FI74011C - FOERFARANDE FOER FRAMSTAELLNING AV NYA THERAPEUTIC EQUIPMENT / 1,2,4 / TRIAZOLO / 4,3-A / QUINOXALIN-4-AMINDERIVAT. - Google Patents

Description

1 74011

Process for the preparation of new therapeutically useful (1,2,4) -triazolo [4,3-a] quinoxalin-4-amine derivatives.

The invention relates to a process for the preparation of new [1,2,4] triazolo [4,3-a] quinoxalin-4-amine derivatives of the formula (I) and their pharmaceutically acceptable acid addition salts,

X1 I

-NR R

Wherein X and X 1 represent hydrogen, fluorine, chlorine, bromine or methoxy, R 1 represents hydrogen, lower alkyl, lower perfluoroalkyl or phenyl and R 2 and represents hydrogen, 2q lower alkyl, phenylalkyl having up to three carbon atoms, or an alkanoyl having 2 to 5 carbon atoms, provided that at least one of the substituents R 2 and R 2 is other than hydrogen, when X and X 1 each represent hydrogen and R 1 represents hydrogen or methyl; or R 2 and R 2 together with the nitrogen atom to which they are attached form a piperazino ring. These compounds have antidepressant and anti-fatigue effects.

Extensive research has been conducted to develop agents that would effectively reduce the symptoms of depression and fatigue-2Q in mammals.

U.S. Pat. No. 3,839,569 and DE Pat. No. 2,249,350 describe the use of S-triazolo [4,3,4-47] quinolines and 1H-imidazo [4,5,6] quinoxalines in agriculture as fungicides. U.S. Patent 4,008,322 describes the use of certain triazolo / 4,3-α7quinox-25 saline derivatives in the phytopathogen Piricularia oryzae.

to combat rice plague caused by

2 74011

It has now surprisingly been found that the novel [1,2,4,7-triazolo [4,3-a] quinoxalin-4-amine derivatives of the formula (I) are useful as antidepressants and anti-fatigue agents. The term "lower alkyl" means 5 alkyl of 1 to 4 carbon atoms, and the term "lower perfluoroalkyl" means perfluoroalkyl of 1 to 4 carbon atoms, such as trifluoromethyl and pentafluoroethyl, etc. Interesting compounds include those wherein X and X 1 each represents hydrogen, is hydrogen, and R 2 and R 2 are each lower alkyl. Preferred compounds are those wherein R 2 and R 3 each represent ethyl.

Another interesting group are compounds wherein X and X 1 are each hydrogen, R 1 is ethyl and R 3 is lower alkyl. Preferred compounds are those wherein R 2 is hydrogen 3a R 3 is ethyl.

Also of interest are those compounds wherein X and X 1 each represent hydrogen, R 3 is lower alkyl and R 3 is acetyl. Preferred compounds are those wherein R 3 is ethyl and R 3 is hydrogen, ethyl or acetyl.

20 .... ...

Further interesting are those compounds wherein at least one of X and X 1 is fluoro, R x is hydrogen or trifluoromethyl, R 2 is hydrogen and R 3 is hydrogen, lower alkyl or alkanoyl having 2 to 5 carbon atoms; or alternatively wherein at least one of X and X 1 is chloro, R 1 is almepi alkyl or trifluoromethyl, R 2 is hydrogen and R 3 is hydrogen, lower alkyl or alkanoyl having 2 to 5 carbon atoms.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts may be prepared by reacting a 4-clone compound of formula R 1 - [==

Wr 35 Cl

X

3 74011

The preparation of compounds of formula (I) can be described by reaction schemes (I) and (II)

Reaction Scheme I

5 -Cl 10 χ1 '--- | ίί <^ ν ^ -NHNH2 «AXJ-ci 111 15 l

RK

20. ~ Wy VSAci ha (excluding X ^ = H; X ^ H) 25

'V

30 X1 V 2ΐ w; ^ x —— nr2r3 ia (excluding X = H; X ^ H) 35 4 7401 1

Reaction Scheme II

jSO = “- Ψ 10 JL J — och3 v’ i 'L * [1-Ν ™ 2 20 3 Ψ

Rv 25 χΐ 1 = ^ 1 wy

χ ^ Κ ^ Νι ^^ 0 (Μ3 VII

30 5 7401 1

* I I

VIII

X 'Ύ 10

Rx t V ^ ’

Vy'Y "15 Ψ 20 1 RN ="

x * 1 I

VYY

'| IB (XX = H; Xtfi) 0 R.

25 XX Z J

6 7401 1

Most of the novel compounds of formula (I) can be prepared according to the method shown in Reaction Scheme (I). The numbering of the phenyl ring and the two heterocyclic rings in Reaction Scheme (I) is the same as used below.

In Reaction Scheme (I) and a compound of formula (IV), a quinoxaline derivative wherein X and each represent hydrogen, fluorine, chlorine, bromine or methoxy, provided that X is always hydrogen when the quinoxaline derivative is monosubstituted in the benzene ring, is treated with a molar excess of hydrazate in a polar, reaction-inert organic solvent such as an alkanol having 1 to 3 carbon atoms, preferably ethanol, at room temperature for about 18 to 24 hours to give an intermediate of formula (III).

The intermediate of formula (III) may be further converted to the corresponding intermediate of formula (IIa) other than lower perfluoroalkyl by treatment with the appropriate alkyl orthoalkanoate or alkyl orthobenzoate, as appropriate, at a temperature between about 80-120 ° C, about 1-24 ° C. hours. In the resulting compound of formula (IIa), R 1 (as hydrogen or alkyl) is determined according to the orthoalkanoate used in the synthesis. Thus, for example, when triethyl orthoformate is used, hydrogen is used, when triethyl orthopropionate R 1 is ethyl and when triethyl orthoisobutyrate R 1 is isopropyl.

The intermediate of formula (III) can also be converted to the corresponding intermediate of formula (IIA) having perfluoroalkyl by treating it with a molar excess of a suitable perfluoroalkanoyl acid such as trifluoroacetic acid or pentafluoropropionic acid, etc., as appropriate, in a conventional manner to give the corresponding 4-hydr. -fluoroalkyl- [1,2,4-7] triazolo [4,3-a] quinoxaline, followed by treatment of the obtained compound with phosphorus oxychloride in the presence of a tertiary amine, for example triethylamine, at elevated temperature to give the corresponding 4-chloro compound.

Intermediate (IIA) (with hydrogen, lower alkyl, lower perfluoroalkyl or phenyl) is then converted to the Z1, 2,4 / triazolo [4,3-a] quinoxalin-4-amine derivative of formula (IA) wherein R2 and R3 mean the same as above except for alkanoyl by treating it with a molar excess of an amine of formula HNR 2 R 3 in a reaction inert organic solvent, preferably N, N-domethylformamide, at a temperature between about 0-60 ° C for about 2-24 hours. For example, preferred compounds of formula (IA) wherein R 2 and R 2 are both ethyl are prepared by treating the appropriate compound of formula (IIA) with diethylamine in N, N-dimethylformamide at room temperature for 2-3 hours. Likewise, preferred compounds of formula (IA) wherein R 2 is hydrogen and R- is ethyl are prepared by treating a compound of formula (IIA)

15 J

monoethylamine in N, N-dimethylformamide at room temperature for 4-5 hours.

N, N-triazolo [4-a] quinoxalin-4-amine derivatives of the formula (IA) in which at least one of the substituents

R 1 and R 2 are alkanoyl having 2 to 5 carbon atoms are prepared

corresponding compounds of formula (IA) wherein at least one of R 2 and R 2 is hydrogen by contacting the latter with a suitable 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 this is not absolutely necessary) at a temperature ranging from about 20 to 140 ° C for a period ranging from half an hour to 24 hours. The molar ratio of acid anhydride to the starting 4-amino compound should be at least 1: 1, and preferably 4: 1 to 30 25: 1, while the amount of tertiary amine used is usually about 25-150% by weight of the above acylating agent (tertiary amine can be used in the reaction as solvent simply using it in excess). Although it is quite possible and sometimes even quite desirable to carry out the reaction without a solvent, there may be cases where the use of a suitable reaction-inert organic solvent is justified. Suitable organic solvents for use herein include neutral reaction-inert anhydrous organic solvents such as acetone, methyl ethyl ketone, benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride, chloroform, ethylene dichloride, ethyl acetate, tetrachloroethane, tetrachloroethane, methyl propionate, ethyl propionate, diethyl ether, diisopropyl ether, di-n-propyl ether, etc. However, as described above, the reaction is usually carried out without a solvent only using an excess of anhydride. Likewise, an excess of tertiary amine reagent 10 can act as a solvent. Preferred tertiary amines for use as solvents and / or catalysts in this reaction include triethylamine, dimethylaniline, pyridine, picoline, lutidine, collidine and quinoline.

The starting materials of formula (IV) in which X and X1 are each hydrogen are already known. Compounds of formula (IV) wherein X 1 is methoxy may be prepared by the method described by G. W. H. Cheeseman et al. Chem. Soc., P. 1170 (1962) .7, and wherein 4-methoxy-o-phenylenediamine is treated with at least an equimolar amount of diethyl oxalate and diethylamine in an inert gas atmosphere, preferably nitrogen, at reflux for about 2-3 hours, followed by treatment with phosphorus oxychloride in a tertiary amine, preferably dimethylamine, at reflux for 1-2 hours.

In Reaction Scheme II, a quinoxaline derivative of formula (IV) wherein X is fluorine, chlorine, bromine or methoxy and X 1 is hydrogen is treated with sodium methoxide in an alcoholic solvent at a slightly elevated temperature (e.g. 4-60 ° C) for about 6-18 hours. to give the corresponding 2-30 chloro-3-methoxyquinazoline derivative of formula (V), which is then treated with hydrazine hydrate in the same manner as above to give the corresponding 2-hydrazino-3-methoxyquinazoline derivative of formula (VI). The latter intermediate (VI) is then converted to the desired 7-subs-35-substituted 4-methoxy-1,2,4,7-triazolo [2,3-a] quinoxaline of formula (VII) using the appropriate orthoester or perfluoroalkanoylic acid in the same manner as described above and the latter compound. is then converted to the corresponding 9 74011 4-hydroxy (see formula (VIII)) and 4-chloro compounds in a conventional manner to give a compound of structural formula IIB wherein X is as defined above (other than hydrogen) and X 1 is hydrogen. This intermediate of formula IIB gives 5 corresponding new end products of formula IB, wherein R 1, 2 3 1 R and R p are all as previously defined and X and X are as defined above, using the reaction methods described above in connection with the descriptions of the final steps of Reaction Scheme I. .

Pharmaceutically acceptable acid addition salts of the novel compounds of formula (I) may be readily prepared by contacting the free base with a suitable mineral acid or organic acid in either an aqueous or suitable organic solvent. The solid salt is then obtained by precipitation-15 mana or by evaporation of the solvent. Suitable pharmaceutically acceptable acid addition salts include hydrochloride, sulfate, bisulfate, myselate, tosylate, nitrate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, succinate, gluconate, etc. Mesylate salts include edulate salts. If desired, compounds of formula (I) may be obtained as bases from acid addition salts by treatment with a suitable base, followed by extraction of the free base with a suitable organic solvent.

The compounds of formula (I) and their acid addition salts have an antidepressant and anti-fatigue effect. The compounds may be administered to a patient in need of treatment, for example, orally or parenterally. Preferably, the compounds are administered orally. In general, these compounds are administered orally in one or more doses ranging from 0.1 to 100 mg per kilogram of body weight of the patient to be treated per day, preferably about 0.5 to 10 mg / kg per day. When the compounds are administered parenterally or intravenously, the dosage may vary between 0.1 and 10 mg per kilogram of body weight of the patient to be treated. However, dosage variation may be necessary depending upon the condition of the patient being treated and the compound being employed.

10 7401 1

The compounds may be administered alone or in combination with pharmaceutically acceptable carriers and diluents, either in single or multiple doses. Suitable pharmaceutical carriers include inert diluents or excipients, sterile aqueous solutions and various organic solvents.

Pharmaceutical preparations prepared by combining the novel compounds of formula (I) or their salts and pharmaceutically acceptable carriers can be easily administered in various dosage forms such as tablets, powders, capsules, lozenges, syrups, etc. These pharmaceutical preparations may, if desired, contain other additives such as flavorings, binders, fillers, etc.

Thus, for oral administration, tablets containing various excipients such as sodium citrate may be used in combination with various anti-adherents such as starch, alginic acid and certain complex silicates, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

The antidepressant and anti-fatigue activity of the compounds of formula (I) can be determined by various standard pharmacological tests, such as the "learned helplessness" or immobility screening model 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 the immobility caused by forced swimming.

The antidepressant activity of the compounds of formula (I) has been studied using a variation of the above-mentioned Porsolf 30 method and the method described by

Wallach and Hedley in Comm. Psychopharm., Vol 3, p.

35 (1979). The compounds were found to be active at the oral doses indicated in the following table. The first compound shown in the table, wherein X, X1, R1 and R335 are hydrogen, has become known from U.S. Patent 4,008,322 as a rice plague pesticide.

11 7401 1 v v- 5 χ -NR2R3 10

Dose X x * R] _ ί mg / kg) H H H H H 32

Cl HHHH 32 * H Cl HHH 10 FHHHH 32 * HFHHH 32 * OCHj HHHH 32 * 2Q HHHH COCH3 32 FHHH C0CH3 32 HFHH COCH3 32 OCH3 HHH COCH3 32 25 XX Rj (mg / kg) 7401 1 12 HHHH CH3 32HHH 2 FHHH C2H5 32 * HFHH C2H5 3 T 2 FFHH C2H5 32 HHHH iso-C3H? 10 H Cl H H iso-C3H7 10

Cl Cl H H iso-C3H? 10 H F H H iso-C3H7 3.2 F F H H iso-C3H? 3.2 OCH3 H H H iso-C3H7 32 H H H COCH3 COCH3 32 H Cl H COCH3 COCH3 32 H H H CH3 CH3 32 H H H C2H5 C2H5 10

Cl H H C2H5 C2H5 32 * H F H C2H5 C2Hs 10 F F H C2H5 C2H5 32 * H Cl H iso-C3H? COCH3 32 H Cl CH3 H H 32 * H Cl CH3 H COCH3 32 H H CH3 H iso-C3H? 32 H Cl CH3 H iso-C3H7 3.2 * H H CH3 C2H5 C2H5 10 H Cl CH3 C2H5 C2H5 32 * H H C2H5 H H 10

Cl H C2H5 H H 3.2 * H Cl C2H5 H H 3.2 ci ci c2h5 H H 10 F H C2H5 H H 32 H H C2H5 H COCH3 1.0 13 XX R1 R2 R3 f mg / kg) 7401 1

Cl H C2H5 H COCH3 32 H Cl C2H5 H COCH3 3 T 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 COC3H7 (n) 32 H Cl C2H5 H COC (CH3) 3 32 HH C2H5 H CH3 10 HH C2H5 H C2H5 3 r2

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

Cl H C2H5 CH3 CH3 32 * H Cl C2H5 C2H5 C2H5 32

Cl Cl C2H5 c2h5 C2H5 10 H F C2H5 C2H5 C2H5 32 F F C2H5 C2H5 C2H5 32 H 0CH3 C2H5 C2H5 C2H5 32

Cl Cl C2H5 -CH2CH2NCH2CH2- 32 * H H iso-C3H? C2H5 C2H5 32 H H iso-C3H7 H C2H5 32 H Cl C2H5 iso-C3H? COCH3 10 14 X X1 Ra R2 R3 (mg / kg) 7401 1 H Cl CF3 HH 3 T 2 * HF CF3 HH 3? 2 H Cl CF3 H COCH3 3? 2 HF CF3 H COCH3 3t2 HH CF3 H C2H5 32 H Cl CF3 H C2H5 32 HF CF3 H C2H5 32 * HH CF3 H iso-C3H? 10 H Cl CF3 H iso-C3H? 3f2 * H F CF3 H iso-C3H7 312 * H H CF3 C2H5 C2H5 32 H Cl CF3 C2H5 C2H5 32 H Cl C2F5 H iso-C3H? 32 H Cl CgH5 H iso-C3H? 32 H H CgH5 C2H5 C2H5 32

Cl Cl C2H5 CH3 CH3 32 * H H C2H5 C2H5 C2H5 10

Cl H C2H5 C2H5 C2H5 32 * * The compound was studied as the mesylate or methanesulfonate salt.

The following examples illustrate the invention. All temperatures are in degrees Celsius.

15 7401 1

MANUFACTURE OF STARTING MATERIALS

Example A

Preparation of 4-chloro-7-fluoro-1,2,4-triazolo [5,3-a] quinoxaline a) Preparation of 2-chloro-6-fluoro-3-methoxyquinazoline 5 By annealing to a dried reaction vessel containing 52 g (0.24 mol) ) 2,3-dichloro-6-fluoroquinoxaline in 500 ml of methanol under a dry nitrogen atmosphere, a solution of 6.6 g (0.29 mol) of sodium dissolved in 650 ml of dissolved solution was slowly added dropwise at 50 ° C. 10 methanol. The resulting reaction mixture was then heated at 50 ° C overnight (i.e., about 16 hours) and the resulting clear solution was allowed to cool to room temperature (* ~ 20 ° C). The reaction mixture was then concentrated in vacuo, after which the remaining material was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to finally give a liquid residue which was chromatographed on a 1000 ml silica gel column with toluene 20 as eluent. Combining the product-only fractions gave 48.3 g (95%) of pure 2-chloro-6-fluoro-3-methoxyquinoxaline, m.p. 93-95 ° C. Mass spectrum: m / 4,212 (P); m / e, 214 (P + 2).

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

To a solution of 47 g (0.22 moles) of 2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml of ethanol was added 27.6 g (0.55 moles) of hydrazine hydrate (26.8 mL). The resulting mixture was stirred at room temperature overnight (i.e., at about 20 ° C for approximately 16 hours). Additional hydrazine hydrate (9.0 mL) was then added, and the final reaction mixture was stirred at room temperature for four hours. The precipitate was filtered and washed with ethanol to give 43.3 g (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline, m.p. 170-174 ° C (dec).

16 7401 1 c) Preparation of 7-fluoro-4-methoxy-1,2,4,4-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 5-thioformate was mechanically heated with stirring in a preheated oil bath at 100 ° C overnight (* ~ 16 hours). The resulting mixture was then cooled to room temperature, and the precipitate thus formed was collected by suction filtration and washed with ethanol to give 11.3 g (72%) of pure 7-fluoro-4-methoxy-1,21.2. 4 / triazolo [4,3-a] quinoxaline, melting point 245-246 ° C (decomposed).

d) Preparation of 7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline A mixture containing 11.3 g (0.52 moles) of 7-fluoro-4- methoxy-1,2,4 / triazolo [1,3-a] quinoxaline, 115 ml of 1N hydrochloric acid and 345 ml of glacial acetic acid were refluxed for 3 hours. At the end of this step, the reaction mixture was cooled to room temperature and poured into ice / water. The resulting mixture was then stirred for 30 minutes and then filtered to remove the precipitate, which was then washed with water and air dried to give 8.9 g (84%) of pure 7-fluoro-4-hydroxy-1,2,4-triazolo / 4,3-α / quinox-25 saline, melting point> 300 ° C. Mass spectrum: m / e, 204 (P).

e) Preparation of 4-chloro-7-fluoro-1,4,2,4-triazolo [4,4-a] quinoxaline

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 8.9 g (0.044 mol) of 7-fluoro-4-hydroxy- [1,2,4] triazolo [1,3-a] quinoxaline and 160 ml of phosphorus oxychloride were charged together. With 8.9 ml of tri-n-propylamine. The reaction mixture was then heated to reflux overnight for about 16 hours and finally cooled to room temperature before being poured into a mixture of ice and water while stirring mechanically. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the resulting solid was then washed with cold water and triturated with ethyl acetate to give 7.0 g (71%) of pure 4-chloro-7-fluoro-1N. 2,4-triazolo [4,3-a] quinoxaline, m.p. 305-308 ° C. Mass spectrum: m / e, 222 (P); m / e, 224 (P + 2).

Example B

4-chloro-1-ethyl-7-fluoro-1,2,4,7-triazolo [4,3-a] 10-quinoxaline a) 1-ethyl-7-fluoro-4-methoxy-1,2,4 Preparation of <7-triazolo, 3-α-quinoxaline

A mixture of 15 g (0.07 mol) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline, i.e. the product of Example 15 A (b), and 250 ml of triethyl orthopropionate was mechanically heated with stirring in a preheated oil bath at 100 °. At overnight ("-16 hours). The resulting mixture was cooled to room temperature (20 ° C), filtered and the resulting precipitate was washed with ethanol to give 11.3 g (64%) of pure 1-ethyl-7- fluoro-4-methoxy-1,2,4,4,7-triazolo [4,3-a] quinoxaline, m.p. 200-202 ° C (decomposed).

b) Preparation of 1-ethyl-7-fluoro-4-hydroxy-1,2,4,7-triazolo, 3-α7-quinoxaline A mixture containing 11.3 g (0.046 mol) of 1-ethyl-7-fluoro-4- methoxy-1,2,4-triazolo [4,3-a] quinoxaline, 115 ml of 1N hydrochloric acid and 345 ml of glacial acetic acid, was heated under reflux for 3 hours. At the end of this step, the reaction mixture was allowed to cool to room temperature, after which it was poured into a mixture of ice and water. The resulting mixture was then stirred for 30 minutes, filtered and the resulting solid was then washed with water and air dried to give 6.6 g (62%) of pure 1-ethyl-7-35 fluoro-4-hydroxide, 2.4 g. ^ 7 triazoles, 3-α7-quinoxaline, 18 7401 1 Melting point> 300 ° C. Mass spectrum: m / e, 232 (P); ra / e 231 (P-1).

c) Preparation of 4-chloro-1-ethyl-7-chloro-1,2,4,7-triazolo-β, 3-α7-quinoxaline 6.6 g (0.028 mol) were placed in a dried reaction vessel with a dry nitrogen atmosphere. 1-ethyl-7-fluoro-4-hydroxide, 2.47 g of triazolo [4] quinoxaline and 120 ml of phosphorus oxychloride together with 6.6 ml of tri-n-propylamine. The reaction mixture was then heated to reflux overnight. over about 16 hours and finally cooled to room temperature before being poured into a mixture of ice and water with mechanical stirring, the resulting aqueous mixture was then stirred at room temperature for 30 minutes, then filtered and the resulting solid was washed with cold water and then dissolved in ethyl acetate. The latter organic solution was then washed with water, saturated aqueous sodium bicarbonate solution and saturated brine before being dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure finally gave a yellow-brown solid which was then triturated with diethyl ether to give 4 g (57%) of pure 4-chloro-1-ethyl-7-fluoro-1,2,4-triazolo [4]. 3-α / quinoxaline, melting point 203-205 ° C. Mass spectrum: m / e 250 (P); m / e, 252 (P + 2); m / e 249 (P-1).

Example C

4,7-Dichloro-dl, 2,47-triazolo [* 4,3-a] quinoxaline 30 a) Preparation of 2,3-dihydroxy-6-chlorooxalaline

A mixture of 100 g (0.07 mol) of 4-chloro-1,2-phenylenediamine and 750 ml of diethyl oxalate was heated under reflux overnight for about 16 hours. At the end of this step, the reaction mixture was cooled to room temperature (* w 20 ° C), filtered and then the product obtained was washed with ethanol and dried to a constant weight of 19 7401 L in air to finally give 140 g of pure 2,3-dihydroxy-6 chloroquinoxaline, melting point> 260 ° C.

b) Preparation of 2,3,6-trichloroquinoxaline A mixture of 140 g (0.70 mol of 2,3-dihydroxy-6-chloroquinoxaline and 326 ml (3.50 mol) of phosphorus oxychloride was heated under reflux overnight (^ 16 hours) and then poured onto ice, the resulting aqueous mixture was then filtered, after which the resulting product was washed with water and air-dried before being dissolved in chloroform, the latter organic solution was then washed with saturated brine and air-dried with anhydrous magnesium sulfate. After removal by filtration and evaporation of the solvent under reduced pressure, a thick slurry was finally obtained, which was recrystallized from a mixture of chloroform and ethanol to give 120 g (74%) of pure 2,3,6-trichloroquinoxaline, m.p. 139-142 ° C. Mass spectrum: m / e, 232 (P), 20 m / e 234 (P + 2), m / e, 236 (P + 4).

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

The slurry containing 11.7 g (0.05 mol) of 2,3,6-trichloroquinoxaline in 140 ml of methanol was heated to 50 ° C, at which temperature a solution containing 1.4 g (0 .06 moles) of sodium dissolved in 140 ml of methanol, over a period of six hours. The resulting mixture was then heated at 50 ° C overnight (1616 hours), after which a further 140 mg of sodium in 20 ml of methanol was added over one hour.

The final reaction mixture was then heated at 50 ° C for two hours and then cooled to room temperature. At the end of this step, the settled mixture was concentrated in vacuo and dissolved in a mixture of chloroform and water. The organic layer was separated and saved, and the aqueous layer was further extracted with chloroform. The various organic (i.e., chloroform) extracts were combined and washed first with water and then with saturated brine, followed by drying over anhydrous magnesium sulfate. After the drying agent 5 was removed by filtration and the solvent was evaporated under reduced pressure, the residue was chromatographed on a column of 250 ml of silica gel with toluene as eluent. Similar fractions were combined to give a white solid containing 9.8 g (86%) of pure 2,6-chloro-3-methoxyquinoxaline, mp 92-95 ° C.

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

A mixture of 4.9 g (0.02 mol) of 2,6-di-15-chloro-3-methoxyquinoxaline and 2.7 g (0.053 mol) of hydrazine hydrate (2.6 ml) in 75 ml of ethanol was stirred at room temperature overnight. above (i.e. at about 20 ° C for approximately 16 hours). At the end of this step, the resulting mixture was filtered and the resulting precipitate was washed with ethanol to finally give 4.4 g (98%) of pure 6-chloro-2-hydrazino-3-methoxyquinoxaline, m.p. 175-179 ° C (decomposed). Mass spectrum: m / e, 224 (P); m / e, 226 (P + 2).

e) Preparation of 7-chloro-4-methoxy-1,2,4,7-triazolo [4,3-a] 25-25 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 with mechanical stirring in a preheated oil bath at 100 ° C overnight (1616 hours). ). The resulting mixture was then cooled to room temperature, and the resulting precipitate was collected by suction filtration and washed with ethanol to give 1.0 g (69%) of pure 7-chloro-4-methoxy-1,2,4-triazolo [1S]. quinoxaline, melting point 250-35 252 ° C.

21 7401 1 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-4H-2,4,4-triazolo [4,3-a] quinoxaline, 35 ml of 5N hydrochloric acid and 105 ml of glacial acetic acid was heated under reflux to 2.5 ml. for an hour. At the end of this step, the reaction mixture was cooled to room temperature and poured into a mixture of ice and water. The resulting mixture was then stirred for 20 minutes, filtered, and the resulting solid was washed with water and air dried to constant weight to finally give 2.6 g (87%) of pure 7-chloro-4-hydroxy- [1,2,4] triazolo [*]. 4,3-α-quinoxaline, melting point> 300 ° C.

g) Preparation of 4,7-dichloro-1,2,4,7-triazolo [4,3-a] quinoxaline

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 2.6 g (0.012 mol) of 7-chloro-4-hydroxy-1,2,4,7-triazolo [3,3-a] quinoxaline and 40 ml of phosphorus oxychloride were charged. together with 2.6 g of 20 tri-n-propylamine. The reaction mixture was then refluxed overnight for about 16 hours and finally cooled to room temperature before being poured into a mixture of ice and water. The resulting aqueous mixture was then extracted with ethyl acetate, and this extract was washed first with water, then with saturated sodium bicarbonate solution, and finally with saturated brine before being dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a yellowish solid was finally obtained as a residue, which was then chromatographed on a column of 200 ml of silica gel, eluting with a mixture of chloroform and methanol (9: 1 by volume). Similar fractions were combined and concentrated in vacuo to give an orange solid containing 1.89 g (66%) of pure 22 7 4 01 1 4,7-dichloro- [1,2,4 <7-triazolo / 4.3]. -7 quinoxaline, melting point 253-256 ° C (decomposed). Mass spectrum: m / e, 238 (P); m / 4 240 (P + 2); m / e, 242 (P + 4).

Example D

5,7-Dichloro-1-ethyl-1,2,4 / triazolo [4,3-a] quinoxaline) a) 7-Chloro-1-ethyl-1,2,4 / triazolo [4/3] Preparation of α / 7-quinoxaline

A mixture of 5.1 g (0.022 mol) of 6-chloro-10β-2-hydrazino-3-methoxyquinoxaline, the product of Example C (d), and 60 ml of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100 °. At C overnight (^ 16 hours). The resulting mixture was then cooled to room temperature (15 ° C), and the resulting precipitate was collected by suction filtration and washed with ethyl ether to give 4.3 g (75%) of pure 7-chloro-1-ethyl-4- methoxy-1,2,4,4-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 containing 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 under reflux overnight and then cooled to room temperature. temperature. The precipitate thus formed was collected by suction filtration and washed with methanol. Finally, 3.7 g (94%) of pure 7-chloro-1-ethyl-4-hydroxy-1,2,4,7-triazolo [4,3-a] quinox-30 saline were obtained, melting point> 300 ° C.

c) Preparation of 4,7-dichloro-1-ethyl-1,2,4-triazolo [4-quinoxaline

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 5.1 g (0.02 moles) of 35 7-chloro-1-ethyl-4-hydroxy-1,2,4,7-triazolo [4,3-a] quinoxy-234,401 1 saline and 75 ml of phosphorus oxychloride together with 5 ml of tri-n-propylamine. The reaction mixture was heated to reflux overnight for about 16 hours and finally cooled to room temperature before being carefully poured onto a mixture of ice and water. The resulting aqueous mixture was then stirred at room temperature for 15 minutes and filtered, and the resulting solid product was then washed with cold water and air dried to constant weight to give 4.2 g (79%) of pure 4,7-dichloro-1-ethyl. -, 2,4, / triazolo [4,3-a] quinoxaline, m.p. 217-220 ° C (decomposed). Mass spectrum: m / e, 266 (P); m / e, 268 (P + 2); m / e, 265 (P-1).

Example E

Preparation of 4-chloro-7-methoxy-1,2,4,7-triazolo [4,3-a] quinoxalinyl (2,3-dihydroxy-6-methoxyquinoxaline) A mixture containing 20 g (0.114 mol) of 4-methoxy -o-phenylenediamine and 11 g (0.114 moles) of triethyl-20 amine dissolved in 200 mL of diethyl oxalate were heated at reflux overnight for about 16 h.When this step was complete, the reaction mixture was cooled to room temperature (20 ° C) and filtered to remove the desired product. After washing with ethanol, 14.8 g (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline, melting point> 300 [deg.] C., were finally obtained Mass spectrum: m / e, 192 (P).

b) Preparation of 2,3-dichloro-6-methoxyquinoxaline By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 14.8 g (0.077 mol) of 2,3-dihydroxy-6-methoxyquinoxaline and 75 ml of phosphorus oxychloride were placed together in 15 ml of: with tri-n-propylamine. The exotherm was then allowed to wake at room temperature (^20 ° C) for 1 hour, after which the mixture was heated to reflux overnight (1616 hours). At the end of this step, the reaction mixture was again allowed to cool to room temperature and finally poured slowly into a mixture of ice and water. The resulting aqueous mixture was then stirred at room temperature for 20 minutes, filtered, and the collected precipitate was washed with water before dissolving in chloroform. This solution was filtered to remove insoluble matter, and the filtrate thus obtained was washed first with water, then with saturated sodium bicarbonate solution, and finally with saturated brine. After the washed solution was concentrated in vacuo and the residue was recrystallized from ethanol, 14.2 g (80%) of pure 2,3-dichloro-6-methoxyquinoxaline remained, 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

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, a solution of 850 mg of sodium soaked in 80 ml of methanol was slowly added to a slurry consisting of 7.1 g of 2,3-dichloro-20 6-methoxyquinoxaline 60 in methanol, at 50 ° C for seven hours. The resulting mixture was then heated at 50 ° C overnight and finally cooled to room temperature. At the end of this step, the settled reaction mixture was concentrated in vacuo, and the residue was then dissolved in chloroform, followed by washing with water and drying over anhydrous magnesium sulfate.

After the drying agent was removed by filtration and the solvent was evaporated under reduced pressure, the residue obtained was then chromatographed on a column of 400 ml of silica gel with toluene as eluent. The appropriate fractions were combined and concentrated in vacuo to give a white solid containing 6.1 g (88%) of pure 2-chloro-3,6-dimethoxyquinoxaline, m.p. 79-81 ° C.

35 Anal, calculated for C1 () H9ClN2O2: C, 53.47? H, 4.04; N, 12.47.

Found: C, 53.29; H, 4.05; N, 12.28.

25 7 4 01 1 d) Preparation of 3,6-dimethoxy-2-hydrazinoquinoxaline

A mixture of 5 g (0.022 mol) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g (0.056 mol) of 5-hydrazine hydrate (2.7 ml) in 75 ml of ethanol was heated at 50 ° C. overnight. At the end of this step, an additional 1.0 ml of hydrazine hydrate was added to the mixture, and the resulting mixture was heated at 50 ° C for six hours. At this point, an additional 1.0 mL of hydrazine hydrate was added, and the final reaction mixture was heated at 50 overnight, after which it was cooled to room temperature. The settled mixture was then filtered and the resulting precipitate was washed with ethanol to finally give 4.1 g (85%) of pure 3,6-dimethoxy-2-hydrazine-15-ninoxaline, m.p. 128-130 ° C (decomposed).

e) Preparation of 4,7-dimethoxy-2,4,4-triazolo [4,3-a] quinoxaline

A mixture of 1.5 g (0.068 mol) of 3,6-dimethoxy-2-hydrazinoxaline and 20 ml of triethyl ortho-20 formate was heated with mechanical stirring in a preheated oil bath at 100 ° C overnight (^16 hours). The resulting mixture was then cooled to room temperature, and the resulting precipitate was collected by suction filtration and washed with ethanol to finally give 1.8 g of pure 4,7-dimethoxy-1,2,4,7-triazolo-1,3- α7 quinoxaline, melting point 238-240 ° C (decomposed). Mass spectrum: m / e, 230 (P); m / e, 231 (P + 1); m / e, 232 (P + 2).

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

A mixture of 1.6 g (0.0069 mol) of 4,7-dimethoxy-1,2,4,7-triazolo [1,3-a] quinoxaline, 16 ml of 1N hydrochloric acid and 48 ml of glacial acetic acid was heated under reflux for 3 hours. At the end of this step, the reaction mixture was poured onto ice and filtered. The product obtained was then collected on a 26 7401 L filter funnel and washed with diethyl ether to finally give 1/19 g (80%) of pure 4-hydroxy-7-methoxy-1,2,2-triazolo [1,3-a] quinoxaline, m.p.> 250 ° C. .

5 g) Preparation of 4-chloro-7-methoxy-1H-2,7-triazolo [3-a] -quinoxaline

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 1.1 g (0.0055 mol) of 4-hydroxy-7-methoxy-1,2,7,7-triazolo [1,3-a] quinoxaline-10 and 15 ml of phosphorus oxychloride 1 were charged. With 0 g of tri-n-propylamine. The reaction mixture was heated to reflux overnight for approximately 16 hours, and finally cooled to room temperature, after which it was poured into a mixture of ice and water. The resulting aqueous mixture was then extracted with ethyl acetate, and the extract was washed first with water and then with saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a residual product remained, which was then chromatographed on a 150 ml silica gel column eluting with a mixture of chloroform and methanol (95: 5 by volume). Similar fractions containing product were combined and concentrated in vacuo to give a residual material which was recrystallized from a mixture of chloroform and diethyl ether to give 400 mg (31%) of pure 4-chloro-7-methoxy-1.2.4 [7] triazolo [4,3-a] 7-quinoxaline, m.p. 266-268 ° C (decomposed). Mass spectrum: m / e, 234 (P); m / e, 236 (P + 2).

30 Example F

4-chloro-1-ethyl-7-methoxy-1,2,4,7-triazolo [4,3-a] quinoxaline a) 1-ethyl-4,7-dimethoxy-1,2,4,7-triazolo [4], Preparation of 3-α-quinoxaline 35 A mixture of 4.0 g (0.018 mol) of 3,6-dimethoxy-2-hydrazinoquinoxaline, the product of Example E (d) 27 7401 1, and 50 ml of triethyl orthopropionate was heated with mechanical stirring. in a preheated oil bath at 100 ° C overnight (^ 16 hours). The resulting reaction mixture was then cooled to room temperature (* - 20 ° C), and the resulting precipitate was collected by suction filtration and washed with ethanol to give 3.3 g (72%) of pure 4,7-dimethoxy-1-ethyl 1,2,3-triazolo [1,3-a] quinoxaline, m.p. 184-188 ° C. Mass spectrum: m / e, 258 (P); m / e, 228 10 (P-30).

b) Preparation of 1-ethyl-4-hydroxy-7-methoxy-β, 2,4,7-triazo-10β, 3-α-quinoxaline

A mixture of 3.3 g (0.013 mol) of 4,7-dimethoxy-1-ethyl-1,2,4-triazolo [4,3-a] quinoxaline, 33 ml of 1N hydrochloric acid and 99 ml of glacial acetic acid was added to the mixture. At the end of this step, the reaction mixture was cooled to room temperature and poured into a mixture of ice and water, then the resulting mixture was stirred for 20 minutes and extracted with ethyl acetate, first washed with saturated brine and then dried over anhydrous magnesium sulfate. was removed by filtration and the solvent was evaporated under reduced pressure to leave a yellowish solid which was finally washed with water and air dried to constant weight to give 1.87 g (67%) of pure 1-ethyl-4-hydroxy-7 -methoxy-1,2,4,7-triazole 1,3-quinoxaline, melting point> 250 ° C.

c) Preparation of 4-chloro-1-ethyl-7-methoxy-1,2,4,7-triazolo-30,4,3a-quinoxaline

By annealing to a dried reaction vessel with a dry nitrogen atmosphere, 1.87 g (0.0076 mol) of 1-ethyl-4-hydroxy-7-methoxy-7'L [2,4,7-triazolo [4,3-a] quinoxaline and 25 ml of phosphorus oxychloride together with 1.8 35 ml tn of tri-n-propylamine. The reaction mixture was then heated to reflux overnight for about 16 hours and finally cooled to room temperature before slowly pouring into a mixture of ice and water. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product thus obtained was then washed with cold water, after which it was dissolved in chloroform. This organic solution was then washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a yellow solid remained, which was triturated in diethyl ether and filtered to give 1.6 g (80%) of pure 4-chloro-1-ethyl-7-methoxy. 1,2,4 / triazolo [1,3-a] quinoquin-15 saline, m.p. 173-175 ° C. Mass spectrum: m / e, 262 (P)? m / e 264 (P + 2); m / e, 261 (P-1).

Example G

4-Chloro-8-fluoro-1,2,4,7-triazolo [1,5-a] quinoxaline_____ 20 a) Preparation of 2,3-dihydroxy-6-fluoroquinoxaline

A mixture containing 26.3 g (0.19 moles) of 4-fluoro-1,2-phenenediamine in the Journal of the American Chemical Society, vol. 75, p. 1294 (1953), 7 and 150 ml of diethyl oxalate, were heated to reflux under 25 nitrogen for 18 hours. At the end of this step, the reaction mixture was cooled to room temperature (* ^ 20 ° C), filtered and the resulting product was then washed four times with 100 ml of ethanol and air dried to constant weight to finally give 19.3 g (80%) of 30 pure 2,3-dihydroxy-6-fluoroquinoxaline, melting point> 300 ° C (melting point 387-390 ° C in the literature. According to U.S. Patent 3,992,378). Mass spectrum: m / e, 180 (P +).

29 7401 1 b) Preparation of 2,3-dichloro-6-fluoroquinoxaline

A mixture of 19 g (0.105 mol) of 2,3-dihydroxy-6-fluoroquinoxaline and 50 ml of phosphorus oxychloride was heated at reflux overnight (16165 hours) and then cooled to room temperature before the mixture was poured into 200 g: I stir the ice vigorously while stirring. The resulting aqueous mixture was then filtered, and the product thus obtained was washed several times with water to give 28.2 g of 2,3-dichloro-10β-6-fluoroquinoxaline, m.p. 148-152 ° C.

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

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

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

A mixture of 10 g (0.047 moles) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml (0.47 moles) of triethyl orthoformate was heated under a nitrogen atmosphere while mechanically stirring in a preheated oil-30 bath at 100 ° C: overnight (* -Ί6 hours). The resulting mixture was cooled to room temperature, and the resulting precipitate was collected by suction filtration, washed three times with 50 ml of ethanol and air-dried to constant weight to give 9.42 g (91%) of pure 4-chloro-8-fluoro. (2,4,4) triazolo [4,3-a] quinoxaline, m.p. 310-312 ° C (decomposed). Mass spectrum: m / e, 224, 223, 222 (P +).

Example H

4-chloro-1-ethyl-8-fluoro [1,2,4] triazolo [4,3-a] -5-quinoxaline;

A mixture of 10.0 g (0.047 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline of the product of Example G (c) and 95 ml (0.47 mol) of triethyl orthopropionate was heated under a nitrogen atmosphere while mechanically heating. stirring in a preheated oil bath at 100 ° C overnight (^ 16 hours). The resulting mixture was cooled to room temperature (20 ° C), the resulting precipitate was collected by suction filtration, washed three times with 50 ml of ethanol and air dried to constant weight to give 7.5 g (65%) of pure 4-chloro-1 -ethyl-8-fluoro-1,2,4,4-triazolo [4,3-a] quinoxaline, m.p. 160-163 ° C (decomposed). Mass spectrum m / e 249, 250, 251, 252 (P +).

Example I

20-chloro-8-fluoro-1-trifluoromethyl-1,2,4,4-triazolo [4,3-a] quinoxaline_a) 8-fluoro-4-hydroxy-1-trifluoromethyl-1,2,4,4 Preparation of triazolo [4,3-a] quinoxaline A mixture of 12.8 g (0.06 mol) of 2-chloro-25R-fluoro-3-hydrazinoquinoxaline in 50 ml (0.65 mol) of trifluoroacetic acid was heated in a dry nitrogen atmosphere at 120 ° C for 24 hours using mechanical agitation to obtain a homogeneous solution. The resulting reaction mixture was then poured into a stirred mixture of ice and water, stirred for a further 30 minutes and filtered. The product thus obtained was then washed with three different portions of water and dried in vacuo at 80 ° C to finally give 12.58 g (77%) of pure 8-fluoro-4-hydroxy-1-trifluoromethyl-1,2,2, 4 <7-triazolo [4 (Za) -35 quinoxaline, m.p. 298-302 ° C. Mass spectrum: m / e, 272 (P +).

31 7401 1 b) Preparation of 4-chloro-8-fluoro-1-trifluoromethyl- (1,2,4) -triazolo [1,3-a] quinoxaline By annealing in a dried three-necked 250 ml reaction vessel under a nitrogen atmosphere was placed 12.5 g (0.046 mol) of 8-fluoro-4-hydroxy-1-trifluoromethyl-1,2,4,7-triazolo [4,3-a] quinoxaline and 85 ml of phosphorus oxychloride and 17.5 ml of tri-n -propylamine. The reaction mixture was then heated at reflux overnight for about 16 hours and finally cooled to 10 room temperature (^ 20Ο0), after which it was slowly poured into 1000 ml of a mixture of ice and water with mechanical stirring. The resulting aqueous mixture was further stirred at room temperature for 30 minutes, after which it was extracted three times with 300 ml of chloroform.

The combined chloroform layers were washed first with saturated aqueous sodium bicarbonate solution, then with water and finally with saturated brine, and finally dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, 20.47 g (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl-1,2,4,4-yellow solid were obtained as a yellow solid. <7-triazolo [4,3-a] quinoxaline, m.p. 135-138 ° C. Mass spectrum: m / e, 292/290 (P +).

25 Example J

4-Chloro-7,8-difluoro-1,2,4,7-triazolo [4,3-a] quinoxaline) a) Preparation of 2,3-dihydroxy-6,7-difluoroquinoxaline A mixture containing 11.3 g (0.0784 moles) of 4,5-difluoro-o-phenylenediamine (U.S. Patent 4,264,600) and 80 ml (0.589 moles) of diethyl oxalate were heated at reflux for 4 hours to give a thick precipitate of product. The precipitated reaction mixture was then cooled to room temperature (* 20 ° C) overnight, filtered and the solid product thus obtained was washed several times with diethyl ether and air dried to constant weight to finally give 15.5 g of pure 2,3-dihydroxy. -6,7-difluoroquinoxaline, melting point> 310 ° C. Mass spectrum: m / e, 198 (P +).

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

A mixture of 15.4 g (0.078 mol) of 2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g (0.187 mol) of phosphorus pentachloride and 20 ml (0.22 mol) of phospho-10-oxychloride was heated under reflux with stirring. for four hours, during which time an additional 20 mL of phosphorus oxychloride was added to facilitate stirring (the reaction mixture became homogeneous in 30 minutes). At the end of this step, the reaction mixture was stirred overnight (<16 hours) at room temperature to give a pale yellow precipitate. The precipitated mixture was then poured into 200 g of a mixture of ice and water and further stirred with further cooling to give a tan solid consisting of 20.9 g of 2,3-dichloro-6,7-difluoroquinoxaline, m.p. 162-164 ° C (dec.). Mass spectrum: m / 4, 238/236/234 (P +).

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

A mixture of 10 g (0.0426 moles) of 2,3-25 dichloro-6,7-difluoroquinoxaline and 5 ml (0.03 moles) of hydrazinohydrate in 200 ml of ethanol was stirred at room temperature for 24 hours to give a rusty red precipitate. The thick slurry was filtered and the resulting product was washed twice with 20 ml of ethanol, dried to constant weight in air to give 5.99 g (67%) of pure 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline, m.p. 212 -215 ° C (dec.). Mass spectrum: m / e, 230 (P); m / e, 232 (P &lt; + &gt;).

33 7 4 01 1 d) Preparation of 4-chloro-7,8-difluoro-1,2,2-triazolo [1,3-a] quinoxaline

A mixture of 5.99 g (0.026 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml (0.18 mol) of triethyl orthoformate was heated at 100 ° C for 24 hours. a red-brown solid was obtained. The resulting slurry was cooled to room temperature and filtered, and the product thus obtained was washed with diethyl ether to finally give 5.15 g (82%) of pure 4-chloro-7,8-difluoro-1,2,4-triazolo "4,3-α7-quinoxaline, melting point> 210 ° C (decomposed). Mass spectrum: m / e, 242/240 (P +).

Example K

4-chloro-6,7-difluoro-1-ethyl- [1,2,4] triazolo-15,4,3,4-quinoxaline_

A mixture of 7.0 g (0.03 mol) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline, the product of Example J (c) and 60 ml (0.30 mol) of triethylorthopropionate was heated. in a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100 ° C for 24 hours. The resulting mixture was cooled to room temperature (* 20 ° C) and the resulting red precipitate was collected by suction filtration, washed twice with diethyl ether and air dried to constant weight to give 4.15 g (52%) of pure 4-chloro-6.7 g. -difluoro-1-ethyl-1,2,2,7-triazolo [1,3-a] quinoxaline, m.p. 185-186 ° C (dec.).

Example L

Preparation of 4,8-dichloro-1-methyl-N, 1,2,4-triazolo [1,3-a] -30-quinoxaline) a) Preparation of 2,6-dichloro-3-hydrazinoquinoxaline

A mixture of 23 g (0.10 moles) of 2,3,6-trichloroquinoxaline and 11 g (0.22 moles) of hydrazine-35 hydrate in 500 ml of ethanol was stirred at room temperature for 34 7 4 01 L (^ 20 ^ ) overnight (<* Ί6 hours). The precipitate thus formed was collected by filtration and washed with ethanol to finally give 22.2 g (97%) of pure 2,6-dichloro-3- * hydrazinoquinoxaline, m.p.> 250 ° C. Mass spectrum: m / e, 228 (P).

b) Preparation of 4,8-dichloro-1-methyl-1,2,4,7-triazolo [4,3-a] quinoxaline

A mixture of 20 g (0.087 mol) of 2,6-dichloro-3-hydrazinoquinoxaline and 160 ml (0.87 mol-10 mol) of triethyl orthoacetate was heated with mechanical stirring in a dry nitrogen atmosphere in a preheated oil bath at 100 ° C: for 20 hours to give a yellow suspension. The resulting mixture was cooled to room temperature and filtered, and the resulting solid was then washed with ethanol and air dried to constant weight to give 10.2 g (46%) of pure 4,8-dichloro-1-methyl- / 1.2 , 4 # 7-triazolo [4,3-a] -quinoxaline, melting point> 280 ° C. Mass spectrum: m / e, 254/252 (P +).

20 Example M

Preparation of 4,8-dichloro-1-trifluoromethyl-1,2,2,7-triazoloquinoxaline (a) 8-Chloro-4-hydroxy-1-trifluoromethyl-1,2,3-triazolo [4,3-a] quinoxaline 25 By annealing to dried 500 ml A 3-necked reaction vessel equipped with a mechanical stirrer, a nitrogen inlet tube and a reflux condenser was charged with 67 mL (0.87 moles) of trifluoroacetic acid. Stirring was started and 20 g (0.087 mol) of 2,6-dichloro-3-hydrazinoquinoxaline, i.e. the product of Example L (a), were added. The resulting mixture was then heated on a steam bath for 24 hours, cooled to room temperature (2020 ° C) and poured into 200 g of a mixture of ice and water. The aqueous mixture thus obtained was stirred for 30 minutes, filtered and the product obtained was 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-1,2,4,7-triazolo [4,3-a] quinoxaline, m.p. 253-255, were finally obtained. ° C (decomposed). Mass spectrum: m / e, 290 / 5,288 (P +).

b) Preparation of 4,8-dichloro-1-trifluoromethyl-α, β, 2,4-triazolo [4,3-a] quinoxaline By annealing in a dried three-necked reaction vessel equipped with a mechanical stirrer, a dropping funnel and a reflux condenser, 14.3 g (0.05 mol) of 8-chloro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline in 100 ml of phosphorus oxychloride were added. To the resulting suspension was added dropwise 19 ml (0.10 moles) of tri-n-15 propylamine over 5 minutes. The resulting reaction mixture was heated to reflux for 20 hours to give a clear dark burgundy solution. At the end of this step, the clear solution thus obtained was cooled to room temperature and poured into 1000 ml of ice water while stirring vigorously. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and then extracted three times with 500 ml of chloroform. The organic extracts were then combined and washed first with water, then with saturated sodium bicarbonate solution, water and finally with saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the desiccant by filtration and evaporation of the solvent under reduced pressure, a yellow solid containing 11.4 g (75%) of pure 4,8-dichloro-1-trifluoromethyl-^ 1.2 4 / triazolo [4,3-a] quinoxaline, melting point 133-135 ° C, Mass spectrum: m / e, 308 (P + 2); m / e, 310 (P + 4).

36 7401 1

Example N

4,8-Dichloro-1-phenyl-1,2,2,4-triazolo [4,3-a] quinoxaline was placed in a 250 ml three-necked reaction vessel equipped with a mechanical stirrer and a reflux condenser. g (0.274 moles) of trimethyl ortho-benzoate preheated to about 70 ° C. Stirring was started and 10.0 g (0.0437 moles) of 2,6-dichloro-3-hydrazinoquinoxaline, the product of Example L (a), was added thereto. The resulting reaction mixture was then heated at about 120 ° C with continuous stirring for 24 hours, after which the mixture was cooled to room temperature (2020 ° C) and stirring was continued overnight for about 16 hours to give a yellow slurry.

This was filtered and the resulting solid product was washed twice with 50 ml of ethanol and air dried to constant weight to give 9.8 g (72%) of crude 4,8-dichloro-1-phenyl-1,2,4,4 triazolo [3-a] quinoxaline, m.p. 305-307 ° C. Mass spectrum 20: m / e 316/314 (P +).

Example 0 2-Chloro-3-hydrazinoquinoxaline 2,3-dichloroquinoxaline (33.5 g, 0.168 mol) was stirred with hydrazine hydrate (18.5 g, 0.369 mol) in 500 ml of ethanol at room temperature overnight (i.e. about 20 ° C). In C for about 16 hours). The thick yellow slurry was filtered and the precipitate was 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 (decomposed).

Mass spectrum: m / e, 194 (P).

Example P

4R-Chloro-1,2,4-triazolo [4,3-a] quinoxaline 2-Chloro-3-hydrazino-quinoxaline (9.0 g, 0.046 mol), the product of Example o, was mixed with triethyl orthoformate (90 ml) at 100 ° C. for an hour. Mixture 37 7401 L was cooled to room temperature and the solid precipitate was collected by filtration and washed with cyclohexane and dried to give 8.8 g (94% yield) of 4-chloro / l. , 2,4'-triazolo [4,3-a] quinoxaline, m.p. 287-290 ° C (decomposed). Mass spectrum: m / e, 204 (P).

Example Q

4-chloro-1-methyl- [1,2,2] triazolo [1,3-a] N

quinoxaline ____ 10 2-Chloro-3-hydrazinoquinoxaline (15.5 g, 0.080 mol), the product of Example O, was stirred with triethyl orthoacetate for 3 hours at 100 ° C. The mixture was cooled to room temperature and the solid precipitate was collected by filtration, washed with ethanol and air dried to give 11.4 g (65% yield) of 4-chloro-1-methyl [1,2] k] triazolo [α] quinoxaline, mp 215-222 ° C. Mass spectrum: m / 3 218 (P).

Example R

4-Chloro-1-ethyl-1,2,4-triazolo [4,3-a] quinoxaline-2-chloro-3-hydrazinoquinoxaline (4.5 g, 0.023 mol), the product of Example O, was stirred with triethyl orthropropionate. (50 ml) at 100 ° C for 1 hour. The mixture was cooled to room temperature, and the white precipitate was collected by filtration and washed with cyclohexane to give 4.5 g (85% yield) of 4-chloro-1-ethyl [1,2,4] triazolo [3], 3-α / quinoxaline, melting point 158-160 ° C. Mass spectrum: m / e, 232 (P).

Example S

4-Chloro-11-propyl- [1,2,4] triazolo [4,3-a] quinoxaline-2-chloro-3-hydrazinoquinoxaline (3.0 g, 0.015 mol) of the product of Example O was stirred with triethyl orthobutyrate. (27 ml) at 100 ° C for two hours.

The mixture was cooled to room temperature and the precipitate was collected by filtration and washed with cyclohexane.

5 O

The crude solid was dissolved in chloroform, and the solution was filtered to remove insoluble material. The chloroform solution was concentrated in vacuo to give a solid which was recrystallized from chloroform to give 1.96 g (53% yield) of 4-chloro-1-propyl- [1,2,4] triazolo [4.3 g]. α7-quinoxaline, mp 173-175 ° C. Mass spectrum: m / e, 246 (P).

Example T

4-Chloro-1-isopropyl-1,2 ', 4-triazolo [1,3-a] quinoxaline-2-chloro-3-hydrazinoquinoxaline (4.0 g, 0.02 mol), the product of Example 0, was stirred. with triethyl orthoisobutyrate (15 ml) at 100 ° C for three 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 hot ethanol to give 2.06 g (40% yield) of 4-chloro-1-isopropyl-1,2,2-triazolo [4,3-a] quinoxaline, m.p. 208-210 ° C. . Mass spectrum: m / e, 246 (P).

PREPARATION OF FINISHED PRODUCTS Example 1 4-Methylamino-1,2,4,7-triazolo /%, 3-α7-quinoxaline 4-chloro-1H-1,2,4-triazolo [3,3-a] quinoxaline (2.0 g, 0 .01 mol), the product of Example P, in N, N-di-25-methylformamide (30 ml) was saturated with monomethylamine gas and stirred at room temperature for 3 hours. Monomethylamine gas was again introduced into the solution, and the solution was stirred at room temperature for another 2 hours. The precipitate was filtered off and washed with Ν, Ν-dimethylformamide. Recrystallization from Ν, Ν-dimethylformamide gave 1.37 g (69% yield) of 4-methylamino- [1,2,4] triazolo [4,5-a] quinoxaline, m.p.> 300 ° C. Mass spectrum: m / e, 199 (P).

Anal. Calcd for C 18 H 28 N 2 O 3: 35 C, 60.29; H, 4.55; N, 35.15.

Found: C, 59.99; H, 4.47; N, 35.11.

39 7401 1

Example 2 4-Dimethylamino [1,2,4] triazolo [4,3-a] quinoxaline Slurr containing 2.0 g (0.01 mol) of 4-chloro-1,2,4,7-triazolo [4 1,3-α <7-quinoxaline (product of Example P5) in N, N-dimethylformamide (30 ml) was saturated with dimethylamine gas and stirred at room temperature overnight. The mixture was poured onto ice and the precipitate was collected by filtration. Recrystallization from ethanol gave 640 mg (44% yield) of 4-dimethyl-10-amino-1,2,4-triazolo [1,5-a] quinoxaline, m.p. 184-186 ° C. Mass spectrum: m / e, 213 (P).

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

Example 3 4-Ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline Slurr containing 2.0 g (0.01 mol) of 4-chloro-η 2, 2,47-triazolo-4.3 α-Quinoxaline (product of Example P) in N, N-dimethylformamide (30 ml) was saturated with 20 monoethylamine gas and stirred at room temperature for 2 hours. Monoethylamine gas was again introduced into the mixture and stirring was continued for 2 hours. The precipitate was removed by filtration and washed with N, N-dimethylformamide. Recrystallization from methanol gave 680 mg (32% yield) of 4-ethylamino - [1,2,4] triazolo-3-α] quinoxaline, m.p. 254-6 ° C. Mass spectrum: m / e, 213 (P) .

Anal. Calcd: Found: C, 61.96; H, 5.20; N, 32.84, found: C, 61.93; H, 5.09; N, 32.72.

Example 4 4-Diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline 4-Chloro-β, 2,4} triazolo [4,3-a] quinoxaline (4.4 g, 0.021 mol), Example P product, was stirred with 35 diethylamine (6.5 mL, 0.063 mol) in N, N-dimethyl-40,701 L-formamide (100 mL) at room temperature for 2 hours. The reaction mixture was poured into ice-water to give a crude precipitate as a product which was then filtered and washed with water. Recrystallization from iso-5-propanol gave 3.36 g (66% yield) of 4-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 117-119 ° C. Mass spectrum: m / e, 241 (P).

Example 5 4-Di-n-propylamino-4H, 2,47-triazolo [4,3-a] 1010-quinoxaline-4-chloro-1,2,2-triazolo-4,19a-quinoxaline (2.0 g, 0.01 mol), the product of Example P, and 3.0 g (0.03 mol) of di-n-propylamine in N, N-dimethylformamide (50 ml) were stirred for 3 hours at room temperature. Recrystallization from cyclohexane (250 ml) gave 1.1 g (41% yield) of 4-di-n-propylamino- [1,2,4 "triazolo [1,3-a] quinoxaline. , melting point 240-242 ° C.

Mass spectrum m / e, 269 (P).

Anal Calcd: C11: C, 66.89; H, 7.11; N, 26.00, found; C, 66.68; H, 6.97; N, 26.12.

Example 6 4-Isopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline-4-chloro-1,2,4,7-triazolo [1,4] quinoxaline (2.0 g, 0.01 mol), the product of Example P, and 1.77 g (0.03 mol) of isopropylamine in N, N-dimethylformamide (30 ml) were stirred at room temperature overnight. The dark solution was poured onto ice and the precipitate formed was filtered off and then washed with water. The crude product was recrystallized from ethanol and then twice from isopropyl ether to give 1.2 g (53% yield) of 4-isopropylamino / 1,2,4,7-triazolo-41,701,3,3-quinoxaline, m.p. 133-135 ° C. Mass spectrum: m / e 222 (P).

Anal Calcd for C 12 H 13 N 5 · 1 / 3.H 2 O: C, 61.79; H, 5.90? N, 30.02.5 Found: C, 61.51; H, 5.89; N, 29.90.

Example 7 4-Diethylamino-1-methyl-1,2,4-triazolo [4,3-a] quinoxaline This compound was prepared by the method of Example 1 using 4-chloro-1-methyl-1,2,4,4 N, N-quinoxaline (product of Example Q) as starting material instead of 4-chloro, 2,4'-triazolo [3,3-a] quinoxaline (product of Example 2) and diethylamine as reagent for di-n-propylamine The obtained crude product was recrystallized from chloroform and then from cyclohexane to give 7.2 g (54%) of pure 4-diethylamino-1-methyl-N, 1,2,4-triazolo [1,3-a] quinoxaline, m.p. 123-5 °. C.

Example 8 4-Amino-1-ethyl-1,2,4,7-triazolo-7,3-α-quinoxaline___

Ammonia gas was introduced into a solution of 1.2 g (0.005 moles) of 4-chloro-1-ethyl-1,2,4,4-triazolo [1,3-a] quinoxaline (product of Example R) in 25 N, N-dimethylformamide (20 ml). ), At 0 ° C for about two minutes. The solution was stirred at 0 ° C for 30 minutes and at room temperature for one hour. The reaction mixture was then poured onto ice and stirred for 20 minutes. The precipitate formed was removed by filtration, washed with water and air dried. Recrystallization from ethanol gave 220 mg (22%) of pure 4-amino-1-ethyl-1H, 2,4-triazolo [4,3-a] quinoxaline, m.p. 284-8 ° C. Mass spectrum: m / e, 213 (P).

Anal Calcd for H 2 O: 35 C, 61.10; H, 5.28; N, 32.39.

Found: C, 61.36; H, 5.14; N, 31.96.

42 7401 1

Example 9 4-Methylamino-1-ethyl-1,2,4,7-triazolo [1,3-a] quinoxaline__

Monomethylamine gas was introduced into 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 r, in N, N-dimethylformamide ( 50 ml) at 0 ° C for two minutes. The reaction mixture was stirred at 0 ° C for 30 minutes, at room temperature for 2 hours, and then poured onto ice and stirred for a further 20 minutes. The precipitate formed was filtered off, washed with water and air-dried. Recrystallization from ethanol gave 1.0 g (88% yield) of 4-methylamino-1-ethyl-1,2,2,4,7-triazolo [4,3-a] quinoxaline, m.p. 271-3 ° C. Mass spectrum: m / e, 227 (P).

Anal Calcd for C 12 H 13 N 5 · 2 - / 8 H 2 O: C, 62.80; H, 5.82; N, 30.51, found; C, 62.72; H, 5.86; N, 30.62.

Example 10 4-Dimethylamino-1-ethyl-1,2,4,7-triazolo [4,3-a] quinoxaline-4-chloro-1-ethyl-1,2,4-triazolo [1,3-a] quinoxaline line (1.2 g, 0.005 mol), the product of Example R, and 676 mg (0.015 mol) of anhydrous dimethylamine in 25 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 onto ice and stirred for 20 minutes. The precipitate thus formed was filtered off and washed with water and air-dried. Repeated work-up from chloroform and then from a mixture of chloroform and cyclohexane gave 510 mg (42% yield) of 4-dimethylamino-1-ethyl-1,2,2,4-triazolo [4,3-a] quinoxaline, m.p. 155-158 DEG C. Mass spectrum: m / e, 241 (P).

35 Anal. H, 6.27; N, 29.02, Found: C, 64.69; H, 6.27; N, 29.32.

43 7401 1

Example 11 1-Ethyl-4-ethylamino-1,2,4,7-triazolo [4,3-a] quinoxaline

Monoethylamine was introduced into a solution of 4-chloro-1-ethyl-5H, 2,47-triazolo [4,3-a] quinoxaline (1.2 g, 0.005 mol), the product of Example R, in N, N-dimethylformamide (50 ml) at 0 ° C for 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 onto ice and the precipitate was filtered off, washed with water and air dried. Recrystallization from ethanol gave 1.0 g (3% yield) of pure 1-ethyl-4-ethylamino-1,2,4,7-triazolo [4,3-a] quinoxaline as a white solid (m.p. 235-238 ° C).

Mass spectrum: m / e, 241 (P).

Anal Calcd 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 12 4-Diethylamino-1-ethyl-β, 2,4,7-triazolo [1,3-a] quinoxaline This compound was prepared by the method of Example 11 using 4-chloro-1-ethyl-1,2,4,7-triazolo. 4'-4,2-α7-quinoxaline (product of Example R) as starting material instead of 4-chloro-25β, 1,2,4-triazolo [1,3-a] quinoxaline (product of Example 2) and diethylamine as reagent instead of di-n-propylamine. The crude product was recrystallized from cyclohexane to give 3.54 g (69% yield) of pure 4-diethylamino-1-ethyl-1,2,4,7-triazolo [4,3-b] quinoxa-30 as a white solid (melting point 98- 100 DEG C. Mass spectrum: m / e, 269 (P).

Example 13 4-Isopropylamino-1-ethyl-2,4,4-triazolo [1,3-a] quinoxaline Isopropylamine (1.77 g, 0.03 mol) was added to a solution containing 4-chloro. -1-ethyl-1,2,4) -triazolo [4,3-a] quinoxaline (2.3 g, 0.01 mol), the product of Example R, in N, N-dimethylformamide (30 ml).

A precipitate formed within 30 minutes. The reaction mixture was then stirred overnight at room temperature. The precipitate was filtered off and washed with N, N-dimethylformamide. Recrystallization from ethanol gave 1.6 g (63% yield) of 4-isopropylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 222-10 ° C. Mass spectrum: m / e, 255 (P).

Anal Calcd for C 18 H 17 N 2 O 2: 14 17 5 C, 65.86; H, 6.71; N, 27.43, Found: C, 65.32; H, 6.76; H, 27.25.

Example 14 4-Ethylamino-1-isopropyl-1,2,4,7-triazolo [4,3-a] quinoxaline

Slurry containing 1.0 g (0.004 mol) of 4-chloro-1'-isopropyl-1,2,4-triazolo [1,3-a] quinoxaline (Product of Example) in N, N-dimethylformamide (15 ml ), Was saturated with raonoethylamine gas and stirred at room temperature for 4 hours. The precipitate was filtered off and washed with Ν, Ν-dimethylformamide to give 220 mg (22% yield) of 4-ethylamino-1-isopropyl-β, 2,47-triazolo [4,3-a] quinoxaline, m.p. 209 -211 ° C. Mass spectrum: m / e, 255 (P). The filtrate was poured onto ice and the precipitate was filtered off, washed with water and recrystallized from methanol and then isopropanol to give a further 200 mg (20% yield) of pure 4-ethylamino-1-isopropyl-1,2,4-30-triazolo [* 4]. 3-α / quinoxaline, melting point 210-11 ° C.

Anal Calc'd: Found: C, 65.86; H, 6.71; N, 27.43, Found: C, 65.53; H, 6.58; N, 27.29.

45 7401 1

Example 15 4-Diethylamino-1-isopropyl-1,2,2-atazrazolo [1,3-a] quinoxaline-4-chloro-1-isopropyl-E, 1,2,4-triazolo [3,3-a] quinoxaline (1.0 g, 0.004 mol), the product of Example T, and 900 mg (0.012 mol) of diethylamine in N, N-dimethylformamide (15 ml) were stirred at room temperature for 4 hours. The reaction mixture was poured onto ice, and the precipitate was filtered off, washed with water and applied to a silica gel column (175 ml), and finally eluted with chloroform. The eluent was evaporated in vacuo to give 850 mg (75% yield) of pure 4-diethylamino-1-isopropyl-1,2,4,4-triazolo [4,3-a] quinoxaline as a white solid (melting point 93). -95 ° C). Mass spectrum: m / e, 283 (P). The pure product (100 mg) was then distilled in vacuo (0.1 mm) at 140-150 ° C to give an analytical sample (80 mg), mp 94-96 ° C.

Anal. Calcd. For C 18 H 20 NC: 16 21 5 20 C, 67.82; H, 7.47; N, 24.71, Found: C, 67.56; H, 7.20; N, 24.50.

Example 16 4-Diethylamino-1-n-propyl-1,2,4, / triazolo

Cl, 1,3-α-quinoxaline 4-chloro-11-propyl-1,2,4 / triazolo [4,3-a] quinoxaline (1.23 g, 0.005 mol), the product of Example S, and 1, 1 g (0.015 mol) of diethylamine in Ν, Ν-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was then poured onto ice. The precipitate was removed by filtration, washed with water and air dried. Recrystallization (twice) from a mixture of ethanol and water gave 1.1 g (78% yield) of pure 4-diethylamino-1-n-propyl-β-triazolo [a] quinoxaline, m.p. 92-94 ° C. Mass spectrum: m / e, 283 (P).

46 7401 1

Anal Calcd for C 19 H 21 N 5 1/8 H 2 O: C, 67.28; H, 7.50; N, 24.52, Found: C, 67.38; H, 7.45; N, 24.73.

Example 17 8-Chloro-4-diethylamino-1-ethyl-1,2,7-triazolo [1,3-quinoxaline] -2,8-dichloro-1-ethyl-1,2,4) triazolo Preparation of 4,3-α-quinoxaline 2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g, 0.0044 mol), the product of Example L (a), was heated to reflux with 15 ml of triethyl orthopropionate. After 4 hours, the mixture was cooled to room temperature. The precipitate was collected by filtration, washed with cyclohexane and air-dried to give 730 mg (62% yield) of 4,8-dichloro-1-ethyl-1,2,4-triazolo / 4,3-quinoxaline, m.p. 250 ° C Mass spectrum: m / e, 266 (P); m / e 268 (P + 2).

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

A mixture of 4,8-dichloro-1-ethyl-E, 1,2,4-triazolo [4,3-a] quinoxaline (7.4 g, 0.028 mol) and 6 g (0.082 mol) of diethylamine N, N in dimethylformamide (150 ml), stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was poured onto ice. The precipitate thus formed was collected by filtration and dissolved in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale solid which was further recrystallized from a mixture of diethyl ether and petroleum ether to give 1.6 g of pure 8-chloro-4-diethylamino-1- ethyl-1,2,4,4-triazolo [1,3-a] quinoxaline, m.p. 105-108 ° C (dec). Mass spectrum: m / e, 303 35 (P); m / e, 305 (P + 2).

47 7 4 01 1

Anal Calcd for C 18 H 18 Cl 2 N 2 O 2: C, 59.30; H, 5.97; N, 23.05, Found: C, 58.92; H, 5.85; N, 22.81.

Example 18 Preparation of 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,4] 7-triazolo [4,3-a] quinoxaline a) Preparation of 2,6,7-trichloro-3-hydrazinoquinoxaline 2.3 .6.7-Tetrachloroquinoxaline (4.4 g, 0.016 moles) and hydrazine hydrate (1.76 g, 0.035 moles) in ethanol (60 mL) were stirred overnight at room temperature. The thick slurry was filtered and washed with ethanol to give 4.9 g of crude 2,6,7-trichloro-3-hydrazinoquinoxaline, mp <260 ° C.

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

b) Preparation of 4,7,8-trichloro-1-ethyl- [1,2,4] triazolo [4,3-b] quinoxaline 2,6,7-trichloro-3-hydrazinoquinoxaline (4.9 g, 0.018 mol) in triethylorthopropionate (50 ml) was heated at 100 ° C for 2 hours. The resulting precipitate was collected by filtration at room temperature and washed with cyclohexane. Recrystallization twice from a mixture of chloroform and cyclohexane gave 2.9 g (54% yield) of pure 1,7,8-trichloro-1-ethyl-1,2,4,7-triazolo [3,3-a] inoxaline as a pink solid (melting point). 198-201 ° C). Mass spectrum: m / e, 300 (P); 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 [1,3-a] quinoxaline A mixture containing 4,7,8-trichloro-1-ethyl- N, N-triazolo [4,3-a (7-quinoxaline (2.9 g, 0.0096 mol)) and 2.1 g (0.0388 mol) of diethylamine in N, N-dimethylformamide (50 ml), stirred at room temperature for 2 hours, the reaction mixture was poured onto ice and stirred for 15 minutes, the precipitate was filtered off, washed with water and air-dried.

48 7 4 01 1

Recrystallization (three times) from isopropanol gave 500 mg (16% yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,2] triazolo [1,3-a] quinoxaline, m.p. 147 -149 ° C. Mass spectrum: m / e, 337 δ (P); m / e, 339 (P + 2).

Anal Calcd for C 15 H 17 Cl 2 N 5: C, 53.26; H, 5.07; N, 20.70, Found: C, 53.05; H, 5.13; N, 20.75.

Example 19 Preparation of 4-diethylamino-1-ethyl-8-methoxy- [1,2,4] triazolo [* 4,3-a] quinoxaline ___ 2) Preparation of 2-chloro-3-hydrazino-6-methoxyquinoxaline

A mixture of 2,3-dichloro-6-methoxyquinoxal-saline (4.2 g, 0.018 mol), the product of Example E (b), and 2.7 ml of hydrazine hydrate in 100 ml of ethanol was heated at reflux for 4 hours. and then stirred at room temperature overnight. The precipitate was removed by filtration and washed with ethanol to give 3.9 g (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline, m.p. 250 ° C. Mass spectrum: m / e, 224 (P); m / e 226 (P + 2).

b) Preparation of 4-chloro-1-ethyl-8-methoxy- [1,2,4} triazolo [4- [4,3-a] quinoxaline 25 Mixture containing 2-chloro-3-hydrazino-6-methoxyquinazoline (1.3 g, 0.0058 mol) and 25 ml of triethyl orthopropionate, were heated at 100 ° C for 4 hours and then stirred at room temperature for 60 hours. The precipitate was removed by filtration and washed with ethanol to give 530 mg (35% yield) of pure 4-chloro-1-ethyl-8-methoxy- [1,2,4] triazolo [3,3-a] quinoxaline, m.p. 198 ° C (dec.). Mass spectrum: m / e, 262 (P); m / e 264 (P + 2).

49 7401 1 c) Preparation of 4-diethylamino-1-ethyl-8-methoxy-1,2,4,4-triazolo [1,3-a] quinoxaline A mixture containing 4-chloro-1-ethyl-8-methoxy- 1,2,4 / Triazolo [7,4-a] quinoxaline (520 mg, 0.002 mol) and 673 mg (0.008 mol) of diethylamine in 10 ml of Ν, Ν-dimethylformaride were stirred at room temperature overnight. The reaction mixture was poured onto ice and the precipitate was filtered off, washed with water and air dried. Recrystallization from a mixture of diethyl ether and petroleum ether gave 140 mg (23% yield) of pure 4-diethylamino-1-ethyl-8-methoxy-1,2,4-triazolo [4,3-a] quinoxaline, m.p. 135-138 ° C. . Mass spectrum: m / e, 299 (P).

Anal Calcd for C 16 H 21 N 5 O 3/8 IVO: 15 C, 63.71; H, 7.10; N, 23.22, Found: C, 63.63; H, 6.88; N, 23.37.

Example 20 4-Diethylamino-1-phenyl-1,2,4,4-triazolo [1,3-a] quinoxalinyl 20a) 4-Chloro-1-phenyl-7,2,4 (triazolo-4,3-a) Preparation of quinazoline 2-Chloro-3-hydrazinoquinazoline (2.2 g, 0.011 mol) was mixed with 6 ml of triethyl orthobenzoate, and the mixture was heated at 100 ° C for 30 minutes to 25 minutes. After the orange mixture was cooled to room temperature, ethanol was added. The precipitate obtained by filtration gave 2.1 g of crude product, which was further purified by trituration in warm methanol, filtered and air-dried to finally give 1.58 g (51%) of pure 4-chloro-1-phenyl-71,2,47-triazolo-7¾ , 3-α7-quinoxaline as an orange solid, b) Preparation of 4-diethylamino-1-phenylthi, 2,47-triazolo-7 *, 3-α / quinoxaline to 1.58 g (0.00563 moles) of 4-chloro-1-phenyl To 35 ml of 2,4, Ν-dimethylformamide was added 1.7 ml of diethylamine. The mixture was stirred overnight at room temperature. The precipitate formed was collected by filtration. , washed with Ν, Ν-dimethylformamide and recrystallized twice from a mixture of hexane and ethyl acetate (3: 1 by volume) to give 555 mg of pure 4-diethylamino-1-phenyl-1,2,4,7-triazolo-ζ, 3-α7-quinoxaline as white in the form of needles (melting point 166-168 ° C).

Anal, calculated: lie: C, 71.60; H, 5.99; N, 22.06, Found: C, 71.86; H, 5.86; N, 22.09.

Example 21 4-Diethylamino-1-trifluoromethyl- [1,2,4] triazolo [10,3,3-a] quinoxaline) a) 4-Hydroxy-1-trifluoromethyl-1,2,4,4-triazolo-3- Preparation of β-quinoxaline 2-Chloro-3-hydrazinoquinoxaline (3.89 g, 0.02 mol), the product of Example 0, was added to 22.8 g (0.20 mol) of cold trifluoroacetic acid (15.4 ml), which was by annealing in a dried reaction vessel surrounded by an ice bath with a nitrogen atmosphere while stirring mechanically. The reaction mixture was then heated to 100 ° C for 3 hours and poured onto ice.

The product obtained was collected by suction filtration, washed with water and air-dried to constant weight. In this way, 3.0 g (60%) of pure 4-hydroxy-1-trifluoromethyl-1,2,4 (7-triazolo [3,3-a] quinoxaline, melting point> 300 DEG C.) were finally obtained, mass spectrum: m / e, 254 ( P).

B) Preparation of 4-chloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline By annealing to a dried reaction vessel under a nitrogen atmosphere, 3.0 g (0.0118 moles) of 4-hydroxy- 1-Trifluoromethyl, 2,47-triazolo [4,3-a] 35-quinoxaline and 30 ml of phosphorus oxychloride in 2.38 g of 51,741 l (0.0236 mol) of triethylamine (3.3 ml). The reaction mixture was then heated at 100 ° C for about 16 hours (i.e., overnight). At the end of this step, the settled 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 extracts were washed with saturated brine and dried over anhydrous magnesium sulfate.

After the drying agent was removed by filtration and the solvent was evaporated under reduced pressure, a residue was obtained, which was then dissolved in hot chloroform and filtered. The filtrate was allowed to stand at room temperature and filtered again. The final filtrate was concentrated in vacuo to finally give 1.4 g of 4-chloro-15-trifluoromethyl, 2,4,7-triazolo [4,3-a] quinoxaline as a brownish solid.

c) Preparation of 4-diethylamino-1-trifluoromethyl-1,2,4,4-triazolo [4,5-b] quinoxaline A mixture containing 700 mg (0.0025 mol) of 4-chloro-20β-1-trifluoromethyl- 1,2,4,7-triazolo [4,3-a] quinoxaline (prepared as described above) and 560 mg (0.0075 mol) of diethylamine (0.8 ml) in 10 ml of N, N-dimethylformamide , was stirred at room temperature overnight and then poured onto ice. The resulting mixture was filtered and the resulting solid product was washed with water and then dissolved in ethyl acetate. This organic solution was washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a pale yellow solid was finally obtained, which was recrystallized from diethyl ether to give pure 4-diethylamino-1-trifluoromethyl-1,2,4,7-triazolo [1,3]. -a ^ quinoxaline. The yield from the first batch, melting at 155-157 ° C, was 260 mg (34%), while the yield from the second batch, melting at 153-156 ° C, was 170 mg (22%).

52 7401 1

Anal. Calcd. C.-H..F, NC: 11: 14 14 3 5 C, 54.37; H, 4.56; N, 22.64, Found: C, 54.08; H, 4.47; N, 23.32.

Example 22 4-Isopropylamino-1-trifluoromethyl-1'-triazolo [5,3-a] quinoxaline_

A mixture of 700 mg (0.0025 moles) of 4-chloro-1-trifluoromethyl-1,2,4,4-triazolo [1,3-a] quinoxaline (product of Example 21b) and 443 mg (0.0075 moles) of isopropylamine (0.64 ml) in 10 ml of Ν, Ν-dimethylformamide, was stirred at room temperature overnight and then poured onto ice. The resulting mixture was filtered and the resulting solid product was washed with water and dissolved in diethyl ether. This ethereal solution was washed with brine and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration and the solvent was evaporated under reduced pressure, a white solid powder was finally recrystallized from diethyl ether to give 550 mg (74%) of pure 4-isopropylamino-1-trifluoromethyl-1,2,4 7-triazolo [1,3-a] quinoxaline, m.p. 185-187 ° C.

Anal Calcd for C 13 H 12 F 3 N 5: H-e: C, 52.88; H, 4.10; N, 23.72, 25 Found: C, 52.73; H, 4.00; N, 23.67.

Example 23 1-Ethyl-4- (N-ethylacetylamino) -E, L, 2,4,7-triazolo [1,3-a] quinoxaline

By annealing in a dried reaction vessel, a mixture of 241 mg (0.001 mol) of 1-ethyl-4-ethylamino-1,2,4-triazolo [1,3-c] quinoxaline (the product of Example 11) and 2.5 g (0.025 mol) of acetic anhydride (2.5 ml) was heated to reflux under a dry nitrogen atmosphere for 3 hours, after which the mixture was allowed to cool to room temperature. At this step, a precipitate formed, and the resulting reaction mixture was poured into water and then extracted with chloroform. The chloroform extracts were combined and washed with water and then dried over anhydrous magnesium sulfate. After removal of the solvent-5 by filtration and evaporation of the solvent under reduced pressure, a solid product was obtained, which was recrystallized once from a mixture of chloroform and diethyl ether to give 160 mg (57%) of 1-ethyl-4- (N-ethylacetylamino) -ζί. , 2,4'-triazolo-10,3-a] quinoxaline, m.p. 185-187 ° C.

Anal Calcd for C 18 H 18 N 2 O 2: C, 63.59; H, 6.05; N, 24.72, Found: C, 63.17; H, 6.05; N, 24.39.

Example 24 4-Acetylamino-1-ethyl-1,2,4,1-triazolo [4,3-a] quinoxaline_

A mixture of 533 mg (0.0025 moles) of 4-amino-1-ethyl- (1,2,4) triazolo [2,3-b] quinoxaline (product of Example 8) was 1.0 g (0.01 moles). acetic anhydride (1.0 mL) in 20 mL of methylene chloride, heated at reflux overnight (* 16 h) and then allowed to cool to room temperature. The resulting clear solution was concentrated in vacuo to give a white solid which was then recrystallized from a mixture of chloroform and diethyl ether to give 520 mg (82%) of pure 4-acetylamino-1-ethyl-1,2,4-triazolo [4,3- α / quinoxaline, melting point 193-195 ° C.

Anal Calcd for C 12 H 13 N 5 O • 30 C, 61.16; H, 5.13; N, 27.43, Found: C, 60.90; H, 5.26; N, 27.66.

Example 25 4-Diacetylamino-1-ethyl-1,2,4,7-triazolo [4,3-b] oxoxaline A mixture containing 5.5 g (0.0258 moles) of 4-amine. No-1-ethyl-1,2,2-triazolo [1,3-a] quinoxaline (product of Example 8) and 25 g (0.25 mol) of acetic anhydride (25 ml) in 60 ml of pyridine containing 100 mg of p- dimethylaminopyridine, was stirred at room temperature overnight (* -18 hours). The resulting mixture was filtered to remove insolubles, and the orange-red filtrate was evaporated under high vacuum to give a dark gummy residue. Addition of water gave pinkish white crystals which were collected by suction filtration, washed with copious amounts of water and dried in vacuo at 50 ° C to give 2.9 g (38%) of 4-diacetylamino-1-ethyl , 2.47 triazolo [4,3-a] quinoxaline, m.p. 157-159 ° C. Recrystallization from a mixture of ethyl acetate and di-15 ethyl ether gave an analytically pure sample (melting point 158-160 ° C). The pure product was further characterized by mass spectrometry and nuclear magnetic resonance data in addition to elemental analysis. Mass spectrum: m / e, 297 (P).

Anal, calculated for C.CH.CNCO2: 15 15 5 2 C, 60.59; H, 5.09; N, 23.56, Found: C, 60.33; H, 5.09; N, 23.41.

Example 26

The following triazolo [4,3-a] quinoxaline-4-amine derivatives were prepared using the methods described in the examples above, starting from the readily available materials in each case: 7,8-bromo-4-diethylamino-1,2,4,7-triazolo [* 4,3-α-30 quinoxaline, m.p. 199-201 ° C.

8-chloro-4-isopropylamino-1,2,4'-triazolo-1,3-quinoxaline, m.p. 177-181 ° C.

4-ethylamino-1-trifluoromethyl-1,2,2,7-triazolo, 3-α-quinoxaline, m.p. 223-225 ° C.

35 1-ethyl-4-ethylamino-8-methoxy-1,2,4,7-triazolo [4,3-a] quinoxaline, m.p. 234-237 ° C.

55 7401 1 4-Diethylamino-8-methoxy- [1,2,4] triazolo [1,3-a] quinoxaline, m.p. 124-126 ° C.

8-chloro-1-ethyl-4-isopropylamino- [1,2,4] -triazolo [3,3-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-chloro-4- (N-isopropylacetylamino) - [1,2,4] -triazolo [1,3-a] quinoxaline, m.p. 148-151 ° C.

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

8-Chloro-1-ethyl-4- (N-isopropylacetylamino) - {1,2,4} -triazo [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.

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-b] 20-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-1H, 2,4-triazolo [4,3-a] quinoxaline, m.p. 239-242 ° C.

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

7.8-Difluoro-4-isopropylamino- [1,2,4] triazolo [30,3,3-a] quinoxaline, m.p. 218-221 ° C.

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

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

4-Diethyl-8-fluoro- [1,2,4] triazolo [2,3-b] quinoxaline, m.p. 151-153 °.

56 7 4 01 1 4-Diethylamino-1-ethyl-8-fluoro-1,2,4] triazolo [2,3-b] quinoxaline, m.p. 94-97 ° C.

7-chloro-4-dimethylamino-l-ethyl ^ T. , 2,4,] triazolo-1,3-a / quinoxaline, m.p. 214-217 ° C.

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

7.8-Dichloro-1-ethyl-4- (N-piperazino) - (1,2,4) -triazolo [3,3-a] quinoxaline, methanesulfonate, melting point 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 [3,3-a] quinoxaline, methanesulfonate, m.p. 216-219 ° C.

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

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

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

7-Chloro-4-diethylamino-β, 2,4] triazolo [4,3-a] quinoxaline, methanesulfonate, m.p. 205-207 ° C.

4-Diethylamino-7,8-difluoro-1,2,4-triazolo-C4,3-α-quinoxaline, methanesulfonate, m.p. 220-223 ° C.

4-Acetylamino-7-chloro-1-ethyl-1,2,4'-triazolo-3,4-quinoxaline, m.p. 210-212 ° C.

30 8-chloro-1-ethyl-4-ethylamino-1,2,2,4] triazolo

Cl, 3- [7] quinoxaline, methanesulfonate, mp 235-238 ° C.

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

35 4-Amino-8-chloro-1-methyl-1,2,4-triazolo (4,3-a] quinoxaline, methanesulfonate, m.p. 213-215 ° C.

57 7401 18 8-Chloro-4-isopropylamino-1-trifluoromethyl, 2,4,7-triazolo [4-a] quinoxaline, methanesulfonate, m.p. 183-185 ° C.

8-Chloro-4-diethylamino-1-methyl- (1,2,4) triazolo-3,5-quinoxaline, methanesulfonate, m.p. 172-175 ° C.

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

4-diacetylamino-8-chloro-1,2,4) triazolo-10,3-quinoxaline, m.p. 208-210 ° C.

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

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

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

7,8-Difluoro-1-ethyl-4-isopropylamino-1,2,4-triazolo [4,3-a] quinoxaline, methanesulfonate, m.p. 151-152 ° C.

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

8-Chloro-4-diethylamino-1-trifluoromethyl, 2,4-triazolo [4,3-c] thioxoxine, hydrate, m.p. 135-136 ° C.

4-Amino-8-chloro-1-trifluoromethyl-1,2,27-triazolo [4,3-b] quinoxaline, methanesulfonate, m.p. 259-261 ° C.

4-ethylamino-8-fluoro-1-trifluoromethyl- [1,2,4] -triazolo [4,3-a] quinoxaline, methanesulfonate, m.p. 180-183 ° C.

8-Fluoro-4-isopropylamino-1-trifluoromethyl, 2,4'-triazolo [4,3-d] quinoxaline, methanesulfonate, m.p. 185-188 ° C.

4-Diethylamino-7,8-difluoro-1-ethyl-N, N-2,4,3-triazolo [3,3-a] quinoxaline, m.p. 109-111 ° C.

58 7401 11-ethyl-4-ethylamino-7-fluoro- [1,2,4] triazolo - (%, 3- [4] quinoxaline, methanesulfonate, m.p. 215-219 ° C).

4-Amino-7-methoxy-1,2,2,4-triazolo [1,3-a] quinoxa-5-line, methanesulfonate, m.p. 262-264 ° C.

8-chloro-4-isopropylamino-1-phenyl-1,2,4,7-triazolo [4,3-a] quinoxaline, m.p. 183-186 ° C.

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

7-Fluoro-4-isopropylamino-E, 1,2,4-triazolo-E, 3,3-α-quinoxaline, methanesulfonate, m.p. 214-216 ° C.

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

4-Diethylamino-8-fluoro-1-trifluoromethyl-1,2,2,7-triazolo [1,3-a] quinoxaline, m.p. 146-149 ° C.

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

8. chloro-4-diethylamino-1-phenyl- (1,2,4) -20 triazolo [4,3-a] quinoxaline, m.p. 194-195 ° C.

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

4-Acetylamino-8-chloro-1-trifluoromethyl, 2,47-triazolo [2,3-b] quinoxaline, mp 215-25 216 ° C.

4-Amino-8-chloro-1-phenyl- (1,2,4) triazolo [4,2-a.] Quinoxaline, methanesulfonate, m.p. 273-275 ° C.

8-chloro-4-ethylamino-1-trifluoromethyl- (1,2,4) -triazolo [2,3-b] quinoxaline, m.p. 228-230 ° C.

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

4-Amino-8-fluoro-1-trifluoromethyl-1,2,4-triazolo [3,3-a] quinoxaline hydrate, m.p. 260-263 ° C.

59 7401 18-Chloro-1-ethyl-4R-phenyl-isopropylamino-1,2,2, k) triazolo [4,3-a] quinoxaline, m.p. 155-157 ° C.

4-amino-1-ethyl-7-fluoro [1,2,4] triazolo [4,3-a] -5-quinoxaline, m.p. 285-289 ° C.

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

4-Acetylamino-8-fluoro-1-trifluoromethyl-10 [1,2,4] triazolo [4/3-a] quinoxaline, m.p. 217-219 ° C.

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

8-Chloro-1-ethyl-4S-phenyl-isopropylamino-15 [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 156-157 ° C.

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

4-Acetylamino- [1,2,4] triazolo [4,3-a] quinoxa-20, m.p. 269-272 ° C.

4-amino-7-fluoro-1,2,4,4-triazolo [4,3-b] quinoxaline, methanesulfonate / mp 246-248 ° C.

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

4-Acetylamino-7-fluoro- [1,2,4] triazolo [1,3-a] quinoxaline, m.p. 290-292 ° C.

8-Chloro-4-isopropylamino-1-pentafluoroethyl, 2,4,7-triazolo [4,3-b] quinoxaline, m.p. 171-174 ° C.

Example 27 8-Chloro-1-ethyl-4-propionylamino-E, 1,2,4-triazolo [1,3-a] quinoxaline

A mixture of 1.25 g (0.005 moles) of 4-amino-8-chloro-1-ethyl-1,2,4,7-triazolo [4,3-a] quinoxaline-35 (melting point 248-253 ° C), the product of Example 26.

60 7 4 01 1 and 15 ml of propionic anhydride were heated at reflux overnight for about 16 hours and then cooled to room temperature (^ 20 ° C). At the end of this step, the reaction mixture was filtered, and the resulting precipitate was dissolved in chloroform. This organic solution was filtered and then washed first with water, then with saturated aqueous sodium bicarbonate solution and finally with saturated brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a residual material was obtained, which was then chromatographed on a 150 ml silica gel column with a mixture of chloroform and methanol (95: 5 by volume) as eluent. Similar product-containing fractions were combined and then concentrated in vacuo to give a crystalline material which was further recrystallized from a mixture of chloroform and ethyl ether to give 540 mg (36%) of pure 8-chloro-1-ethyl-4-propionylamino. 1,2,4-triazolo [4,3-a] quinoxaline, m.p. 212-215 ° C.

Anal Calcd for C 18 H 18 ClN 3 O 2: C, 55.36; H, 4.64; N, 23.06, Found: C, 54.91; H, 4.59; N, 22.76.

Claims (3)

1. A process for the preparation of therapeutically useful 1, 2.47 triazolo 4,3,3-quinoxaline-4-amine derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof; N is hydrogen, fluorine, chlorine, bromine or methoxy, is hydrogen, lower alkyl, lower perfluoroalkyl or phenyl, and R 2 and R 2 represent hydrogen, lower alkyl, phenylalkyl having not more than three carbon atoms in the alkyl moiety or alkanoyl having 2-5 carbon atoms, provided that at least one of the substituents of R2 and R3 is other than hydrogen, where X and X1 each represent hydrogen and R * is hydrogen or methyl ? or R 2 and R 2 together with the nitrogen atom to which they are attached form a piperazine ring, characterized in that a 4-chloro compound of the formula R 1 = X 1 ρ = · Ν (II) -C1 X where X, X 3 and the same as above are reacted with an amine of the formula HNR 2 R 2, wherein R 2 and R 2 are the same as above, except alkanoyl, to give a corresponding 4-amino compound, and if if desired, a obtained 4-amino compound of formula (I) is reacted wherein at least one of the substituents R