DD215545A5 - METHOD FOR PRODUCING A (1,2,4) TRIAZOLO (4,3-A) CHIN-OXALIN-4-AMINE DERIVATIVE - Google Patents

Abstract

A series of novel (1,2,4) triazolo (4,3-a) quinoxalin-4-amine derivatives wherein the amino group is optionally substituted by lower alkyl, phenylalkyl of up to 3 carbon atoms in the alkyl group or alkanoyl of 2 to 5 carbon atoms or alternatively the amine group completes a piperazino ring, the quinoxaline ring is optionally substituted by fluoro, chloro, bromo or methoxy and the triazole ring is optionally substituted by lower alkyl, lower perfluoroalkyl or phenyl is disclosed. These new compounds are useful for the treatment of depression-related symptoms. Also pharmaceutical compositions containing novel compounds of the invention are disclosed.

Description

A method for producing a / Ί, 2, 4_ / triazolo / 4, 3-a_ / Chin

oxaiin-4-amine derivative

Field of application of the invention

The invention relates to a process for preparing a series of novel Ί, 2,4 / triazolo / 4,3-a. / Quinoxaline-4-amine derivatives and their pharmaceutically acceptable acid addition salts useful as antidepressants and anti-fatigue agents are.

Characteristic of the known technical solutions

An intensive search for agents that are effective in reducing the symptoms of depression and fatigue in mammals.

US-PS 3,839,569 and DE-PS / 2,224,935O disclose the use of triazolo / 4,3-a. / Quinoxalines as fungicides in U.S. Pat

Agriculture. US Pat. No. 4,008,322 discloses the use of a series of triazolo / 4,3-a-7-quinoxaline derivatives to control rice blast caused by the phytopathogenic Piricularia oryzae.

Aim and presentation of the essence of the invention

The invention relates to a process for preparing novel / 1,2,4-triazolo / 4,3-aquinoxalin-4-amine derivatives which are useful as antidepressants and anti-fatigue agents

(I)

and the pharmaceutically acceptable acid addition salts thereof, wherein _v .

X and X 'are each selected from hydrogen, fluorine, and methoxy;

Chlorine, bromine

R is selected from hydrogen, lower alkyl, lower perfluoroalkyl and phenyl, and

R ₂ and Ro are each selected from hydrogen, lower alkyl, phenylalkyl having up to three carbon atoms in the alkyl radical and alkanoyl having from two to five carbon atoms, with the proviso that at least one of R ₉ and R 0 always has a meaning other than hydrogen,

1 when X and X are each hydrogen and R is hydrogen or methyl; or R and R, taken together, complete a tiperazine ring.

For the purposes of the present specification and claims, lower alkyl is taken to mean alkyl of 1 to 4 carbon atoms and lower perfluoroalkyl is perfluoroalkyl of 1 to 4 carbon atoms, such as trifluoromethyl and pentafluoroethyl, etc.

An interesting group of compounds is those in which X and X are each hydrogen, R _{1 is} hydrogen and R "and R _{3 are} each lower alkyl. Preferred compounds include those wherein R ₉ and R _{7 are} both ethyl.

Another group of compounds according to the invention are those wherein X and X are each hydrogen, R _{1 is} ethyl and R is lower alkyl. Preferred compounds are those wherein R _{9 is} hydrogen and R, is ethyl.

Yet another group of compounds according to the invention are those wherein X and X are each hydrogen, R. is lower alkyl and R _{3 is} acetyl. Preferred compounds include those wherein R _{1 is} ethyl and R _{2 is} hydrogen, ethyl or acetyl. '>

Another group of interesting compounds according to the invention are those wherein at least one of X and X is fluoro, R _{1 is} hydrogen or trifluoromethyl, R _{9 is} hydrogen and R _{3 is} hydrogen, lower alkyl or alkanoyl of two to five carbon atoms or alternatively wherein at least one X and X are chlorine, R is lower alkyl or trifluoromethyl, R _{2 is} hydrogen and R-, hydrogen, lower alkyl or alkanoyl having two to five carbon atoms.

Also included in the invention are pharmaceutical compositions comprising an antidepressant fatigue effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent.

hold. Preferred pharmaceutical compositions are those containing the preferred compound of formula Ij as described above

The invention also includes a method of treating depression and fatigue in a mammal in need of such treatment, wherein the mammal is administered an antidepressant / fatigue-counteracting amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. Preferred compounds for use in this method of treatment are the preferred compounds of Formula I, as described above. , '..., ·.

The majority of the new compounds of the formula I can be prepared according to the reaction sequence shown in Reaction Scheme I. The numbering of the phenyl ring and the two heterocyclic rings in Scheme I is that used throughout the description.

In Scheme I, a compound of Formula IV, a quinoxaline derivative wherein X and X are each hydrogen, fluoro, chloro, bromo or methoxy, with the proviso that X is always hydrogen when the ghinaoxaline derivative is monosubstituted in the benzene ring is treated with an excess molar amount of hydrazine hydrate in a polar, reaction inert organic solvent, such as an alkanol of 1 to 3 carbon atoms, preferably ethanol, at room temperature for about 18 to 24 hours to give an intermediate compound of formula III.

The intermediate compound of formula III can then be converted to the corresponding intermediate of formula HA, wherein R _{1 has} a meaning other than lower perfluoroalkyl, by treatment with a suitable alkyl orthoalkanoate or alkyl orthobenzoate, as the case may be, at a temperature between 80 and 120 ° C be converted for about 1 to 24 hours. In the antisense compound of formula HA R. (as hydrogen or alkyl) is replaced by the one used in the synthesis

Orthoalkanoate determined. For example, when triethylorthoformate is used, R is hydrogen when triethylorthopropionate is used, R _{1 is} ethyl, and when triethylorthoisobutyrate is used, R _{1 is} isopropyl. ₄

The intermediate compound of formula III can also be incorporated in the. corresponding intermediate of formula IIA, wherein R _{1 is} lower perfluoroalkyl, by conventional treatment with a molar excess of a suitable perfluoroalkanoic acid, such as trifluoroacetic acid or pentafluoropropionic acid, etc., depending on the situation, to give the corresponding 4-hydroxy-1 - to give perfluoroalkyl-1,2,27-triazolo / 4,3-a_ / quinoxaline, followed by treatment of the latter compound with phosphorus oxychloride in the presence of a tertiary amine such as triethylamine at elevated temperatures to afford the corresponding compound. To give chlorine compound.

Intermediate IIA (where R _{1 is} hydrogen, lower alkyl, lower perfluoroalkyl , or phenyl) is then converted into a [Λ , 2 , AJ- triazolo / 4,3-aynoxinoxalin-4-amine derivative of formula IA, wherein R ~ and R, are each as previously defined, except that they have a meaning other than alkanoyl, by treating with a molar excess amount of an amine of formula R ₃ in a reaction inert organic solvent, preferably N, N-dimethylformamide, at a temperature between about 0 ° and 60 C converted for about 2 to 24 hours. For example, the preferred compounds of formula IA wherein R ₂ and R are both ethyl are prepared by treating the appropriate compound of formula IIA with diethylamine in N, N-dimethylformamide at room temperature for 2-3 hours. Similarly, preferred compounds of formula IA wherein R _{2 is} hydrogen and R _{3 is} ethyl are prepared by treating a compound of formula IIA with monoethylamine in N, N-dimethylformamide at room temperature for 4-5 hours.

[Λ , 2,4_7-triazolo / 4,3-a / quinoxalin-4-amine derivatives of the formula IA,

wherein at least one of R2 and R-. Alkanoyl of two to five carbon atoms are prepared from the corresponding compounds of formula IA, wherein at least one; R ₂ and R 1 is hydrogen, by bringing the latter together with the appropriate alkanoic anhydride under substantially anhydrous conditions. This reaction may be carried out in the presence of an organic base, such as a tertiary amine, as a catalyst (although not absolutely necessary) at a temperature in the range of about 20 to about 140 C for about 0.5 to about 24 hours. The molar ratio of acid anhydride to 4-amino starting material should be at least about 1: 1, and preferably about 4: 1 to about 25: 1, while the amount of tertiary amine employed is normally about 25 to 150% by weight of the aforementioned acylating agent ( the tertiary amine can be used as the reaction solvent simply by using an excess). Although it is quite possible and in some cases even highly desirable to carry out the reaction in the absence of a solvent, there may be instances when the use of a suitable reaction-inert organic solvent is clearly indicated. Suitable organic solvents for use in this context include neutral, reaction-inert anhydrous organic solvents such as acetone, methyl ethyl ketone, benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride, chloroform, ethylene dichloride, tetrachloroethane, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, diethyl ether , Diisopropyl ether, di-n-propyl ether and the like. However, as stated previously, the reaction is usually carried out in the absence of such solvent simply by using an excess of acid anhydride. Likewise, an excess of the tertiary amine can serve as a solvent as a reagent. Preferred tertiary amines for use as solvents and / or as catalytic reagents in this reaction include triethylamine, dimethylaniline, pyridine, picoline, lutidine, collidine and quinoline. , -.

The starting materials of formula IV wherein X and X are each hydrogen are well known in the art. Compounds of formula IV in which X is methoxy can be prepared by the method of GWH Cheeseman (J., Soc., P. 1170 (1962)), wherein 4-methoxy-o-phenylenediamine hydrochloride is at least an equimolar amount Diethy] oxalate and diethylamine under an inert gas atmosphere, preferably nitrogen, treated at reflux for about 2 to 3 hours and then treated with phosphorus oxychloride in a tertiary amine, preferably dimethylaniline, at reflux temperatures for 1 to 2 h.

In Reaction Scheme II, a quinoxaline derivative of the formula IV in which X is fluoro, chloro, bromo or methoxy and X is hydrogen is reacted with sodium methylate in an alcoholic solvent medium at slightly elevated temperatures (eg 40-60 ° G) for a period of time 6 to 18 h to the corresponding 2-chloro-3-methoxychinoxalin derivative of formula V, which is then treated with hydrazine hydrate in the same manner as before to the corresponding 2-hydrazine-3-methoxychinoxalin derivative of the formula VI. The latter intermediate (VI) is then subsequently converted into the desired 7-substituted-4-methoxy / 1,2,4_ / triazolo / 4,3- aJ-ghyoxaline derivative of the formula VII by using a suitable orthoester or perfluoroalkanoic acid in the same manner as described above, and the latter compound is then subsequently converted to the corresponding 4-hydroxy (see formula VIII) and 4-chloro compounds according to a conventional procedure to obtain a. Compound of the structural formula HB, wherein X is as defined above (ie has a meaning other than hydrogen) and X is hydrogen. This intermediate of formula HB then leads to the corresponding novel end-products of formula IB wherein R ₁ , R ₉ and R t are all as previously defined and X and X are as above, merely by applying previously in connection with the discussion of the last steps of the overall scheme I describe the same reaction modes.

Also, the pharmaceutically acceptable acid addition salts of the novel compounds of formula I are embraced by the invention. These salts are readily prepared by contacting the free base with a suitable mineral or organic acid in either aqueous solution or in a suitable organic solvent. The solid salt can then be obtained by precipitation or by concentration of the solvent. The pharmaceutically acceptable acid addition salts of the invention include, but are not limited to, hydrochloride, sulfate, bisulfate, mesylate, tosylate, nitrate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, succinate, gluconate, and the like. Mesylates are preferred. If desired, the compounds of formula I can be used as the free base. from the acid addition salts by treatment with a suitable base and subsequent extraction of the free base with a suitable organic solvent.

The compounds of formula I and their pharmaceutically acceptable acid addition salts have activity as antidepressants and anti-fatigue agents and are thus of therapeutic value in the treatment of depression and fatigue related symptoms. The compounds may be administered to a subject in need of treatment by a number of conventional routes of administration, including orally, intravenously and parenterally. Preferably, the compounds are administered orally. In general, these compounds will be administered orally in one or more doses between about 0.1 and 100 mg / kg of body weight of the subject to be treated per day, preferably about 0.5 to 10 mg / kg per day. If parenteral or intravenous administration is desired, then these compounds may be administered at doses between about 0.1 and 10 mg / kg of body weight of the individual to be treated per day. However, there will necessarily be some variation in dosage depending on the condition of the individual to be treated and the particular compound used. , . "· · ·.

Reaction scheme I

^ ₁ Cl

Cl

NHNH,

Cl

IV

III

HA (excludes X ¹ = H;

NR ₂ R ₃ IA (excludes X ¹ = H;

Scheme II

IV

Cl OCH.

N>

 NHNH, OCHo V-

VI

OCH. VII

The compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents in either single or multiple doses. Suitable pharmaceutical carriers include inert diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of Formula I or their salts and pharmaceutically acceptable carriers are readily administered in a variety of dosage forms, such as tablets, powders, capsules, troches, syrups and the like. These pharmaceutical compositions may, if desired, contain other ingredients such as flavoring agents, excipients, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as sodium citrate, may be used together with various disintegrating agents, such as starch, alginic acid and certain complex silicates, together with binding agents, such as polyvinylpyrrolidone, sucrose, gelatin and acacia resin.

The activity of the compounds of the invention as antidepressants and anti-fatigue agents is determined by various standard pharmacological tests, including e.g. Porsolt's test model of "learned helplessness", i. the immobility induced by forced swimming in rats (R.D. Porso.lt et al., European J. Pharmacol., 47, 379 (1978)). Pharmaceutical agents of this type which are therapeutically active in humans are known to reduce immobility induced by forced swimming in this model.

Exemplary embodiments

The invention is illustrated by the following examples. It should be understood, however, that the invention is not limited to the specific details of these examples. All temperatures are given in C

Production A

4-chloro-7-fluoro / Ί, 2,47triazolo / "4,3-aquinoxaline

a) Preparation of 2-chloro-6-fluoro-3-methoxyquinoxaline

Into a flamed reaction flask with a slurry of 52 g (0.24 mol) of 2,3-dichloro-6-fluoroquinoxaline in 500 ml of methanol under a dry nitrogen atmosphere was slowly added at 50 ° C a solution of 6.6 g (0.2 9 mol ) Sodium dissolved in 650 ml of methanol, added dropwise. The resulting reaction mixture was then heated at 50 ° C overnight (ie, for 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 and the residual material was subsequently concentrated in dissolved chloroform, washed with water and ^water;. dried anhydrous magnesium sulfate After filtration of the drying agent and removal of the solvent under reduced pressure, a liquid residue was ultimately obtained which was then chromatographed on a 1000 ml silica gel column, eluted with toluene. The product-only pooled fractions then yielded 48.3 g (95%) of pure 2-chloro-6-fluoro-3-methoxyquinoxaline, mp 93-95 ° C. Mass Spec: m / e, 212 (P) 'm / e 214 (P + 2).

b) Preparation of 6-fluoro-2-hydrazino-3-methoxyquinoxaline

To a solution of 47 g (0.22 mol) of 2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml of ethanol was added 27.6 g (0.55 mol) of hydrazine hydrate (26.8 ml) · The resulting mixture was stirred at room temperature overnight, (ie at about 20 ° C for about 16 h). An additional amount of hydrazine hydrate (9.0 ml) was then added and the final reaction mixture was stirred at room temperature for 4 h. The precipitate was then filtered and washed with ethanol to give 43.3 g (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline, m.p. 170-174C

(Zers.) To surrender. ;

c) Preparation of 7-fluoro-4-methoxy- / '1, 2, 4_ / triazolo / 4, 3-a _ / - quinoxaline

A mixture of 15 g (0.072 mol) eoxychinoxaline and 250 ml triethyl orthoformate was heated with mechanical stirring in a preheated oil bath at TOO C overnight (ca 16h). The resulting mixture was then cooled to room temperature and the precipitate formed was then collected by suction and washed with ethanol to give, in the end, 11.3 g (72%) of pure 7-fluoro-4-methoxy / 1, 2,4 / triazolo / " 4,3-a_ / quinoxaline, m.p. 245-246 ° C (dec.).

d) Preparation of 7-fluoro-4-hydroxy / "1, 2, 4, / triazolo /" 4,3-a / quinoxaline

A mixture of 11.3 g (0.52 mol) of 7-fluoro-4-methoxy / '1, 2,4. / Triazolo / 4,3-a_7chinoxalin, 115 ml of 1 N hydrochloric acid and 345 ml of glacial acetic acid was refluxed for 3 h , Thereafter, the reaction mixture was cooled to room temperature and poured onto ice / water. The resulting mixture was then stirred for 30 minutes and then filtered to remove the precipitate, which was then washed with water and air dried to yield 8.9 g (84%) of pure 7-fluoro-4-hydroxy- / '1, 2, 47triazolo / 4, 3-aJOhinoxaline, mp> 300 ° C. Mass spectrum: m / e

204: (P) .... ;

e) Preparation of 4-chloro-7-fluoro / 1, 2, 4, / triazolo / "4, 3-a./quinoxaline

In a flamed reaction flask under nitrogenous nitrogen atmosphere were 8.9 g (0.044 mol) of 7-fluoro-4-hydroxy- / 1,2, 4 _J 7triazolo / 4, 3-a / quinoxaline and 1 60 ml Phosphoroxy.chlorid n mat. ¹ R, 9 ml tri-n-propylarcin added. The reaction

The mixture was then refluxed overnight for about 16 h and finally cooled to room temperature before being poured onto ice / water with mechanical stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered and the resulting solid product was then washed with cold water and triturated with ethyl acetate to give 7.0 g (71%) of pure 4-chloro-7-fluoro / Ί, 2,4 / -triazolo / 4, 3-a./quinoxaline, mp 3O5-3O8 ° C. Mass spectrum: m / e 222 (P); m / e 224 (P + 2J. \ -

Production B

4-chloro-1-ethyl-7-fluoro- / ~ 1, 2, 47-triazolo / 4, 3-a./quinoxaline

a) Preparation of 1-ethyl-7-fluoro-4-methoxy-jf1, 2, 47-triazolo - / "4,3-a_7-quinoxaline _:

A mixture of 15 g (0.07 mol) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline, product of Preparation A (b), and 250 ml of triethylorthopropionate was heated to 100 ° C. overnight with mechanical stirring in a preheated oil bath (approx 16 h). The resulting mixture was cooled to room temperature (ca. ₄ 20 C) cooled, filtered and the recovered precipitate washed with ethanol to 1.1,3 g (64%) of pure 1-ethyl-7-f luor-4-methoxy- / 1, 2,4_ / triazolo / 4, sa / quinoxaline, mp. 200-202 C (dec.).

b) Preparation of 1-ethyl-7-fluoro-4-hydroxy / 1,2,4_7triazolo- / 4,3-a_ / quinoxaline

A mixture of 11.3 g (0.046 mol) of 1-ethyl-7-fluoro-4-methoxy- / 1, 2,47triazolo / ~ 4,3-aynoxinoxaline, 115 ml of 1N hydrochloric acid and 345 ml of glacial acetic acid was refluxed for 3 hours , Thereafter, the reaction mixture was cooled to room temperature and poured onto ice / water. The resulting mixture was then stirred for 30 minutes, filtered, and the recovered solid product was then washed with water and air-dried to yield finally 6.6 g (62%).

nes 1-ethyl-7-fluoro-4-hydroxy- / "1,2-Ajtriazo- Jafi , 3-a./quinoxaline, m.p.> 30 <231 (P-1).

M.p.> 300 ° C, to yield. Mass spectrum .: m / e 232 (P); m / e

c) Preparation of 4-chloro-1-ethyl-7-fluoro - / "1, 2, 4 _ / - triazolo - /" 4,3-a_7chinoxalin

In a flamed reaction flask under dry nitrogen atmosphere were 6.6 g (0.028 mol) of 1-ethyl-7-fluoro-4-hydroxy - / * 1,2,4_ / triazolo / 4,3-a / quinoxaline and 120 ml of phosphorus oxychloride brought together with 6.6 ml of tri-n-propylamine. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being poured onto ice / water with mechanical stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the resulting solid product was then washed with cold water and then dissolved in ethyl acetate. The latter organic solution was then washed successively with water, saturated aqueous sodium bicarbonate solution and saturated brine before being dried over anhydrous magnesium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, a yellow-brown solid product was finally obtained, which was then triturated with diethyl ether to give 4 g (57%) of pure 4-chloro-1-ethyl-7-fluoro. "1, 2, 4.7triazolo /" 4, 3-a_ / quinoxaline, m.p. 203-205C. Mass spectrum: m / e 250 (P); m / e 252 (P + 2); m / e 249 (P-1).

Production C '

4, 7-DiChIOrZ ^- I, 2, 4 / triazolo / "4, 3-a / chinoxaljn.

a) Preparation of 2, S-dihydroxy-e-chloroquinoxaline

A mixture of 100 g (0.07 mol) of 4-chloro-1,2-phenylenediamine and 750 ml of diethyl oxalate was refluxed overnight for about 16 h.

cooks. Then the reaction mixture was cooled to room temperature (about 20 ^° C.), filtered and the product obtained was subsequently washed with ethanol and air-dried to constant weight to give, finally, 140 g of pure 2S-dihydroxy-G-chloroquinoxaline, mp> 260 ° C. to surrender.

b) Preparation of 2,3,6-trichloroquinoxaline

A mixture of 140 g (0.70 mol) of 2, S-dihydroxy-6-chloroquinoxaline and 326 ml (3.50 mol) of phosphorus oxychloride was refluxed overnight (ca 16h) and then poured onto ice. The resulting aqueous mixture was then filtered and the recovered product was then washed with water and air dried before dissolving in chloroform. The latter organic solution was then washed with saturated brine and air dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a thick slurry was finally obtained, which was recrystallized from chloroform / ethanol to give 120 g (74%) of pure 2,3,6-trichloroquinoxaline, m.p. 142 C mass spectrum: m / e 232 (P); m / e 234 (P + 2); m / e 236 (P + 4) ...

c) Preparation of 2, o-dichloro-S-methoxyquinoxaline

A slurry of 11.7 g (0.05 mol) of 2,3,6-trichloroquinoxaline in 140 ml of methanol was heated to 50 ° C, whereupon a solution of 1.4 g (0.06 mol) of sodium dissolved in 140 ml of methanol , was added dropwise over 6 h. The resulting mixture was then warmed to 50 C overnight (about 16 h), after which another 140 mg of sodium in 20 ml of methanol were added over 1 h. The final reaction mixture was then heated to 50 C for 2 h and cooled to room temperature. Then the spent mixture was concentrated in vacuo and dissolved in chloroform / water. The organic phase was separated and stored, and the aqueous phase was further extracted with chloroform. The various organic (i.e., chloroform) extracts were combined

1S-

and washed successively with fresh portions of water and saturated brine, then dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, the residue was chromatographed on a silica gel column of 2 ml and eluted with toluene. Equal fractions were combined to ultimately afford a white solid (86%) reinem2,6-dichloro-3 methoxyquinoxalin of 9.8 g ~, mp. 92-95 ⁰ C, was.

d) Preparation of 6-chloro-2-hydrazinep-3-methoxyquinoxaline ^:

A mixture of 4.9 g (0.02 mol) of 2, e-dichloro-S-methoxyquinoxaline and 2.7 g (0.053 mol) of hydrazine hydrate (2.6 ml) in 75 ml of ethanol was added at room temperature overnight (ie at About 20 ⁰ C for about 16 h). Then, the resulting mixture was filtered and the recovered precipitate was washed with ethanol to finally 4.4 g (98%) of pure 6-chloro-2-hydrazino-3-methoxychinoxalin, mp 175-179 ° C (dec.) To deliver. Mass spectrum: m / e 224 (P); m / e 226 (P + 2).

e) Preparation of 7-chloro-4-methoxy- / 1,2,4-triazole / 4,3-a / quinoxaline

A mixture of 1.4 g (0.0062 mol) of o-chloro-hydrazino-S-imethoxychinoxaun and 20 ml of triethyl orthoformate was heated with mechanical stirring in a preheated oil bath to 100 ° C over NaGht (about 16 h). The resulting mixture was then cooled to room temperature and the precipitate formed was then filtered off with suction and washed with ethanol to yield 1.0 g (69%) of pure 7-chloro-4-methoxy - / * 1, 2, 4_ / triazolo / 4, 3-a / quinoxaline, m.p. 25O-252 ° C.

f) Preparation of 7-chloro-4-hydroxy-1,2,4-triazolo / 4,3-a7

quinoxaline

A mixture of 3.4 g (0.014 mol) of 7-chloro-4-methoxy / Ji, 2, AJ- triazolo / 4, -3-a / quinoxaline, 35 ml of 1 N hydrochloric acid and 105 ml of vinegar was 2.5 h refluxed. Subsequently, the reaction mixture was cooled to room temperature and poured onto ice / water. The resulting mixture was stirred for 20 minutes, filtered, and the recovered solid product was washed with water and air-dried to constant weight to yield finally 2.6 g (87%) of pure 7-chloro-4-hydroxy- / "1,2,4-triazole" _/ £ 4, 3-a / quinoxaline, mp> 300 ° C.

g) Preparation of 4,7-dichloro- / "1,2,4 / triazolo / 4,3-a / quinoxaline

In an ignited reaction flask under dry nitrogen atmosphere was added 2.6 g (0.012 mol) of 7-chloro-4-hydroxy- / 1, 2,4_ / triazolo / 4,3-a_ / quinoxaline and 40 ml of phosphorus oxychloride together with 2, 6 ml of tri-n-propylamine brought. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being poured slowly onto ice / water. The resulting aqueous mixture was then extracted with ethyl acetate, and the latter extract was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated brine, before being dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a yellowish, solid product was finally obtained as a residue, which was then chromatographed on a 200 ml silica gel column and then eluted with chloroform / methanol (9: 1 volumes). Equal fractions were then combined and concentrated in vacuo to finally afford an orange solid product consisting of 1.89 g (66%) of pure 4,7-DiChIOr.l, 2, 4, / triazolo / 4, 3. a / quinoxaline, m.p. 253-256 ° C (dec.). Mass spectrum: m / e 238 (P); m / e 240 (P + 2); m / e 242 (P + 4).

Production D

4, 7-dichloro-1-ethyl / 1, 2, 3-4./triazolo/4 ρ a_7chino xalin

a) Preparation of 7-chloro-1-ethyl-4-methoxy- / 1/2, 4, / triazoio / 4, 3-a_7quinoxaline

A mixture of 5.1 g (0.022 mol) of 6-chloro-2-hydrazino-3-methoxyquinoxaline, the product of Preparation C (d), and 60 ml of triethylorthopropionate was stirred at 100 ° C. overnight with mechanical stirring in a water-heated oil bath ( approx. 16 h). The resulting mixture was then cooled to room temperature (about 20 ⁰ C) and the precipitate formed .., followed by suction and washed with diethyl ether, to finally 4.3 g (75%) of pure 7'-chloro-1-ethyl-4 -methoxy / 1,2,4triazolo / 4,3-a / quinoxaline, m.p. 221-223 ° C.

"." I

b) Preparation of 7-chloro-1-ethyl-4-hydroxy- / "1, 2,4-yriazolo-

[A, 3-a7quinoxaline ... · ':.

A mixture of 4.3 g (0.0072 mol) of 7-chloro-1-ethyl-1, 4-hydroxy-. / 1, ^^ ytriazolo / ^, 3-a7quinoxaline, 40 ml of 1N hydrochloric acid and 60 ml of methanol was refluxed overnight and then cooled to room temperature. The precipitate formed was then filtered off with suction and washed with methanol. Thus, finally, 3.7 g (94%) of pure 7-chloro-1-ethyl-4-hydroxy-i, 2,47triazolo / 4- , 3-aJ- quinoxaline, mp> 300 ° C were obtained.

c) Preparation of 4, 7-dichloro-1 -ethyl-BR, 2, 4,. / triazolo / "4 _{t-3 t} chinöxalin AJ.

5.1 g (0.02 mol) of 7-chloro-1-ethyl-4-hydroxy-7f1, 2,4 / triazolo / 4,3-a_7-quinoxaline and 75 ml of phosphorus oxychloride were combined into a flamed reaction flask under a dry nitrogen atmosphere brought with 5 ml of tri-n-propylamine. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being slow

was poured on ice / water. The resulting aqueous mixture was then stirred at room temperature for 15 minutes and filtered and the resulting solid product was then washed with cold water and air-dried to constant weight to finally yield 4.2 g (79%) of pure 4,7-dichloro-1-ethyl- / '1, 2,47triazolo / 4, 3- ^ a_7quinoxaline, m.p. 217-22O ° C (dec.). Mass spectrum: m / e 266 (P); m / e 268 (P + 2); m / e 265 (P-1).

Production E

4-chloro-7-methoxy / 1, 2,4,7-triazolo / 4,3-a / quinoxaline

a) Preparation of 2,3-dihydroxy-6-methoxyquinoxaline

A mixture of 20 g (0.114 mol) of 4-methoxy-o-phenylenediamine and 11 g (0.114 mol) of triethylamine dissolved in 200 ml of diethyl oxalate was refluxed overnight for about 16 hours. Then the reaction mixture was cooled to room temperature (20 ° C) and filtered to remove the desired product. After washing with ethanol, 14.8 g ultimately (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline, m.p.. C obtained> 300 ^0th Medium range: m / e 192 (P). , J

b) Preparation of 2, S-dichloro-e-methoxyquinoxaline

Into an ignited reaction flask under a dry nitrogen atmosphere were placed 14.8 g (0.077 mol) of 2,3-dihydroxy-6-methoxyquinoxaline and 75 ml of phosphorus oxychloride together with 15 ml of tri-n-propylamine. The exothermic reaction mixture was then stirred at room temperature (about 20 C) for 1 h and then refluxed overnight (about 16 h). Then the reaction mixture was cooled back to room temperature and close. lent slowly to ice / water. The resulting aqueous mixture was then stirred at room temperature for 20 minutes, filtered, and the resulting precipitate washed with water before being dissolved in chloroform. This solution was then filtered,

Λΐ | ;:: -; - ../ ; [; '': -A. ''':, - \ " ^: ."'22-.' ,. - ' /.-.Kr'i -' > / '' - V.. ' , '. \

to remove insoluble material, and the filtrate thus obtained was washed successively with water, saturated sodium bicarbonate solution and saturated brine. Concentration of the washed solution in vacuo followed by recrystallization of the residue from ethanol gave 14.2 g (8%) of pure 2,3-dichloro-e-methoxyquinoxaline, mp 156-159 ° C. Mass spectrum: m / e 228 (P); m / e 230 (P + 2); m / e 232 (P + 4).

c) Preparation of 2-chloro-S, 6-dimethoxyquinoxaline

In a flamed reaction flask under dry nitrogen atmosphere was / slowly a solution of 850 mg, dissolved in 80 ml of methanol, to a slurry of 7.1 g of 2,3-dichloro-6-methoxychinoxalin in 60 ml of methanol at 50 C on 7 h given. The resulting mixture was then heated at 50 ° C overnight and finally cooled to room temperature. Thereafter, the spent reaction mixture was concentrated in vacuo, and the residue was then dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, the resulting residue was then chromatographed on a column with 400 ml of silica gel, then eluted with toluene. The good fractions were combined and concentrated in vacuo to finally afford a white solid which consisted of 6.1 g (88%) of pure 2-chloro-3,6-methoxyquinoxaline, m.p. 79-81 ° C.

Analysis for C ₁₀ HgClN ₂ O ₂ :

Calc .: C 53.47 H 4.04 12.47 Found: C 53.29 H 4.05 12.28

d) Preparation of 3,6-dimethoxy-2-hydrazinoquinoxaline

A mixture of 5 g (0.022 mol) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g (0.056 mol) of hydrazine hydrate (2.7 ml) in 75 ml

would be heated to 5O ° C overnight. Then, another ml of hydrazine hydrate was added to the mixture, and the resulting mixture was heated at 50 ° C for 6 hours. Now, another ml of hydrazine hydrate was added and the final reaction mixture was heated to 50 ° C overnight before being cooled to room temperature. The spent mixture was then filtered and the recovered precipitate was washed with ethanol to give 4.1 g. (85%) of pure 3, e-dimethoxy-hydrazinoquinoxaline, m.p. 128-130 ° C (dec.). to surrender.

, e) Preparation of 4,7-dimethoxy / 1, 2,4 / triazolo / 4,3-a_7quinoxaline

A mixture of 1/5 g (0.068 mol) of 3,6-dimethoxy-2-hydrazinoquinoxaline and 20 ml of triethyl orthoformate was heated to 100 C overnight (about 16 hours) with mechanical stirring in a preheated oil bath. The resulting mixture was then cooled to room temperature and the precipitate formed is then filtered off with suction and washed with ethanol to ultimately 1.8 g of pure 4,7-dimethoxy / 1, 2, 47 triazolo ^r / '4, 3-a / quinoxaline, m.p. 238-24O ° C (decomp.). Mass spectrum: m / e 230 (P); m / e 231 (P + 1);

m / e 232 (P + 2).

'. '·' -. '·'

f) Preparation of 4-hydroxy-7-methoxy- / 1,2 _/ 4-yriazolo / '4,3-a7-quinoxaline

A mixture of 1.6 g (0.0069 mol) of 4,7-dimethoxy- / 1, 2,4 / triazolo [A , 3-a_ / quinoxaline, 16 ml of 1N hydrochloric acid and 48 ml of glacial acetic acid was refluxed for 3 hours , Then the reaction mixture was poured onto ice and filtered. The recovered product was then collected on a filter funnel and washed with diethyl ether to give, in the end, 1.19 g (80%) of pure 4-hydroxy-7-methoxy- / 1,4,4-triazolo / 4,3-a7-quinoxaline, m.p. 25O ° C to deliver.

g) Preparation of 4-chloro-7-methoxy- / "1, 2,47triazolo / 4 _r 3-aJ- quinoxaline ·

'''^:; ... .. - 24 -',

Into an ignited reaction flask under a dry nitrogen atmosphere, 1.1 g (0.0055 mol) of 4-hydroxy-7-methoxy / -1,2,4_ / triazolo / -4,4-a7-quinoxaline and 15 ml of phosphorus oxychloride were added together with 1 , O ml of tri-n-propylamine brought. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being poured slowly onto ice / water. The resulting aqueous mixture was then extracted with ethyl acetate, and this extract was washed successively with water and saturated brine before being dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a residual product was finally obtained, which was then chromatographed on a 150 ml silica gel column and eluted with chloroform / methanol (95: 5 volumes). Equal product-containing fractions were then combined and concentrated in vacuo to finally give a residual material which was recrystallized from chloroform / diethyl ether to give 400 ml (31%) of pure 4-chloro-7-methoxy / 1, 2, 4_. / triazolo / 4,3-a_7quinoxaline, m.p. 266-268 C (dec.). Mass spectrum: m / e 234 (P); m / e 236 (P + 2).

Production F

' 4-Chloro-i-ethyl-7-methoxy- / T, 2, 4, 7-triazolo / 4,3-a-7-quinoxaline

a) Preparation of 1-ethyl-4,7-dimethoxy- / "1,2,4_ / triazolo / 4,3-aJ- quinoxaline.

A mixture of 4.0 g (0.018 mol) of 3,6-dimethoxy-2-hydrazine-oxazine, the product of Preparation E (d), and 50 ml of triethylorthopropionate was added with mechanical stirring in a preheated oil bath overnight (ca. ) at 100 C heated. There; The reaction mixture was then cooled to room temperature (about 20 ° C) and the precipitate formed was then filtered off with suction and washed with ethanol to finally 3.3 g (72%) of pure 4.7

Dimethoxy-1-ethyl / Ί, 2,4-triazolo / 4,3-a / quinoxaline, mp 1 84-188 ° C. Mass spectrum: m / e 258 (P); m / e 228 (P-). 30).

b) Preparation of 1-ethyl-4-hydroxy-7-methoxy / '1, 2,4 / triazolo - / "4,3-a_ / quinoxaline.

A mixture of 3.3 g (0.013 mol) of 4, 7-dimethoxy-1 -ethyl / 1, 2, A] - triazolo / 4, 3-a_ / quinoxaline, 33 ml of 1 η hydrochloric acid and 99 ml of glacial acetic acid was added 2 h refluxed. Thereafter, the reaction mixture was cooled to room temperature and poured onto ice / water. The resulting mixture was then stirred for 20 minutes and extracted with ethyl acetate. This extract was then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a yellowish solid product was finally obtained, which was washed with water and air-dried to constant weight to finally yield 1.87 g (67%) of pure 1-ethyl-4-hydroxy -7-methoxy ^ / 1, 2, 4_7triazolo / ~ 4, 3-a./quinoxaline, mp> 250 ° C.

c) Preparation of 4-chloro-1-ethyl-7-methoxy- 1,2,2,4-triazolo / 4,3-a / quinoxaline

ν ''.

, / "1, 2, 4_7triazolo /" 4 3-a / quinoxaline and 25 ml of phosphorus oxychloride - In a reaction flask aüsgeflammten (0.0076 mol) of 1-ethyl-4-hydroxy-7-methoxy 1.87 g under a dry nitrogen atmosphere along with 1.8 ml of tri-n-propylamine. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being poured slowly onto ice / water. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the resulting solid product was then washed with cold water and then dissolved in chloroform. This latter organic solution was then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent

'''''- ²⁶ - ..' ..:. :. '. :

Finally, a yellow solid product was obtained under reduced pressure, which was triturated with diethyl ether and filtered to give, in the end, 1.6 g (80%) of pure 4-chloro-1-ethyl-7-methoxy - 1, 2, 4_7triazoles · / 4, 3-a_ / quinoxaline, mp 173-175 ° C. Mass Spec: m / e 262 (P); m / e 264 (P + 2); m / e 261 (PT) ' .- '' .- '.

Creation G.

4-Chloro-8-fluoro-1, 2, 4-triazolo / 4,3-a-7-quinoxaline

a) Preparation of 2,3-dihydroxy-6-fluoroquinoxaline

A mixture of 26.3 g (0.19 mol) of 4-fluoro-1,2-phenylenediamine (Journal of the American Chemical Society, Vol. 75, p. 1294 (1953)) and 150 ml of diethyl oxalate was added under a nitrogen atmosphere 18 h refluxed. Thereafter, the reaction mixture was cooled to room temperature (about 20 C), filtered and the recovered product was then washed with four 100 ml portions of ethanol and air-dried to constant weight to yield 19.3 g (80%) of pure 2,3-dihydroxy 3-fluoroquinoxaline, mp> 300 ° C (lit. mp 387-39 ° C according to US-PS 3,992,378). Mass spectrum: m / e 180 (P +).

b) Preparation of 2,3-dichloro-6-fluoroquinoxaline

A mixture of 19 g (0.105 mol) of 2,3-dihydroxy-6-fluoroquinoxaline and 50 ml of phosphorus oxychloride was refluxed overnight (about 16 h) and then cooled to room temperature before pouring onto 200 g of ice with good stirring. The resulting aqueous mixture was then filtered and the recovered product was washed several times with water to finally yield 28.2 g of 2,3-dichloro-6-fluoroquinoxaline, m.p. 148-152 ° C.

c) Preparation of 2-chloro-6-fluoro-3-hydrazinoquinoxaline

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

d) Preparation of 4-chloro-8-fluoro - / "1, 2, 4_7triazolo / 4,3-a / quinoxaline

A mixture of 10 g (0.047 mol) of 2-chloro-6-fluoro-3-hydrazinochinoxalin and 80 ml (0.47 mol) of triethyl orthoformate was added under a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100 ⁰ C overnight (ca. 16 h). The resulting mixture was cooled to room temperature and the resulting precipitate was then filtered off with suction, washed with three 50 ml portions of ethanol and air-dried to constant weight to finally yield 9.42 g (91%) of pure 4-chloro-8-fluoro-1 To give 2,47triazole O / 4 _/ 3-aquinoxaline, mp 310-312 ° C, (dec.) Mass Spectrum: m / e 224, 223, 222 (P +).

Production H

4-Chloro-1-ethyl-8-fluoro-1, 2, 4-triazolo / 4,3-a, 7-quinoxaline

A mixture of 10.0 g (0.047 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline, the product of Preparation G (c), and 95 ml of (0.47, MoI) triethylorthopropionate was added under an atmosphere of nitrogen under mechanical pressure The resulting mixture was cooled to room temperature (about 20 C) and the resulting precipitate was then filtered off with suction, washed with three 50 ml portions of ethanol and constant weight in a preheated oil bath at iOO ° C overnight air dried to

finally 7.5 g (65%) of pure 1-chloro-1-ethyl-efuuro- / 1,2,4 / -triazolo / 4,3-a_ / quinoxaline, m.p. 160-163 C (dec.) to surrender. Mass spectrum: m / e 249, 250, 251, 252 (P +).

Production I '...'

4-Chloro-8-fluoro-1-trifluoromethyl- / 1, 2,4_ / triazolo / 4, 3-a_7quinox aline. ' ,

a) Preparation of 8-fluoro-4-hydroxy-1-trifluoromethyl / ~ 1 , 2,4- triazolo / ~ 4, 3-a_ / quinoxaline '

A mixture of 12.8 g (0.06 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline in 50 ml (0.65 mol) trifluoroacetic acid was heated under a dry nitrogen atmosphere to 120 ° C for 24 hours with mechanical stirring to give a homogeneous To give solution. The resulting Reaktiomsgemisch was then poured while stirring on ice / water, stirred for a further 30 min and filtered. The product thus obtained was then washed with three separate portions of water and dried in vacuo at 80 ° C.,. to finally 12.58 g '(77%) of pure 8-fluoro-4-hydroxy-1-trifluoromethyl-1-1,2, Aj triazolo / 4,3-a / quinoxaline, m.p. 298-3O2 ° C to surrender. Mass spectrum: m / e 272 (P +).

b) Preparation of 4-chloro-8-fluoro-1-trifluoromethyl 1-1,2, A- triazolo / 4,3-a_7-quinoxaline,

Into a 250 ml three-necked flask under dry nitrogen atmosphere was added 12.5 g (0.046 mol) of 8-fluoro-4-hydroxy-1-trifluoromethyl 1-1, 2,4-triazolo / 4,3-aquinoline and 85 ml of phosphorus oxychloride brought with 17.5 ml of tri-n-propylamine. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature (about 20 ° C) before being poured slowly onto 1000 ml of ice / water with mechanical stirring. The resulting aqueous mixture was then stirred for a further 30 minutes at room temperature,

then extracted with three 300 ml portions of chloroform. The combined chloroform layers were then washed successively with saturated aqueous sodium bicarbonate solution, water and saturated brine, and finally dried over anhydrous magnesium sulfate. After filtering off the drying agent and stripping the solvent under reduced pressure, a yellow, solid product was finally obtained which was prepared from 10.47 g (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl- / 1.2 , 4JtXXaZoIo / ^, 3-aquinoxaline, mp. 135-138 ° C, consisted. , Mass spectrum: m / e 292/290 (P +). Production J

4-Chloro-7,8-difluoro - / "1,2,4_7triazolo / 4,3-a_7quinoxaline .") Preparation of 2,3-dihydroxy-6,7-difluoroquinoxaline

A mixture of 11.3 g (0.0784 mol) of 4,5-difluoro-o-phenylenediamine (U.S. Patent 4,264,600) and 80 ml (0.589 mol) of diethyl oxalate was refluxed for 4 hours to give a thick product precipitate. The spent reaction mixture was then cooled to room temperature (20 ° C) overnight, filtered, and the resulting solid product was then washed several times with diethyl ether and air dried to constant weight to finally 15.5 g of pure 2,3-dihydroxy-6,7 -difluorochinoxaline, mp> 310 ° C to give. Mass spectrum: m / e 198 (P +).

b) Preparation of 2,3-dichloro-6,7-difluoroquinoxaline

A mixture of 15.4 g (0.078 mol) of 2,3-dihydroxy-6,7-difluorochinoxaline, 39 g (0.187 mol) of phosphorus pentachloride and 20 ml (0.22 mol) of phosphorus oxychloride was refluxed with stirring for 4 h, with another 20 ml of phosphorus oxychloride was added to facilitate stirring (the reaction mixture became homogeneous within 30 minutes). After that, the reaction was.

tion mixture stirred overnight (about 16 h) at room temperature to give a pale yellow precipitate. The spent mixture was then poured onto 200 g of ice / water and further stirred with additional cooling to give a tan solid which was prepared from 20.9 g of 2,3-dichloro-6,7-difluorochihoxaline, mp 162-164 ° C (Zers.), Existed. Mass spectrum: m / e 238/236/234 (P +).

c) Preparation of 2-chloro-6,7-difluoro-3-hydrazinochirioxalin

A mixture of 10 g (0.0426 mol) of 2,3-dichloro-6,7-difluorochinoxaline and 5 ml (0.03 mol) of hydrazine hydrate in 200 ml of ethanol was stirred at room temperature for 24 hours to give a rust-red precipitate , The thick slurry was filtered and the recovered product was washed with two 20 ml portions of ethanol, then dried to constant weight to finally give 5.99 g (67%) of pure 2-chloro-6,7-difluoro-3. hydrazinoquinoxaline, m.p. 21'2-215 ° C (dec.). Mass spectrum: m / e 230 (P); m / e 232 (P +).

d) Preparation of 4-chloro-7,8-difluoro - / "1,2,4_7triazolo / 4,3-a_ / - quinoxaline

A mixture of 5.99 g (0.026 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml (0.18 mol) of triethylorthoformate was heated at 100 ° C for 24 hours to give a reddish brown solid. The resulting slurry was then cooled to room temperature and filtered, and the recovered product was then washed with diethyl ether to give, in the end, 5.15 g (82%) of pure 4-chloro-7,8-difluoro / 1,2,4_7triazole "/ 4, 3 -a.Zinoxaline, mp> 210 ° C (dec.) To give. Mass spectrum: m / e 242/240 (P +).

Production ¹ K

4-chloro-6,7-difluoro-1-ethyl-1-1,2,74-triazolo / 4,3-aquinoxaline A mixture of 7.0 g (0.03 mol) 2-chloro-6,7- difluoro-3-hydraz-

inochinoxaline, the product of Preparation J (c), and 60 ml (0.30 mole) of triethylorthopropionate were heated under nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100 ° C for 24 hours. The resulting mixture was cooled to room temperature (about 20 ° C) and the resulting red precipitate was then filtered off, washed with two separate portions of diethyl ether and air-dried to constant weight, to finally 4.15 g (52%) of pure 4-chloro-6, 7-difluoro-1-ethylene, 2,4-triazole / 4,3-aquinoxaline, m.p. 185-186 C (dec.).

Production L

4,8-dichloro-1-methyl- / ~ 1,2,4-triazolo / -4,4-a7quinoxaline

a) Preparation of 2,6-dichloro-6-hydrazinoquinoxaline

A mixture of 23 g (0.10 mol) of 2,3,6-trichloroquinoxaline and 11 g (0.22 mol) of hydrazine hydrate in 500 ml of ethanol at room temperature (about 2 0 ° C) overnight (about 16 h ) touched. The resulting precipitate was filtered off and washed with ethanol to give, in the end, 22.2 g (97%) of pure 2, 6-dichloro-S-hydrazinoquinoxaline, Schrr.p. > 25O ° C, to surrender. Mass spectrum: m / e 2 28

b) Preparation of 4,8-dichloro-1-methyl- / * 1,2,4-triazolo / 4,3- & 3- quinoxaline

A mixture of 20 g (0.087 mol) of 2, e-dichloro-S-hydrazine-oxine and 160 ml (0.87 mol) of triethyl orthoacetate was heated with mechanical stirring under a nitrogen atmosphere in a preheated oil bath at TOO C for 20 h to give a yellow suspension result. The resulting mixture was cooled to room temperature and filtered, and the recovered solid product was then washed with ethanol and air-dried to constant weight to finally yield 10.2 g (46%) of pure 4,8-dichloro-1-methyl-1. / 1, 2,47triazolo / 4,3-aquinoxaline, mp> -28 ° C, too

result. Mass spectrum: m / e 254/252 (P +). _r

Production M

4,8-dichloro-1-trifluoromethyl - / "1, 2 , 4 / triazolo / "4,3-aquinoxaline

a) Preparation of 8-chloro-4-hydroxy-1-trifluoromethyl 1-1, 2, AJ- triazolo / 4,3-a7-quinoxaline

Into a flamed 500 ml three-necked flask with mechanical stirrer, nitrogen inlet tube and reflux condenser was placed 67 ml (0.87 mol) of trifluoroacetic acid. Stirring was started and 20 g (0.087 mol) of 2, e-dichloro-S-hydrazinequinoxaline, the product of Preparation L (a), was added. The resulting reaction mixture was then heated on a steam bath for 24 h, cooled to room temperature (ea. 20 ° C) and poured onto 200 g of ice / water. The resulting aqueous mixture was then stirred for 30 minutes, filtered and the recovered product was then washed several times with water and air-dried to constant weight (needed about 18 hours). Thus, finally, 14.3 g (57%) of pure 8-chloro-4-hydroxy-1-trifluoromethyl- / "1, 2, 4_7triazolo- / 4,3-a. / Quinoxaline, mp. 253-255 ° C. (Dec.), Mass spectrum: m / e 290/288 (P +).

b) Preparation of 4,8-dichloro-1-trifluoromethyl- / '! , 2, 4 _ / - triazolo / 4,3-a_7quinoxaline

Into a flared 250 ml three-necked flask with mechanical stirrer, dropping funnel and reflux condenser under nitrogen purge 14.3 g (0.05 mol) of 8-chloro-4-hydroxy-1-trifluoromethyl- / "1, 2, 4_7triazolo / 4, 3rd Then, 19 ml (0.10 mol) of tri-n-propylamine was added dropwise over 5 minutes to the resulting suspension, and the resulting reaction mixture was refluxed for 20 hours to give a clear, dark maroon The resulting clear solution was then cooled to room temperature and poured onto 1000 ml of ice / water with vigorous mechanical stirring.

 : '' '- 33 -' ''.

V '

The resulting aqueous mixture was then stirred at room temperature for 30 minutes and then with three 500 ml portions of chloroform. extracted. These latter organic extracts were then combined and then washed successively with water, saturated aqueous sodium bicarbonate solution, water and saturated brine, then dried over anhydrous magnesium sulfate. After filtering off the drying agent and stripping the solvent under reduced pressure, a yellow solid was finally obtained which was prepared from 11.4 g (75%) of pure 4,8-dichloro-1-trifluoromethyl-, 2,4,7-triazolo- ( A ₁ 3-a-7-quinoxaline, mp 133-135 ° C, mass spectrum: m / e 308 (P + 2); m / e 310 (P + 4).

Production N i

4,8-dichloro-1-phenyl- / ~ 1,2,4-triazolo / 4,3-a-7-quinoxaline ;

ι -I

In a 2 50 ml three-necked flask with mechanical stirrer ur | d reflux condenser, 50.0 g (0.274 mol) of trimethyl orthobenzoate were brought, which was preheated to about 70 C. War. Stirring was started and 10.0 g (0.0437 mole) of 2, e-dichloro-S-hydrazinoquinoxaline, product of Preparation L (a), was added. The resulting reaction mixture was then heated to about 120 ° C with continued stirring for 24 h, then cooled to room temperature (20 ° G) and passed overnight for about 16 h to give a yellow slurry. This was then filtered and the recovered solid product was then washed with two 50 ml portions of ethanol and dried to constant weight to finally yield 9.8 g (72%) of crude 4,8-dichloro-1-phenyl. , 2, 4- triazolo / ~ 4,3-a / quinoxaline, m.p. 305-307 C, mass spectrum: m / e 316/314 (P +).

Example 1 - ",

2-chloro -3 - hydrazinequinoxaline

2,3-dichloroquinoxaline (33.5 g, 0.168 mol) was treated with hydrazine

hydrate (18.5 g, 0.369 mol) in 500 ml of ethanol at room temperature overnight (ie at about 20 ° C for about 16 h). The dik-. Ke, yellow slurry was filtered and the precipitate washed with ethanol. The precipitated material was recrystallized from hot methanol to give 13.5 g (41% yield) of 2-chloro-3-hydrazinochinoxalin, mp. 181 ⁰ C (dec.). Mass spectrum: m / e 194 (P).

Example 2

4-chloro / * 1,2,4,7-triazolo / 4,3-a7-quinoxaline

2-Chloro-3-hydrazinequinoxaline (9.0 g, 0.046 mol), product of Example 1, was stirred with triethyl orthoformate (90 mL) at 100 ° C for 1 h. The mixture was cooled to room temperature and the solid precipitate filtered off, washed with cyclohexane and dried to give 8.8 g (94% yield) of 4-chloro-2f1, 2,4ytriazolo / 4, S-aJ'quinoxaline, m.p. 29O ° C (Zers.) To surrender. Mass spectrum: m / e 204 (P).

Example 3 .

4-chloro-1-methyl- / "1,2,4_7triazolo /" 4,3-a_7-quinoxaline

2-Chloro-3-hydrazinoquinoxaline (15.5 g, 0.080 mol), product of Example 1, was stirred with triethyl orthoacetate at 100 ° C for 3 hours. The mixture was cooled to room temperature and the. solid precipitate, washed with ethanol and air dried to give 11.4g (65% yield) of 4-chloro-1-methyl- / "1,2,4_7triazolo / 4,3-aquinoline-quinine, m.p. 215-222 ° C Mass spectrum: m / e 218 (P).

Example 4 ⁱ

4-Chloro -1- ethyl- / 1,2,2,4-triazolo / 4,4-3-quinoxaline 2-Chloro-3-hydrazinoquinoxaline (4.5 g, 0.023 mol), product of

Example 1 was stirred with triethylorthopropionate (50 ml) at 100 C for 1 h. The mixture was cooled to room temperature and the white precipitate filtered off and washed with cyclohexane to give 4-chloro-I-ethylene 4.5 g (85% yield), 2.4 / triazolo / 4 _f 3-a7 ~ quinoxaline, mp. 158-16O ° C, to surrender. Mass spectrum: m / e 232 (P).

Example 5

'. 4-chloro-1-n-propyl-1/2, 4-triazolo-4,4-3-aquinoxaline

2-Chloro-3-hydrazinoquinoxaline (3.0 g, 0.015 mol), product of Example 1, was stirred with triethylorthobutyrate (27 ml) at 100 ° C for 2 h. The mixture was cooled to room temperature and the precipitate filtered off and washed with cyclohexane. The crude solid was taken up in chloroform and filtered to remove insoluble material. The chloroform solution was concentrated in vacuo to a solid which was recrystallized from chloroform to give 1.96 g (53% yield) of 4-chloro-1-n-propyl- / "1,2,4-triazolo / 4,3-a / quinoxaline Mp 173-175 ° C, mass spectrum: m / e 246 (P).

Example 6

4-chloro-1-isopropyl - / "1,2,7triazolo / 4,3-aquinoxaline

Z-chloro-S-hydrazinequinoxaline (4.0g, 0.02mol), product of Example 1, was stirred with triethylorthoisobutyrate (15ml) at 100 ° C for 3h. The solution was cooled to room temperature and the precipitate filtered and washed with ethanol. The crude solid was recrystallized from 300 mL of hot ethanol to give 2.06 g (40% yield) of 4-chloro-1-isopropyl- / "1,2,4-triazolo / 4,3-a / quinoxaline, m.p. 210 C, mass spectrum: m / e 24.6 (P).

Example 7 . 4-methyl- / "Ty 2, 4-triazolo / ~ 4,3-aquinoxaline

® 4-Chlorotif, 2,47triazolo- / "4,3-aquinoxaline (2, Og, 0.01 mol), product of Example 2, in Ν, Ν-dimethylformamide (30 ml) was saturated with monomethylamine gas and added for 3 h Monomethylamine gas was again bubbled into the solution and the solution was stirred at room temperature for a further 2 hours The precipitate was filtered off and washed with Ν, Ν-dimethylformamide Recrystallization from Ν, Ν-dimethylformamide gave 1.37 g (69% yield ) 4-Methylamino- / * 1, 2, 4-ystriazole / "4/ 3-aJ- chincxaline, m.p.> 300 ° C. Mass spectrum: m / e 199 (P).

Analysis for C ₁₀ H ₉ N ₅ :

Calc .: 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, 4j triazolo ^r / '4, 3-a7chinoxalin

A slurry of 2.0 g (0.01 mol) of 4-chloro- / "1,2,7triazolo / 4,3-a_7-quinoxaline (product of Example 2) in Ν, Ν-dimethylformamide (30 ml) was washed with ., saturated dimethylamine and stirred at room temperature overnight the mixture was poured onto ice and the precipitate filtered off recrystallization from ethanol gave 640 mg (44% yield) of 4-dimethylamino - / "1, 2, 4J ⁷ triazolo / 4,3- a7quinoxaline, mp 184-186 ° C. Mass spectrum: m / e 213 (P).

Analysis for C.-H'N ₅₁

Calc .: C, 61.96, H, 5.20, N, 32.84, F: C, 62.26, H, 5.43, N, 32.92

Example 9

4-Ethylamino- / "1,2,4_7triazolo / 4,3-a. / Quinoxaline

A slurry of 2.0 g (0.01 mol) of 4-chloro- / "1, 2,4_7triazolo / 4,3 -aJ- quinoxaline (product of Example 2) in N, N-dimethylformamide (30 ml) was washed with Monoethylamine gas was saturated and stirred at room temperature for 2 h Monoethylamine gas was again bubbled through the mixture and stirring was continued for 2 h The precipitate was filtered off and washed with N, N-dimethylformamide Recrystallization from methanol afforded 680 mg (32% strength) of 4-ethylamino - / '1,2, 4./triazolo/"4, 3-a_7quinoxaline, mp "254-6 ° C. Mass spectrum: m / e 213 (P).

Analysis for C ₁ -H ₁₁ N-:

Calc .: C 61.96 H 5.20 N 32.84 Found: C 61.93 H 5.09 N 32.72

Example 10

4-diethylamino- / 1,2,2,7-triazolo / 4,3-aquinoxaline

4-Chloro- / 1, 2,47triazolo / 4,3-, a-quinoxaline (4.4 g, 0.021 mol), product of Example 2, was treated with diethylamine (6.5 mL, 0.063 mol) in N , N-dimethylformamide (100 ml) at room temperature for 2 h The reaction mixture was poured onto an ice / water mixture to give a crude precipitate as a product, which was then filtered and washed with water Recrystallization from isopropanol gave 3 , 36 g (66% yield) of 4-diethylamino - / * 1,2,4-triazolo / 4,3-a_7-quinoxaline, mp 117-119 ° C. Mass spectrum: m / e 241 (P).

Example 11

4-Di-n-propylamino- / "1,2,7,4-triazolo /" 4, S-a / quinoxaline

4-chloro- / "1, 2,4-yliazolo /" 4,3-aquinoxaline (.2., O g, 0.01 mol), product of Example 2, and 3.0 g (0.03 mol) of di- n-Propylamine in N, N-dimethylformamide (50 ml) was stirred at room temperature for 3 h. The solution was poured on ice to form a precipitate which was filtered off and air dried. Recrystallization from cyclohexane (250 mL) afforded 1.1 g (41% yield) of 4-di-n-propylamino / ~ 1,2,4,7triazolo / 4,3-aJ- quinoxaline, m.p. 24O-242 ° C. Mass spectrum: m / e 269 (P).

Analysis for C ₁ CH ₁ QN ₁ -:

calc .: C 66.89 H 7.11 N 26.00

Found: C 66.68 H 6.97 N 26.12 '

Example 12 .

4-isopropylamirto - / * 1, 2, 4_7triazolo / "4, S-

-Z ^- I, 2,47triazolo / 4,3-a7-quinoxaline (2.0 g, 0, 01 mol), product of Example 2, and 1.77 g (0.03 mol) of isopropylamine in N, N-dimethylformamide ( 30 ml) were stirred overnight at room temperature. The dark solution was poured onto ice and the precipitate formed was filtered off and washed with water. The crude product was recrystallised from ethanol and then twice from isopropyl ether to give 1.2 g (53% yield) of 4-isopropylamino- / "1,2,4_7triazolo / * 4,3-aquinoxaline, mp 133-5 ° C Mass spectrum: m / e 222 (P).

Analysis for

C ..: C 61.73 H 5.90 N 30.02 F .: C 61.51 H 5.89 N.29.90

Example 13:

4-diethylamino-1-methyl-, 2,4,4-triazolo / -4,4-3-a-quinoxaline

This compound was prepared by the method of Example 11 using 4-chloro-1-methyl- ~ 1,2,4-yliazolo / "4,3-a-7-quinoxaline (product of Example 3) as starting material instead of 4-chloro /" 1, 2, 4-triazolo / 4,3-aquinoxaline (product of Example 2) and diethylamine as reagent in place of di-n-propylamine The product obtained was recrystallized from chloroform and then from cyclohexane to give 7.2 g (54 % Yield) of pure 4-diethylamino-1-methyl- / 1,2,4-triazolo / 4,3-a / quinoxaline, m.p. 12 3-12 5 ° C.

Example 14

4-amino-1-ethyl- / "1,2,7,7-triazolo /" 4,3-a-7-quinoxaline

Ammonia gas was passed through a solution of 1.2 g (0.005 mol) of 4-chloro-1-ethyl / 1,2,4] triazolo / 4,3-aquinoxaline (product of Example 4) in N, N-dimethylformamide (20 ml) at ⁰ ° C. for about 2 minutes. The solution was stirred at 0 C for 30 min and at room temperature for 1 h. The reaction mixture was then poured onto ice and stirred for 20 minutes. The precipitate formed was filtered off, washed with water and air dried. Recrystallization from ethanol afforded 220 mg (22% yield) of pure 4-amino-1-yl 1-1,2,4_7triazolo / 4,3-a_ / quinoxaline, m.p. 284-288 ° C mass spectrum: m / e 213 (P).

Analysis for C ₁₁ H ₁₁ Nc-IZoH ₂ O:

Calc .: C 61.10 H 5.2.8 N 32.39 Found: C 61.36 H 5.14 N 31.96

Example 15 ' 4-methylamine-1-ethyl- / "!, 2, 47triazolo / "4,3-a / quinoxaline

Monomethylamine gas was passed through a solution of 4-chloro-1-ethyl- / Ϊ, ^, vtriazolo / ^^ - a / chihoxaline (1.2 g, 0.005 mol), product of Example 4, in N, N-dimethylformamide (50 ml) is stirred for 0 C 2 min. The reaction mixture was stirred at ⁰ ° C. for 30 min, at room temperature for 2 h and then poured onto ice and stirred for a further 20 min. The precipitate formed was filtered off, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g (88% yield) of 4-methylamino-1-ethyl- / * 1,2,4 triazolo / "4,3-a7-quinoxaline, mp 271-273 ° C. Mass Spec: m / e 227 (P).

Analysis for C ₁₂ H ₁₃ N ₅ -VSH ₂ O:

Calc .: C 62.80 H 5.82 N 30.51 F. C 62.72 H 5.86 N 30.62

Example 16

4-Dimethylamino-i-ethyl- / "1,2,7,7-triazolo / 4-, 3-a7-quinoxaline

4-Chloro-1-ethyl- / * 1,2,4_ / triazolo- / "4,3-a / quinoxaline (1.2 g, 0.005 mol), product of Example 4, and 676 mg (0.015 mol) of anhydrous Dimethylamine in Ν, Ν-dimethylformamide (50 ml) was 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 filtered off, washed with water and air-dried Recrystallization from chloroform and then from chloroform / cyclohexane. 510 mg (42% yield) yielded 4-dimethylamino-1-ethyl- / "1,2,4_7triazolo / 4-4,3-a_ / quinoxaline, mp 155-158 ° C. Mass spectrum: m / e 241. (P). '

- "41 -

Analysis for C ₁ OH ₁₁ -N ₁ -:

Calc .: C 64.71 H 6.27 N 29.02 F: C 64.69 H 6.27 N 29.32

Example 17

1-ethyl-4-ethylamino / ~ 1, 2, 4 _J 7triazolo / "4, 3-a_7chinoxalin

Monoethylamine was prepared by a solution of 4-chloro-1-ethyl- f] , 2,47triazolo / * 4,3-a7-quinoxaline (1.2 g, 0.005 mol), product, of Example 4, in Ν, Ν-dimethylformamide ( 50 ml) at OC for about 2 min. The clear solution was stirred at 0 C for 30 min and at room temperature for 2 h. The reaction mixture was then poured onto ice and the precipitate filtered off, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g (83% yield) of pure 1-ethyl-4-ethylamino-, 2,4,4-triazolo / 4,3-a / quinoxaline as a white solid (m.p. 238 ° C) * mass spectrum: m / e 241 (P).

Analysis for C ₁₃ M ₁₅ N c- >'

Calc.: C, 64.71 H 6.27 N 29.02 F: C 64.57 H 6.20 N 29.15

Example 18

4-diethylamino-1-ethyl - / * 1, 2, 4 _- 7triazolo / 4, S-aJ ^ quinoxaline

This compound was prepared by the method of Example 11, starting from 4-chloro-1-ethyl- / * 1, 2,4_7triazolo / 4,3-a_7-quinoxaline (product of Example 4) as starting material instead of 4-chloro-1 , 2, 4 / triazolo / 4,3-aquinoxaline (product of Example 2) and diethylamine as reagent instead of di-n-propylamine / The crude product was recrystallized from cyclohexane to give 3.54 g (69% yield). pure 4-diethylamino-1-ethyl ^ / * 1, 2,4 _- 7triazolo / "4,3-aynoxinoxaline as a white solid (m.p.

ζω ., mass spectrum: m / e- 269 (P).

Isopropylamiin; (Tt ,, 77 g ?, 0.03 MOiL); became too; a solution of 4-ChOiOiE- 1i-eth ^ 3i ^/: _f li, 2,, 4i / triazQa; o / _4! , _; 3-a7ghinoxaline (2 , 3 g, 0.01 mol)) Produfct des; Example: 4 in 13 ,, N-Dime thy If brmamid (30 ml) given, Inuerhaslb 3 © i mdin formed; Precipitation ;. The ReaMicmsgemiseh; was then stirred overnight at room temperature - the NiL noble beating; was filtered off and washed with N, N-dimeth-

; gjewaschera., Recrystallization 3με ethanol gave t, ß gs ({63% yield)] 4-Isopropyl-T-ethyl- / 1, 2,4J- ^ mp., 222-224 ° .. Mas sen spectrum:

Analysis for C, HL N;, - ::

:: G 6 & J6 m 6,, 71; N 27.43 gef ..:. _: C & 5,3i2 H <6 _r 7'6 N: 27 ^ 25

Example 20

4 ^ ^ -ethyl mJnQ I JSOPrOPyI-ZT , 2, AJ triazolo / ^, 3-a ^ quinoxaline

A slurry of 1.0 gi (Q, 004 MOI) 4-chloro-1-isopropyl-ZFI, 2,4J-triazolo-1-yl-quinoxaline (product of Example 6) in N, N-dimethylformamide; (15 ml) was saturated with monoethylamine-gas and; stirred at room temperature A 'h .. The precipitate was ABFI; litriert undi with N, N-Dimethy formamide washed to 220 mg! (22% yield) 4 ~ ethylamino-1 -isopropy 1- / 1, 2, 4 / triazolo / " 4,3-aJ- quinoxaline, m.p. 209-21 'Ii ⁰ G, .- Mass spectrum: m / e 255 (Pl.

The filtrate was then poured onto ice and the precipitate filtered off, washed with water and recrystallised from methanol and then from isopropanol for an additional 200 mg (20% yield) of pure 4-ethylamino-1-isopropyl- / 1, 2,4,7-triazolo / 4,3-aJ- quinoxaline, m.p. 210-211 ° C.

Analysis for C ₁₄ H ₁₇ N,.:

Calc .: C 65.86 H 6.71 N 27.43, m.p. C 65.53 H 6.58 N 27.29

Example 21

4-diethylamino-1-isopropyl - / "1, 2,47triazolo / 4,3-a7-quinoxaline

2-Chloro-i-isopropyl-Z'i, 2,4_7triazolo / 4,3-aquinoxaline (1, Og, ~ "0.004 mol), product of Example 6, and 900 mg (0.012 mol), diethylamine in N, N The reaction mixture was poured onto ice and the precipitate filtered off, washed with water and placed on a column of silica gel (175 ml) and finally eluted with chloroform The eluate was concentrated in vacuo to give To give 850 mg (75% yield) of pure 4-diethylamino-i-isopropyl - / "1,2,4_7triazolo / f4,3-a_7-quinoxaline as a white solid (mp 93-95 ^e C). Mass spectrum: m / e 283 (P). The pure product (100 mg) was then distilled under vacuum (13.3 Pa or 0.1 mm) at 140 ° to 150 ⁰ C, to give the analytical sample (80 mg), mp. 94-96 ° C.

Analysis for C ₁ ^ Hp ₁ N ₁ -:

Calc .: C 6 7.82 H 7,4 7 N 24,71 F: C 67,56 H 7,20 N 24,50

Example 22

4-diethylamino-1-n-propyl-, -1,4,4-triazolo / 4,3-a., Quinoxaline

4-Chloro-1-n-propyl - '', 2,47triazolo / 4,3'-aquinoxaline (1.23 g, 0.005 mol), product of Example 5, and 1.1 g (0.15 mol) Diethylamine in Ν, Ν-dimethylformamide (15 ml) was stirred for 2 h at room temperature, the reaction mixture was then poured onto ice, the precipitate was filtered off, washed with water and air dried (twice) crystallization from ethanol / water afforded 1.1 g (78% yield) of pure 4-diethylamino-1-n-propyl - / "1, 2,47triazolo / 4,3-a7-quinoxaline, mp 92-94 ⁰ C. mass spectrum. m / e 283 (P) ,

Analysis for ^c -j6 ^H 21 ^N 5 * ¹ / ^{8H <} 2 ^0:

Calc .: C 67.28 H 7.50 N 24.52 Found: C 67.38 H. 7.45 N 24.73

Example 23 ν

_< 8-Chloro-4-diethylamino-1-ethyl- / '1, 2,47triazolo /' 4,3-a_7quinoxaline

a) Preparation of 4,8-dichloro-1-ethyl- / "1, 2, 47-triazolo /" 4,3-aJ- quinoxaline. ,

2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g, O, OO44 mol), product of Preparation L (a) _r , was refluxed with 15 ml of triethylorthopropionate for 4 hours and cooled to room temperature. The precipitate was filtered off, washed with cyclohexane and air dried to give 730 mg (62% yield) of 4,8-dichloro-T-ethyl- / "1 _/ 2,47triazolo /" 4,3-aquinoxaline, mp> 25 ° C to surrender. Mass spectrum: m / e 266 (P); m / e 268 (P + 2).

b) Preparation of 8-chloro-4-diethylamino-1-ethyl- / '1, 2,47-triazolo / T4,3-47-quinoxaline

4,8-dichloro-1-ethyl- / "1, 2,47triazolo /" 4,3-aquinoxaline (7.4 g, 0.028 mol) and 6 g (0.082 mol) diethylamine in N, N-dimethylformamide (150 mL ) were stirred at room temperature for 4 h. The reaction mixture was filtered and the filtrate

Poured ice. The precipitate formed was then filtered off and taken up in chloroform. The chloroform layer was then dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo to a near-white solid, which was later recrystallized from diethyl ether / petroleum ether to give 1.6 g of pure 8-chloro-4-diethylamino-ethyl / Ί, 2 / to give 47triazolo / _{4/3-a7chinoxalin,} mp. 105-108 ⁰ C (dec.). Mass spectrum: m / e 303 (P); m / e 305 (P + 2).

Analysis for

C 59.30 H 5.97 N 23.05 F: C 58.92 H 5.85 N 22.81

Example 24

7,8-Dichloro-4-diethylamino-1-ethyl- / ' 1,2,4 -triazolo / -4,4 -s- quinoxaline

a) Preparation of 2,6,7 ~ trichloro-3-hydrazino-quinoxaline

2,3,6,7-Tetrachloroquinoxaline (4.4 g, 0.016 mol) and 1.76 g (0.035 mol) of hydrazine hydrate in ethanol (60 mL) were stirred overnight at room temperature. The thick slurry was filtered and washed with ethanol to give 4.9 g of crude 2,6,7-trichloro-3-hydrazinoquinoxaline, mp <26 ° C. Mass spectrum: m / e 262 (P); m / e 264 (P + 2).

b) Preparation of 4 _/ 7,8-trichloro-1-ethyl- / "1, 2,47triazoio- / 4,3-a7-quinoxaline

^

2,6-T-trichloro-S-hydrazinoquinoxaline (4.9 g, 0.018 mol) in triethylorthopropionate (50 ml) was heated at 100 ^° C. for ² hours. The aehi Idete precipitate was filtered off at room temperature and washed with cyclohexanes. Recrystallization twice from chloroform / cyclohexane then gave 2.9 g (54% yield) of pure 1, 7,8-trichloro-1-ethyl- / 1, 2, 47-

tr ia zolo / 4, 3-a_7chinoxal in as a pink solid (mp 198-201 ° e). Mass spectrum: m / e 300 (P); m / e 302 (P + 2); m / e 304 (P + 4); m / e 306 (P + 6).

c) Preparation of 7,8-dichloro-4-diethylamino-1-ethyl- / "T, 2,4_7-triazolo / 4,3-a_7-quinoxaline

4,7,8-trichloro-1-ethyl-1,2,2-triazolo / 4,3-aquinoxaline (2.9 g, 0.0096 mol) and 2.1 g (0.0388 mol) of diethylamine in N The reaction mixture was poured onto ice and stirred for 15 minutes The precipitate was filtered off, washed with water and air dried (3 times) recrystallization from isopropanol then gave 500 mg (16%). Yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl- / * 1,2,4-triazolo / 4,3-a_7-quinoxaline, m.p. 147-149 ° C. Mass spectrum: m / e 337 (P); m / e 339 (P + .2).

Analysis for C ₁ JH ₁₇ Cl ₂ N ₁ .:

Calc .: C 53.26 H 5.07 N 20.70 Found: C 53.05 H 5.13 N 20.75.

Example 25 :

4-diethylamino-v1-ethyl-8-methoxy - / "1, 2 _/ 47triazolo /" 4, 3-a_7chin oxalin '. \ '

a) Preparation of 2-chloro-3-hydrazino-6-methoxy-quinoxaline

^, S-dichloro-e-methoxyquinoxaline (4.2g, 0.018mol), product of Preparation E (b), and 2.7ml of hydrazine hydrate in 100ml of ethanol were heated at reflux for 4 hours and stirred at room temperature overnight. The precipitate was filtered off, washed with ethanol, and 3.9 g (97% yield) of 2-chloro-S-hydrazino-o-methoxyquinoxaline, Sciuup .. <i25O ° C, ζμ give. Mass spectrum: m / e 224 (P), m / e 226 (P + 2).

b) Preparation of 4-chloro-1-ethyl-8-methoxy- ~ 1,2,4_ / triazolo- £ 4,3-a_7quinoxaline

^2-chloro-i -3-hydrazino-6-methoxyquinoxaline (1, 3 g, 0.0058 mol) and 25 ml of triethyl orthopropionate was stirred for 4 h 60 h at 100 ⁰ C. and at room temperature. The precipitate was filtered off and washed with ethanol. Recrystallization from ethanol then afforded 530 mg (35% yield) of pure _{4-chloro-1-ethyl-8-methoxy-l} in / 2,4_7triazolo / 4, 3-a_7chinoxalin, mp. 196-198 ⁰ C. (Dec.)

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

c) Preparation of 4-diethylamino-1-ethyl-8-methoxy- ~ 1,2- A-triazolo / 4,3-a_ / quinoxaline

4-Chloro-1-ethyl-8-methoxy- ~ 1, 2,47triazolo / 4,3-a_7-quinoxaline (520 mg, 0.002 mol) and 673 mg (0.008 mol) of diethylamine in 10 ml of N, N-dimethylformamide were added Room temperature stirred overnight. The reaction mixture was poured onto ice and the precipitate filtered off, washed with water and air dried. Recrystallization from diethyl ether and petroleum ether then afforded 140 mg (23% yield) of pure 4-diethylamino-1-ethyl-8-methoxy - / "1, 2, 4_7triazolo / 4, 3-a_7chinoxalin, mp, 135-138 ^0C.

 Mass spectrum m / e 299 (P).

Analysis for C ₁ ^ ₂₁ N ₅ O * 1 / 8H ₂ O:

Calc .: C 6 3.71 H 7.10 N 23.22 Found: C 63.6-3 H 6.88 N 23.37

Example 26 , "'!

4-diethylamino-1-phenyl - / '1, 2 _/ 47triazolo / "4.3 ~ a7chinoxalin

a) Preparation of 4-chloro-1-phenyl - / * 1, 2,47triazolo / "4,3-a7 quinoxaline ^!

^ -Chloro-S-hydrazinochinoxalin (2.2 g, 0.011 mol) was mixed with 6 ml Triethylorthobenzoat and 30 min at ⁰ TOO G heated. After cooling the orange mixture to room temperature, ethanol was added. Filtration of the resulting precipitate gave 2.1 g. The crude product was further purified by trituration with warm methanol, followed by filtration and flash drying to finally afford 1.58 g (51%) of pure 4-chloro-1-phenyl- ~ 1,2,4triazolo / 4,3-a7-quinoxaline as an orange solid. ,

b) Preparation of 4-diethylamino-1-phenyl- / * 1, 2,47-triazolo [A , 3-a / quinoxaline

To 1.58 g (0.00563 mol) of 4-chloro-1-phenyl-1-, 2,4-triazolo- / "4,3-a-quinoxaline dissolved in 1.5 ml of N, N-dimethylformamide _{r was} added 1.738 ml of diethylamine The mixture was stirred at room temperature overnight The formed precipitate ^x was collected by filtration, washed with N, N-dimethylformamide and recrystallized twice from hexane / ethyl acetate (3: 1 by volume) to give 555 mg of pure 4-diethylamino-i -phenyl- [Λ , 2,47triazolo / 4,3-a7-quinoxaline as white needles (mp 166-168 ° C).

Analysis for C ₁ QH ₁₉ N ₅ :

Calc .: C 71.60 H 5.99 N 22.06 Found: C 71.86 H 5.86 N 22.09.

Example 27

4-diethylamino-1 -trif luormethyl- /! ", 2,47triazolo /" 4, 3-a7chinoxalin '\'

a) Preparation of 4-hydroxy-1-trifluoromethyl- / 1,2,47-triazolo- / 4,3-aquinoxaline

2-Chloro-3-hydrazinoquinoxaline (3.89 g, 0.02 mol), product of Example 1, is added to 22.8 g (0.20 mol) of cold trifluoro-

Acetic acid (15.4 ml) in a flamed, surrounded by an ice bath reaction flask under a dry nitrogen atmosphere with mechanical stirring. The reaction mixture was then heated to 100 ⁰ C for 3 h and poured onto ice. The resulting product was then filtered off, washed with water and air-dried to constant weight. Thus, 3/0 g (60%) of pure 4-hydroxy-1-trifluoroethyl- / "1 _/ 2,47triazolo / 4,3-a_7-quinoxaline, mp> 300 ° C., were finally obtained, mass spectrum: m / e 254 ( P).::

b) Preparation of 4-chloro-1-trifluoromethyl-1,2,4,7-triazolo- / * 4,3-a-7-quinoxaline

In a flamed reaction flask under a dry nitrogen atmosphere 3.0 g (0.0118 MPI) 4-hydroxy-i-trifluoromethyl were - / "1, 2 _/ 4_7triazolo /" 4,3-a_7chinoxalin and 30 ml of phosphorus oxychloride in 2.38 g (0.0236 mol) of triethylamine (3.3 ml). The reaction mixture was then heated at 100 ° C for about 16 hours (ie overnight). Then the spent mixture was cooled to room temperature, concentrated in vacuo and then partitioned between ice, water and ethanol, then extracted with ethyl acetate. The latter extract was then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a residue was obtained / which was then dissolved in hot chloroform and filtered. This latter filtrate could then stand overnight at room temperature and was filtered again. The final filtrate was then concentrated in vacuo, finally by 1.4 g of 4-chloro-1 -trif trifluoromethyl / _{"1/2 /} 4-7'triazolo / 4, 3-a_7chinoxalin to give in form of a brownish solid.

c) Preparation of 4-diethylamino-1-trifluoromethyl-1, 2,4J-triazolo / 4,3-a / quinoxaline

A mixture of 700 mg (0.0025 mol) of 4-chloro-1-trifluoromethyl-, 2,47-triazolo / 4,3-a / quinoxaline (prepared as described above) and 560 mg (0.0075 mol) Diethylamine (0.8 ml) in

-5Q-

10 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight and then poured onto ice. The resulting mixture was then filtered and the recovered solid product was washed with water and then dissolved in ethyl acetate. The latter organic solution was then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration of the drying agent and removal of the solvent under reduced pressure, a pale yellow solid was finally obtained, which after recrystallization from diethyl ether pure 4-diethylamino-1-trif luormethyl- / "!, 2, 4 / triazolo ~ /" 4.3 * a7quinoxaline gave. The yield of the first, bei'155-157 ⁰ C melting amount was 260 mg (34%), while the yield of the second melting at 153-156 ⁰ C Volume 170 mg (22%) was. '.

Analysis for C.H., .F ^ N ^:

Calc .: C 54.37 H 4.56 N 22.64 Found: C 54.08 H 4.47 N 23.32.

Example 28 .

4-isopropylamino-T-trifluoromethyl - / "1, 2, 4ytriazolo / 4, 3-AJ _chinpxalin: ·

A mixture of 700 mg (0.0025 mol) of 4-chloro-1-trifluoromethyl-1/1, 2,47triazolo / 4,3-aquinoxaline (product of Example 27b) and 443 mg (0.0075 mol) of isopropylamine (0.64 ml) in 10 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight and then poured onto ice The resulting mixture was then filtered and the recovered solid product was washed with water and then dissolved in diethyl ether It was then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent and stripping the solvent under reduced pressure, a white, solid powder was finally obtained, which after a single recrystallization

Diethyl ether 550 mg (74%) of pure 4-isopropylamino-1-trif luorinethyl -. / ^, 2, 4_7triazolo / "4, 3-a_ / quinoxaline, m.p. 185-187 ⁹ C, resulted.

Analysis for ^c i3 ^H i2 ^F 3 ^N 5 ^:

Calc .: C 52.88 H 4.10 N 23.72 F .: C 52.73 H 4.00 Ν 23.67.

Example 29

i-ethyl-4- (N-ethylacetylamino) - / 1, 2,4-yliazolo / 4,3-a7chine

oxalin   , '

A mixture of 241 mg (0.001 mol) of i-ethyl-4-ethylamino / Ί, 2 _/ 47triazolo / 4,3-a / quinoxaline (product of Example 17) and 2.5 g (0.025 mol) of acetic anhydride (2, 5 ml). in an ignited reaction flask was refluxed under dry nitrogen atmosphere for 3 h (140 ⁰ C) and then allowed to cool to room temperature. Now the precipitate formed and the resulting reaction mixture were poured into water and extracted with chloroform. The chloroform extracts were combined / washed with water and then dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a solid product was obtained which, after recrystallizing once from chloroform / diethyl ether, 160 mg (57%) of 1-ethyl-4- (N-ethylacetylamino) -1,2,4-triazolo / 4,3-a7-quinoxaline, m.p. 185-187 ° C.

Analysis for C ₁₁ -H ₁₇ N ₁ -O:

Calc .: C 63.59 H 6 ₇ O5 N 24.72 Found: C 63.17 H 6.05 N 24.39.

Example 30

4-Acetylamino-1-ethyl- / "1,2,47-triazolo /" 4,3-a-7-quinoxaline

A mixture of 533 mg (0.0025 mol) of 4-amino-1-ethyl- / "1, 2,47-triazolo / 4,3-a7-quinoxalaline (product of Example 14) and 1.0 g (0, 1 mol) of acetic anhydride (1.0 ml) in 20 ml of methylene chloride was refluxed overnight (about 16 hours) and then allowed to cool to room temperature, and the resulting clear solution was concentrated in vacuo to a white, solid substance, which was then precipitated Chloroform / ethyl ether to give 520 mg (82%) of pure 4-acetylamino-1-ethyl-ΖΊ, 2,47triazolo / 4,3-a ^ quinoxaline, m.p. 193-195 ° C.

Analysis for C ₁ ^ H ₁₃ N ₅ O: ·

Calc .: C 61.16 H 5.13 N 27.43 Found: C 60.90 H 5.26 N 27.66.

Example 31 ,

_- / "1,2,47triazolo / 4,3-aquinoxaline

A mixture of 5.5 g (0.0258 mol) of 4-amino-i-ethyl- / "1 ; 2,4- triazolp / 4,3-a / quinoxaline (product of Example 14) and 25 g (0, 25 moles) of acetic anhydride (25 ml) in 60 ml of pyridine containing 100 mg of p-dimethylaminopyridine was stirred at room temperature overnight (about 18 hours) The resulting slurry was then filtered to remove the insoluble constituents and orange-red filtrate was then concentrated under high vacuum to a dark resinous residue. After adding water, pinkish-white crystals were obtained and these were filtered off under suction, washed with a copious amount of water and dried in vacuo at 50 ⁰ C in order to finally 2.9 g (38%) 4-diacetylamino-1-ethyl- / i, 2,47triazolo / '4,3-aJ-quinoxaline, mp. 157-159 ⁰ C to give. recrystallization of the latter material from ethyl acetate / di-ethyl ether then gave an analysis-pure sample (mp.158-16O ⁰ C). The pure product was analyzed by mass spectroscopy and nuclear magnetic resonance data further characterizing the elemental analysis

Siert. Mass spectrum: m / e 297 (P) Analysis for C ₁₅ H ₁₅ N ₅ O ₃ :

Calcd .: C 60.59 H 5.09 N 23.56 Found: C 60.33 H 5.09 N 23.41.

Example 32

The following Ί, 2,4 / triazolo / 4, S-s were prepared according to the procedures used in the previous Preparations and Examples, starting from readily available materials in each case:

7,8-dibromo-4-diethylamino- [1,2,4] trlazolo [4,3-a] quinoxaline, Schirp. 199-201 ⁰ C.

8-chloro-4-isopropylamino-il, 2,4] triazolo [4,3-a] quinoxaline, m.p. 177-181 ° C.

4-Ethylamino-1-trifluoro-methyl- [1,2,4-triazolo-4,3-a] quinoxaline, bp 223-225 ° C.

1-Ethyl-ethylamino-e-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, mp. 234-237 ° C.

4-Edethylamino-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, mp 124-126 ° C.

8-chloro-1-ethyl-4-isopropylamino-11 '»2,4] triazolo [4,3-a] quinoxaline, Schrrp. 189-191 ⁰ C.

4- (N-? Iperazino) -tl, 2,4] triazolo [4,3-a] quinoxaline, mp. 160-162 ⁰ C.

8-chloro-4- (N-piperazino) - [l, 2,4] triazolo [4,3-a] quinoxaline, mp 253-256 ° C.

8-Ehlor - -4- (N-isopropylacetylamino) - [l, 2,4] triazolo [4,3-a] quinoxaline, b.p. 148-151 ° C.

4-Acetylamino-8-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, Schrap. 203-205 ⁰ C.

8-chloro-1-ethyl-4- (N-isopropylacetylamino) -1,2,4-triazolot4,3-a] trhinoxaline, mp. 155-158 ° C.

7,8-Dlchlor -4- (N-isopropylacetylamino) - [1,2, a] triazolo [4,3-a] quinoxaline, m.p. 207-210 ⁰ C..

4-Amino-7,8-dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] -

'j. - '

quinoxaline, mp.> 260 ⁰ C.

A-Atnino-S-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, mp. 248-253 ° C.

4-acetylamino-7,8-dichloro-1-ethyl- [l, 2,4] triazolo [4,3-a] quinoxaline, Schit. 230-232 ⁰ C.

8-fluoro -4-isopropylaTnino- [1,2,4] triazolo [4,3-a] quinoxaline, mp. 215-217 ⁰ C.

4-ethylamino-8-fluoro - [l, 2,4] triazolo [4,3-a] quinoxaline, Schinp, 239-242 ⁰ C.

l-ethyl-8-fluoro-4-isopropylamino- [1,2,4] triazolo [A, 3-a] quinoxaline, Schrtp. 209-212 ⁰ C.

7,8-Difluoro-4-isopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline, Schrtp. 218-221 ⁰ C.

1-ethyl-4-ethylamino-8-fluoro- [1,2,4] triazole [4,3-a] quinoxaline, Schit. 231-233 ° C.

: 7,8-Difluoro-ethylamino- [1,2,4] triazolo [4,3-a] -

quinoxaline, mp. 208-211 ⁰ C.

4-Diethylanino-8-fluoro [1,2,4] triazole [4,3-a] quinoxaline, m.p. 151-153 ° C.

4-Diethylamino-1-ethyl-8-flupr - [1,2,4] triazolo [4,3-a] quinoxaline, mp. 94-97 ° C.

7-Chloro-4-dimethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline-methane-sulphonate (mesylate), m.p. 214-217 ° C. , '' *

7-Chloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 172-175 ° C.

7,8-Dichloro-1-ethyl-4- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline τ-methane sulfonate, mp 252-255 ° C.

7,8-dichloro-4-dimethylaminoO'-l-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-methane sulfonate, m.p. 216-219 ^P C.

^ -Acetylamino-l-ethyl-S-fluoro - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 203-205 ⁰ C..

4-Amino-7-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] -

quinoxaline - methan_sulfonat, mp 240-243 ⁰ C..

7-chloro-l-ethyl-4-ethylamino [l, 2,4] triazolo [4,3-a] quinoxaline methane sulfonate, m.p. 187-189 ° C.

7-chloro -4-diethylamino [1,2,4] triazolo [4,3-a] quinoxaline-methane-sulfonate, mp. 205-207 ⁰ C-.

4-Diethylamino-7,8-difluoro - [1,2,4] triazolo [4,3-a] quinoxaline methane sulfonate, Schrap. 220-223 ⁰ C.

, 4-acetylamino-7-chloro-1-ethyl- [1,2,4] triazolo

[4, 3-a] quinoxaline, mp. 210-212 ⁰ C.

8-chloro-1-ethyl-4-ethylamino [l, 2,43triazolot4,3-a] -

quinoxaline methane sulphonate ^ mp. 235-238 ⁰ C.

4-Amino-7-chloro [1,2,4] triazolo [4,3-a] quinoxaline methane sulfonate, m.p. 279-282 ° C.

^ -A-mino-e-chloro -l-methyl- [1,2,4] triazolo [4,3-a] quinoxaline methane-sulfonate, mp. 213-215 ⁰ C.

8-chloro-4-isopropylamino-1-trifluoro-methyl- [1,2,4] -triazolo [4,3-a] quinoxaline-sulfonyl-sulfonate. 183-185 ° C.

8-chloro-4-diethylamino-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline methane sulfonate, m.p. 172-175 ⁰ C,

4-Diacetylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 211-214 ° C.

4-Diacetylamino-8-chloro - [I, 2,4] triazolot4,3-a] -

chLnoxalin, mp. 208-210 ⁰ C.

8-ehlor -4-isopropylamino-l-methyl- [1,2,4] triazolo [4,3-a] chinoxalinmethan-sulfonate, mp. 206-208 ⁰ C.

4- ^ ethylamino-1-methyl-8-chloro [1,2,4] triazolo [4,3-a] quinoxaline, mp 262-264 ° C.

8-Chloro-1-ethyl-A-trimethylacetylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 211-213 ° C.

7,8-Difluoro-1-ethyl-4-isopropylamino [l, 2,4] triazolo [4,3-a] quinoxaline methane sulfonate, 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-trifluoro-ethyl [1,2,4] triazolo [4,3-a] cinoxaline hydrate, Sclmip. 135-136 ⁰ C.

4-amino-8-chloro-1-trifluoromethyl [1,2,4} triazolo [4,3-a] quinoxaline-methanesulfonate ₇ % by wt. 259-261 * 0 ^ u:

4-ethylamino-8-fluoro -.l-trifluoro-methyl- [l ·, 2, 4] -, 3-a] quinoxaline-methane-sulfonate, mp -. 180-183 ⁰ C.

8-fluoro -4-isopropylamino-l-trifluoro-methyl-tl ^^ jsa] quinoxaline -. Methane-sulfonate, m.p. .1.85.-188 ⁰ C..

4-diethylamino-7,8-difluoro-1-ethyl- [1,2,4] triazolo [4i3-a] x ehinoxaline, Schit. 109-111 ⁰ C. · .. ". .:. ',.

l egg. hyl-4-ethylamino-7-f luor - [l, 2,4] triazolo [4,3-a] quinoxaline - methane-sulfonate, m.p. 215-219 ⁰ C.

tl, 2,4] triazolo [4,3-a] quinoxaline-methane-sulfonate, m.p. 262-264 ⁰ C.

8-chloro-4-isopropenylamino-l-phenyl- [1,2,4] triazolo - [1,3-a] quinoxaliri, mp 183-186 ° C. , ;;

8-chloro-4-ethylamino-1-phenyl- [1,2,4] triazolo [4,3-a] cinoxaline, mp 254-256 ° C. ^:

7-Fluoro-4-isopropylamino [l, 2,4] triazolot4,3-a] -quinoxaline-methane-sulfonate, m.p. 214-216 ° C. -

1-Ethylamino-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline methane sulfonate, m.p. 216-218 ° C

1-diethylamino-8-fluoro-1-trifluoro-methyl [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 146-149 ° C.

7,8-dichloro-1-ethyl-4-isopropylamino [l, 2,4] triazolo [4,3-a] quinoxaline, mp 197-198 ° C.

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

l <-acetylamino-1-ethyl-7-fluoro-1,4-triazolo [4,3-a] -quinoxaline, m.p. 273-275 ° C.

1-Acetylamino-8-chloro-1-trifluoro-methyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 215-216 ° C. :

4-Amino-8-chloro-1-phenyl- [1,2,4] triazolo [4,3-a] -. , · .. .. _: . quinoxaline methane sulfonate, m.p. 273-275 ° C.

8-chloro-4-ethylamino-1-trifluoro-methyl- [1,2,4] -. ;, Triazolo [4,3-a] quinoxaline, m.p. 228-230 ⁰ C..

1-Ethyl-7-fluoro-4-isopropylamino- [1,2,4] triazoloro [4,3-a] quinoxalirimethanesulfonate, m.p. 178-181 ° C. ., ..- ..

4-Amino-8-fluoro -1-trifluoro-methyl- [1,2,4] triazolo [4,3-a J quinoxaline hydrate, Schnp. 260-263 ⁰ C.

• 8-chloro-1-ethyl-1-R-phenylisopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline, mp. 155-157 ° C.

4-Amino-1-ethyl-7-fluoro- [I, 2,4] triazolo [4j3-alquinoxaline, bp 285-289 ° C

* 4-amino-l-ethyl-7-methoxy- [l, 2,4] triazolo [4,3-a] -tphinoxalin - methanrsulfonat, Schnp 255-258 ⁰ C..

^ -Acetylamino-e-fluoro -1-trifluoro-methyl- [1,2,4] -triazoloiA, 3-a] quinoxaline, Schnp. 217-219 ⁰ C.

4-acetylamino-l-ethyl-7-methoxy-II, 2,4] triazolo [4,3-a] quinoxaline, mp. 202-205 ⁰ C.

8-chloro -l-ethyl-4S-phenylisopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline, Schnp. 156-157 ⁰ C.

4-acetylamino-8-fluoro -. [1,2,4] triazolo [4,3-a] quinoxaline, Schnp 240-242 ⁰ C.

4-Acetylamino- [1,2,4] triazolo [4,3-a] fehinoxaline, mp 269-272 ° C.

4-amino-7-fluoro - [1,2,4] triazolo [4,3-a] chinoxalinmethan-sulfonate, Schnp 246-248 ⁰ C..

4-Amino-8-fluoro -. [L, 2,4] triazolo [4,3-a] chinoxalinmethan-sulfonate, m.p. 176-178 ⁰ C.

4-Amino-7-fluoro [l, 2,4] triazolo [4,3-a] quinoxaline, Sclinp. 290-292 ⁰ C.

8-chloro -4-isopropylamino-l-pentafluoro-ethyl-11,2,4] triazolo [4,3-a] quinoxaline, Schnp. 171-174 ⁰ C.

Example 33

8-chloro-1-ethyl-4-propionylamino- / "1,2" -benzetriazolo / ^, 3-a7- quinoxaline, ... · ·, '···''','.'',.

A mixture of 1.25 g (0.005 mol) of 4-AmXnO-B-chloro-1-ethyl- / 1 ^^^ triazolo / ^^ - aJquinoxaline (mp 248-253 ⁰ C), one in Example 32> chriebenes product, and 15 ml of propionic anhydride was refluxed for about 16 hours overnight and then cooled to room temperature (about 20 ⁰ C) is cooled. Then the

 leh.de- reaction mixture is filtered and the recovered Nieder-

'' .. - '/.

then dissolved in chloroform. The latter organic solution was then filtered and washed successively with water, saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the drying agent and removing the solvent under reduced pressure, a residue material was obtained, which was then chromatographed on a 150 ml silica gel column and then eluted with chloroform / methanol (95: 5 volumes). Equal product-containing fractions were combined and then concentrated in vacuo to a crystalline material which was later recrystallized from chloroform / ethyl ether to finally afford 540 mg (36%) of pure 8-chloro-i-ethyl-4-propionyl-amino-Zi to give 2, 4_7 tr iazolo / "4, 3-a_7chinoxalin, mp 212-215 ° ^C..:

Analysis for

calc .: C 55.36 H 4.64 N 23.06

Found: C 54.91 H 4.59 N 22.76

Claims (10)

invention claim A process for the preparation of a 1, 2, 4-triazolo- / 4,3-a-quinoxalin-4-amine derivative of the formula (I) ΛNR ₂ R ₃ and its pharmaceutically acceptable acid addition salts, wherein X and X are each selected from hydrogen, fluoro, chloro, bromo and methoxy; R _{1 is selected} from hydrogen, lower alkyl, lower perfluoroalkyl and phenyl, and R ₂ and R-. in each case selected from hydrogen, lower alkyl, phenylalkyl having up to 3 carbon atoms in the alkyl radical and alkanoyl having 2 to 5 carbon atoms, with the proviso that at least one of R and R ₃ always has a meaning other than hydrogen, if X and X each hydrogen sind'und R is hydrogen or methyl; or R "and R _{3 taken} together complete a piperazino ring, characterized in that a corresponding 4-chloro compound of the formula (IIAoderllB) wherein X, X and an amine of the formula HNR-R .., in which each as previously defined, with and R ^ are each as previously defined, except that they have a meaning other than alkanoyl, reacted to the corresponding 4-amino compound and, if necessary, the thus obtained 4-amino compound wherein at least one of R ₂ and R is hydrogen, reacted with a suitable alkanoic anhydride to give the desired 4-amine derivative with the requisite alkanoyl radical and, if desired, a compound of formula (I) is converted to a pharmaceutically acceptable acid addition salt. 2. The method according to item 1, characterized in that the amination reaction is carried out using a molar excess of amine of formula, HNR ₀ R- in a reaction-inert organic solvent. 3. The method according to item 2, characterized in that dimethylformamide is used as the reaction-inert organic solvent. , 4. The method of item 2, characterized in that the amination reaction is carried out at a temperature of about .0 to about 60 ⁰ C for about 2 to about 24 h. Cri A process according to item 1, characterized in that the acylation of the 4-amino compound is carried out under substantially anhydrous conditions using at least an equimolar amount of the appropriate alkanoic anhydride. 6. The method according to item 5, characterized in that the molar ratio of the acid anhydride to the 4-amino starting material is in the range of about 1: 1 to about 25: 1. 7. The method of item 1, characterized in that the acylation of the 4-amino compound at a temperature in the range of about 2O to about 14O ° C for about 0.5 to about 24 h is performed. 8. The method according to item 1, characterized in that the acylation of the 4-amino compound is carried out in the presence of a neutral, reaction-inert, anhydrous organic solvent. 9. The method according to item 8, characterized in that the neutral, reaction-inert, anhydrous organic solvent is a halogenated hydrocarbon. 10. The method according to item T, characterized in that the prepared [Λ, 2,47Triazolo / 4,3-a7-quinoxalin-4-amine derivative 1-ethyl-4-ethylamino - / "1, 2,4. / Triazolo / 4, 3-a ^ quinoxaline.