 0.01 molar equivalents can be used up to a multiple molar excess relative to benzofurazan-1-oxide. The preferred amount is normally about 0.1 to 1.0 molar equivalents.

In those cases where the basic catalyst is a liquid at the reaction temperature, it may, if desired, be used in such a sufficient excess that the addition of a solvent is unnecessary.

The compounds of formula II and formula III are generally contacted with each other in approximately equimolar amounts, although an excess of either component also results in the formation of compounds of formula T. In those cases where the compound of formula III is a liquid at the reaction temperature, it can be used as a reaction solvent if desired.

The products of the present process are isolated from the reaction medium by standard methods. For example, in cases where the product precipitates during the reaction, it can simply be recovered by filtration. Alternatively, if the product does not self-precipitate, it can often be made to precipitate upon completion of the reaction by diluting the reaction medium with a non-solvent such as hexane or water. Another method of getting rid of the product is to remove the solvents by evaporation, after which the crude product thus obtained is partitioned between water and a water-immiscible organic solvent. After separation of the two phases obtained, the product-containing phase is evaporated to give the product.

Acetoacetamides of formula III can be readily prepared by known 12. ...

by reaction between diketenem and an amine of the appropriate formula NHR R (see RN Lacey, "Advance in Organic Chemistry, Methods and Results", Tnterscience Publishers, Inc. New York, 19 ^ 0, Vol. II, p. 2 ^ 8-2 ^ 9).

The compounds of formula I are sometimes prepared by a modification comprising the following two-step sequence: (1) diketene is reacted with a suitable amine in one of the solvents listed above, and (?) A solution of the acetoacetamide derivative thus produced is treated directly with 5-cyanobenzofurazan-1-oxide. In the second step of this reaction series, the same reaction times and temperatures described above are used. When using this particular variant, the basic catalyst may be added separately before the second step, or alternatively may be suitably used simply 12. .....

in the first step an excess of the amine of formula NHR R with respect to diketenem. In this case, for the second step, an unreacted amine is present in the reaction mixture, which acts as a catalyst.

In some cases, a further modification is used to prepare the compounds of formula I in which the acetoacetamide component is replaced by an equimolar amount of enamine formed by the reaction of acetamide with a primary or, preferably, secondary amine. These amines are prepared by well-known methods (e.g., see Szmuszkovicz, "Advances in Organic Chemistry, Methods and Results," Interscience Publishers, Inc., New York, 1963, vol. TV, pp. 1-113), and typical amines suitable for use. are morpholine, pyrrolidine, piperidine, N-methylcyclohexylamine and dialkylamines such as dimethylamine, diethylamine and dibutylamine. With this latter variant, it is not necessary to add a basic catalyst in addition to the amine used to form the enamine.

5-Cyanobenzofurazan-1-oxide is prepared from U-chloro-3-nitrobenzonitrile by treatment with an azide ion-giving compound, and pyrolysis of the lt-azido-3-nitrobenzonitrile thus produced. U-azido-3-nitrobenzonitrile is prepared by reacting a substantially equimolar amount of N-chloro-3-benzonitrile with a source of azide ion in a polar organic solvent such as acetonitrile, N, N-dimethylformamide, Ν, Ν-dimethylacetyl, N-dimethylacetamide, N , in dimethyl sulfoxide or a lower alkanol such as methanol, ethanol or isopropanol at a temperature in the range of about 0 ° C to about 30 ° C for several hours, e.g. about 1 * to about 2 hours. Typically used azide ion sources include metal salts of hydrazonic acid such as sodium azide and potassium azide, ammonium azide, amine salts of hydrazonic acid such as ethylammonium azide, dibutylammonium azide, dimethylammonia azide (triethylammonium azide), triethylammonium azide, pyridinium azide, pyridinium azide , such as trimethylsilyl azide and triethyl azide. The conversion to benzofurazan-1-oxide can then be carried out simply by heating the solution of U-azido-3-benzonitrile thus produced. In general, temperatures of about 1 + 0 ° C to about 160 ° C, preferably about 60 ° C to about 100 ° C are used in this second step, and the reaction usually takes a few hours, e.g. about 2 to about 10 hours, when the temperature is in the range of about 60 ° C to about 100 ° C. 5-Cyanobenzofurazan-1-oxide can be isolated by quenching the solvent by evaporation. It is also possible to use a process variant in which the formation of azido-3-nitrobenzonitrile is carried out in a water-miscible organic solvent. In this case, when the conversion of 1 * -azido-3-nitrobenzonitrile is complete, the reaction medium is diluted with excess water, and the product is then extracted with a water-immiscible organic solvent. The i * -azido-3-nitrobenzonitrile solution thus obtained is then heated to effect pyrolysis completely as described above, and then the solvent can be removed by evaporation to give cyanobenzofurazan-1-oxide. Suitable water-immiscible solvents for use in this conversion include esters such as ethyl acetate and butyl acetate, aromatic hydrocarbons such as benzene, toluene, and '' selenium, and chlorinated hydrocarbons such as chloroform and methylene chloride.

Although cyanobenzofurazan-1-oxide is shown as the 5-isomer, it actually exists as a dynamic tautomer in a mixture containing both the 5- and 6-isomers.

6 59998

O

t ΝΓ 1

. N NCV _ N

γγ \ _Λ γγ \ l o

In addition, the presence of this tautomeric equilibrium in the starting material in the process described above for the preparation of the compounds of formula I produces a mixture of 6- and 7-cyanoquinoxaline-1,1 + -dioxides. The ratio of isomers obtained varies depending on several different factors, such as, for example, the structure of the reactants, the reaction temperature, the reaction solvent and the method chosen for isolating the product. In some cases, significant amounts of both isomers are obtained, while in other cases the other isomer is clearly predominant. If desired, the mixture of the two isomers can be separated into its components by customary methods, such as, for example, fractional crystallization or chromatography. In most cases, the identification of isomers has not been performed, and the nomenclature used for antibacterial quinoxaline-1,1-dioxides in this patent is intended to include either the 6- or 7-isomer or a mixture thereof.

. . . 1.2

Compounds of formula I in which either R and R are either 3 k. 3 lt .. ......

CH 2 CH 2 NR 7 R or CH 2 CH 2 CH 2 NR R, form acid addition salts, and all such acid addition salts are considered to be within the scope of this invention. The salts are formed by well known methods, such as by combining a solution of basic quinoxaline-1,1 * -dioxide in a suitable solvent (e.g. water, acetone, methanol, ethanol or butanol) with a solution containing an equimolar amount of the appropriate acid. If salt precipitates, it is recovered by filtration. Alternatively, it can be recovered by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. Although the compounds of the present invention are intended for therapeutic use, it is most preferred to use pharmaceutically acceptable salts, other than these salts may be prepared for a variety of other uses. Such uses include, for example, the isolation and purification of certain compounds and the major conversion of pharmaceutically acceptable salts and their non-salt counterparts. Of particular value are sulfates, hydrochlorides, hydrobromides, nitrates, phosphates, citrates, tartrates, pamoates, ammonones, perchlorates, sulfosalicylates and p-toluenesulfonates.

The in vitro antibacterial activity of the present invention can be demonstrated by a conventional two-fold serial dilution technique in brain-heart infusion broth (Difco). The broth is inoculated with bacteria and the test quinoxaline-1,1 + dioxide is added, then incubated overnight under anaerobic conditions. The next day, the test result is read with the naked eye. The minimum contraceptive concentration (MIC) of the test compound τ 59998 is the lowest concentration that prevents turbidity, i. inhibits the growth of microorganisms. The in vitro activity of several compounds of the present invention is shown in Table I.

The quinoxaline-1,1-dioxides of this invention also show antibacterial activity in vivo. To determine such activity, the test compound is administered to mice infected intraperitoneally around pathogenic bacteria. The test compound is administered according to a multiple dose regimen and using either oral (PO) or subcutaneous (SC) drug administration. The bacterial inoculum varies from 1 to 10 times the amount that kills 100% of the mice under the experimental conditions. At the end of the experiment, the activity of the compound is determined by counting the number of survivors of the treated animals. The results are also shown in Table I, which shows the ability of the compounds to protect mice from lethal doses of Streptococcus pyogenes and Escherichia coli.

Table I

MIC Percent protection1 (jig / ml)

The compound Strept. Esch. Strep. Esch.

pyogenes coli pyogenes coli 6 (7) -cyano-3-methyl-Sc po sc quinoxaline-2-carboxamide-1-dioxide <0.39 <0.39 100 90 80 6 (7) -cyano-N-3 -dimethyl-quinoxaline-2-carboxamide-1H-dioxide 0,78 <0,39 100 100 90 6 (7) -cyano-Ν, Ν-3-trimethylquinoxaline-2-carboxamide-1, U dioxide <0.39 6.25 100 90 0 6 (7) -cyano-N-ethyl-3-methylquinoxaline-2-carboxamide-1H-dioxide <0.39 1.56 100 100 0 6 (7) -cyano-N- (2-hydroxy-ethyl) -3-methylquinoxaline-2-carboxamide-1,1-dioxide 6,25 6,25 90 100 30 6 (7) -cyano-N- (2 - (n, N-dimethylamino (ethyl) -3-methylquinoxaline-2-carboximide-1,1-dioxide <0.39 3.12 70 100 0

Dosage of test compound in protective experiments Strept. against pyogenes is 50 mg / kg body weight and against E. coli is 25 mg / kg body weight.

8 59998

The in vitro and in vivo activity of the compounds of the invention against some gram-positive and gram-negative microorganisms was compared to the activity of structurally related compounds known from U.S. Pat. No. 3,660,391 having the same direction of action. The experiments were performed as described above. The results are shown in the following tables, in which compounds A-E are prepared according to the present invention and compounds P-T. are compounds of U.S. Patent 3,660,391.

0 0 A ”23 i c-NRir

qfrV

0 R1__R3

Compound A CN H H

Compound B CN CH 2 H

Compound C CN (CH 2 Cl 2 H

Compound D CN CH2CH3 H

Compound E CN (CH2) 2N (CH3) 2H

Compound P H H H

Compound Q H CH 3 H

Compound R H (CH 2 Cl 2 H

Compound S H CH 2 CH 3 H

Compound T H (CH 2) 2 N (CH 3) 2 H

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In vivo comparative test

Surviving experimental animals,%

Streptococcus pyogenes Escherichia coli 50 mg / kg, p.o. 50 mg / kg, s.c. 25 mg / kg, s.c.

Compound C 100 90 30

Compound D 100 100 10

Compound E 100 100 0

Compound R0 0 100

Compound S 0 20 100

Compound T 10 JO

The in vitro antibacterial activity of the quinoxaline-1-dioxides of this invention makes them valuable industrial antimicrobicides, e.g. in water treatment, mucus control, paint preservatives and wood preservatives, as well as topical disinfectants. When these compounds are used topically, it is often convenient to mix the active ingredient with a non-toxic carrier such as a vegetable or mineral oil or an ointment base. Likewise, it may be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, concentrations of about 0.01 to 10% by weight of active ingredient are most conveniently employed. the whole composition.

The in vivo activity of the quinoxaline-1,4-dioxide compounds of this invention makes them useful in the treatment of bacterial infections in animals and are of particular value as growth promoters in animals, especially pigs, cattle and poultry. When the compounds are used in animals for these purposes, they may be administered orally or parenterally, i. intramuscularly, subcutaneously or intraperitoneally, at a dose of about 1 to about 100 mg / kg body weight.

In general, however, doses of about 5 to about 50 mg / kg body weight have been found to be sufficient. The compounds may be administered alone or may be combined with various diluents and carriers according to standard veterinary practice.

When the compounds of this invention are intended for parenteral use, they may be combined with diluents such as water, isotonic saline, isotonic dextrose, Ringer's solution, or anhydrous diluents such as vegetable oils (cottonseed oil, sesame oil, corn oil) or dimethyl sulfoxide. In general, buffers, local anesthetics and / or inorganic salts are also added to obtain the desired pharmaceutical properties.

For oral use, the quinoxaline-1,10-dioxides of this invention can be combined with various diluents, including aqueous and non-aqueous diluents and solid diluents, to form capsules, tablets, lozenges, troches, dry mixtures, suspensions, solutions, and dispersions.

The compounds of this invention have particularly valuable use as animal growth promoters.

Low addition of one or more of the quinoxaline-1, U-dioxides described herein to healthy animals, both ruminants and others, such that these animals receive the product over a prolonged period of time at a level of about 1 ppm to 100 ppm, usually about 5 ppm to about 50 ppm mixed with their feed. , especially for most of their active growth time, causes an increase in growth rate and improves feeding efficiency (the number of kilograms of feed needed to produce one kilogram of body weight). Examples of animals that can be treated in this way are poultry (chickens, ducks, turkeys), cattle, sheep, dogs, cats, pigs, rats, mice, horses, goats, mules, rabbits, minks, etc. Beneficial effect on growth rate and feeding efficiency is beyond what is normally achieved by nutritionally complete diets that contain all the nutrients, vitamins, minerals, and known factors known to affect the maximum healthy growth of such animals. Animals thus gain marketing size faster and with less feed. Quinoxaline-1,4-dioxides may be mixed into the animal's feed or administered in equivalent amounts with the animal's water.

The following examples are presented to illustrate the invention.

Example 1 6 (7) -Cyano-3-methylquinoxaline-2-carboxamide-1,1-dioxide

A mixture of 5-cyanobenzofurazan-1-oxide (500 mg, 0.0031 mol) and acetoacetamide (310 mg, 0.0031 mol) was performed by Chick and Wilsmore, J. Chem. Soc., London, 1978 (1910)) in 10 ml of tetrahydrofuran is cooled to 5 ° C, then treated with a U drop of U0 # in aqueous methylamine, with 1 drop of catalyst per hour being added every first four hours. The reaction mixture is then stirred overnight at room temperature to form a crystalline precipitate. The precipitate is filtered, washed with tetrahydrofuran to give 10 mg (5% yield) of 6 (7) -cyano-3-methylquinoxaline-2-carboxamide-1,1-dioxide, m.p. 232-236 ° C (decomposes).

Analysis

calculated from the formula C ^ HgN ^ O ^ (%): C 5 ^ »1H H 3.3 N 22.9 found (%): C 53.8 H 3, ^ N 22, U

Example 2 6 (7) -Cyano-N, N, 3-trimethylquinoxaline-2-carboxamide-1,1-dioxide.

Reaction of 1.6 g (0.01 mol) of 5-cyanobenzofurazine-1-oxide with N, N-dimethylacetoacetamide (1.29 g, 0.01 mol) according to the procedure of Example 1 gives 1.07 g (* + 0% yield) 6 (7) -cyano-N, N, 3-trimethyl-quinoxaline-2-carboxamide-1,1-dioxide, melting point 18-190 ° C.

i2 59998

Analysis calculated for C 13 H 12 NO 3 (Percent): c 57.5 H U, 5 N 20.6 Found (%): C 56.8 H U, 5 N 20.5.

Example 3 6 (7) -Cyano-N, 3-dimethylquinoxaline-2-carboxamide-1,1-dioxide A stirred solution of 0.8 U g (0.01 mol) of diketene in 50 ml of acetic acid. tonitrile, cooled to 5 ° C, then 2.3 ml (0.011 mol) of a 1.78 N solution of raethylamine in methanol are added dropwise to the solution. During the addition, the temperature is kept below 10 ° C. At the end of the addition, the temperature of the solution is again adjusted to 5 ° C, then a solution of 5-cyanobenzofurazan-1-oxide (1.6 g, 0.01 mol) in 20 ml of acetonitrile is added dropwise while cooling sufficiently to maintain the temperature of the reaction mixture. Below ° C. At the end of the latter addition, the reaction mixture is allowed to warm to room temperature, then stirred overnight. The precipitated solid precipitate is filtered to give 1.3 g of crude product, m.p. 203-20 ° C (dec.). Recrystallization of this crude product from methanol gives 0.65 g of 6 (7) -cyano-N, 3-dimethylquinoxaline-2-carboxamide-1,1-dioxide, m.p. 218-220 ° C.

Analysis calculated for the formula C ^ H ^ qN ^ O ^ (percent): C 55.8 H 3.9 N 21.7 found (percent): C 55.2 H, 1 N 21.2

Example k

The preparation procedure of Example 3 is repeated using an equimolar amount of the appropriate amine instead of the methyl amine used therein to give the following compounds: 0 i3 5 9 9 9 8

Analysis

Sp. Calculated (%) Found {%) R2_ (jC) _C HNCH N_CH2CH3 206-207 57, * + * +, δ 20.6 56.9 * +, δ 20.8 * CH2CH2OH 185-186 52.5 * + , * + 18.8 52.7 H, 3 19.2 CH 2 CH 2 N-169-171 57.1 5, * + 22.3 56.7 5.5 22.9 (ch 3) 2 * This compound has been isolated and analyzed hemi-hydrate.

Preparation 5-Cyanobenzofurazan-1-oxide A stirred solution of U-chloro-3-nitrobenzonitrile (U8.0 g, 0.263 mol) (Le Fevre and Turner, J. Chem. Soc., London, 1113 in 360 ml of dimethyl sulfoxide is treated 17.0 g (0.263 mol) of sodium azide are added portionwise at room temperature, the resulting solution is stirred overnight at room temperature, then poured into 2.0 ml of water, the aqueous solution thus obtained is extracted with 1,000 ml of ethyl acetate, then the organic extract is washed with water and dried over anhydrous sodium sulfate.

The dried solution is concentrated in vacuo to about half volume, then heated to reflux for 3 hours. The ethyl acetate solution is then cooled to room temperature and the rest of the solvent is evaporated in vacuo to give * + 1.2 g (97% yield) of 5-cyanobenzofurazan-1-oxide, m.p. 73-76 ° C. Analysis calculated for C 13 H 3 N 3 O 2 (%): C 52.2 H 1.9 N 26.1 Found (%): C 52.1 H 2.3 N 25.8.

Claims (3)

4, for the preparation of 6- or 7-cyano-3-methylquinoxaline-2-carboxamide-1,1 + -dioxide derivatives according to CH 3 O and their acid addition salts, wherein in formula 1.2. the cyano substituent is in the 6- or 7-position, R and R denote hydrogen, an alkyl group containing 1 to 1 carbon atoms, 2-hydroxyethyl, 3-hydroxypropyl, CH 2 CH 2 NR 2 R 2 or CH 2 CH 2 CH 2 NR 4 R 1 * group in which R 1 and R 2 are alkyl groups having 1 to 3 carbon atoms, characterized in that the compound of formula NC N YY \ 4r 0 is reacted with the compound of formula (i) 0. R rt it / CH_C - CH0C - N III 3. A compound of formula N.2 or an enamine thereof, wherein R 1 and R 2 are as defined above, or (ii) a diketene and a compound of formula / R 1 CH0N IV 3, wherein R 1 and R 2 are as defined above. the same as above, and if desired, pharmaceutically acceptable salts are prepared from the obtained compounds.