DK163432B - Analogy process for preparing [1,2,4]triazolo[4,3- a]quinoxaline-4-amine derivatives or pharmaceutically acceptable acid addition salts thereof - Google Patents

Description

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DK 163432B

The invention relates to an analogous process for the preparation of novel [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivatives of the general formula I or pharmaceutically acceptable acid addition salts thereof as set forth in claim 1. , which compounds are useful as antidepressants and antidepressants.

There is an intensive search for agents that are effective in reducing the symptoms of mammalian depression and fatigue.

US Patent No. 3,839,569 and DE Pat.

2,249,350 discloses the use of s-triazolo [4,3-a] quinoxalines and 1H-imidazo [4,5-b] quinoxalins, respectively, as agricultural fungicides. U.S. Patent No. 4,008,322 discloses the use of a variety of triazolot4,3-a] quino-15 xaline derivatives to combat crack widening caused by the phytopathogenic organism Piricularia oryzae.

According to the invention, it has been found that the novel [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivatives of formula I are useful as antidepressants and fatigue-reducing agents.

A group of interesting compounds are those in which X and X 2 are both hydrogen, R 2 is hydrogen, and and R 2 are each independently ^ alkyl. Preferred compounds are those wherein R 2 and R 2 are both ethyl.

Another group of compounds which can be prepared by the process of the invention are those in which X and X1 are both hydrogen, R 1 is ethyl and R 1 is C 1-6 alkyl. Preferred compounds are those wherein R R is hydrogen and R ^ is ethyl.

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Yet another group of compounds which can be prepared by the process of the invention are those wherein X and X1 are both hydrogen, R 1 is 4 alkyl, and is acetyl. Preferred compounds are those wherein 5 is ethyl and is hydrogen, ethyl or acetyl.

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A further group of interesting compounds which can be prepared by the process of the invention are those in which at least one of X and X is fluorine, R 1 is hydrogen or trifluoromethyl, is hydrogen, and R 2 is hydrogen, C alkyl or alkanoyl having 2-5 carbon atoms, or alternatively wherein at least one of X and X 1 is chloro, R 1 is C 1-6 alkyl or trifluoromethyl, R 2 is hydrogen and R 2 is hydrogen, -5 carbon atoms.

The compounds of the invention can be used in the form of pharmaceutical compositions containing an antidepressant and / or 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. Preferred pharmaceutical compositions are those containing the preferred compounds of formula I as described above.

The present compounds of the general formula I or pharmaceutically acceptable acid addition salts thereof are prepared by the process according to the invention, which is characterized by the characterizing part of claim 1.

The majority of the compounds of formula I can be prepared by the reaction sequence shown in Scheme I. The numbering of the two heterocyclic rings and the phenyl ring in Scheme I is that which

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3 is reversed throughout the description and requirements. ' In Scheme I, a compound of formula IV, a quinoxaline derivative, wherein X and each are hydrogen, fluorine, chlorine, bromine or methoxy, is treated with 5 X being always hydrogen when the quinoxaline derivative is monosubstituted in the benzene ring, with an excess molar amount of hydrazine hydrate. in a polar reaction inert organic solvent, such as an alkanol having 1-3 carbon atoms, preferably ethanol, at room temperature -10 for from about 18 to about 24 hours to form an intermediate of formula III.

The intermediate III can then be converted to the corresponding intermediate of formula IIA, which is different from perfluoroalkyl, by treatment with a suitable alkyl orthoalkanoate or alkyl orthobenzoate at a temperature of from about 80 to about 120 ° C for from about 1 to about 24 hours. In the resulting compound of formula IIA, (as hydrogen or alkyl) is determined by the particular orthoalkanoate used in the synthesis. For example, if if triethyl orthoformate is used, R 2 is hydrogen; if triethyl orthopropionate is used, R 1 is ethyl and if triethyl orthoisobutyrate is isopropyl.

The intermediate III may also be converted to the corresponding intermediate of formula IIA wherein R 1 is C 1-8 perfluoroalkyl, by treatment with an excess molar amount of a suitable perfluoroalkanoic acid, such as trifluoroacetic acid or pentafluoropropionic acid, in conventional manner to form the corresponding to 4-30 hydroxy-1-perfluoroalkyl- [1,2,4] triazolo [4,3-a] quinoxaline, followed by treatment of the latter compound type with phosphorus oxychloride in the presence of a tertiary amine such as triethylamine, at elevated formation temperature 4

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of the corresponding 4-chloro compound.

The intermediate XIA (wherein hydrogen, C ^ _ alkyl alkyl, perf perfluoroalkyl or phenyl) is then converted to a [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivative of formula IA wherein R 2 and R 2 have the meaning previously defined, except that they cannot be alkanoyl, by treatment with an excess molar amount of an amine of the formula HNR 2 R 2 in a reaction inert organic solvent, preferably N, N-dimethylformamide, at a temperature of from about 0 to about 60 ° C for about 2 to about 24 hours.

Eg. For example, the preferred compounds of formula IA wherein R 2 and R 2 are both ethyl are prepared by treating the appropriate compound of formula II A with diethylamine in N, N-dimethylformamide at room temperature for 2-3 hours. Likewise, the preferred compounds of formula IA wherein R 2 is hydrogen and R 1 are ethyl are prepared by treating a compound of formula II A with monoethylamine in N, N-dimethylformamide at room temperature for 4-5 hours.

[1,2,4] The triazolo [4,3-a] quinoxaline-4-amine derivatives of formula IA, wherein at least one of R2 and is alpha-canoyl of 2-5 carbon atoms, are prepared from corresponding compounds of formula IA wherein at least one 25 of R 2 and R 2 is hydrogen by contacting the latter with the appropriate alkanoic anhydride under substantially anhydrous conditions. This reaction can 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 from about 20 up to about 140 ° C for a period of about 1 2 to about 24 hours. The molar ratio between acid anhydride and the 4-amino starting material should be at least about 1: 1 and preferably from about 4: 1 to about 1: 1.

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5 is about 25: 1, while the amount of tertiary amine used is usually from about 25 to about 150 weight percent. of the aforementioned acylating agent (the tertiary amine can be used as reaction solvent 5 by using only an excess thereof). While it is absolutely possible and even in some cases very desirable to carry out the reaction in the absence of a solvent, there may be cases where the use of a suitable reaction-inert organic solvent will be clearly appropriate. Suitable organic solvents for use in this connection include neutral, reaction-inert anhydrous solvents such as acetone, methyl ethyl ketone, benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride, chloroform, ethylene dichloride, tetrachloroethane, methyl acetate, ethyl acetate, isopropyl acetate, isopropyl acetate, , diethyl ether, diisopropyl ether and di-n-propyl ether. However, as stated above, the reaction is generally carried out in the absence of such a solvent by using only an excess of anhydride. Similarly, an excess of the tertiary amine may also serve as a solvent. 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 11 / wherein X and X * are both hydrogen are well known in the art. Compounds of formula IV wherein X 1 is methoxy may be prepared by the method of G. W. H. Cheeseman [J. Chem. Soc., P. 1170 (1962)], whereby 4-methoxy-o-phenylenediamine hydrochloride is treated with at least one equimolar amount of diethyl oxalate and diethylamine under an inert gas atmosphere, preferably nitrogen, at the reflux temperature of from about

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2 to about 3 hours, followed by treatment with phosphorus oxychloride in a tertiary amine, preferably dimethylaniline, at the reflux temperature for 1-2 hours.

In Scheme II, a quinoxaline derivative of formula IV wherein X is fluorine, chlorine, bromine or methoxy is treated and is hydrogen, with sodium methoxide in an alcoholic solution medium at slightly elevated temperature (e.g., 40-60 ° C) for a period of time. of from about 10 6 to about 18 hours to form the corresponding 2-chloro-3-methoxyquinoxaline derivative of formula V, which is then treated with hydrazine hydrate in the same manner as before to form the corresponding 2-hydrazino-3 -methoxyquinoxaline derivative of formula VI. The latter intermediate (VI) is then converted to the desired 7-substituted 4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline derivative of formula VII using a suitable ortho ester or with perfluoroalkanoic acid in the same manner as previously described, and the latter compound is then successively converted to the corresponding 4-hydroxy- (see formula VIII) and 4-chloro compound. by conventional procedure to form a compound of structural formula IIB wherein X has the above meaning (i.e., different from hydrogen), and Xx is hydrogen. This intermediate of formula IIB then leads to the corresponding novel products of formula IB wherein R 1, R 5 and R 2 all have the meaning given above and X and X 1 have the above meaning simply by using the reaction procedure. , as previously described in connection with the discussion of the final steps of the total Scheme I.

The pharmaceutically acceptable acid addition salts of the novel compounds of formula I can also be prepared according to the invention. These salts can easily be produced.

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7 is contacted by contacting the free base with a suitable mineral acid or organic acid either 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 acid addition salts which can be prepared by the process of the invention include, e.g. the hydrochlorides, sulphates, hydrogen sulphates, mesylates, tosylates, nitrates, phosphates, acetates, lactates, malates, fumarates, citrates, tartrates, succinates and gluconates. The mesylate salts are preferred. If desired, the compounds of formula I as the free base can be formed from the acid addition salts thereof by treatment with a suitable base, followed by extraction of the free base with a suitable organic solvent.

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

DK 163432B

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.REACTION SHEET II

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11

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 salts thereof and pharmaceutically acceptable carriers are readily administered in a variety of dosage forms such as tablets, powders, capsules, lozenges, syrups and the like. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as sodium citrate may be used with various degradation agents such as starch, alginic acid and certain complex silicates, and with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia gum.

The activity of the compounds of the present invention as antidepressants and anti-fatigue agents is determined by various standard pharmacological tests, including e.g. Porcelain's screening model for "learned relief-25", ie. immobility induced by forced swimming in rats [R. D. Porsolt et al., European J.

Pharmacol., 47, 379 (1978)]. Pharmaceutical agents of this type, which are therapeutically effective in humans, are known to reduce immobility induced by forced swimming in this model.

The process according to the invention is illustrated in more detail by the following examples, and the preparation of starting materials is illustrated in the preparations.

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PREPARATION A

4-Chloro-7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline a) Preparation of 2-chloro-6-fluoro-3-methoxyquinoxaline In a flame-dried reaction flask containing a slurry of 52 g (0.24 mol) of 2,3-dichloro-6-fluoroquinoxaline in 500 ml of methanol under a dry nitrogen atmosphere were added slowly and dropwise at 50 ° C a solution of 6.6 g (0.29 mol) of sodium dissolved in 650 ml of methanol. The resulting mixture was then heated to 50 ° C overnight (i.e., for a period of about 16 hours), and the clear solution thus obtained was allowed to cool to room temperature (about 20 ° C). The reaction mixture was then concentrated in vacuo and the residue dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a liquid residue was finally obtained, which was then chromatographed on a 1000 ml silica gel column 20 followed by elution with toluene. The combined fractions containing only product then gave 48.3 g (95%) of pure 2-chloro-6-fluoro-3-methoxyquinoxaline, m.p.

93-95 ° C. Mass spectrum: 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 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 (i.e., about 20 ° C for about 16 hours). Then an additional amount of hydrazine hydrate (9.0 ml) was added and the

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13 final reaction mixture was stirred at room temperature for 4 hours. The precipitate was then filtered off and washed with ethanol to give 43.3 g (94¾) of pure 6-fluoro-2-hydrazino-3-5 methoxyquinoxaline, m.p. 170-174 ° C (decomp.).

c) Preparation of 7-fluoro-4-methoxy [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 15 g (0.072 mol) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline and 250 ml of triethyl orthoformate 10 was heated under mechanical stirring in a preheated oil bath at 100 ° C overnight (about 16 hours).

The resulting mixture was then cooled to room temperature and the resulting precipitate was recovered by suction filtration and washed with ethanol to give 11.3 g (72¾) of pure 7-fluoro-4-methoxy- [1.2 4] triazolo [4,3-ajquinoxaline, m.p. 245-246 ° C (decomp.).

d) Preparation of 7-fluoro-4-hydroxy- [1,2,4] tria] olo- [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] quinoxaline, 115 ml of 1 N 2 hydrochloric acid and 345 ml of glacial acetic acid were heated at reflux for 3 hours. After completing this step, the reaction mixture was cooled to room temperature and poured out over ice / water. The resulting mixture was stirred for 30 minutes and then filtered to remove the precipitate, which was then washed with water and air dried to give 8.9 g (84¾) of pure 7-fluoro-4-hydroxy- [1, 2,4] triazolo [4,3-a] quinoxaline, m.p.

30> 300 ° C. Mass Spectrum: m / e 204 (P).

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E) Preparation of 4-chloro-7-fluoro- [1,2,4] triazolo- [4,3-a] quinoxaline In a flame-dried reagent flask under a dry non-nitrogen atmosphere, 8.9 g (0.044 mol) of 7- fluoro-4-5 hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline and 160 ml of phosphorus oxychloride together with 8.9 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 out over 10 ice / water under mechanical stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product thus obtained was washed with cold water and triturated with ethyl acetate to give 7.0 g (71%) of pure 4-chloro at last. -7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 305-308 ° C. Mass spectrum: m / e 222 (P), m / e 224 (P + 2).

PREPARATION B

4-Chloro-1-ethyl-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline 20 a) Preparation of 1-ethyl-6-fluoro-4-methoxy- [1,2, 4] triazolo [4,3-a] quinoxaline

A mixture of 15 g (0.07 mol) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline, the product of Preparation A (b), and 250 ml of triethyl orthopropionate was heated under mechanical stirring in a preheated oil bath to 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature (about 20 ° C) filtered and the recovered precipitate was washed with ethanol to give 11.3 g (64%) of pure 1-ethyl-7-30 fluoro-4-methoxyphosphate. [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

200-202 ° C (decomp.).

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B) Preparation of 1-ethyl-7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3-ajquinoxaline

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 5N hydrochloric acid and 345 ml of glacial acetic acid was obtained. heated under reflux for 3 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice / water. The resulting mixture was then stirred for 30 minutes, filtered, and the recovered solid product then washed with water and air dried to give 6.6 g (62 / ¾) 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 / e 231 (P-1).

C) Preparation of 4-chloro-1-ethyl-7-fluoro [1,2,4J-triazolo [4,3-a] quinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, 6.6 g (0.028 mol) was placed. 1-ethyl-7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline and 120 ml of phosphorus oxychloride 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 over ice / water under mechanical stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product thus obtained was washed with cold water and then dissolved in ethyl acetate. The latter organic solution was then successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine before being dried over anhydrous magnesium sulfate. After removing the desiccant by filtration and the solvent by evaporation under reduced pressure,

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16 finally obtained a light brown solid which was then triturated with diethyl ether to give 4 g (57¾) of pure 4-chloro-1-ethyl-7-fluoro- [1,2,4] triazolo [4.3 -a] quinoxaline, mp, 203-205 ° C.

Mass spectrum: m / e 250 (P), m / e 252 (P + 2), m / e 249 (P-1).

PREPARATION C

4,7-Dichloro- [1,2,4] triazolo [4,3-a] quinoxaline a) Preparation of 2,3-dihydroxy-6-chloroquinoxaline A mixture of 100 g (0.07 mol) of 4-chloro -1,2-phenylene diamine and 750 ml diethyl oxalate were heated at reflux overnight (about 16 hours). Upon completion of this step, the reaction mixture was cooled to room temperature (about 20 ° C), filtered, and the recovered product was then 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) Preparation of 2,3,6-trichloroquinoxaline 20 A mixture of 140 g (0.70 mol) of 2,3-dihydroxy-6-chloro-quinoxaline and 326 ml (3.50 mol) of phosphorus oxychloride was heated at reflux overnight (about 16 hours) and then poured over ice. The resulting aqueous mixture was then filtered and the recovered product washed with water and air dried, then dissolved in chloroform. This organic solution was then washed with saturated brine and air dried over anhydrous magnesium sulfate. After removing the desiccant by filtration and the solvent at evaporation under reduced pressure,

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17 obtained a thick slurry which was recrystallized from chloroform / ethanol to give 120 g (74 µl) of pure 2,3,6-trichloroquinoxaline, m.p. 139-142 ° C. Mass spectrum: m / e 232 (P), m / e 234 (P + 2), m / e 236 (P + 4).

c) Preparation of 2,6-dichloro-3-methoxyquinoxaline

A slurry of 11.7 g (0.05 mole) of 2,3,6-trichloroquinoxaline in 140 ml of methanol was heated to 50 ° C, then a solution of 1.4 g of 10 (0.06 mole) of sodium was added dropwise. in 140 ml of methanol over 6 hours. The resulting mixture was heated to 50 ° C overnight (about 16 hours), followed by further addition of 140 mg of sodium in 20 ml of methanol over 1 hour. The final reaction mixture was heated to 50 ° C for 2 hours and then cooled to room temperature. Upon completion of this step, the spent mixture was concentrated in vacuo and dissolved in chloroform / water. The organic phase was separated and stored and the aqueous phase further extracted with chloroform. The various organic (i.e., chloform) extracts were combined and successively washed with fresh portions of water and saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, the residue was chromatographed on a column of 250 ml of silica gel and eluted with toluene. Equal fractions were combined to give a white solid of 9.8 g (86 µg) of pure 2,6-dichloro-3-30 methoxyquinoxaline, m.p. 92-95 ° C.

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D) Preparation of 6-chloro-2-hydrazino-3-methoxyquinoxaline

A mixture of 4.9 g (0.02 mol) of 2,6-dichloro-3-methoxyquinoxaline and 2.7 g (0.033 mol) of hydrazine hydrate (2.6 ml) in 75 ml of ethanol was stirred at room temperature overnight. 5 above (i.e., at about 20 ° C for about 16 hours). Upon completion of this step, the resulting mixture was filtered and the recovered precipitate washed with ethanol to give 4.4 g (98%) of pure 6-chloro-2-hydrazino-3-methoxyquinoxaline, m.p.

175-179 ° C (decomp.). Mass spectrum: m / e 224 (P), m / e 226 (P + 2).

e) Preparation of 7-Chloro-4-methoxy- [1,2,4] triazolo- [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 heated under mechanical stirring in a preheated oil bath to 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature and the resulting precipitate then recovered by suction 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, m.p. 250-252 ° C.

f) Preparation of 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 1N 2 hydrochloric acid and 105 ml of glacial acetic acid were heated at reflux for 2.5 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice / water. The resulting mixture was stirred for 20 minutes, filtered, and the recovered solid product

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19 washed with water and air dried to constant weight to give 2.6 g (87%) of pure 7-chloro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline, mp.

> 300 ° C.

3 g) Preparation of 4,7-dichloro [1,2,4] triazolo [4,3-a] quinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, 2.6 g (0.012 mol) of 7-chloro were placed -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. The reaction mixture was then heated under reflux overnight (about 16 hours ) and finally cooled to room temperature before being slowly poured over ice / water. The resulting aqueous mixture was extracted with ethyl acetate and the extract was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent 20 by evaporation under reduced pressure, a yellow solid was finally obtained, which was then chromatographed on a 200 ml silica gel column and eluted with chloroform / methanol (9: 1 v / v). One s fractions were combined and concentrated in vacuo to give an orange solid product consisting of 1.89 g (66%) of pure 4,7-dichloro [1.2.4] triazolo [4,3-aquinoxaline, mp. 253-256 ° C (decomp.). Mass spectrum: m / e 238 (P), m / e 240 (P + 2), m / e 242 (P + 4).

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PREPARATION D

4,7-Dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline a) Preparation of 7-chloro-1-ethyl-4-methoxy- [1,2,4] - triazolo [4,3-a] quinoxaline 5 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 triethyl orthopropionate was heated under mechanical stirring. in a preheated oil bath to 100 DC overnight (about 16 hours). The resulting mixture was cooled to room temperature (about 20 ° C) and the resulting precipitate was collected by suction filtration and washed with diethyl ether to give 4.3 g (75%) of pure 7-chloro-1 -ethyl-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 221-223 ° C.

B) Preparation of 7-chloro-1-ethyl-4-hydroxy- [1,2,4] triazolo [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 1N hydrochloric acid and 60 ml of methanol was heated at reflux overnight and then cooled to room temperature.

The precipitate formed was collected by suction filtration and washed with methanol. Thus, 3.7 g (94%) of pure 7-chloro-1-ethyl-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline were obtained, m.p. > 300 ° C.

C) Preparation of 4,7-dichloro-1-ethyl- [1,2,4] triazolo- [4,3-a] quinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, 5.1 g (0, (2 mol) 7-chloro-1-ethyl-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline and 75 ml

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21 phosphorus oxychloride together with 5 ml of tri-n-propylamine. The reaction mixture was then heated under reflux overnight (about 16 hours) and finally cooled to room temperature before being slowly poured over ice / water. The resulting aqueous mixture was stirred at room temperature for 15 minutes and filtered and the solid product thus obtained was washed with cold water and air dried to constant weight to give 4.2 g (79%) of pure 4.7 -dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 217-220 ° C (decomp.). Mass spectrum: m / e 266 (P), m / r 268 (P + 2), m / e 265 (P-1).

PREPARATION E

4-Chloro-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline a) Preparation of 2,3-dihydroxy-6-methoxyquinoxaline

A mixture of 20 g (0.114 mole) of 4-methoxy-o-phenylene diamine and 11 g (0.114 mole) of triethylamine dissolved in 200 ml of diethyl oxalate was heated at reflux overnight (about 16 hours). After completion of this step 20, the reaction mixture was cooled to room temperature (about 20 ° C) and filtered to separate the desired product. After washing with ethanol, 14.8 g (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline was finally obtained, m.p. 300 ° C. Mass spectrum: m / e 192 (P).

B) Preparation of 2,3-dichloro-6-methoxyquinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, 14.8 g (0.077 mole) of 2,3-dihydroxy-6-methoxyquinoxaline and 75 ml of phosphorus oxychloride were placed together with 15 ml. tri-n-propylamine. The exothermic reaction mixture was then stirred at room temperature (about 20 ° C) 22

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for one hour and then heated under reflux overnight (about 16 hours). After completing this step, the reaction mixture was again cooled to room temperature and finally poured slowly over 5 ice / water. The resulting aqueous mixture was stirred at room temperature for 20 minutes, filtered and the recovered precipitate washed with water before dissolving in chloroform. The latter solution was then filtered to remove insoluble material, and the filtrate was washed with water, saturated sodium hydrogen carbonate solution, and saturated brine. Concentration of the washed solution in vacuo followed by recrystallization of the residue from ethanol gave 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) Preparation of 2-chloro-3,6-dimethoxyquinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, slowly a solution of 850 mg of sodium in 80 ml of methanol was slowly introduced into a slurry of 7.1 g of 2,3-dichloro-6 -methoxyquinoxaline in 60 ml of methanol at 50 ° C over 7 hours. The resulting mixture was then heated to 50 ° C overnight and finally cooled to room temperature. Upon completion of this step, the spent reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform, followed by washing with water and drying over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, the residue was chromatographed on a column of 400 ml of silica gel, followed by elution with toluene. The good fractions were combined and concentrated in vacuo to give a white solid of 6.1 g (88 µl) of pure 2-chloro-3.6-35 methoxyquinoxaline, mp 79-81 ° C .

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23

Analysis calculated for C C ^HgClClCl C ^: C 53.47, H 4.04, N 12.47; Found: C, 53.29; H, 4.05; H, 12.28.

d) Preparation of 3,6-dimethoxy-2-hydrazinoquinoxaline 5 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 of ethanol was heated to 50 ° C overnight.

After completing this step, an additional 1.0 ml of hydrazine hydrate was added to the mixture and the resulting mixture was heated to 50 ° C for 6 hours. Then another 1.0 ml of hydrazine hydrate was added and the final reaction mixture was heated to 50 ° C overnight, then cooled to room temperature. The reaction mixture was then filtered and the recovered precipitate washed with ethanol to give 4.1 g (85%) of pure 3,6-dimethoxy-2-hydrazino-quinoxaline, m.p. 128-130 ° C (decomp.).

e) Preparation of 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 were heated under mechanical stirring in a preheated oil bath to 100 ° C overnight (about 16 hours). The resulting mixture was cooled to room temperature and the precipitate formed was recovered by suction filtration and washed with ethanol to give 1.8 g of pure 4,7-dimethoxy- [1,2,4] triazolo [4, 3-a] quinoxa-lin, m.p. 238-240 ° C (decomp.). Mass spectrum: m / e 230 (P), m / e 231 (P + 1), m / e 232 (P + 2).

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F) Preparation of 4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 1.6 g (0.0069 mole) of 4,7-dimethoxy- [1,2,4] triazolo [4,3-a] quinoxaline, 16 ml of 1N 2 hydrochloric acid 5 and 48 ml of glacial acetic acid was heated at reflux. in 3 hours. After completing this step, the reaction mixture was poured over ice and filtered. The recovered product was then collected on the filter funnel and washed with diethyl ether to finally give 1.19 g (80%) of pure 4-hydroxy-7-methoxy [1,2,4] triazolo [4.3 -ajquinoxaline, m.p. > 250 ° C.

g) Preparation of 4-chloro-7-methoxy- [1,2,4] triazolo- [4,3-a] quinoxaline In a flame-dried reaction flask under a dry nitrogen atmosphere, 1.1 g (0.0055 mol) was placed. ) 4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a]: quinoxaline and 15 ml of phosphorus oxychloride together with 1.0 ml of tri-n-propylamine. The reaction mixture was then refluxed overnight (about 16 hours) and finally cooled to room temperature, then slowly poured over ice / water. The resulting aqueous mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine, then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a residue was finally obtained which was chromatographed on a 150 ml silica gel column and then eluted with chloroform / methanol (95: 5 v / v). Equal 30 fractions containing the product were then combined and concentrated in vacuo to give a residue which was recrystallized from chloroform / diethyl ether to give 400 mg (31%) of pure 4-chloro-7-

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Methoxy [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

266-268 ° C (decomp.). Mass spectrum: m / e 234 (P), m / e 236 (P + 2).

PREPARATION F

4-Chloro-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline (a) Preparation of 1-ethyl-4,7-dimethoxy- [1,2,4 ] triazolo [4,3-a] quinoxaline

A mixture of 4.0 g (0.018 mol) of 3,6-dimethoxy-2-10 hydrazinoquinoxaline, the product of Preparation E (d), and 50 ml of triethyl orthopropionate was heated under mechanical stirring in a preheated oil bath to 100 ° C overnight ( about 16 hours). The reaction mixture was then cooled to room temperature (about 20 ° C), and the precipitate formed was then recovered by suction filtration and washed with ethanol to give 3.3 g (72%) of pure 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) Preparation of 1-ethyl-4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 3.3 g (0.013 mole) of 4,7-dimethoxy-1-ethyl- [1.2.4] triazolo [4,3-a] quinoxaline, 33 ml of 1N hydrochloric acid and 99 ml of glacial acetic acid was heated at reflux for 2 hours. 25 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice / water. The resulting mixture was stirred for 20 minutes and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the desiccant at

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Filtration and the solvent by evaporation under reduced pressure afforded a yellow solid which was washed with water and air dried to constant weight to give finally 1.87 g (67%) of pure 1-ethyl-4 hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. > 250 ° C.

c) Preparation of 4-chloro-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline In a flame-dried reaction 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 oxychloride together with 1.8 ml of tri-n-propylamine . The reaction mixture was then heated at reflux overnight (about 16 hours) and then cooled to room temperature and slowly poured over ice / water. The resulting aqueous mixture was stirred at room temperature for 30 minutes and filtered, and the solid product thus obtained was washed with cold water and then dissolved in chloroform. The organic solution was washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a yellow solid was obtained which was triturated with diethyl ether and filtered to give 1.6 g (80%) of pure 4-chloro-1 finally. -ethyl-7-methoxy- [1,2,4] triazolo- [4,3-a] quinoxaline, m.p. 173-175 DC. Mass spectrum: m / e 262 (P), m / e 264 (P + 2), m / e 261 (P-1).

27

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PREPARATION G

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

A mixture of 26.3 g (0.19 mol) of 4-fluoro-1,2-phenylene-3 diamine [Journal of the American Chemical Society, Vol.

75, page 1294 (1953)] and 150 ml of diethyl oxalate were heated at reflux under a nitrogen atmosphere for 18 hours. After completion of this step, the reaction mixture was cooled to room temperature (about 10 ° C), filtered and the recovered product then washed with four 100 ml portions of ethanol and air dried to constant weight to give 19.3 g. (80%) pure 2,3-dihydroxy-6-fluoroquinoxaline, m.p. 300 ° C (literature mp 387-390 ° C, according to US Patent No. 3,992,378). Mass spectrum: m / e 180 (P +).

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

A mixture of 19 g (0.105 mole) of 2,3-dihydroxy-6-fluoroquinoxaline and 50 ml of phosphorus oxychloride was heated at reflux overnight (about 16 hours) and then cooled to room temperature and poured over 200 g of ice with good stirring. The resulting aqueous mixture was then filtered and the recovered product was then washed several times with water to give finally 28.2 g of 2,3-dichloro-6-fluoroquinoxaline, m.p.

148-152 ° C.

c) Preparation of 2-chloro-6-fluoro-3-hydrazine quinoxaline

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)

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28 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. Then, the precipitate 5 was filtered off and washed several times with ethanol, followed by air drying to constant weight to give 20.7 g (93%) of pure 2-chloro-6-fluoro-3-hydrazinoquinoxaline, m.p. 190-192 ° C (decomp.).

D) Preparation of 4-chloro-8-fluoro- [1,2,4] triazolo- [4,3-a] quinoxaline

A mixture of 10 g (0.047 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml (0.47 mol) of triethyl orthoformate was heated under a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100 ° C.

overnight (about 16 hours). The resulting mixture was cooled to room temperature and the precipitate formed was recovered by suction filtration, washed with three 50 ml portions of ethanol and air-dried to constant 20 weight to give 9.42 g (91%) of pure 4-chloride at last. 8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 310-312 ° C (decomp.). Mass spectrum: m / e 224, 223, 222 (P +).

PREPARATION 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-hydrazinoalkylinoxaline, the product of Preparation G (c). and 95 ml (0.47 mole) of triethyl orthopropionate were heated under a nitrogen atmosphere with mechanical stirring 30 in a preheated oil bath at 100 ° C overnight (about 16 hours). The resulting mixture was cooled to

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29 room temperature (about 20 ° C) and the resulting precipitate was recovered by suction filtration, washed with three 50 ml portions of ethanol and air dried to constant weight to give 7.5 g (65%) of 5 pure 4-chloro -1-ethyl-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 160-163 ° C (decomp.). Mass spectrum: m / e 249, 250, 251, 252 (P +).

PREPARATION I

4-Chloro-8-fluoro-1-trifluoromethyl- [1,2,4-triazolo [4,3-a] quinoxaline] 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-hydrazine quinoxaline in 50 ml (0.65 mol) of trifluoroacetic acid was heated under a dry nitrogen atmosphere to 120 ° C for 24 hours. hours under mechanical stirring to give a homogeneous solution. The reaction mixture was then poured over ice / water with stirring, stirred for an additional 30 minutes and filtered. The obtained product was washed with three separate portions of water and dried in vacuo at 80 ° C to finally obtain 12.58 g (77%) of pure 8-fluoro-4-hydroxy-1-trifluoro-methyl - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 298-302 ° C. Mass spectrum: m / e 272 (P +).

B) Preparation of 4-chloro-8-fluoro-1-trifluoromethyl- [1.2.4] triazolo [4,3-a] quinoxaline In a flame-dried 250 ml three-necked reaction flask under a dry nitrogen atmosphere was placed 12.5 g (0.046 mol 8-fluoro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a-quinoxaline and 85 ml of phosphorus oxychloride together with 17.5 ml

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30 tri-n-propylamine. The reaction mixture was then heated under reflux overnight (about 16 hours) and then cooled to room temperature (about 20 ° C) and slowly poured over 1000 ml of ice / water under mechanical stirring. The resulting aqueous mixture was stirred for an additional 30 minutes at room temperature and then extracted with three 300 ml portions of chloroform. The combined chloroform layers were successively washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and finally dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a yellow solid was obtained, consisting of 10.47 g (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl [1.2 Triazolo [4,3-a] - quinoxaline, m.p. 135-138 ° C. Mass Spectrum: m / e 292/290 (P +).

PREPARATION J

4-Chloro-7,8-difluoro- [1,2,4Itriazolo [4,3-ajquinoxaline 20 a) 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 No. 4,264,600) and 80 ml (0.589 mol) of diethyl oxalate was heated at reflux for 4 hours to give a thick precipitate of 25 product. The reaction mixture was then cooled to room temperature (about 20 ° C) overnight, filtered, and the solid product obtained was washed several times with diethyl ether and air dried to constant weight to give 15.5 g of pure 2,3-dihydroxy. -6.7-30 difluoroquinoxaline, m.p. ^ 310 ° C. Mass spectrum: m / e 198 (P +).

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

A mixture of 15.4 g (0.078 mole) of 2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g (0.187 mole) of phosphorus pentachloride and 20 ml (0.22 mole) of phosphorus oxychloride was heated under reflux and stirring for 15 minutes. 4 hours, during which an additional 20 ml of phosphorus oxychloride was added to facilitate stirring (the reaction mixture becomes homogeneous within 30 minutes). After completing this step, the reaction mixture was stirred overnight (about 16 hours) at room temperature to give a pale yellow precipitate. The reaction mixture was then poured over 200 g of ice / water and further stirred under cooling to give a light brown solid consisting of 20.9 g of 2,3-dichloro-6,7-15 difluoroquinoxaline, m.p. 162-164 ° C (decomp.). Mass Spectrum: m / e 238/236/234 (P +).

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

A mixture of 10 g (0.0426 mole) of 2,3-dichloro-6.7-20 difluoroquinoxaline and 5 ml (0.03 mole) 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 washed with two 20 ml portions of ethanol, followed by 25 air drying at constant weight to give 5.99 g (67%) of pure 2-chloro-6,7-difluoro -3. hydrazinoquinoxaline, m.p. 212-215 ° C (decomp.). Mass spectrum: m / e 230 (P), m / e 232 (P +).

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d) Preparation of 4-chloro-7,8-difluoro- [1,2,4] triazolo- [4,3-a] quinoxaline

A mixture of 5.99 g (0.026 mole) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml (0.18 mole) of triethyl-5 orthoformate was heated to 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 washed with diethyl ether to give 5.1 g (82%) of pure 4-chloro-7,8-difluoro [1 , 2,4] triazolo [4,3-a] - quinoxaline, m.p. 210 ° C (decomp.). Mass Spectrum: m / e 242/240 (P +).

PREPARATION K

4- Chloro-6,7-difluoro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 7.0 g (0.03 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline, the product of Preparation J (c), and 60 ml (0.30 mol) of triethyl orthopropionate were heated under a nitrogen atmosphere with mechanical stirring 20 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 recovered by suction filtration, washed with two separate portions of diethyl ether and air dried to constant weight to give finally 4.15 g (52%). ) pure 4-chloro-6,7-difluoro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

185-186 ° C (decomp.).

4,8-Dichloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline 33

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PREPARATION L

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

A mixture of 23 g (0.10 mol) of 2,3,6-trichloroquinoxaline 5 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 separated by filtration and washed with ethanol to give 22.2 g (97%) of pure 2,6-dichloro-10 3-hydrazinoquinoxaline, m.p. > 250 ° C. Mass Spectrum: m / e 228 (P).

b) Preparation of 4,8-dichloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 20 g (0.087 mole) of 2,6-dichloro-3-hydrazino-quinoxaline and 160 ml (0.87 mole) of triethyl orthoacetate was heated by mechanical stirring under a dry nitrogen atmosphere in a preheated oil bath at 100 ° C. 20 hours to form a yellow suspension. The resulting mixture was cooled to room temperature and filtered, and the recovered solid was washed with ethanol and air dried to constant weight to give 10.2 g (46 SO of pure 4,8-dichloro-1-methylene). [1,2,4] triazolo [4,3-a] quinoxaline, m.p.> 280 ° C. Mass spectrum: m / e 254/252 (P +).

4,8-Dichloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline

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PREPARATION M

a) Preparation of 8-Chloro-4-hydroxy-1-trifluoromethyl-3-methyl [1,2,4] triazolo [4,3-a] quinoxaline In a flame-dried 500 ml three-necked reaction flask equipped with mechanical stirrer, nitrogen feed tube and reflux 67 ml (0.87 mol) of trifluoroacetic acid was applied. Stirring was started and 20 g (0.087 mol) of 2,6-dichloro-3-hydrazinoquinoxaline, the product of Preparation L (a), was added. The reaction mixture was then heated on a steam bath for 24 hours, cooled to room temperature (about 20 ° C) and poured over 200 g of ice / water. The aqueous mixture thus obtained was stirred for 30 minutes, filtered, and the recovered product washed several times with water and air dried to constant weight (required about 18 hours).

In this way, 14.3 g (57%) of pure 8-chloro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. . 253-255 ° C (decomp.). Mass Spectrum: m / e 290/288 (P +).

b) Preparation of 4,8-dichloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline In a flame-dried 250 ml three-necked reaction flask equipped with mechanical stirrer, dropping funnel and reflux, and under nitrogen rinsing, 14.3 g (0.05 mole) of 8-chloro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline was placed in 100 ml of phosphorus oxychloride. To the resulting suspension was added dropwise 30 ml (0.10 mol) of tri-n-propylamine over 5 minutes. The reaction mixture was then heated below 35

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reflux for 20 hours to obtain a clear dark burgundy solution. After completing this step, the solution was cooled to room temperature and poured over 1000 ml of ice / water under vigorous mechanical stirring. The resulting aqueous mixture was stirred at room temperature for 30 minutes and then extracted with three 500 ml portions of chloroform. The organic extracts were combined and then successively washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a yellow solid was finally obtained, which consisted of 11.4 g (75%) of pure 4,8-dichloro-1-trifluoromethyl [1 , 2,4] triazolo [4,3-ajquinoxaline, m.p. 133-135 ° C. Mass spectrum: m / e 308 (P + 2), m / e 310 (P + 4).

PREPARATION N

4,8-Dichloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline In a 250 ml three-necked reaction flask equipped with mechanical stirrer and reflux, 50.0 g (0.274 mole) of trimethyl orthobenzoate were placed, which had been preheated to approx. 70 ° C. Stirring was started and 10.0 g (0.0437 mol) of 2,6-dichloro-3-hydrazinoquinoxaline, the product of Preparation L (a), was added. The reaction mixture was then heated to ca. 120 ° C with continued stirring for 24 hours, followed by cooling to room temperature (about 20 ° C) and stirring overnight (about 16 hours) to form a yellow slurry.

The slurry was filtered and the recovered solid product was washed with two 50 ml portions of ethanol and air dried to constant weight to give 9.8 g (72 µg) of crude 4,8-dichloro-1-phenyl 1 - [1,2,4] tria- 36

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zolo [4,3-a] quinoxaline, stnp. 305-307 ° C. Mass Spectrum: m / e 316/314 (P +).

EXAMPLE 1 2-Chloro-3-hydrazinoquinoxaline 5 2,3-Dichloroquinoxaline (33.5 g, 0.168 mole) was stirred with hydrazine hydrate (18.5 g, 0.369 mole) in 500 mL of ethanol at room temperature overnight (i.e., at ca. 20 ° C for about 16 hours). The thick 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-hydrazinoquinoxaline, m.p. 181 ° C (decomp.). Mass spectrum: m / e 194 (P).

EXAMPLE 2 4-Chloro- [1,2,4] triazolo [4,3-a] quinoxaline 2-Chloro-3-hydrazinoquinoxaline (9.0 g, 0.046 mol), the product of Example 1, was stirred with triethyl orthoform. mlat (90 ml) at 100 ° C for 1 hour. The mixture was cooled to room temperature and the solid precipitate was collected by filtration, washed with cyclohexane and dried to give 8.8 g (94% yield) of 4-chloro [1,2,4] triazolo [4 3-a] quinoxaline, m.p. 287-290 ° C (decomp.). Mass Spectrum: m / e 204 (P).

EXAMPLE 3 4-Chloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline 2-Chloro-3-hydrazinoquinoxaline (15.5 g, 0.080 mol), the product of Example 1, was stirred with triethyl ortho-37

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acetate for 3 hours at 100 ° C. The mixture was cooled to room temperature and the solid precipitate collected by filtration, washed with ethanol and air dried to give 11.4 g (65% yield) of 4-chloro-5-methyl-[1,2,4] triazolo [4,3-a] quinoxaline, m.p.

215-222 ° C. Mass Spectrum: m / e 218 (P).

Example 4 4-Chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline 2-Chloro-3-hydrazinoquinoxaline (4.5 g, 0.023 mole), produced from Example 1 , was stirred with triethyl orthopropionate (50 ml) at 100 ° C for 1 hour. The mixture was cooled to room temperature where the white precipitate was collected by filtration and washed with cyclohexane to give 4.5 g (85% yield) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

158-160 ° C. Mass Spectrum: m / e 232 (P).

EXAMPLE 5 4-Chloro-1n-propyl [1,2,4] triazolo [4,3-a] quinoxaline 2-Chloro-3-hydrazinoquinoxaline (3.0 g, 0.015 mole), produced from Example 1 , was stirred with triethyl ortho-butyrate (27 ml) at 100 ° C for 2 hours. The mixture was cooled to room temperature and the precipitate was collected by filtration and washed with cyclohexane. The crude product was taken up in chloroform and filtered to remove 25 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-1n-propyl [1,2,4] triazolo [4 , 3-a] quinoxaline, m.p. 173-175 ° C. Mass Spectrum: m / e 246 (P).

4-Chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline EXAMPLE 6 38

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2-Chloro-3-hydrazinoquinoxaline (4.0 g, 0.02 mol), the product of Example 1, was stirred with triethyl ortho-3 isobutyrate (15 ml) at 100 ° C for 3 hours. The solution was cooled to room temperature and the precipitate was collected by filtration and washed with ethanol. The crude product was recrystallized from 300 ml of warm ethanol to give 2.06 g (40% yield) of 4-chloro-10-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline, mp.

208-210 ° C. Mass Spectrum: m / e 246 (P).

EXAMPLE 7 4-Methylamino [1,2,4] triazolo [4,3-a] quinoxaline 4-chloro [1,2,4] triazolo [4,3-a] quinoxaline (2.0 g, 0 The product of Example 2 in N, N-dimethylformamide (30 ml) was saturated with monomethylamine gas and stirred at room temperature for 3 hours. Monomethylamine gas was again bubbled into the solution and the solution was stirred at room temperature for a further two hours. The precipitate was separated by filtration and washed with N, N-dimethylformamide. Recrystallization from N, N-dimethylformamide gave 1.37 g (69% yield) of 4-methylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 300 ° C. Mass spectrum: m / e 199 (P).

Analysis calculated for C C ^H ^N ^: C 60.29, H 4.55, N 35.15; Found: C 59.99, H 4.47, N 35.11.

4-Dimethylamino- [1,2,4] triazolo [4,3-a] quinoxaline EXAMPLE 8 39

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A slurry of 2.0 g (0.01 mole) of 4-chloro [1,2,4] triazolo [4,3-a] quinoxaline (the product of Example 2) in 5 N, N-dimethylformamide (30 ml) was saturated with dimethylamine gas and stirred at room temperature overnight.

The mixture was poured over ice and the precipitate was collected by filtration. Recrystallization from ethanol gave 640 mg (44% yield) of 4-dimethylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 184-186 ° C. Mass spectrum: m / e 213 (P).

Analysis calculated for C 61.96, H 5.20, N 32.84 $ found: C 62.26, H 5.43, N 32.92.

EXAMPLE 9 4-Ethylamino [1,2,4] triazolo [4,3-a] quinoxaline

A slurry of 2.0 g (0.01 mole) of 4-chloro [1,2,4] triazolo [4,3-a] quinoxaline (the product of Example 2) in N, N-dimethylformamide (30 ml ) was saturated with mono-ethylamine gas and stirred at room temperature for 2 hours.

Monoethylamine gas was again bubbled through the mixture and stirring was continued for 2 hours. The precipitate was recovered by filtration and washed with N, N-dimethylformamide. Recrystallization from methanol gave 680 mg (32% yield) of 4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 254-256 ° C. Mass spectrum: m / e 213 (P) ·

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

4-Diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline EXAMPLE 40

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4-Chloro [1,2,4] triazolo [4,3-a] quinoxaline (4.4 g, 0.021 mol), the product of Example 2, was stirred with diethylamine (6.5 ml, 0.063 mol) in N N-dimethylformamide 5 (100 ml) at room temperature for 2 hours. The reaction mixture was poured over an ice / water mixture to form a crude product precipitate which was filtered off and washed with water. Crystallization from isopropyl alcohol gave 3.36 g (66% yield) of 4-diethylamino- [1,2,4] -10 triazolo [4,3-a] quinoxaline, m.p. 117-119 ° C. Mass spectrum: m / e 241 (P).

Example 11 4-Di-n-propylamino- [1,2,4] triazolo [4,3-a] quinoxaline 4-Chloro- [1,2,4] triazolo [4,3-a] quinoxaline (2,0 g, 0.01 mole), the product of Example 2, and 3.0 g (0.03 mole) of di-n-propylamine XN, N-dimethylformamide (50 ml) were stirred for 3 hours at room temperature. The solution was poured over ice to form a precipitate which was separated by filtration and air dried. Recrystallization from cyclohexane (250 ml) gave 1.1 g (41% yield) of 4-di-n-propylamino [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 240-242 ° C. Mass Spectrum: m / e 269 (P).

Analysis calculated for 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 41

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4-Chloro- [1,2,4] triazolo [4,3-a] quinoxaline (2.0 g, 0.01 mole), the product of Example 2, and 1.77 g (0.03 5 mole) of isopropylamine in N, N-dimethylformamide (30 ml) was stirred at room temperature overnight. The dark solution was poured over ice and the precipitate formed was separated by filtration and washed with water. The crude product was recrystallized from ethanol and then 10 times from isopropyl ether to give 1.2 g (53% yield) of 4-isopropylamino- [1,2,4] triazolo [4,3-aj-quinoxaline, m.p. . 133-135 ° C. Mass Spectrum: m / e 222 (P).

Analysis calculated for C 12 H 13 N 5 * 1 / 3H 2 O: C 61.79, H 5.90, N 30.02; Found: C, 61.51; H, 5.89; N, 29.90.

Example 13 4-Diethylamino-1-methyl ~ [1,2,4] triazolo [4,3-a] quinoxaline

This compound was prepared by the procedure of Example 11 using 4-chloro-1-methyl-[1,2,4-triazolo [4,3-ajquinoxaline (the product of Example 3) as the starting material instead of 4-chloro [1.2.4] triazolo [4,3-ajquinoxaline (the product of Example 2) and diethylamine as a reagent instead of di-n-propylamine. The crude 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-ajquinoxaline, m.p. . 123-125 ° C.

4-Amino-1-ethyl- [1,2,4] triazolo [4,3] quinoxaline EXAMPLE 14 42

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Ammonia gas was bubbled through a solution of 1.2 g (0.005 mol) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] -5 quinoxaline (the 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 minutes and at room temperature for 1 hour. The reaction mixture was then poured over ice and stirred for 20 minutes. The precipitate formed was recovered by filtration, washed with water and air dried. Recrystallization from ethanol gave 220 mg (22% yield) of pure 4-amino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 284-288 ° C. Mass spectrum: m / e 213 (P).

Analysis: Calculated for C ^^ .H ^ 1/6 ^O: C 61.10, H 5.28, N 32.39; Found: C, 61.36; H, 5.14; N, 31.96.

EXAMPLE 15 4-Methylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline 20 Monomethylamine gas was bubbled through a solution of 4-chloro-1-ethyl- [1,2,4 ] triazolo [4,3-a] quinoxaline (1.2 g, Q005 mol), the product of Example 4, in N, N-dimethylformamide (50 ml) at 0 ° C for 2 minutes. The reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 2 hours and then poured over ice and stirred for another 20 minutes. The precipitate formed was separated by filtration, washed with water and air dried. Recrystallization from ethanol gave 1.0 g (88% yield) of 4-methylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

271-273 ° C. Mass Spectrum: m / e 227 (P).

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43

Analysis calculated for * 1/8 O: 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 [4,3-a] quinoxaline 4-Chloro-1-ethyl [1,2,4] triazolo [4,3-a] quinoxaline (1.2 g, 0.005 mol), the product of Example 4, and 676 mg (0.015 mol) of anhydrous dimethylamine in N, N-dimethylformamide (50 ml) were stirred at 0 ° C for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 20 minutes. The precipitate formed was separated by filtration, washed with water and air dried. Recrystallization from chloroform and then from chloroform / cyclohexane gave 510 mg (42¾ yield) of 4-dimethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 155-158 ° C. Mass spectrum: m / e 241 (P).

Analysis calculated for; C, 64.71; H, 6.27; N, 29.03; Found: C, 64.69; H, 5.27; N, 29.32.

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

Monoethylamine gas was bubbled through a solution of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (1.2 g, 0.005 mol), the product of Example 4, in N N-dimethylformamide (50 ml) at 0 ° C for about 2 minutes. The clear solution was stirred at 0 ° C for 30 minutes and at room temperature for 2 hours. The reaction mixture was then poured over ice and the precipitate was separated by firewood

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44 filtration, washed with water and air dried. Recrystallization from ethanol gave 1.0 g (83¾ yield) of pure ethyl-4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline as a white solid, m.p. 235-238 QC. Mass spectrum: m / e 241 (P).

Analysis calculated for C 13 H 15 N 5: 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 [4,3-a] quinoxaline

This compound was prepared by the procedure of Example 11 using 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (the product of Example 4) as starting material instead of 4-chloro - [1,2,4] -15 triazolo [4,3-a] quinoxaline (the product of Example 2) and diethylamine as a reagent instead of di-n-propylamine.

The crude product was recrystallized from cyclohexane to give 3.54 g (69¾ yield) of pure 4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline 20 as a white substance , 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

Isopropylamine (1.77 g, 0.03 mol) was added to a solution of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (2.3 0.01 mole), the product of Example 4, in N, N-dimethylformamide (30 ml). Within 30 minutes, a precipitate formed. The reaction mixture was then stirred

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45 overnight at room temperature. The precipitate was separated by filtration and washed with N, N-dimethylformamide. Recrystallization from ethanol gave 1.6 g (63¾ yield) of 4-isopropylamino-1-ethyl- [1,2,4] triazolo [4,3-aj-quinoxaline, m.p. 222-224 ° C. Mass spectrum: m / e 255 (P).

Analysis calculated for C 14 H 17 N 5: 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 [4,3-a] quinoxaline

A slurry of 1.0 g (0.004 mol) of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-aquinoxaline (the product of Example 6) in N, N-dimethylformamide ( 15 ml) was saturated with monoethylamine gas and stirred at room temperature for 4 hours. The precipitate was separated by filtration and washed with N, N-dimethylformamide to give. 220 mg (22¾ yield) 4-ethylamino-1-isopropyl- [1,2,4] triazolo-20 [4,3-a] quinoxaline, m.p. 209-211 ° C. Mass spectrum: m / e 255 (P).

The filtrate was then poured over ice and the precipitate was separated by filtration, washed with water and recrystallized from methanol and then from isopropyl alcohol to give another 200 mg (20¾ yield) of pure 4-ethylamino-1-isipropyl alcohol. [1,2,4] triazolo [4,3-aj-quinoxaline, m.p. 210-211 ° C.

Analysis calculated for ^ 24 ^17 ^5: δ 5.86, H 6.71, N 27.43; Found: C 65.53, H 6.58, N 27.29.

4-Diethylamino-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline 46

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Example 21 4-Chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline 5 (1.0 g, 0.04 mol), the product of Example 6, and 900 mg (0.012 diethylamine in N, N-dimethylformamide (13 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured over ice and the precipitate was separated by filtration, washed with water and placed on a 10 column of silica gel (175 ml) and finally eluted with chloroform. The eluent was evaporated in vacuo to give 850 mg (75 µl yield) of pure 4-diethylamino-1-isepropyl- [1,2,4] triazolo [4,3-a] quinoxaline as a white substance. mp. 93-95 ° C. Mass Spectrum: m / e 283 (P). The pure product (100 mg) was then distilled in vacuum (0.1 mmHg) at 140-150 ° C to give the analytical sample (80 mg), m.p. 94-96 ° C.

Analysis C calculated for C 67.82, H 7.47, N 24.71 $ 20 found: C 67.56, H 7.20, N 24.50.

Example 22 4-Diethylamino-1-n-propyl- [1,2,4] triazolo- [4,3-a] quinoxaline 47

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4-Chloro-1n-propyl [1,2,4] triazolo [4,3-a] quinoxaline 5 (1.23 g, 0.005 mol), the product of Example 5, and 1.1 g (0.015 mol) diethylamine in N, N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was then poured over ice. The precipitate was collected by filtration, washed with water 10 and air dried. Recrystallization (twice) from ethanol / water yielded 1.1 g (7855 yield) of pure 4-diethylamino-1-n-propyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 92-94 ° C. Mass Spectrum: m / e 283 (P).

Analysis: 15 calculated for ^ 26 ^ 21 ^ 5 * ^ 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] triazolo [4,3-a] quinoxaline 20 a) Preparation of 4,8-dichloro-1-ethyl- [1,2 , 4] triazolo- [4,3-a] quinoxaline.

2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g, 0.0044 mol), the product of Preparation L (a), was heated under reflux with 15 ml of triethyl orthopropionate for 4 hours and cooled to room temperature. The precipitate was recovered by filtration, washed with cyclohexane and air dried to give 730 mg (62¾ yield) of 4,7-dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline. , m.p. > 250 ° C. Mass spectrum: m / e 266 (P), m / e 30 (P + 2).

48

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b) Preparation of 8-chloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline.

4.8 Dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (7.4 g, 0.028 mole) and 6 g (0.082 mole) diethylamine in 5 N, N-dimethylformamide ( 150 ml) was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate poured over ice. The precipitate formed was collected by filtration and taken up in chloroform. The chloroform layer was then dried over 10 anhydrous magnesium sulfate, filtered and evaporated in vacuo to give an almost white solid, which upon recrystallization from diethyl ether / petroleum ether afforded 1.6 g of pure 8-chloro-4-diethylamino-1-ethyl ether.

[1.2.4] triazolo [4,3-a] quinoxaline, m.p. 105-108 ° C

15 (decomp.).

Mass spectrum: m / e (P), m / e 305 (P + 2).

Analysis: Calculated for C 15 H 18 ClN 5: C 59.30, H 5.97, N 23.05; Found: C, 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) Preparation of 2,6,7-trichloro-3-hydrazino Quinoline 2,3,6,7-Tetrachloroquinoxaline (4.4 g, 0.016 mole) and 1.76 g (0.035 mole) 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-3-30 hydrazinoquinoxaline, m.p. 260 ° C.

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

49

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b) Preparation of 4,7,8-trichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline.

2,6,7-Trichloro-3-hydrazinoquinoxaline (4.9 g, 0.018 mol) in triethyl orthopropionate (50 ml) was heated 5 to 100 ° C for 2 hours. The precipitate formed was collected by filtration at room temperature and washed with cyclohexane. Recrystallization from chloroform / cyclohexane twice then gave 2.9 g (54¾ yield) of pure 1,7,8-trichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline as a pink fabric, 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) Preparation of 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline.

4,7,8-Trichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (2.9 g, 0.0096 mol) and 2.1 g (0.0388 diethylamine in N, N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 15 minutes. The precipitate was separated by filtration, washed with water and air dried. Recrystallization (three times) from isopropyl alcohol then gave 500 mg (16¾ yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 147-149 ° C.

Mass spectrum: m / e 337 (P), m / e 339 (p + 2).

Analysis: Calculated for C ^ HH ClCl ^: C 53.26, H 5.07, N 20.70 Found: C 53.05, H 5.13, N 20.75.

EXAMPLE 25 50

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4-Diethylamino-1-ethyl-8-methoxy- [1,2,4] triazolo- [4,3-a] quinoxaline a) Preparation of 2-chloro-3-hydrazino-6-methoxyquinoxaline 2.3 -Dichloro-6-methoxyquinoxaline (4.2 g, 0.018 mol), the product of Preparation E (b), and 2.7 ml of hydrazine hydrate in 100 ml of ethanol were heated at reflux for 4 hours and stirred at room temperature overnight 10 . The precipitate was collected by filtration and washed with ethanol to give 3.9 g (97¾ yield), m.p. <250 ° C.

Mass spectrum: m / e (P), m / e 226 (P + 2).

b) Preparation of 4-chloro-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline.

2-Chloro-3-hydrazino-6-methoxyquinoxaline (1.3 g, 0.0058 mol) and 25 ml of triethyl orthopropionate were heated to 100 ° C for 4 hours and stirred at room temperature for 60 hours. The precipitate was collected by filtration and washed with ethanol. Recrystallization from ethanol then gave 539 mg (35 ° C yield) of pure 4-chloro-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a) -quinoxaline, m.p. 196-198 ° C. (Decomp.).

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

C) Preparation of 4-diethylamino-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline.

4-Chloro-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline (520 mg, 0.002 mol) and 673 mg (0.008 mol) diethylamine in 10 ml of N, N -dimethylformamide was stirred

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51 at room temperature overnight. The reaction mixture was poured over ice and the precipitate separated by filtration, washed with water and air dried. Recrystallization from diethyl ether and petroleum ether gave then 140 mg (23¾ yield) of pure 4-diethylamino-1-ethyl-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 135-138 DC.

Mass Spectrum: m / e 299 (P).

Analysis 10 calculated for Ο- ^ Ι ^ Ν, -Ο * 1/81 ^ 0: C 63.71, H 7.10, N 23.22; Found: C 63.63, H 6.88, N 23.37.

EXAMPLE 26 4-Diethylamino-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline-lin a) Preparation of 4-chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline.

2-Chloro-3-hydrazinoquinoxaline (2.2 g, 0.011 mol) was mixed with 6 ml of triethyl orthobenzoate and heated to 100 ° C for 30 minutes. After cooling the orange mixture to room temperature, ethanol was added. Filtration of the resulting precipitate afforded 2.1 g of crude product which was further purified by rubbing off with hot methanol, followed by filtration and air drying to give 1.58 g (51¾) of l-Phenyl [1,2,4] triazolo [4,3-a] quinoxa-lin as an orange substance.

b) Preparation of 4-diethylamino-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline.

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52

To 1.58 g (0.00563 mol) of 4-chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline dissolved in 15 ml of N, N-dimethylformamide was added 1.738 ml diethylamine. The mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with Ν, Ν-dimethylformamide and recrystallized twice from hexane / ethyl acetate (3: 1 v / v) to give 555 mg of pure 4-diethylamino-1-phenyl- [1,2 , 4] triazolo [4,3-a] quinoxaline in the form of white 10 needles, m.p. 166-168 ° C.

Analysis calculated for C 19 H 19 N 5: 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- [1,2,4] triazolo [4,3-a] quinoxaline A) Preparation of 4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [ 4,3-a] quinoxaline.

2-Chloro-3-hydrazinoquinoxaline (3.89 g, (0.02 mol), the product of Example 1) was added to 22.8 g (0.20 mlol) of cold trifluoroacetic acid (15.4 ml) under a dry nitrogen atmosphere In a flame-dried reaction flask surrounded by an ice bath and under mechanical stirring, the reaction mixture was then heated to 100 ° C for 25 hours and poured over ice. The resulting product was collected by suction filtration, washed with water and air-dried to constant weight. 3.0 g (60 µl) of pure 4-h <ydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline were obtained, m.p.

30> 300 ° C.

Mass Spectrum: m / e 254 (P).

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b) Preparation of 4-chloro-1-trifluoromethyl- [1,2,4] -tri] olo [4,3-a] quinoxaline.

Into a flame-dried reaction flask under a dry nitrogen atmosphere was placed 3.0 g (0.0118 mol) of 4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline and 30 ml of phosphorus oxychloride. in 2.38 g (0.0236 mole) of triethylamine (3.3 ml). The reaction mixture was then heated to 100 ° C for about 16 hours (i.e. overnight). After completion of this step, the reaction mixture was cooled to room temperature, concentrated in vacuo and then partitioned between ice water and ethanol, followed by extraction with ethyl acetate. The latter extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a residue was obtained which was then dissolved in hot chloroform and filtered. The filtrate was allowed to stand overnight at room temperature and was filtered again. The final filtrate was then concentrated in vacuo to give 1.4 g of 4-chloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline in the form of a brownish tan fabric.

c) Preparation of 4-Diehylamino-1-trifluoromethyl-25 [1,2,4] triazolo [4,3-a] quinoxaline.

A mixture of 700 mg (0.0025 mol) of 4-chloro-1-trifluoro-methyl- [1,2,4] triazolo [4,3-a] quinoxaline (prepared as described above) and 560 mg (0.0075 mole of diethylamine (0.8 ml) in 10 ml of N, N-dimethylformamide was stirred at room temperature overnight and then poured over ice. The resulting mixture was filtered and the solid product recovered washed with water and then dissolved in ethyl acetate. The organic solution was

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54 washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a pale yellow solid was finally obtained, which upon recrystallization from diethyl ether gave pure 4-diethylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline. The yield of the first amount was 260 mg (34%), melting at 155-157 ° C, while the yield of the other amount was 170 mg (22%), melting at 153-156 ° C.

Analysis calculated for 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] triazolo- [4,3-a] quinoxaline

A mixture of 700 mg (0.0025 mol) of 4-chloro-1-trifluoro-methyl- [1,2,4] triazolo [4,3-a] quinoxaline (product 20 of Example 27b) and 443 mg (0, Isopropylamine (0.64 ml) in 10 ml of N, N-dimethylformamide was stirred at room temperature overnight and then poured over ice. The resulting mixture was filtered and the recovered solid product washed with water and dissolved in diethyl ether. The ether solution was washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a white solid powder was finally obtained which after a recrystallization from diethyl ether gave 550 mg (74%) of pure 4-isopropylamino. 1-Trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 185-187 ° C.

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55

Found: C, 12.5, C, 55.88; 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 [4,3-a] quinoxaline.

A mixture of 241 mg (0.001 mole) of 1-ethyl-4-ethyl-amino- [1,2,4] triazolo [4,3-a] quinoxaline (the product of Example 17) and 2.5 g (0.025 mole) acetic anhydride (2.5 ml) under a dry nitrogen atmosphere in a flame-dried reaction flask was heated under reflux (140 ° C) for 3 hours and then allowed to cool to room temperature. A precipitate was formed and the resulting reaction mixture was poured into water and then extracted with chloroform.

The chloroform extracts were combined, washed with water and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and the solvent by evaporation under reduced pressure, a solid product was obtained which, after recrystallization from chloroform / diethyl ether, gave 160 mg (57%) of 1-ethyl-1- (N-ethylacetylamino) -1. 2,4-triazolo [4,3-a] quinoxaline, m.p. 185-187 ° C.

For C 25 H 17 N 5 O: C 63.59, H 6.05, N 24.72 found: C 63.17, H 6.05, N 24.39.

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EXAMPLE 30 4-Acetylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture of 533 mg (0.0025 mol) of 4-amino-1-ethyl-5 [1,2,4] triazolo [4,3-a [quinoxaline (the product of Example 14) and 1.0 g (0, Acetic acid anhydride (1.0 ml) in methylene chloride (20 ml) was heated under reflux overnight (about 16 hours) and then allowed to cool to room temperature. The resulting 10 clear solution was concentrated in vacuo to give a white solid which upon recrystallization from chloroform / diethyl ether gave 520 mg (82? 6) of pure 4-acetylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 193-195 ° C.

Found: 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 [4,3-a] -20 quinoxaline

A mixture of 5.5 g (0.0258 mol) of 4-amino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (the product of Example 14) and 25 g (0.25 mole) of acetic anhydride (25 ml) in 60 ml of pyridine containing 100 mg of p-25 dimethylaminopyridine was stirred at room temperature overnight (about 18 hours). The resulting slurry was filtered to remove insoluble material and the orange-red filtrate was then evaporated under high vacuum to give a dark rubbery residue. After the addition of water became

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57 obtained pink to white crystals and these were collected by suction filtration, washed with an abundant amount of water and dried in vacuo at 50 ° C to give 2.9 g (38%) of 4-diacetyl-5 amino. -1-ethyl1- [1,2,4] triazolo [A, 3-a] quinoxaline, m.p.

157-159 ° C. Recrystallization of the latter materials from ethyl acetate / diethyl ether then gave an analytically pure sample (mp 158-160 ° C). The pure product was further characterized using 10 mass spectroscopy and magnetic nuclear resonance data in addition to elemental analysis.

Mass Spectrum: m / e 297 (P).

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

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EXAMPLE 52

The following [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivatives were prepared using the procedures described in the preceding Preparations 5 and Examples from readily available materials in each cases: 7,8-Dibromo-4-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 199-201 ° C.

8-Chloro-4-isopropylamino- [1,2,4-] triazolo [4,3-a] quinoxaline, m.p. 177-181 ° C.

4-Ethylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 223-225 ° C.

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

4-Dethylamino-8-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 124-126 ° C.

8-Chloro-1-ethyl-4-isopropylamine [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. 253-256 ° C.

8-C-chloro-4- (N-isopropylacetylamino) - [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-isopropylacetylamino) -1,2,4-triazolo [4,3-a] quinoxaline, m.p. 155-158 ° C.

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

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59 4-Amino-7,8-dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] 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 [4,3-a] 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.

1-Ethyl-4-ethylamino-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 231-233 ° C.

7.8- Difluoro-4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxa-lin, m.p. 208-211 ° C.

4-Diethylamino-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxalin, 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-Ghloro-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 [4,3-a] quinoxaline methanesulfonate, m.p. 172-175 ° C.

7.8- Dichloro-1-ethyl-4- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline 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.

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4-Acetylamino-1-ethyl-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 203-205 ° C.

4-Amino-7-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxa-linemethanesylphonate, m.p. 240-243 ° C.

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

7- Chloro-4-diethylamino [1,2,4-triazolo [4,3-a] quinoxa-linemethanesulfonate, m.p. 205-207 ° C.

4-Diethylamino-7,8-difluoro- [1,2,4] triazolo [4,3-a] -quinoxaline methanesulfonate, m.p. 220-223 ° 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 [4,3-a] 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-A.mino-8-chloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 213-215 ° C.

8-Chloro-4-isopropylamino-1-trifluoromethyl- [1,2,4] -20 triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 183-185 ° C.

8-Chloro-4-diethylamina-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 172-175 ° C.

4-0i acetyl amino- [1,2,4] triazolo [4,3-a] quinoxaline, 211-214 ° C.

4-Oiacetylamino-8-chloro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 208-210 ° C.

8-Chloro-4-isopropylamino-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 206-208 ° C.

4-Acetylamino-1-methyl-8-chloro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 262-264 ° C.

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61 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] quinoxylin methanesulfonate, m.p. 131-152 ° C.

4-n-Butyrylamino-8-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 185-187 ° C.

8-6hlor-4-diethylamino-l-trifluoromethyl- [l, 2,4] tria-zolo [4,3-a] quinoxalinhydrat, mp. 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.

7- 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 [4,3-a] quinoxaline methanesulfonate, m.p. 215-219 ° C.

4-Amino-7-methoxy [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 262-264 ° 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- [1,2,4] triazolo [4,3-a] -quinoxaline, m.p. 254-256 ° C.

7-Fluoro-4-isopropylamino [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 214-216 σ0.

4-Ethylamino-7-fluoro [1,2,4] triazolo [4,3-a] quinoxa-linemethanesulfonate, m.p. 216-218 DC.

4-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.

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62

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 [4,3-a] 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 [4,3-a] 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.

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

4-Acetylamino-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 240-242 ° C.

4-Acetylamino- [1,2,4-] triazolo [4,3-a] quinoxaline, m.p.

269-272 ° C.

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63 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 DC.

4-Acetylamino-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

A mixture of 1.23 g (0.005 mol) of 4-amino-8-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, (mp 248-253 ° C), a product reported in Example 32 and 15 ml of propionic anhydride was heated under reflux overnight (about 16 hours) and then cooled to room temperature (about 20 ° C). Upon completion of this step, the reaction mixture was filtered and the recovered precipitate dissolved in chloroform. The organic solution was filtered and then successively washed with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the desiccant 25 by filtration and the solvent by evaporation under reduced pressure, a residue was obtained which was then chromatographed on a 150 ml silica gel column and eluted with chloroform / methanol (95: 5 v / v). Equal fractions containing the product were combined and then concentrated in vacuo to give a crystalline material which was later recrystallized from chloroform

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64 diethyl ether to give 540 mg (36 36) of pure 8-chloro-1-ethyl-4-propionylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 212-215 ° C.

For C 14 H 14 Cl 1 N 5: C 55.36, H 4.64, N 23.06; Found: C, 54.91; H, 4.59; N, 22.76.

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€ 5

BIOLOGICAL TESTING

The test used to detect rapid onset of antidepressant activity in rats is a modification of the method described by R.D.

Porsolt et al. in the European Journal of Pharmacology, 5 vols. 47, page 379 (1978), and which makes use of the subjective observation method developed for Wallach and Hedley mice [Comm. Psychophar., Vol. 3, page 33 (1979)]. As with the original Porsolt method, male Sprague-Dawley (Charles River) rats weighing 280-325 g were placed in individual plastic cylinders (45 cm high x 22 cm in diameter) containing water at 25 ° C to a height of 25 cm. On day 1, the rats were placed in the swimming tanks for a 15 minute training period. During the first 10 minutes, the rats were typically observed swimming around in the tank looking for a mid section to escape. By the end of the 15-minute period, after experiencing escape being "hopeless," the rats had taken on an immobile position and remained floating in the tank until taken up.

Twenty-four hours after the initial training period, 10 rats were dosed orally with medium or test compound and were typically returned to the individual tanks. The medium used for these purposes was 90 vol.% Physiological saline solution (0.9% aqueous sodium chloride solution), 5 vol.% Ethanol and 5 vol. prepared by dissolving or suspending the test compound in ethanol and "Emulphor" followed by dilution with physiological saline solution.

30 Beginning 2 minutes after immersion, the dosed rats were assessed every 30 seconds for escape-directed behavior in a total of 10 observations. If the rat remained motionless, floating passively, it was rated "1" for motionless. If the rat seemed to try to avoid

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66 getting out of the tank (heavy swimming or diving), a rating of "0" was recorded. All rats were assessed within 30 seconds. Thus, based on a series of 10 observations, a rat that remained 5 completely immobile for the duration of the test would have a number of "10", while a rat exhibiting escape behavior would have a smaller number. Typically, the medium-treated rats were found to exhibit mean numbers of 8-9, while antidepressant treatments 10 reduce this immobility (i.e., antagonize "abandonment" or "hopelessness") in a dose- and chronicity-dependent manner. In these circumstances, a compound was considered to be active if the response between the mean treated animals and the control group (i.e.

15 animals receiving the medium alone) were judged to be statistically significant when compared to results obtained from known standard antidepressant treatments such as REM sleep deprivation and electroconvulsive shock (ECS).

In other words, a compound was considered to be 20 active if a statistically significant reduction in immobility was noted.

Accordingly, the following [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivatives were tested for rapid onset of antidepressant activity in rats using the above-described modified

Porsolt et al. swim test procedure and was found to be orally active at the dosage levels listed below. (The first compound, wherein X, x \ R 2, R 5, and R 2 are all hydrogen, is disclosed by B.A. Dreikorn 30 et al. In U.S. Patent No. 4,008,322 as a means of controlling crack welding):

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67 RX \ nk2R3

Dosage "1 r p r (mg./kg) .X X R1 R2 __ Η Η Η Η H 32

Cl Η Η Η H 32 * H Cl Η Η H 10 p Η Η Η H 32 * HF Η Η H 32 * OCH3 Η Η Η H 32 * Η Η Η H COCH3 32 F η Η H COCH3 32 HF Η H COCH3 32 OCH3 Η η η COCH3 32

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Dosage X X1 R2 * 2 R3 (mg / kg) Η Η. Η H CH3 32 HH HH C2H5 3.2 FH HH * C2H5 32 * HF Η H ^ 2 ^ 5 ^^ FF Η H ^ * 2 ^ 5 HH HH iso-C3H7 10 H Cl Η H iso ~ C3H7 10 - ci cl Η H iso-C3H7 10 HF HH iso-C3H? 3.2 p F HH iso-C3H7 3, 2 OCH3 Η Η H iso-C3H? 32 HH H COCH3 COCH3 32 H Cl H COCH3 COCH3 32 H H H CH3 CH3 32 HH H C2H5 C2H5 10

Cl Η H C2H5 C2H5 32 * HF H C2H5 C2H5 10 F F H ^ 2 ^ 5 ^ 2 ^ 5 H Cl H iso-C3H? COCH3 32 H Cl CH3 Η H 32 * H Cl CH3 H COCH3 32 Η H CH3 H iso-C3H7 32 H Cl CH3 H iso-C3H? 3, 2 * Η H CH3 C2H5 C2H5 10 H Cl CH3 C2H5 C2H5 32 * Η H C2H5 Η H 10

Cl H C2H5 Η H 3.2 * H Cl C2H5 Η H 3.2 ci ci c2h5 H H 10 F H C2H5 Η H 32 Η H C2H5 H COCH3 I »0

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69

Dosage 1 - D (mg / kg) x X »i ^ 2 ^ 3

Cl H C2 H5 H COCH3 · 32 H Cl 'C2H5 H COCH3 3.2

Cl Cl C2H5 H COCH3 3.2 FH C2H5 H COCH3 3.2 HF C2H5 H COCH3 3.2 H Cl C2H5 H COC2H5 3.2 H Cl C2H5 H COC3H2 (n) 32 - H Cl C2H5 H COC (CH3) 3 32 Η H C2H5 H CH3 10 Η H C2H5 H C2H5 3.2

Cl H C2H5 H C2H5 32 * H Cl C2H5 H C2H5 32 * F. H C2H5 H C2H5 32 * H F C2H5 H C2H5 32 Η H C2H5 H iso-C3H? 32 H Cl C2H5 H iso-C3H? 3.2

Cl Cl C2H5 H iso-C3H? 32 H F C2H5 H iso-C3H? 10 F F C2H5 H iso-C3H7 32 * Η H C2H5 COCH3 COCH3 10 Η H C2H5 C2H5 COCH3 32 Η H C2H5 CH3 CH3 3.2

Cl H C2H5 CH3 CH3 32 * H Cl C2H5 C2H5 C2H5 32 ci ci c2h5 c2h5 c2h5 10 H F C2H5 C2H5 C2H5 32 F F C2H5 C2H5 C2H5 32, H OCH3 C2Hs C2H5 C2H5 32

Cl Cl C2H5 -CH2CH2NCH2CH2- 32 * Η H iso-C3H? C2H5 C2H5 32 Η H iso-C3H7 H C2H5 32 H Cl C2H5 iso-C3H? COCH3 10

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70

Dosage x x1 Rj r2 r3 (mg Ag) H Cl CF3 Η H 3.21 HF CF3 Η H 3.2 H Cl CF3 H COCH3 3.2 HF CF3 H COCH3 3.2 Η H CF3 H C2H5 32 H Cl CF3 H C2H5 32 HF CF3 H C2K5 321 Η H CF3 H isO “C3H? 10 H Cl CF3 H iso-C3H7 3.21 H F CF3 H iso-C3H7 3, 21 Η H CF3 C2H5 C2Hs 32 H Cl CF3 C2H5 C2H5 32 H Cl C_Fc H iso-C, H_ 32 H Cl CgHg H iso-C3H? 32 Η H C6H5 C2H5 C2H5 32

Cl Cl C2H5 CH3 CH3 321 Η B C2H5 C2H5 C2H5 10

Cl H C2H5 C2H5 C2H5 321

The compound was tested as the mesylate (i.e., methanesulfonate) salt.

Claims (3)

1. Analogy method for the preparation of therapeutically active [1,2,4] triazolo [4,3-a] quinoxaline-4-amine n derivatives of the general formula: R1 \ --- N xl .. N j , N II I (I) Μ A_nr2r3 wherein X and each are selected from hydrogen, 5 fluorine, chlorine, bromine and methoxy, R 1 is selected from hydrogen, (C 1 -C 2) alkyl, C 1 -C 2) perfluoroalkyl and phenyl, and R 2 and each are selected from hydrogen, C 1 -C 4 alkyl, phenyl (C 1 -C 4) alkyl and (C 2 -C 3) alkanoyl, or R 2 and R 2 together with the nitrogen atom to which they are attached form a piperazine ring, at least one of R 2 being and always different from hydrogen when X and X 1 are both hydrogen and R 2 being hydrogen or methyl, or pharmaceutically acceptable acid addition salts thereof , characterized in that a corresponding 4-chloro-15 compound of the formula: wherein X, X1 and is as defined above is reacted with an amine of the formula HNR 1 R 2, wherein R £ and R ^ are as defined for R £ and Rj above, except that they are different from alkanoyl to form the corresponding 4-amino compound, upon which a 4-amino compound thus formed, wherein at least one of R 1 and is hydrogen, if desired, is reacted with an appropriate alkanoic anhydride to form a 4 -amino derivative having the desired alpha-canoyl moiety, and the compound of formula (I) formed, 10 if desired, is converted into a pharmaceutically acceptable acid addition salt thereof. Process according to claim 1 for the preparation of 1-ethyl-4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline, characterized in that the corresponding starting materials are used. Process according to claim 1 for the preparation of 8-fluoro-4-isopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline, characterized in that corresponding starting materials are used.