HU187544B - Process for preparing /1,2,5/triazolo/4,3-a/quinoxalina-4-amine derivatives - Google Patents

Abstract

The present invention relates to novel 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivatives of formula (I), wherein the amino group is optionally substituted by lower alkyl, phenylalkyl; wherein the alkyl moiety is substituted with up to 3 carbon atoms or C 2-5 alkanoyl or the amino group is part of the piperazine group; the quinoxal ring is optionally substituted with fluorine, chlorine, bromine or methoxy and the triazole ring is optionally substituted by lower alkyl, lower perfluoroalkyl or phenyl. The new compounds are useful for treating depressive symptoms. The invention also relates to a process for the preparation of pharmaceutical compositions comprising the novel compounds. -1-

Description

The present invention relates to a series of novel 4-amino [1,2 ', 4] triazolo [4,3-a] quinoxaline derivatives and their pharmaceutically acceptable acid addition salts which are useful as anti-depression and fatigue agents.

Intensive research has focused on the production of compounds that reduce the symptoms of depression and fatigue in mammals.

U.S. Pat. No. 3,839,569 and German Patent No. 2,249,350 disclose the use of triazolo [4,3-a] quinoxalines as agricultural fungicides. U.S. Patent No. 4,008,322 discloses a series of triazolo [4,3-a] quinoxaline derivatives which are useful in controlling rice fever caused by the phytopathogenic Piricularia oryzae.

The present invention relates to the preparation of novel 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivatives which are useful as anti-depression and fatigue agents.

More particularly, the present invention (I) compounds of the general formula: - wherein X and ^X1 are hydrogen, fluorine, chlorine or bromine atom or a methoxy group; R 1 is hydrogen, lower alkyl, lower perfluoroalkyl or phenyl, and

R ₂ and R 1 are hydrogen, lower alkyl, phenylalkyl containing up to 3 carbon atoms in the alkyl moiety, or C 2 -C 5 alkanoyl, provided that at least one of R ₂ and R ₃ is different from hydrogen when X and X * are each hydrogen and R is hydrogen or methyl; obsession

R ₂ and R ₃ together with the adjacent nitrogen atom form a piperazino group, as well as pharmaceutically acceptable acid addition salts thereof.

As used herein and in the claims, lower alkyl means C1-4 alkyl and lower perfluoroalkyl means C1-4 perfluoroalkyl, such as trifluoromethyl, pentafluoroethyl.

An important class of compounds are those derivatives wherein X and X ¹ are each hydrogen, R, hydrogen, and R ₂ and R ₃ are each lower alkyl. Preferred compounds are those wherein R ₂ and R _{3 are} ethyl.

Another preferred group of compounds of the present invention are those wherein X and X ¹ are hydrogen, R ¹ , ethyl and R ¹ is lower alkyl. Preferred compounds are those wherein R _{2 is} hydrogen and R _{3 is} ethyl.

Another preferred group of compounds of the invention include those compounds wherein X and X ¹ is hydrogen, R _is a lower alkyl group and R ₃ is acetyl. Preferred ones are those wherein R 1 is ethyl and R _{2 is} hydrogen, ethyl or acetyl.

An important group of compounds of the invention are those wherein at least one of X and X ¹ is fluoro, R ^{1 is} hydrogen or trifluoromethyl, R ^{2 is} hydrogen and R ^{3 is} hydrogen, lower alkyl, or C 2 -C 5 alkanoyl; or wherein at least one of X and X * is chloro, R ^{1 is} lower alkyl or trifluoromethyl, R ^{2 is} hydrogen, R ^{3 is} hydrogen, lower alkyl or C 2 -C 5 alkanoyl.

The present invention also provides pharmaceutical compositions for the treatment of depression and fatigue comprising as an active ingredient an effective amount of a compound of formula (I) or an acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. Preferred are pharmaceutical compositions containing the aforementioned preferred compounds of formula (I).

The compounds of the present invention are useful for reducing depression or fatigue in a mammal in the form of a pharmaceutical composition comprising an effective amount of a compound of formula (I) or an acid addition salt thereof. For this purpose, the compounds mentioned above among the preferred compounds of formula (I) are preferred.

Most of the novel compounds of formula I can be prepared by the reaction scheme outlined in Scheme A. The numbering of the benzene and the two heterocycles as shown in Scheme A is used throughout.

A) Scheme (IV) of general formula: - wherein X and X ¹ is hydrogen, fluorine, chlorine, bromine or methoxy, with the proviso that X is always hydrogen when the compound of formula (IV) The monosubstituted quinoxaline derivative in the benzene ring is reacted with 1 molar excess of hydrazine hydrate in a polar organic solvent, such as C 1-3 alkanol, preferably ethanol, at room temperature for about 18-24 hours. This gives the intermediate of formula (III).

The intermediate of formula (III) is then converted to the corresponding intermediate of formula (IIA), wherein R is not lower perfluoroalkyl, with a suitable alkyl orthoalkanoate or alkyl orthobenzoate at 80 ° C and 120 ° C. At about 1 to about 24 hours. In the resulting compound of formula IIA, R 1 (hydrogen or alkyl) is defined as the orthoalkanoate used in the synthesis. For example, when triethyl orthoformate is used, R 1 is hydrogen, if triethyl orthopropionate, then R _{1 is} ethyl, if triethyl orthobutyrate, R _{1 is} isopropyl.

The intermediate of formula (III) can also be converted to the corresponding compound of formula (IIA) wherein R1 is a lower C ?? perfluoroalkyl group by the addition of a molar excess of a suitable perfluoroalkanoic acid such as trifluoroacetic acid, pentafluoro propionate

-2- 187,544 acids are obtained in the usual manner to give the corresponding 4-hydroxy-1- (perfluoroalkyl) - [1,2,4] triazolo [4,3-a] quinoxaline, which is a tertiary amine such as triethylamine. is reacted with phosphorus oxychloride under heating, so that it is suitable

A 4-chloro derivative is formed.

The intermediate of formula IIA wherein R, hydrogen, lower alkyl, lower perfluoroalkyl, or phenyl is represented by formula IA

Is converted to the 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivative where R ₂ and R _{3 are} as defined above, except alkanoyl, in a molar excess of HNR ₂ R ₃ with an amine in an organic solvent inert to the reaction, preferably N, N-dimethylformamide, at a temperature between 0 ° C and 60 ° C for 2-24 hours. For example, the preferred compounds of formula IA, wherein R ₂ and R ₃ are ethyl, are prepared by reacting the corresponding compound of formula IIA with diethylamine, Ν, Ν-dimethylformamide, at room temperature, for 2 hours. The reaction was allowed to proceed for 3 hours. Similarly, preferred compounds of formula IA wherein R _{2 is} hydrogen and R _{3 is} ethyl are prepared by reacting a compound of formula IIA with monoethylamine, Ν, Ν-dimethylformamide at room temperature for 4-5 minutes. hours.

The 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivatives of formula IA wherein at least one of R ₂ and R ₃ is C 2 -C 5 alkanoyl are prepared by the appropriate method (IA). ), wherein at least one of R ₂ and R ₃ is hydrogen, by reaction with a suitable alkanoic anhydride under suitable conditions. This reaction is carried out in the presence of an organic base such as tertiary amine as a catalyst (although not necessarily required). It is carried out at a temperature between 20 ° C and 140 ° C for 24 hours. The molar ratio of the starting material containing the 4-amino group to the acid anhydride should be at least 1: 1, preferably 4: 1 to 25: 1, while the amount of tertiary amine used is 25-150% by weight of the aforementioned acylating agent. (tertiary amine can also be used as a solvent simply by taking it in excess). Although it is sometimes quite probable, and in some cases highly desirable, to carry out the reaction without solvent, there may be cases where its use is strongly recommended. Suitable organic solvents for this purpose are inert anhydrous organic solvents such as acetone, methyl ethyl ketone, benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride, tetrachloride and the like. ethane, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, diethyl ether, diisopropyl ether, di (n-propyl) ether and the like. However, as mentioned above, the reaction is generally carried out in the absence of such a solvent, with only an excess of anhydride. Similarly, an excess of the tertiary amine reagent may serve as a solvent. Preferred tertiary amines for use in this reaction as solvent and / or catalyst include triethylamine, dimethylaniline, pyridine, picoline, lutidine, collidine and quinoline.

The starting materials of formula (IV) - wherein X ¹ and X ⁵ are hydrogen are well known. Compounds of formula IV wherein X * is methoxy,

GWH Cheeseman [J. Chem. Soc., 1170 (1962)]. 4-methoxy-phenylenediamine hydrochloride with an equimolar amount of ash ^{of 10} with diethyl oxalate and diethylamine in an inert gas, preferably nitrogen, at reflux temperature, for 2-3 hours, and the product was a tertiary amine, preferably dimethylaniline phosphorus oxychloride was heated ^{to 15} for 1-2 hours.

Scheme B depicts a quinoxaline derivative of formula (IV) wherein:

X is fluorine, chlorine, bromine or methoxy and X ¹ is hydrogen - ²⁰ in an alcoholic solvent, (e.g., 40-60 ° C) with approximately under gentle heating with sodium methoxide

For 6-18 hours, the corresponding 2-chloro-3-methoxyquinoxaline derivative of formula (V) is formed, which is then reacted with hydrazine hydrate as described above to give the 2-hydrazino compound of formula (V1). 3-methoxyquinoxaline is obtained. The latter intermediate [VI] is directly converted to the desired 7-substituted 4-methoxy [1,2,4] triazolo [4,3-a] quinoxaline derivative of formula VII with a suitable orthoester or perfluoroalkanecarboxylic acid as described above, and then converting the latter compound to the corresponding 4-hydroxy and then 4-chloro compounds of formula VIII in a known manner to give compounds of formula IIB wherein X is as defined above (i.e., other than hydrogen) and X ¹ is hydrogen. These intermediates of formula (IIB) eventually lead to the corresponding new end products of general formula (IB) - in which R 1. R ₂ and R ₃ are as defined above and X and

X ^I is as defined above - used in reactions described in the last steps of the method of Scheme where A) represents.

The present invention also encompasses the preparation of pharmaceutically acceptable acid addition salts of the novel compounds of formula (I). These salts are readily prepared by reaction of the free base with a suitable mineral or organic acid in aqueous solution or in a suitable organic solvent. The solid salt can then be obtained by precipitation or by evaporation of the solvent. The pharmaceutically acceptable salts of the present invention include, but are not limited to, hydrochloride, sulfate, hydrogen sulfate, mesylate, tosylate, nitrate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, succinate, gluconate, and the like. Mesylate salts are preferred. If desired, the free base compounds of formula (I) are prepared from their acid addition salts with an appropriate base followed by extraction of the free base with a suitable organic solvent.

The compounds and pharmaceutically acceptable acid addition salts of formula (I) and depression ₆₅ against fatigue agents and accordingly gyó3

-3187,544 are of major medical importance in treating symptoms associated with depression and fatigue. The compounds may be administered to a subject in need of conventional treatment, such as oral, intravenous and parenteral administration. The compounds are preferably administered orally, generally in amounts of 0.1 to 100 mg / kg / day, preferably 0.5 to 10 mg / kg / day. However, the dosage will necessarily vary depending upon the individual being treated and the compound employed.

The compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents, in single or multiple doses. Suitable pharmaceutical carriers are, for example, inert diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions prepared from the novel compound of formula (I) or salts thereof and pharmaceutically acceptable carriers can be administered in various dosage forms such as tablets, powders, capsules, lozenges, syrups and the like. These compositions may, if desired, contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, for oral administration, tablets may contain various excipients such as sodium citrate, various disintegrating agents such as starch, alginic acid or certain complex silicates, binders such as polyvinylpyrrolidone, sucrose, gelatin and arabic gum.

The effects of the compounds of the present invention on depression and fatigue were determined by various standard pharmacological tests, including Porsolt's "taught inertia" (i.e., forced swimming immobility in rats, [RD Porsolt et al., European Journal Pharmacol., 47, 379). (1978)], a therapeutic model that is known to reduce forced swimming-immobility in this model.

The invention is illustrated by the following examples. However, it should be noted that the invention is not limited to the details described in these examples.

Example A

4-Chloro-7-fluoro- [1,2,4,4] triazolo [4,3-a] quinoxaline a) 2-Chloro-6-fluoro-3-methoxy-quinoxaline

To a suspension of the flame-dried flask, 52 g (0.24 mol) of 2,3-dichloro-6-fluoroquinoxaline in 500 ml of methanol under a nitrogen atmosphere at 6.0 g (0.29 mol) of sodium in 500 ml methanol solution was added dropwise. The resulting reaction mixture was kept at 50 ° C overnight (i.e., about 16 hours) and the resulting clear solution was allowed to cool to room temperature (about 20 ° C). The reaction mixture was then concentrated in vacuo, the residue was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate. The desiccant is filtered off and the solvent is evaporated off under reduced pressure to give a liquid residue which is chromatographed on a column containing 1000 ml of silica gel eluting with toluene. The fractions containing product only were combined to give 48.3 g (95%) of pure 2-chloro-6-fluoro-3-methoxyquinoxaline, m.p. 93-95'C. MS: m / e 212 (P); m / e 214 (P + 2).

b) 6-Fluoro-2-hydrazino-3-methoxy-quinoxaline g (0.22 mol) of 2-chloro-6-fluoro-3-methoxy-quinoxaline was dissolved in 1000 ml of ethanol, 26.8 ml (27.6 g; 0.55 mol) of hydrazine hydrate are added. The resulting mixture was stirred overnight at room temperature (about 16 hours, about 20'C). A further 9.0 moles of hydrazine hydrate were added and the mixture was stirred at room temperature for 4 hours. At this time, the precipitate was filtered off and washed with ethanol

43.3 g (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline are obtained, m.p. 170-174C.

c) A mixture of 7-fluoro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline g (0.072 mol) in 6-fluoro-2-hydrazino-3-methoxyquinoxaline and 250 ml triethyl orthoformate under mechanical stirring, in an oil bath at 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with ethanol to give 11.3 g (72%) of pure

7-Fluoro-4-methoxy- [1,2,4] triazolo [4,3-] quinoxaline is obtained, m.p. 245-246 ° C.

d) 7-Fluoro-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 7-fluoro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline (11.3 g, 0.52 mol), 1N hydrochloric acid (115 ml) and glacial acetic acid (345 ml) was heated at reflux for 3 hours. After boiling, the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was stirred for 30 minutes and then the precipitate was filtered, washed with water and air dried to give 8.9 g (84%) of pure 7-fluoro-4-hydroxy [1,2,4] triazolo [4,3a] quinoxaline. m.p.> 300 ° C. MS: m / e 204 (P).

e) 4-Chloro-7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline

In a flame-dried flask, under dry nitrogen, 8.9 g (0.044 mol) of 7-fluoro-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline, followed by 160 ml of phosphorus oxychloride and , 9 ml of tri (n-propyl) amine are added. The reaction mixture is then refluxed overnight for about 16 hours, cooled to room temperature and poured into ice water with stirring. The resulting aqueous mixture was stirred for 30 minutes, the solid product was filtered off, washed with cold water and then triturated with ethyl acetate to give 7.0 g (71%)

-4187 544 pure 4-chloro-7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline is obtained, m.p. 305-308'C. MS: m / e 222 (P); m / e 224 (P + 2).

Example B.

4-Chloro-1-ethyl-7-fluoro- [1,2,4] triazolof 4,3-a] quinoxalir

a) 1-Ethyl-7-fluoro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline g (0.07 mol) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline (prepared according to Example Ab) and 250 ml of triethyl orthopropionate was stirred at 100 ° C overnight (about 16 hours) in a preheated oil bath. The resulting mixture was cooled to room temperature (about 20 ° C), and the precipitate was filtered and washed with ethanol to give 1.1 g (64%) of pure 1-ethyl-7-fluoro-4-methoxy [1,2,4] triazolo [4 3-a] quinoxaline is obtained, which melts at 200-202 ° C.

b) 1-Ethyl-7-fluoro-4-hydroxy-1,2,4] triazolo [4,3] quinoxaline

A mixture of 11.3 g (0.046 mol) of 1-ethyl-7-fluoro-4-methoxy [1,2,4] triazolo [4,3-a] quinoxaline, 115 ml of 1N hydrochloric acid and 345 ml of glacial acetic acid is refluxed for 3 hours. . After refluxing, the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was stirred for 30 minutes, filtered and the resulting solid was washed with water and air-dried to give 6.6 g (62%) of pure 1-ethyl-7-fluoro-4-hydroxy [1,2,4] triazolo [4 3-a] quinoxaline, m.p.> 300'C. Mass Spectrum: m / e 232 (P), m / 2 231 (P-1).

c)

4-Chloro-1-ethyl-7-fluoro- [1,2,4] triazolof 4,3-a] quinoxaline

In a flame-dried flask under dry nitrogen, 6.6 g (0.028 mol) of l-ethyl-7-fluoro-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline, 120 ml of phosphorus oxychloride and Tri-n-propylamine (6.6 ml) was added. The reaction mixture was refluxed overnight for about 16 hours, then cooled to room temperature and poured into ice water with stirring. The resulting aqueous solution was stirred for 30 minutes at room temperature, filtered, and the resulting solid was washed with cold water and dissolved in ethyl acetate. The latter organic solution was washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the desiccant, the solvent was evaporated under reduced pressure to give a tan solid which was treated with diethyl ether to give pure 4-chloro-1-ethyl-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline. Yield: 4g (57%), m.p. 203-205 ° C.

MS: m / e 250 (P); m / e 252 (P + 2); m / e 249 (P-1).

Example C

4,7-Dichloro-1,2,4-triazolof 4,3-a J-quinoxaline a) 2,3-Dihydroxy-6-chloroquinoxaline 100 g (0.07 mol) 4-chloro-1,2-phenylene diamine and a mixture of 750 ml of diethyl oxalate was refluxed overnight for about 16 hours. After refluxing, the reaction mixture was cooled to room temperature (about 20 ° C), filtered, and the resulting product was washed with ethanol and air dried to constant weight to give 140 g of pure 2,3-dihydroxy-6-chloroquinoxaline, m.p.> 260 '. C.

b) 2,3,6-Trichloroquinoxaline

A mixture of 140 g (0.70 mol) of 2,3-dihydroxy-6-chloroquinoxaline and 326 ml (3.50 mol) of phosphorus oxychloride was refluxed overnight (about 16 hours) and then poured onto ice. The resulting aqueous mixture was filtered and the separated solid was washed with water and air dried. It is then dissolved in chloroform, washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The desiccant was removed by filtration, the solvent was evaporated in vacuo and a thick slurry was formed which was recrystallized from chloroform-ethanol to give 120 g (74%) of pure 2,3,6-trichloroquinoxaline, m.p. 139-141 ° C. .

MS: m / e 232 (P); m / e 234 (P + 2); m / e 236 (P + 4).

c) 2,6-Dichloro-3-methoxyquinoxaline

A suspension of 11.7 g (0.05 mol) of 2,3,6-trichloroquinoxaline in 140 ml of methanol is heated to 50 ° C and a solution of 1.4 g (0.06 mol) of sodium in 140 ml of methanol is added dropwise. during the lesson. The resulting mixture was kept at 50 ° C overnight (about 16 hours), and an additional 140 mg of sodium dissolved in 20 ml of methanol was added over 1 hour. The resulting reaction mixture was heated at 50 ° C for 2 hours and then cooled to room temperature. The mixture was then concentrated in vacuo and dissolved in a mixture of chloroform and water. The organic phase is separated and set aside, the aqueous phase is extracted with chloroform. The various chloroform phases were combined, washed with clear water and then with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off in vacuo and the residue was chromatographed on a column of silica gel (250 mL) eluting with toluene. The same fractions were combined to give 9.8 g (86%) of a white solid, m.p. 92-95'C, 2,6-dichloro-3-methoxyquinoxaline.

d) 6-Chloro-2-hydrazino-3-methoxyquinoxaline

4.9 g (0.02 mol) of 2,6-dichloro-3-methoxyquinoxaline and

A mixture of hydrazine hydrate (2.7 g, 0.053 mol; 2.6 ml) in ethanol (75 ml) was stirred at room temperature overnight (about 20 ° C and 16 hours). thereafter

The resulting mixture was filtered and the resulting precipitate was washed with ethanol to give 4.4 g (98%) of pure 6-chloro-2-hydrazino-3-methoxyquinoxaline, m.p. 175-179 ° C.

Mass Spectrum: m / e 224 (P); m / e 226 (P + 2).

e)

7-Chloro-4-methoxy- [1,2,4] triazolof 4,3-a] quinoxaline

A mixture of 1.4 g (0.0062 mol) of 6-chloro-2-hydrazino-3-methoxyquinoxaline and 20 ml of triethyl orthoformate was kept under stirring in a preheated oil bath at 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with ethanol to give 1.0 g (69%) of pure 7-chloro-4-methoxy [1,2,4] triazolo [4,3-a] quinoxaline. mp 250-252 ° C.

f)

7-Chloro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 3.4 g (0.014 mol) of 7-chloro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, 35 ml of IN hydrochloric acid and 105 ml of glacial acetic acid is refluxed for 2.5 hours. After refluxing, the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was stirred for 20 minutes and then filtered, washed with water and air-dried to constant weight. 2.6 g (87%) of pure 7-chloro-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p.> 300'C.

g) 4,7-Dichloro-1,2,4] triazolo [4,3-a] quinoxaline

In a flame-dried flask under a dry nitrogen atmosphere, 2.6 g (0.012 mol) of 7-chloro-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline followed by 40 ml of phosphorus oxychloride and 2.6 ml of tri (n-propyl) amine is added. The reaction mixture is then refluxed overnight (about 16 hours) and, after cooling to room temperature, is slowly poured into an ice / water mixture. The resulting aqueous mixture was then extracted with ethyl acetate, and the ethyl acetate extract was washed with water, saturated aqueous sodium bicarbonate, and saturated sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was removed in vacuo. The resulting yellowish solid was chromatographed on a column of silica gel (200 mL) using a 9: 1 by volume mixture of chloroform and methanol as eluent. The same fractions were combined and evaporated in vacuo to give 1.89 g (66%) of pure solid as an orange solid.

4,7-dichloro- [1,2,4] triazolo [4,3-a] quinoxaline is obtained, m.p. 253-256 ° C with decomposition.

Mass Spectrum: m / e 238 (P); m / e 240 (P + 2); m / e 242 (P + 4).

Example D

4,7-Dichloro-1-ethyl-f 1,2,4] triazolo [4,3-a] quinoxaline a)

7-Chloro-1-ethyl-4-methoxy-1,2,4-triazolof 4,3-a Jkino ⁵ xalm

5.1 g (0.022 mol) was prepared according to Example C.d)

It was mechanically stirred in ^{a 10} square overnight, heated in a preheated oil bath for 6-chloro-2-hydrazino-3-methoxy-quinoxaline and 60 ml of triethyl orthopropionate 100 ° C (about 16 hours). The resulting mixture was filtered, cooled and the precipitate formed is suction at room temperature (~ 20 ° C) and then washed with diethyl ether to give finally 4.3 g (75%) of pure ¹⁵ 7-chloro-l-ethyl-4-methoxy- [l , 2,4] triazolo [4,3-a] quinoxaline, m.p. 221-223 ° C.

b) ²⁰ 7-Chloro-1-ethyl-4-hydroxy- [1,2,4] triazolof 4,3-a] quinoxaline

A mixture of 4.3 g (0.0072 mol) of 7-chloro-1-ethyl-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline, 40 ml of IN hydrochloric acid and 60 ml of ²⁵ methanol was added overnight. reflux and cool to room temperature. The precipitate formed is filtered off and washed with methanol. That way eventually

3.7 g (94%) of pure 7-chloro-1-ethyl-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p.

c)

4,7-Dichloro-1-ethyl-1,2,4-triazolof-4,3-a Jinoxaline

In a flame-dried flask under a dry nitrogen atmosphere, 5.1 g (0.02 mol) of 7-chloro-1-ethyl-4-hydroxy [1,2,4] triazolo [4,3-a] quinoxaline and 75 ml of phosphorus oxy chloride and 5 ml of tri (n-propyl) amine. The reaction mixture was refluxed overnight for about 16 hours, then cooled to room temperature and poured slowly into ice / water. The resulting aqueous mixture was then stirred for 15 minutes at room temperature, and the resulting solid was washed with water and air-dried to constant weight. 4.2 g (79%) of pure 4,7-dichloro-1-ethyl [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 217-220 ° C. Mass Spectrum: m / e 266 (O); m / e 268 (P + 2); m / e 265 (P-1).

Example E

4-Chloro-7-methoxy- [1,2,4] triazolof 4,3-a] quinoxaline a) 2,3-Dihydroxy-6-methoxyquinoxaline

A mixture of 20 g (0.114 mol) of 4-methoxy-1,2-phenylene diamine and g (0.114 mol) of triethylamine is heated with 200 ml of diethyloxalate overnight for about 16 hours. After refluxing, the reaction mixture was cooled to room temperature (about 20 ° C) and the precipitated product was filtered off. After washing with ethanol, 14.8 g (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline are finally obtained, m.p.> 300'C. Mass Spectrum: m / e 192 (P).

I

-6187,544

b) 2,3-Dichloro-6-methoxyquinoxaline

14.8 g (0.077 mol) of 2,3-dihydroxy-6-methoxyquinoxaline and 75 ml of phosphorus oxychloride and 15 ml of tri-n-propylamine were placed in a flame-dried flask under a dry nitrogen atmosphere. The exothermic reaction mixture was then stirred for 1 hour at room temperature (20'C) and then refluxed overnight for about 16 hours. After refluxing, the reaction mixture was again cooled to room temperature and slowly poured into an ice / water mixture. The resulting aqueous mixture was stirred at room temperature for 20 minutes, the precipitate was filtered off, washed with water and dissolved in chloroform. The chloroform solution was filtered to remove the insoluble material and the resulting filtrate was washed with water, saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution. The washed solution was concentrated in vacuo and the residue was recrystallized from ethanol to give 14.2 g (80%) of pure 2,3-dichloro-6-methoxyquinoxaline, m.p. 156-159 ° C.

Mass Spectrum: m / e 228 (P); m / e 230 (P + 2); m / e 232 (P + 4).

c) 2-Chloro-3,6-dimethoxyquinoxaline

A solution of 850 mg of sodium in 80 ml of methanol is added slowly to a suspension of flame-dried flask, under dry nitrogen, in a solution of 7.1 g of 2,3-dichloro-6-methoxyquinoxaline in 60 ml of methanol at 50 ° C. The resulting mixture was then kept at 50'C overnight and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was chromatographed on a column of 400 mL of silica gel using chloroform as eluent. The product-containing fractions were combined and concentrated in vacuo to give 6.1 g (88%) of pure 2-chloro-3,6-dimethoxyquinoxaline as a white solid, m.p. 79-81 ° C.

Analysis for C ₁₀ H ₉ CIN ₂ O _2: Calcd: C 53.47%, H 4.04%, N 12.47%; Found: C 53.29%, H 4.05%, N 12.28%.

d) 3,6-Dimethoxy-2-hydrazino-quinoxaline

A mixture of 5.0 g (0.022 mol) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g (0.056 mol, 2.7 ml) of hydrazine hydrate in 75 ml of ethanol is kept at 50 ° C overnight. A further 1 ml of hydrazine hydrate was then added and the resulting mixture heated at 50 'C for 6 hours. Then 1.0 ml of hydrazine hydrate was added again and the mixture was kept at 50 ° C overnight and then cooled to room temperature. The resulting precipitate was filtered off and washed with ethanol to give 4.1 g (85%) of pure 3,6-dimethoxy-2-hydrazinoquinoxaline, m.p. 128-130 ° C.

e) 4,7-Dimethoxy- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 1.5 g (0.068 mol) of 3,6-dimethoxy-2-hydrazinoquinoxaline and 20 ml of triethyl orthoformate was heated in a heated oil bath at 100 ° C overnight (about 16 hours) with mechanical stirring. The resulting mixture was then cooled to room temperature, and the resulting precipitate was filtered off and washed with ethanol. This gives 1.8 g of pure 4,7-dimethoxy- [1,2,4] triazolo [4,3-a] quinoxaline, melting at 238-240 'Con.

MS; m / e 230 (P); m / e 231 (P + 1); m / e 232 (P + 2).

4-Hydroxy-7-methoxy- [1,2,4] triazolof 4,3-a] quinoxaline

A mixture of 1.6 g (0.0069 mol) of 4,7-dimethoxy- [1,2,4] triazolo ²⁰ [4,3-a] quinoxaline, 16 ml of IN hydrochloric acid and 48 ml of glacial acetic acid is refluxed for 3 hours. After completion of boiling, the reaction mixture was poured onto ice and filtered. The product collected on the filter was washed with diethyl ether to give 1.19 g (80%) of pure 4-hydroxy-7-methoxybenzo [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 250'C.

g)

4-Chloro-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline 30

In a flame-dried flask under a dry nitrogen atmosphere, 1.1 g (0.0055 mol) of 4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline and 15 ml of phosphorus oxychloride were added. 0 ml tri (n-propyl) 35 amine was added. The reaction mixture was refluxed overnight for about 16 hours, then cooled to room temperature and poured slowly into ice / water. The resulting aqueous mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed with water and brine (40 mL) and dried over anhydrous magnesium sulfate. After removal of the desiccant, the solvent was evaporated in vacuo and the resulting residue was chromatographed on a silica gel column (150 mL) using chloroform 45: methanol (95: 5) as eluent. The same fractions containing product were combined and evaporated in vacuo to give a residue which was recrystallized from chloroform / diethyl ether to give 400 mg (31%) of pure 4-chloro-7-methoxy [1,2,4] triazolo [4,3-a]. quinoxaline is obtained, which melts at 266268 ° C.

Mass Spectrum: m / e 234 (P); m / e 236 (P + 2).

Example F.

4-Chloro-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

a) 1-Ethyl-4,7-dimethoxy-1 1,2,4] triazolo [4,3-a] quinoxa60 ^lin

A mixture of 4.0 g (0.018 mol) of 3,6-dimethoxy-2-hydrazinoquinoxaline prepared in Example Ed and 50 ml of triethyl orthopropionate was heated under mechanical stirring in ₆₅ preheated oil baths to 100 ° C.

-7187 544 nights (about 16 hours). The resulting reaction mixture was then cooled to room temperature (about 20 ° C) and the precipitate was filtered off with suction and washed with ethanol to give 3.3 g (72%).

4,7-Dimethoxy-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 184-188'C.

Mass Spectrum: m / e 258 (P); m / e 228 (P-30).

b) 1-Ethyl-4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3a] quinoxaline

A mixture of 3.3 g (0.013 mol) of 4,7-dimethoxy-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, 33 ml of 1N hydrochloric acid and 9 ml of glacial acetic acid was refluxed for 2 hours. After boiling, the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was stirred for 20 minutes and then extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure to give a yellow solid which was washed with water and air dried to constant weight. 1.87 g (67%) of pure 1-ethyl-4-hydroxy-7-methoxy [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

> 250 'C.

<7

4-Chloro-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

In a flame-dried flask under a dry nitrogen atmosphere, 1.87 g (0.0076 mol) of 1-ethyl-4-hydroxy-7-methoxy [1,2,4] triazolo [4,3-a] quinoxaline and 25 ml of phosphorus were added. oxychloride and 1.8 ml of tri (npropyl) amine. The reaction mixture was refluxed overnight for about 16 hours, then cooled to room temperature and slowly poured into ice water. The resulting aqueous mixture was stirred at room temperature for 30 minutes, then filtered and the resulting solid was washed with cold water and dissolved in chloroform. The organic solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure and the yellow solid residue was triturated with diethyl ether to give 1.6 g (80%) of pure 4-chloro-ethyl-7-methoxy [1,2,4] triazolo [4 3-a] quinoxaline, m.p. 173-175'C.

Mass Spectrum: m / e 262 (O); m / e 264 (P + 2); m / e 261 (P-1).

Example G

4-Chloro-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline a) 2,3-Dihydroxy-6-fluoroquinoxaline

A mixture of 26.3 g (0.19 mol) of 4-fluoro-1,2-phenylene diamine (Journal of the American Chemical Society, Vol. 75, 1294 (1953)) and 150 ml of diethyl oxalate is heated to reflux under nitrogen. hours. After refluxing, the reaction mixture was cooled to room temperature (about 20 ° C), filtered, and the product isolated four times,

Wash with 100-100 mL ethanol and air dry to constant weight. This gave 19.3 g (80%) of pure product

2,3-dihydroxy-6-fluoro-quinoxaline is obtained, m.p.> 300 'C (literature melting point: 387-390' C according to U.S. Patent 3,992,378).

Mass Spectrum: m / e 180 (P +).

b) A mixture of 2,3-dichloro-6-fluoroquinoxaline g (0.105 mol) of 2,3-dihydroxy-6-fluoroquinoxaline and 50 ml of phosphorus oxychloride was refluxed overnight (about 16 hours) and then to room temperature. cool and pour over 200 g of ice with vigorous stirring. The resulting aqueous mixture was filtered and the resulting product was washed several times with water to yield

28.2 g of 2,3-dichloro-6-fluoroquinoxaline are obtained, m.p. 148-152'C.

c) 2-Chloro-6-fluoro-3-hydrazino-quinoxaline

To a suspension of 28.2 g (0.105 mol) of 2,3-dichloro-6-fluoroquinoxaline in 500 ml of ethanol is added 15 ml (0.31 mol) of hydrazine hydrate over 2 minutes to give a dark red suspension. This mixture was stirred at room temperature under nitrogen for 20 hours. The precipitate was filtered off, washed several times with ethanol and air-dried to constant weight. 20.7 g (93%) of pure 2-chloro-6-fluoro-3-hydrazinoquinoxaline are obtained, m.p. 190-192 ° C with decomposition.

d) 4-Chloro-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline g (0.047 mol) 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml (0.47 mol) The mixture of triethyl orthoformate was heated under nitrogen atmosphere in a preheated oil bath at 100 ° C overnight with mechanical stirring (about 16 hours). The resulting mixture was cooled to room temperature, and the resulting precipitate was filtered off with suction, washed 3 times with 50 ml each of ethanol and air dried to constant weight. This gives 9.42 g (91%) of pure 4-chloro-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 3 DEG-312 DEG C. with decomposition. Mass Spectrum: m / e 224, 223, 222 (P +).

Example H.

4-Chloro-1-ethyl-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 10.0 g (0.047 mole) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline from Example Gc and 95 ml (0.47 mole) of triethyl orthopropionate was stirred under nitrogen in a preheated oil bath. Keep at 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature (about 20 ° C) and the precipitate formed was suction filtered, washed 3 times with 50 ml of ethanol and air dried to constant weight. There was thus obtained 7.5 g (65%) of tis-8187 544 ta 4-chloro-1-ethyl-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 160-163 ° C. -ori, melts during decomposition.

Mass Spectrum: m / e 249, 250, 251, 252 (P +).

Example I

4-Chloro-8-fluoro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline

8-Fluoro-4-hydroxy-1- (trifluoromethyl) - [1,2,4] triazolof 4,3-a] quinoxaline

12.8 g (0.06 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 50 ml (0.65 mol) of trifluoroacetic acid were heated at 120 ° C under a dry nitrogen atmosphere for 24 hours while stirring mechanically. a homogeneous solution is formed. The resulting mixture was then poured into ice water with stirring, stirred for an additional 30 minutes and filtered. The product was washed three times with water and dried in vacuo at 80 ° C. Yield: 12.58 g (77%) of pure 8-fluoro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 298-302 ° C. melted. Mass Spectrum: m / e 272 (P +).

b)

4-Chloro-8-fluoro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline

In a flame-dried 250 mL three-necked flask under a dry nitrogen atmosphere, 12.5 g (0.046 mol) of 8-fluoro-4-hydroxy-1- (trifluoromethyl) [1,2,4] triazolo [4,3- a) Quinoxaline and 85 ml of phosphorus oxychloride and 17.5 ml of tri (n-propyl) amine are added. The reaction mixture is refluxed overnight (about 16 hours), then cooled to room temperature (about 20 ° C) and then poured slowly into 1000 ml of ice-water with mechanical stirring. The resulting aqueous mixture was then stirred for an additional 30 minutes at room temperature and then extracted 3 times with 300 ml of chloroform. The combined chloroform phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was evaporated in vacuo to give 10.47 g (79%) of pure 4-chloro-8-fluoro-1- (trifluoromethyl) - [1,2,4] triazolo [4] as a yellow solid. 3ajquinoxaline, m.p. 135-138 ° C. Mass Spectrum: m / e 292/290 (P +).

Example J.

4-Chloro-7,8-difluoro- [1,2,4] triazolo [4,3-a] quinoxaline a) 2,3-Dihydroxy-6,7-difluoroquinoxaline

A mixture of 4,5-difluoro-1,2-phenylenediamine (US 4,264,600) (11.3 g, 0.0784 mol) and diethyl oxalate (80 ml, 0.589 mol) was heated to reflux for 4 hours and product precipitates as a thick precipitate. The mixture was cooled to room temperature (about 20 'C) overnight and then filtered, the resulting solid was washed several times with diethyl ether and air-dried to constant weight. 15.5 g pure

2,3-dihydroxy-6,7-difluoro-quinoxaline is obtained, m.p.> 310'C. Mass Spectrum: m / e 198 (P +).

b) 2,3-Dichloro-6,7-difluoroquinoxulin

A mixture of 15.4 g (0.078 mol) of 2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g (0.187 mol) of phosphorus pentachloride and 20 ml (0.22 mol) of phosphorus oxychloride was refluxed for 4 hours while additional phosphorus oxychloride (20 ml) was added to facilitate stirring (the reaction mixture became homogeneous within 30 minutes). After completion of reflux, the reaction mixture was stirred overnight (16 hours) at room temperature to give a light yellow precipitate. The mixture was poured into 200 g of ice water and stirred with further cooling to give 20.9 g of a tan solid, 2,3-dichloro-6,7-difluoroquinoxaline, m.p. 162-164 ° C with decomposition. . Mass Spectrum: m / e 238/236/234 (P +).

c) 2-Chloro-6,7-difluoro-3-hydrazino-quinoxaline

A mixture of 10.0 g (0.426 mol) of 2,3-dichloro-6,7-difluoroquinoxaline and 5 ml (0.03 mol) of hydrazine hydrate in 200 ml of ethanol is stirred at room temperature for 24 hours while a rust-red precipitate forms. The dense slurry was filtered and the separated precipitate was washed twice with 20-20 mL of ethanol and air-dried to constant weight to give 5.99 (67%) of pure 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline. mp 212-215 ° C with decomposition. Mass Spectrum: m / 2 230 (P); m / e 232 (P +).

d)

4-Chloro-7,8-difluoro- [1,2,4] triazolo [4,3-a] quinoxaline

2.99 g (0.026 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml (0.18 mol) of triethyl orthoformate were heated at 100 ° C for 24 hours to give a tan solid. formed. The resulting slurry was cooled to room temperature, filtered and the isolated product washed with diethyl ether to give

5.15 g (82%) of pure 4-chloro-7,8-difluoro- [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 210 DEG C. with decomposition.

Mass spectrum: m / e 242/240 (P +).

Example K.

4-Chloro-6,7-difluoro-1-ethyl- [1,2,4] tria: ol [4,3a] quinoxaline

A mixture of 7.0 g (0.03 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline prepared in Example Jc and 60 ml (0.30 mol) of triethyl orthopropionate was added under a sodium atmosphere in a preheated oil bath. The mixture is heated at 100 ° C for one hour with mechanical stirring. The resulting mixture was cooled to room temperature (about 20 ° C) and the resulting reddish precipitate was suction filtered, washed twice with diethyl ether and air-dried to constant weight.

187,544 after all. 4.15 g (52%) of pure 4-chloro-6,7-difluoro-1-ethyl [1,2,4 '] triazolo [4,3-a] quinoxaline are obtained, m.p. 185-186 ° C, with decomposition.

Example L

4,8-Dichloro-1-methyl- [1,2,4] triazolof 4,3-a] quinoxaline a) 2,6-Dichloro-3-hydrazinoquinoxaline g (0.10 mol) 2,3,6- A mixture of trichloroquinoxaline and 11 g (0.22 mol) of hydrazine hydrate in 500 ml of ethanol was stirred at room temperature (about 20 ° C) overnight (about 16 hours). The resulting precipitate was collected by filtration, washed with ethanol to give 22.2 g (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p.> 250 ° C. Mass Spectrum: m / e 228 (P).

b)

4.8-Dichloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 20.0 g (0.087 mole) of 2,6-dichloro-3-hydrazinoquinoxaline and 160 ml (0.87 mole) of triethyl orthoacetate was maintained under mechanical stirring in a dry nitrogen atmosphere in a preheated oil bath for 20 hours. while a yellow slurry is formed. The resulting mixture was cooled to room temperature and filtered, and the resulting solid was washed with ethanol and air-dried to constant weight. This gave 10.2 g (46%) of pure 4,8-dichloro-1-methyl- [1,2,4] triazolo [3,4-a] quinoxaline, m.p.> 280 DEG C. Mass spectrum: m / e 254/252 (P +).

Example M.

4.8- Dichloro-1- (trifluoromethyl) - (1,2,4] triazolo [4,3] quinoxaline a)

8-Chloro-4-hydroxy-1- (trifluoromethyl) - [1,2,4] triazolof 4,3-a-quinoxaline

To a flame-dried 500 ml three-necked flask equipped with a mechanical stirrer, a nitrogen inlet tube and a reflux condenser was placed 67 ml (0.87 mol) of trifluoroacetic acid. Under stirring, 20 g (0.087 mol) of 2,6-dichloro-3-hydrazinoquinoxaline prepared according to Example L.a) are added. The resulting mixture was heated on a steam bath for 24 hours, then cooled to room temperature (about 20 ° C) and poured into 200 g of ice-water. The resulting aqueous mixture was stirred for 30 minutes and then filtered, the product isolated was washed several times with water and air-dried to constant weight (about 18 hours). 14.3 g (57%) of pure 8-chloro-4-hydroxy-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. Melting point C decomposes. Mass Spectrum: m / e 290/288 (P +).

b)

4.8- Dichloro-1- (trifluoromethyl) - [1,2,4] triazolof 4,3-i Jkinoxalin ⁵ In a flame-dried, 250 ml, three-necked flask, fitted with a mechanical stirrer, a dropping funnel and a reflux condenser, 14.3 g (0.05 mol) of 8-chloro-4-hydroxy-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline in nitrogen stream and ¹⁰ ml of phosphorus oxy chloride. To the resulting suspension was added dropwise 19 ml (0.10 mol) of tri (npropyl) amine over 5 minutes. The reaction mixture is then refluxed for 20 hours to give a dark wine red solution. After the reflux period was complete, the clear solution was poured into ¹⁵ thus obtained 1000 ml of ice water with vigorous stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and then extracted 3 times with 500 ml of chloroform (500 ml). The organic extracts were combined, washed with water ^20, solely with a saturated aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. Finally, 11.4 g (75%) of ²⁵ pure 4,8-dichloro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline are obtained in the form of a yellow solid, m.p. 133-135'C. Mass Spectrum: m / e 308 (P + 2); m / e 310 (P + 4).

Example N.

4.8-Dichloro-1-phenyl- (1,2,4] triazolo [4,3-a] quinoxaline

Into a 250 mL three-necked flask equipped with a mechanical stirrer and reflux condenser was placed 50.0 g (0.274 mol) of trimethyl orthobenzoate, previously heated to about 70 ° C. Stirring was started and 10.0 g (0.0437 mol) of 2,6-dichloro-3-hydrazinoquinoxaline prepared according to Example La) was added. The resulting reaction mixture was heated to about 120 ° C and stirred at this temperature for 24 hours. It is then cooled to room temperature (about 20 ° C) and stirred overnight for about 16 hours ₄₅ to form a yellow slurry. The suspension was filtered, and the resulting solid was washed 2 times with 50 ml of ethanol, air dried to constant weight to give 9.8 g (72%) of crude 4,8-dichloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 305-307 ° C.

Mass Spectrum: m / e 316/314 (P +).

Example 1

2-Chloro-3-hydrazino-quinoxalin

33.5 g (0.168 mol) of 2,3-dichloroquinoxaline were stirred with 18.5 g (0.369 mol) of hydrazine hydrate in 500 ml of ethanol at room temperature (about 20 ° C) for ⁶⁰ hours (about 16 hours). The thick yellow slurry was filtered and the precipitate was washed with ethanol. The precipitate was recrystallized from hot methanol to give 13.5 g (41%) of 2-chloro-3-hydrazinoquinoxaline, m.p. 181 DEG C. (decomposition). Mass Spectrum: m / e 194 (P).

-101. 187,544

Example 2

4-Chloro- [1,2,4] triazolof 4,3-ayloxaline

2-Chloro-3-hydrazinoquinoxaline (9.0 g, 0.046 mol) prepared in Example 1 was stirred with 90 ml triethyl orthoformate at 100 ° C for 1 hour. The mixture was cooled to room temperature and the solid precipitate was collected and washed with cyclohexane and dried. Yield: 8.8 g (94%) of 4-chloro [1,2,4] triazolo [4,3] quinoxaline, m.p. 287-290 ° C.

MS; m / e 204 (P).

Example 3

4-Chloro-1-methyl-1,2,4] triazolof 4,3-a] quinoxaline

15.5 g (0.080 mol) of 2-chloro-3-hydrazinoquinoxaline prepared in Example 1 are stirred with triethyl orthoacetate at 100 ° C for 3 hours. The mixture was cooled to room temperature, the solid precipitate was filtered off, washed with ethanol and air dried. This gives 11.4 g (65%) of 4-chloro-1-methyl- [1,2,4] triazolo [4,3a] quinoxaline, m.p. 215-222 ° C. MS: m / e 218 (P).

Example 4

4-Chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

4.5 g (0.023 mol) of 2-chloro-3-hydrazinoquinoxaline prepared in Example 1 are stirred with 50 ml of triethyl orthopropionate at 100 ° C for 1 hour. The mixture was cooled to room temperature and the white precipitate was collected by filtration and washed with cyclohexane. 4.5 g (85%) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 158-160'C. Mass Spectrum: m / e 232 (P).

Example 5

4-Chloro-1- (n-propyl) - [1,2,4] triazolof 4,3-a] quinoxaline

3.0 g (0.015 mol) of 2-chloro-3-hydrazinoquinoxaline from Example 1 are stirred with 27 ml of triethyl orthobutyrate at 100 ° C for 2 hours. After cooling to room temperature, the precipitate was filtered off and washed with cyclohexane. The crude solid was taken up in chloroform and the insoluble material was removed by filtration. The chloroform solution was concentrated in vacuo to give a solid which was recrystallized from chloroform. 1.96 g (53%) of 4-chloro-1- (n-propyl) - [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 173-175 ° C. Mass Spectrum: m / e 246 (P).

Example 6

4-Chloro-1-isopropyl- [1,2,4] triazolof 4,3-a] quinoxaline

4.0 g (0.02 mol) of the 2-chloro-3-hydrazinoquinoxaline obtained in Example 1 are stirred with triethyl ortho-isobutyrate at 100 ° C for 3 hours. The solution was cooled to room temperature, and the precipitate was filtered off and washed with ethanol. The crude solid was recrystallized from 300 ml of hot ethanol to give 2.06 g (40%) of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 208-210 ° C. . MS:

⁵ m / e 246 (P).

Example 7

4- (Methylamino) -f-1,2,4-triazolof-4,3-a Jinoxaline

2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline from Example 2 are saturated with 30 ml of N, N-dimethylformamide with monomethylamine gas and the mixture was stirred at room temperature for 3 hours. Monomethylamine was then re-introduced into the solution and stirred at room temperature for an additional 2 hours. The precipitate was collected by filtration and washed with Ν, Ν-dimethylformamide. Recrystallization from Ν, Ν-dimethylformamide gave 1.37 g (69%) of 4- (methylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p.> 300'C. MS: m / e 199 (P).

Anal. Calcd for C ₁₀ H ₉ N ₅ : C, 60.29; H, 4.55; N, 35.15; Found: C, 59.99; H, 4.47; N, 35.11.

Example 8

4- (Dimethylamino) - [1,2,4] triazolof 4,3-a] quinoxaline

A suspension of 2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 2 in 30 ml of Ν-dimethylformamide was saturated with dimethylamine gas. and stirred at room temperature overnight. The mixture was poured onto ice, and the precipitate was filtered off and recrystallized from ethanol to give 640 mg (44%) of 4- (dimethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 184-186. 'C.

MS: m / e 213 (P).

Analysis results for ChHjjNj formula:

Found: C, 61.96; H, 5.20; N, 32.84; Found: C, 62.26; H, 5.43; N, 32.92.

Example 9

4- (Ethylamino) -f 1,2,4-triazolof 4,3-a Jinoxaline

A suspension of 2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 2 in 30 ml of N, N50 dimethylformamide was treated with monoethylamine gas. saturated and stirred at room temperature for 2 hours. Monoethylamine was then bubbled through the mixture again and stirring continued for a further 2 hours. The precipitate was filtered and washed with ₅₅ Ν, Ν-dimethylformamide. Recrystallization from methanol gave 680 mg (32%) of 4- (ethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 254-256 ° C. MS: m / e 213 (P).

Analysis calculated for C ^ 61HΗΗNítottO C: C, 61.96; H, 5.20; N, 32.84; Found: C, 61.93; H, 5.09; N, 32.72.

II

-11187,544

GOOD. example

4- (Diethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline

4.4 g (0.21 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 2 in 100 ml of N, N-dimethylformamide are 6.5 ml (0.063 mol). with diethylamine at room temperature for 2 hours. The reaction mixture was poured into ice water to solidify the crude product, which was filtered and washed with water. Recrystallization from isopropanol gave 3.36 g (66%) of 4- (diethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 117-119 'C. Mass Spectrum: m / e 241 (P).

Jl. example

4- [Di (n-propyl) -amino] - [1,2,4] triazolo [4,3a] quinoxaline

2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 2 and 3.0 g (0.03 mol) of di (n- propyl) amine in 50 ml of N, N-dimethylformamide at room temperature for 3 hours. The solution is poured onto ice to precipitate the product in solid form. The precipitate was filtered and air-dried, recrystallized from 250 ml of cyclohexane to give 1.1 g (41%) of 4- [di (n-propyl) amino] [1,2,4] triazolo [4,3-a] quinoxaline. mp: 240-242 ° C. Mass Spectrum: m / e 269 (P).

Analysis for C ₁₅ H ₁₉ N ₅ O Calculated: C 66.89%, H 7.11%, N 26.00%; Found: C, 66.68; H, 6.97; N, 26.12.

Example 12

4- (Isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline

2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 2 and 1.77 g (0.03 mol) of isopropylamine were obtained. ml of N, N-dimethylformamide was stirred at room temperature overnight. The dark solution was poured onto ice and the precipitate was collected by filtration and washed with water. The crude product was recrystallized from ethanol then twice from isopropyl ether to give 1.2 g (53%) of 4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. C. Mass Spectrum: m / e 222 (P).

Analysis results for C, jH _u Nj · 1/3 H ₂ O:

Calculated: C 61.79%, H 5.90%, N 30.02%; Found: C, 61.51; H, 5.89; N, 29.90.

Example 13

4- (Dimethylamino) -1-methyl- [1,2,4] triazolo [4,3a] quinoxaline

This compound is all. Example 4 was prepared using 4-chloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline as the product of Example 3 starting from the 4-chloro [1,2, 4] triazolo [4,3-a] quinoxaline, and diethylamine instead of di (n-propyl) amine. The crude product was recrystallized from chloroform followed by cyclohexane to give 7.2 g (54%) of pure 4- (dimethylamino) -1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 123 -125'C.

Example 14

4-Amino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

1.2 g (0.005 mol) of a solution of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 4 in 20 ml of Ν, Ν-dimethylformamide bubbling ammonia gas through. The solution was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. The reaction mixture was poured onto ice and stirred for 20 minutes. The precipitate was collected by filtration, washed with water and air dried. Recrystallization from ethanol gave 220 mg (22%) of pure 4-amino-1-ethyl-1,2,4] triazolo [4,3-a] quinoxaline. Melting point: 271-273 ° C. Mass Spectrum: m / e 227 (P).

Analysis for C ₁₂ H _i3 Nj · 1.8 H ₂ O Calcd:

Calculated: C, 62.80; H, 5.82; N, 30.51; Found: C, 62.72; H, 5.86; N, 30.62.

Example 16

4- (Dimethylamino) -1-ethyl- [1,2,4] triazolo [4,330] quinoxaline

A solution of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (1.2 g, 0.005 mol) in N, N-dimethylformamide (50 ml) was prepared as described in Example 4. 676 mg of 35 (0.015 mol) in anhydrous dimethylamine were stirred at 0 ° C for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured onto ice and stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water and air dried. Recrystallization from chloroform 40 followed by a mixture of chloroform and cyclohexane yielded 510 mg (42%) of 4- (dimethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 155-158. 'C. MS:

m / e 241 (P).

Analysis CijHi ₅ N ₅ O Calculated: C 64.71%, H 6.27%, N 29.02%; Found: C, 64.69; H, 6.27; N, 29.32.

Example 17 1-Ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline

1.2 g (0.005 mole) of 55 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 4 were treated with

In a solution of Ν, Ν-dimethylformamide, monoethylamine was bubbled through at 0 ° C for two minutes. The clear solution was stirred at 0 ° C for 30 minutes at room temperature for 2 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, washed with water and air dried. Recrystallization from ethanol gave 1.0 g (83%) of pure 1-ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline as a white solid; melting point ₆ g: 235-238 ° C. Mass Spectrum: m / e 241 (P)

-12187 544

Analysis for C _u H _s N i O Calculated: C 64.71%, H 6.27%, 'N 29.02%; Found: C, 64.57; H, 6.20; N, 29.15.

Example 18

4- (Diethylamino) -1-ethyl- [1,2,4] triazolo [4,3a] quinoxaline

This compound is all. Prepared according to Example 4 instead of the 4-chloro [1,2,4] triazolo [4,3-a] quinoxaline obtained in Example 2 instead of the 4-chloro-1-ethyl- [1,2 4] triazolo [4,3-a] quinoxaline and diethylamine in place of di (n-propyl) amine. The crude product was recrystallized from cyclohexane to give pure 4- (diethylamino) -1-ethyl-1,2,4] triazolo [4,3-a] quinoxaline (3.54 g, 69%) as a white solid, m.p. 98-100 ° C. Mass Spectrum: m / e 269 (P).

Example 19

4- (Isopropylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

To a solution of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline from Example 4 (2.3 g, 0.01 mol) in 30 ml of Ν, Ν-dimethylformamide Isopropylamine (1.77 g, 0.03 mol) was added. Within 30 minutes a precipitate formed. The reaction mixture was then stirred at room temperature overnight. The precipitate was collected by filtration and washed with Ν, Ν-dimethylformamide. Recrystallization from ethanol gave 1.6 g (63%) of 4- (isopropylamino) -1-ethyl [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 222-224'C. MS: m / e 255 (P).

Analysis for C ₄ H ₁₇ N ₅ O Calculated: C 65.86%, H 6.71%, N 27.43%; Found: C 65.32%, H 6.76%, N 27.25%.

Example 20

4- (Ethylamino) -1-isopropyl- [1,2,4] triazolo [4,3a] quinoxaline

A suspension of 1.0 g (0.004 mol) of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline, prepared in Example 6, in 15 ml of Ν, Ν-dimethylformamide saturated with monoethylamine gas and stirred at room temperature for 4 hours. The precipitate was collected by filtration and washed with Ν, Ν-dimethylformamide to give 220 mg (22%) of 4- (ethylamino) -isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. mp 209-211 ° C. MS: m / e 255 (P).

The filtrate was then poured onto ice and the precipitate was filtered, washed with water and recrystallized from methanol then isopropanol to give additional 200 mg (20%) of pure 4- (ethylamino) -1-isopropyl- [1,2,4] triazolo [4 3-a] quinoxaline, m.p. 210-211 ° C.

Analysis for C ₄ H ₁₇ N ₅ O Calculated: C 65.86%, H 6.71%, N 27.43%; Found: C 65.53%, H 6.58%, N 27.29%.

Example 21

4- (Diethylamino) -1-isopropyl- [1,2,4] triazolol 4,3a] quinoxaline

1.0 g (0.004 mol) of Example 6 was prepared

A mixture of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline and 900 mg (0.012 mol) of diethylamine in 15 ml of Ν, Ν-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, washed with water and applied to a column containing 175 ml of silica gel and eluted with chloroform. The eluate was concentrated in vacuo to give 850 mg (75%) of pure 4- (diethylamino) -1-isopropyl- [1,2,4] triazolo [4,315a] quinoxaline as a white solid, m.p. 93-95 'C. Mass Spectrum: m / e 283 (P). 100 mg of the pure product are then distilled under vacuum (0.1 mm) at 140-150 ° C to give an analytical sample, m.p. 94-96 ° C.

Analysis for C ₁₆ H ₂ N ₅ O Calculated: C 67.82%, H 7.47%, N 24.71%; Found: C, 67.56; H, 7.20; N, 24.50.

Example 22

4- (Diethylamino) -1- (n-propyl) - [1,2,4] triazolol 4,3a] quinoxaline

1.23 g (0.005 mole) of 4-chloro-1- (n-propyl) - [1,2,4] triazolo [4,3-a] quinoxaline, prepared according to Example 5, was treated with Ν, Ν-dimethyl. formamide (1.1 g, 0.015 mol) was stirred at room temperature for 2 hours. The reaction mixture was then poured onto ice. The precipitate was collected by filtration, washed with water and air dried. Recrystallization twice from ethanol / water gave 1.1 g (78%) of pure 4- (diethylamino) -1- (n-propyl) - [1,2,4] triazolo [4,3-a] quinoxaline. . Mass Spectrum: m / e 283 (P). Melting point: 92-94 ° C.

Analytical results for C ₆ H ₂₁ N ₅ -1/8 H ₂ O:

Calculated: C 67.28%, H 7.50%, N 24.52%; Found: C, 67.38; H, 7.45; N, 24.73.

Example 23

8-Chloro-4- (diethylamino) -1-ethyl- [1,2,4] triazolol 4,3a] quinoxaline

the)

4,8-Dichloro-1-ethyl- [1,2,4] triazolol [4,3-a] quinoxaline

1.0 g (0.0044 mole) of 2,6-dichloro-3-hydrazinoquinoxaline prepared in Example La) is refluxed with 15 ml of triethylorthopropionate for 4 hours and then cooled to 55 room temperature. The precipitate was collected by filtration, washed with cyclohexane and air-dried to give 730 mg (62%) of 4,8-dichloro-1-ethyl] 1,2,4] triazolo [4,3-a] quinoxaline, m.p.> 250 'C. Mass Spectrum: m / e 266 (P), 268 ( ^{P + 2} )

-13187 544

b)

8-Ktor-4- (diethylamino) -1-ethyl- [1,2,4] triazolo [4,3a] quinoxaline

7.4 g (0.028 mol) of 4,8-dichloro-1-ethyl- [1,2-4] triazolo [4,3-a] quinoxaline and 6 g (0.082 mol) of diethylamine in 150 ml of Ν, Ν-dimethyl -formamide was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was poured onto ice. The precipitate thus formed is filtered off and taken up in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an off-white solid which was recrystallized from diethyl ether / petroleum ether to give 1.6 g of pure 8-chloro-4- (diethylamino) -1-. of ethyl [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 105-108 ° C with decomposition. Mass Spectrum: m / e 303 (P); m / e 305 (P + 2).

Analysis for C _{5 H) 8} C1N _5: Calcd: C 59.30%, H 5.97%, N, 23.05; Found: 58.92%, H 5.85%, N 22.81%.

Example 24

7,8-Dichloro-4- (diethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

a) 2,6,7-Trichloro-3-hydrazinoquinoxaline

4.40 g (0.016 mol) of 2,3,6,7-tetrachloroquinoxaline and 1.76 g (0.035 mol) of hydrazine hydrate in 60 ml of ethanol are stirred at room temperature overnight. The thick slurry was filtered and washed with ethanol to give 4.9 g of crude 2,6,7-trichloro-3-hydrazinoquinoxaline, m.p. <260 ° C. MS: m / e 262 (P); m / e 264 (P + 2).

b)

4.7.8- Trichloro-1-eyl- [1,2,4] triazolo [4,3-a] quinoxaline

2,6,7-Trichloro-3-hydrazinoquinoxaline (4.9 g, 0.018 mol) was treated with triethyl orthopropionate (50 ml) at 100 ° C for 2 hours. The resulting precipitate was collected by filtration at room temperature and washed with cyclohexane. Recrystallize twice from a mixture of chloroform and cyclohexane to give 2.9 g (54%) of pure

4.7.8-Trichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline is obtained in the form of a pink solid, m.p. 198-201 ° C.

Mass Spectrum: m / e 300 (P); m / e 302 (P + 2); m / e 304 (P + 4); m / e 306 (P + 6).

c)

7,8-Dichloro-4- (diethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

2.9 g (0.0096 mol) of 4,7,8-trichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline and 2.1 g (0.0388 mol) of diethylamine Stir in 50 ml of Ν, Ν-dimethylformamide at room temperature for 2 hours. The reaction mixture was poured onto ice and stirred for 15 minutes. The precipitate was filtered off, washed with water and air dried. Recrystallize three times from isopropanol to give

500 mg (16%) of pure 7,8-dichloro-4- (diethylamino) ethyl [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 147-149 ° C.

Mass Spectrum: m / e 337 (P); m / e 339 (P + 2). Analysis: Calculated for C ₁₅ H ₁₇ Cl ₂ N ₅ : C, 53.26; H, 5.07; N, 20.70; Found: C, 53.05; H, 5.13; N, 20.75.

^1U Example 25

4- (Dimethylamino) -1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

obtained in a) 2-Chloro-3-hydrazino-6-methoxy-quinoxalin ¹⁵ 4.2 g (0.018 mole) of Eb) Example

2,3-Dichloro-6-methoxy-quinoxaline and 2.7 ml of hydrazine hydrate in 100 ml of ethanol are refluxed for 4 hours and stirred overnight at room temperature. The precipitate was collected by filtration, washed with ethanol at ²⁰ to yield 3.9 g (97%) of 2-chloro-3-hydrazino-6-methoxy-quinoxaline, mp: <250'C. Mass Spectrum: m / e 224 (P); m / e 226 (P + 2).

b)

4-Chloro-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

2-Chloro-3-hydrazino-6-methoxy-quinoxaline (1.3 g, 0.0058 mol) and triethyl orthopropionate (25 ml) were kept at 100 ° C for 4 hours and stirred at room temperature for 60 hours. The precipitate was filtered off and washed with ethanol. Recrystallization from ethanol gave 530 mg (35%) of pure 4-chloro-1-ethyl-8-methoxy- ³⁵ [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 196-198 ° C (dec.). ).

MS: m / e 262 (P); m / e 264 (P + 2).

_C )

4- (Diethylamino) -1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

520 mg (0.002 mol) of 4-chloro-1-ethyl-8-methoxy- [1,2,4] 45 triazolo [4,3-a] quinoxaline and 673 mg (0.008 mol) of diethylamine in 10 ml of Ν, Ν-dimethyl -formamide mixture was stirred overnight at room temperature. The reaction mixture is poured onto ice and the precipitate is filtered off, washed with water and air dried. Recrystallization from a mixture of diethyl ether and petroleum ether afforded pure 4- (diethylamino) -1-ethyl-8-methoxy [1,2,4] triazolo [4,3-a] quinoxaline (140 mg, 23%), m.p. : 135-138'C. Mass Spectrum: m / e 299 (P).

Analysis for C _BC H ₂ O _and N ₂ O · H% kép55 establishing 'Calculated: C 63.71%, H 7.10%, N 23.22%; Found: C 63.63%, H 6.88%, N 23.27%.

-14187,544

Example 26

4- (Diethylamino) -1-phenyl-1,2,4 / triazolof 4,3a Jquinoxaline

a) 4-Chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline

2.2 g (0.011 mol) of 2-chloro-3-hydrazinoquinoxaline are mixed with 6 ml of triethyl orthobenzoate and kept at 100 ° C for 30 minutes. The orange mixture was cooled to room temperature and ethanol was added. The resulting precipitate was filtered to give 2.1 g of crude product which was purified by warm methanol treatment, filtered and air dried to give 1.58 g (51%) of pure 4-chloro-1-phenyl- [1,2,4] triazolo [ 4.3aquinoxaline is obtained in the form of an orange solid.

4- (Diethylamino)] -phenyl- [1,2,4] triazolo [4,3a] quinoxaline

4-Chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline (1.58 g, 0.00563 mol) was dissolved in N, N-dimethylformamide (15 mL) followed by diethyl ether (1.738 mL). as we add it. The mixture was stirred overnight at room temperature. The precipitate was collected by filtration, washed with Ν, Ν-dimethylformamide and recrystallized twice from hexane: ethanol (3: 1) to give pure 4- (diethylamino) -1-phenyl [1,2,4] triazolo [555 mg]. 4.3-a] quinoxaline is obtained in the form of white needles, m.p. 166-168 ° C.

Analysis for C ₁₉ H ₁₉ N _S O Calculated: C 71.60%, H 5.99%, N 22.06%; Found: C, 71.86; H, 5.86; N, 22.09.

Example 27

4- (Diethylamino) -1- (trifluoromethyl) -f 1,2,4] triazolof 4,3-a] quinoxaline a)

4-Hydroxy-1- (trifluoromethyl) - [1,2,4] triazolo [4,3a] quinoxaline

2-Chloro-3-hydrazinoquinoxaline (3.89 g, 0.02 mol), prepared in Example 1, was added to cold trifluoroacetic acid (22.8 g, 0.20 mol, 15.4 ml) in a flame-dried, in an ice-cold flask, under mechanical stirring, in a dry nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 3 hours and then poured onto ice. The product obtained is suctioned, washed with water and air-dried to constant weight. In this way 3.0 g (60%) pure

4-Hydroxy-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline is obtained, m.p.> 300 ° C. Mass Spectrum: m / e 254 (P).

b)

4-Chloro-1- (trifluoromethyl) - [1,2,4] triazolof 4,3-quinoxaline

In a flame-dried flask, under dry nitrogen, 3.0 g (0.0118 mole) of 4-hydroxy-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline was charged and 30 ml of phosphorus were added. oxychloride and triethylamine (2.38 g, 3.3 mL, 0.0236 mol) were added. The reaction mixture was heated to 100 ° C for about 16 hours (i.e., overnight). After heating, the mixture was cooled to room temperature, concentrated in vacuo, partitioned between ice, water and ethanol and extracted with ethyl acetate. The latter extract was then washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in hot chloroform and the solution filtered. The filtrate was allowed to stand overnight at room temperature and then filtered again. The final filtrate was concentrated in vacuo to give 1.4 g of 4-chloro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline as a tan solid.

c)

4- (Diethylamino) -1- (trifluoromethyl) - [1,2,4] triazolof 4,3-a] quinoxaline

700 mg (0.0025 mol) of 4-chloro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline prepared as described above and 560 mg (0.0075 mol). 0.8 mL) of diethylamine in 10 mL of Ν, Ν-dimethylformamide was stirred at room temperature overnight and then poured onto ice. The resulting mixture was filtered and the separated solid was washed with water and dissolved in saturated ethyl acetate. The latter organic solution was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was evaporated in vacuo to leave a light yellow solid which was recrystallized from diethyl ether to give pure 4- (diethylamino) -1- (trifluoromethyl) [1,2,4] triazolo [ 4.3-a] quinoxaline is obtained. The first precipitate was 260 mg (34%), m.p. 155-157 ° C, and the second precipitate 170 mg (22%), m.p. 153-156 ° C.

Analysis for C ₁₄ H ₁₄ F N _{3 S:} Calcd: C 54.37%, H 4.56%, N 22.64%; Found: C, 54.08; H, 4.47; N, 23.32.

Example 28

4- (Isopropylamino) -1- (trifluoromethyl) - [1,2,4] triazolof 4,3-a] quinoxaline

700 mg (0.0025 mol) of 4-chloro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 27b) and 443 mg (0 (0075 mol) of isopropylamine was stirred with 10 ml of Ν, Ν-dimethylformamide at room temperature overnight and then poured onto ice. After filtration, the separated solid was washed with water and dissolved in diethyl ether. The ethereal solution was then washed with brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to give a white solid which was recrystallized once from diethyl ether to give pure 4- (isopropylamino) -1-trifluoromethyl-550 mg (74%). 2,4] triazolo [4,3] quinoxaline, m.p. 185-187 ° C.

-15187 544

Analysis Found C ₃ H ₁₂ F ₃ N i: C 52.88%, H 4.10%, N 23.72%; Found: C, 52.73; H, 4.00; N, 23.67.

Example 29 1-Ethyl-4- (N-ethylacetylamino) - [1,2,4] triazolo [4,3a] quinoxaline

241 mg (0.001 mol) of 1-ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, prepared according to Example 17, and 2.5 g of A mixture of acetic anhydride (0.025 mol, 2.5 ml) was heated in a flame-dried flask at 140 ° C under a stream of dry nitrogen for 3 hours, then allowed to cool to room temperature, whereupon a precipitate formed. The reaction mixture was poured into water and extracted with chloroform. The chloroform extracts were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the solid product was recrystallized once from chloroform / diethyl ether to give 160 mg (57%) of 1-ethyl-4- (N-ethylacetylamino) -1,2,4] triazolo [4,3-a] quinoxaline, m.p. 185-187 ° C.

Analysis for C _1S H ₁₇ N ₅ O: Calc: C 63.59%, H 6.05%, N 24.72%; Found: C 63.17%, H 6.05%, N 24.39%.

Example 30

4- (Acetylamino) -1-ethyl- [1,2,4] triazolo [4,3a] quinoxaline

533 mg (0.0025 mol) of 4-amino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 14 and 1.0 g (1.0 ml) were obtained. A mixture of acetic anhydride (0.01 mol) in methylene chloride (20 ml) was refluxed overnight (about 16 hours) and then allowed to cool to room temperature. The resulting clear solution was concentrated in vacuo and the white solid was recrystallized from chloroform / diethyl ether to give pure 4-acetylamino-ethyl- [1,2,4] triazolo [4,3-d] (520 mg, 82%). a] quinoxaline, m.p. 193-195'C.

Analysis for C ₃ H _s N _I3 O: Calc: C 61.16%, H 5.13%, N 27.43%; Found: C, 60.90; H, 5.26; N, 27.66.

Example 31

4- (Diacetylamino) -1-ethyl-1,2,4] triazolo [4,3a] quinoxaline

5.5 g (0.0258 mole) of 4-amino-1-ethyl] 1,2,4] triazolo [4,3-a] quinoxaline prepared in Example 14 and 25 g (0.25 mole). (25 ml) of acetic anhydride in 60 ml of pyridine containing 100 mg of p-dimethylaminopyridine was stirred at room temperature overnight (about 18 hours). The resulting suspension was filtered to remove the insoluble material and the orange filtrate concentrated under high vacuum to give a dark gum. Addition of water precipitates pinkish-white crystals which are filtered off with suction, washed with copious amounts of water and dried in vacuo at 50 ° C. 2.9 g (38%) of 4- (diacetylamino) -1-ethyl [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 157-159 ° C. This product was recrystallized from ethyl acetate / ether ^{5 to} give an analytically pure sample, m.p. 158-160 ° C. The pure product was characterized by mass spectra and NMR data in addition to eum analysis. Mass Spectrum: m / e 297 (P).

^u Analysis for C ₁₅ H ₁₅ NjO ₂ O Calculated: C 60.59%, H 5.09%, N 23.56%; Found: C, 60.33; H, 5.09; N, 23.41.

¹⁵ Example 32

The following 4-amino [l, 2,4] triazolo [4,3-a] quinoxaline derivatives are prepared by the methods of the examples described above, starting each case available materials terribly Paper ^20:

7.8-dibromo-4- (diethylamino) - [1,2,4] triazolo [4,3] quinoxaline, m.p. 199-201 C;

8-chloro-4- (isopropylamino) - [1,2,4] triazolo [4,3a] quinoxaline, m.p. 177-181 'C;

4- (ethylamino) -1-trifluoromethyl-1,2,4] triazolo [4,3-a] quinoxaline, m.p. 223-225 ° C;

ethyl 4- (ethylamino) -8-methoxy- [1,2,4] triazolo [4,3a] quinoxaline, m.p. 234-237 ° C;

4- (diethylamino) -8-methoxy- [l, 2,4] triazolo [4,3- ³⁰ a] quinoxaline, m.p. 124-126'C;

8-chloro-1-ethyl-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 189-191 ° C;

4- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 160-162'C;

8-chloro-4- (N-piperazino) -] 1,2,4] triazolo [4,3-a] quinoxaline, m.p.

8-chloro-1-ethyl-4- (N-isopropyl-N-acetylamino)] 1,2,4] triazolo] 4,3-a] quinoxaline, m.p. 148-151 ° C;

4- (acetylamino) -8-chloro-1-ethyl] 1,2,4] triazolo [4,3-a] quinoxaline, m.p. 203-205 ° C;

8-chloro-1-ethyl-4- (N-isopropyl-N-acetylamino) [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 155-158'C;

7,8-dichloro-4- (N-isopropyl-N-acetylamino) [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 207-210'C;

4-amino-7,8-dichloro-1-ethyl] -1,2,4] triazolo [4,3a] quinoxaline, m.p.> 260'C;

4-amino-8-chloro-1-ethyl] 1,2,4] triazolo [4,3-a] quinoxaline, m.p. 248-253 'C;

4- (acetylamino) -7,8-dichloro-1-ethyl] 1,2,4] triazolo [4,3-a] quinoxaline, m.p. 230-232 ° C;

8-fluoro-4- (isopropylamino) - [1,2,4] triazolo [4,355a] quinoxaline, m.p. 215-217'C;

4- (ethylamino) -8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 239-242 'C;

1-ethyl-8-fluoro-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 209-212 ° C;

7,8-Difluoro-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 218-221 ° C;

ethyl 4- (ethylamino) -8-fluoro [1,2,4] triazolo [4,3a] quinoxaline, m.p. 231-233 'C;

7.8-Difluoro-4- (ethylamino) - [1,2,4] triazolo [4,3- ₆₅ ] quinoxaline, m.p. 208-211 ° C;

-16187 544

4- (diethylamino) -8-fluoro- [1,2,4] triazolo [4,3a] quinoxaline, m.p. 151-153'C;

4- (diethylamino) -1-ethyl-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 94-97 'C;

7-chloro-4- (dimethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate) (mesylate), m.p. 214-217'C;

7-chloro-4- (diethylamino) * 1-ethyl- [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p. 172-175 ° C;

7.8-dichloro-1-ethyl-4- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 252-255 ° C;

7.8-dichloro-4- (dimethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 168-171 ° C;

7.8-dichloro-4- (dimethylamino) -1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 216-219'C;

4- (acetylamino) -1-ethyl-8-fluoro [1,2,4] triazolo [4,3a] quinoxaline, m.p. 203-205'C;

4-amino-7-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 240-243 C);

7-chloro-1-ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p. 187-189 ° C;

7-Chloro-4- (diethylamino) - [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p.

205-207C;

4- (dimethylamino) -7,8-difluoro [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p.

220-23'C;

4- (acetylamino) -7-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 210-212 ° C;

8-chloro-1-ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p. 235-238 ° C;

4-amino-7-chloro- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 279-282'C;

4-amino-8-chloro-1-methyl- [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p.

213-215'C;

8-chloro-4- (isopropylamino) -1- (trifluoromethyl) [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 183-185'C;

8-chloro-4- (diethylamino) -1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 172-175 ° C;

4- (diacetylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 211-214 ° C;

4- (diacetylamino) -8-chloro [1,2,4] triazolo [4,3a] quinoxaline, m.p. 208-210'C;

8-chloro-4- (isopropylamino) -1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p.

206-208C;

4- (acetylamino) -1-methyl-8-chloro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 262-264'C;

8-chloro-1-ethyl-4- (trimethylacetylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 211-213 ° C;

7.8-Difluoro-1-ethyl-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 151-152 ° C;

4- (n-butyrylamino) -8-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 185-187'C;

8-chloro-4- (diethylamino) -1- (trifluoromethyl) [1.2.4] triazolo [4,3-a] quinoxaline hydrate, m.p. 135-136 ° C;

4-amino-8-chloro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p.

259-261 'C;

4- (ethylamino) -8-fluoro-1- (trifluoromethyl) [1.2.4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 180-183'C;

8-fluoro-4- (isopropylamino) -1- (trifluoromethyl) [1.2.4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 185-188'C;

4- (diethylamino) -7,8-difluoro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 109-111 ° C;

1-ethyl-4- (ethylamino) -7-fluoro [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate, m.p. 215-219 'C);

4-amino-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 262-262 C);

8-chloro-4- (isopropylamino) -1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 183-186 ° C;

8-chloro-4- (ethylamino) -1-phenyl 1- [1,2,4] triazolo [4,3] quinoxaline, m.p. 254-256 ° C;

7-Fluoro-4- (isopropylamino) - [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p.

214-216C;

1- (ethylamino) -7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 216-218'C);

- (diethylamino) -8-fluoro-1- (trifluoromethyl) [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 146-149'C;

7,8-dichloro-1-ethyl-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 197-198'C;

8-chloro-4- (diethylamino) -1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 194-195'C;

4- (acetylamino) -1-ethyl-7-fluoro [1,2,4] triazolo [4,3a] quinoxaline, m.p. 273-275 ° C;

4- (acetylamino) -8-chloro-1- (trifluoromethyl) [1.2.4] triazolo [4,3-a] quinoxaline, m.p.

215-216'C;

4-amino-8-chloro-1-phenyl- [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p. 273-275 ° C;

8-chloro-4- (ethylamino) -1- (trifluoromethyl) [1.2.4] triazolo [4,3-a] quinoxaline, m.p. 228-230 ° C;

ethyl 7-fluoro-4- (isopropylamino) - [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate), m.p. 178-181 ° C;

4-amino-8-fluoro-1- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] quinoxaline hydrate, m.p.

260-263'C;

8-chloro-1-ethyl-4R- (phenylisopropylamino) [1.2.4] triazolo [4,3-a] quinoxaline, m.p. 155-157 ° C;

4-amino-1-ethyl-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 285-289 'C;

4-amino-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3a] quinoxaline (methanesulfonate), m.p. 255-258 ° C;

4- (acetylamino) -8-fluoro-1- (trifluoromethyl) [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 217-219'C;

4- (acetylamino) -1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 202-205 ° C;

8-Chloro-1-ethyl-4S- (phenylisopropylamino) 17

-171

187,544 [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 156-157 ° C;

4- (acetylamino) -8-fluoro [1,2,4] triazolo [4,3] quinoxaline, m.p. 240-242 ° C;

4- (acetylamino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 269-272 'C;

4-amino-7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 246-248 ° C;

4-amino-8-fluoro [1,2,4] triazolo [4,3-a] quinoxaline (methanesulfonate, m.p. 176-178'C;

4-amino-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 290-292 'C;

8-chloro-4- (isopropylamino) -1- (pentafluoroethyl) [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 171-174'C.

Example 33

8-Chloro-1-ethyl-4- (propionylamino) - [1,2,4] triazolo [4,3-a] quinoxaline

1.25 g (0.005 mol) of 4-amino-8-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, prepared according to Example 32, m.p. 248-253. A mixture of C and 15 mL of propionic anhydride was refluxed overnight for about 16 hours and then cooled to room temperature (about 20 C). The resulting mixture was filtered and the precipitate was dissolved in chloroform. The organic solution was filtered and then washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give a residue which was chromatographed on a silica gel column (150 ml) using a 95: 5 mixture of chloroform and methanol as eluent. The same fractions containing the product were combined and concentrated in vacuo to give a crystalline material which was recrystallized from chloroform / ethyl ether to give pure 8-chloro-1-ethyl-4- (propionylamino) - [1,2, 540 mg (36%)]. 4] triazolo [4,3-a] quinoxaline, m.p. 212215C.

Analysis for C ₁₄ H _I4 C1NjO: Calcd: C 55.36%, H 4.64%, N 23.06%; Found: C, 54.91; H, 4.59; N, 22.76.

Claims (3)

Patent claims A process for the preparation of 4-amino [1,2,4] triazolo [4,3-a] quinoxaline derivatives of the general formula (I) X and X ¹ are hydrogen, fluoro, chloro, bromo or methoxy; R 1 is hydrogen, lower alkyl, lower perfluoroalkyl, or phenyl; R ₂ and R ₃ are hydrogen, lower alkyl, phenylalkyl having up to 3 carbon atoms or C 2 -C 5 alkanoyl, provided that at least one of R ₂ and R ₃ is different from hydrogen, when X and X ¹ are each hydrogen and R ^{1 is} hydrogen or methyl, or R ₂ and R ₃ together with the adjacent nitrogen form a piperazino group - and pharmaceutically acceptable acid addition salts thereof, characterized in that they have the appropriate general formula (IIA) and (IIB). reacting a compound of formula (X, X * and R 1) as defined above with an amine of formula HNR ₂ R ₃ wherein R ₂ and R ₃ are as defined above, except for the alkanoyl group, to give the corresponding 4-amino compound, and, if desired, a 4-amino compound thus obtained wherein at least one of R ₂ and R ₃ is hydrogen an appropriate alkane carboxylic acid anhydride and / or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt thereof. (Priority: October 17, 1983) 2. A process according to claim 1 for the preparation of 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivatives of the formula I and their pharmaceutically acceptable acid addition salts having the formula: X and X ¹ are hydrogen, chlorine or methoxy, Rj is hydrogen, lower alkyl or phenyl, R ₂ and R 1 are hydrogen, lower alkyl or acetyl, provided that at least one of R ₂ and R ₃ is different from hydrogen when X and X ¹ are each hydrogen and R ^{1 is} hydrogen or methyl, the substance used is a compound of the formula (IIA) or (IIB) and HNR ² R ¹ wherein X, X ¹ , R ¹ , R 2 and R 1 have the meanings given herein. (Priority: October 18, 1982). 3. A process according to claim 1 or 2, characterized in that the amination reaction is carried out in the presence of a molar excess of HNR ₂ R ₁ - R ₂ and R _{3 having} the meaning given in claim 1 or 2, under organic conditions. in a solvent. (Priority: 10, 1983). 17). The process according to claim 3, wherein the inert organic solvent used in the reaction is dimethylformamide. (Priority: October 18, 1982) The process of claim 3, wherein the amination reaction is carried out at a temperature of about 0 'C to about 60' C for a reaction time of 2 to 24 hours. (Priority: October 18, 1982) The process of claim 1, wherein the acylation of the 4-amino compound is carried out under substantially anhydrous conditions with at least an equimolar amount of the corresponding alkanoic anhydride. (Priority: October 18, 1982) The process according to claim 6, wherein the molar ratio of the acid anhydride to the starting 4-amino compound is 1: 1 to 25: 1. (Priority: October 18, 1982) The process according to claim 1, wherein the acylation of the 4-amino compound is at 20 ° C and -18187 544 The reaction is carried out at a temperature between 140 ° C and a reaction time of 2-24 hours. (Priority: October 18, 1982) 9. The process of claim 1, wherein the 4-amino compound is acylated in a neutral, inert, organic solvent. (Priority: October 18, 1982) The process according to claim 9, wherein the inert, inert organic solvent used under the reaction conditions is a halogenated hydrocarbon solvent. (Priority: October 18, 1982) 11. A process according to claim 1 for the preparation of 1-ethyl-4- (ethylamino) - [1,2,4] triazolo [4,3-a] quinoxalir, wherein the starting materials are suitably substituted. (Priority: October 18, 1982) 12. A process for the preparation of a pharmaceutical composition comprising one or more compounds of formula (I) as defined in claim 1, wherein X, X ', R' are. R ₂ and R ₃ are as defined in claim ⁵ the first meaning - or a pharmaceutically acceptable acid addition salt thereof to prepare a medicament making usual carriers and / or excipients into a pharmaceutical composition. (Priority: October 17, 1983) 13. The process of claims 12 and 2, wherein the active ingredient is one or more compounds of formula (I) prepared by the process of claim 2, wherein X, X ¹ , R ¹ , R ₂ and R ₃ - or 15 pharmaceutically acceptable salts thereof. (Priority: October 18, 1982) 3 page drawing