CS248711B2 - Production method of the/l1,2,4/triazol/4,3-a/chinoxaline-4-amin derivatives - Google Patents

Description

The invention describes a group of novel [1,2,4] triazolo [4,3-a] quinoxaline-4-amine derivatives and their pharmaceutically acceptable acid addition salts, which are useful as antidepressants and anti-fatigue agents.

Intensive efforts have been made to find agents that would be effective in suppressing the symptoms of depression and fatigue in mammals.

U.S. Patent 3,839,569 and West German Patent 2,249,350 disclose the use of s-triazolo [4,3-a] quinoxalines and 1H-imidazo [4,5-b] quinoxalines as agricultural fungicides. U.S. Patent No. 4,008,322 describes the use of a series of triazolo [4,3-a] quinoxaline derivatives for combating fungal disease of rice caused by the phytopathogen Piricularia oryzae.

The invention relates to novel [1,2,4] triazolo [4,3-a] chrnoxalin-4-amine derivatives which are useful as antidepressants and as anti-fatigue agents. In particular, the invention provides compounds of formula I

in which

X and X ^{1 * * * V} are independently selected from the group consisting of hydrogen, fluorine, chlorine and bromine atoms, and methoxy,

R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 perfluoroalkyl group or a phenyl group; and

R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, phenylalkyl of up to 3 carbon atoms and C 2 -C 5 alkanoyl groups, provided that they are: X and X ¹ are hydrogen and R is hydrogen or methyl, then at least one of R and R3 is not hydrogen, or

R 2 and R 3 together form a piperazine ring, and pharmaceutically acceptable acid addition salts thereof.

In the following, lower alkyl groups denote alkyl groups having 1 to 4 carbon atoms with lower perfluoroalkyl groups denote perfluoroalkyl groups having 1 to 4 carbon atoms such as trifluoromethyl, pentafluoroethyl and the like.

One group of interesting compounds according to the invention is formed by those compounds of formula (I) in which X and X are hydrogen, R1 is hydrogen and R2 and R3 are each lower alkyl. Preferred compounds include those wherein both R2 and R3 are ethyl.

Another group of interesting compounds of the invention are those in which X and χΐ are hydrogen, R1 is ethyl and R3 is lower alkyl. Preferred compounds of this group are those wherein R2 is hydrogen and R3 is ethyl.

Another group of interesting compounds of the invention are those in which X and X1 are hydrogen, R1 is lower alkyl and R3 is acetyl. Preferred compounds of this group include those wherein R 1 is ethyl and R 2 is hydrogen, ethyl or acetyl.

Yet another interesting group of compounds of the invention are those wherein at least one of X and X1 is fluoro, R1 is hydrogen or trifluoromethyl, R2 is hydrogen, and R3 is hydrogen, lower alkyl or alkanoyl having 2; to 5 carbon atoms, or alternatively wherein at least one of X and X ¹ is chlorine, R 1 is lower alkyl or trifluoromethyl, R 2 is hydrogen and R 3 is hydrogen, lower alkyl or alkanoyl of 2 to 5 atoms carbon.

The invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. Preferred are those pharmaceutical compositions comprising the preferred compounds of Formula I described above.

The present invention also provides a method of treating depression and tiredness in a mammal in need thereof, comprising administering to said mammal an antidepressant or anti-depressant drug. an anti-fatigue effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. Preferred agents for this method of treatment are the preferred compounds of formula I described above.

Most of the novel compounds of formula (I) can be prepared by the sequence of reactions shown in Scheme I. The numbering of the phenyl ring and the two heterocyclic rings shown in Scheme I is used throughout.

Scheme. AND

2Л Р-Г7

8/11

N.

, «Ϊ / 1

NHNH Cl '2. (Itr), ^(Α '1.

(except * · Xb1 · ^Xy - ^-H) :

In Reaction Scheme I, a compound of formula IV, which is a quinoxaline derivative wherein X and X ¹ independently of one another are hydrogen, F, Cl or • Br, or methoxy group provided that if the quinoxaline derivative is monosubstituted on the benzene ring, X is only hydrogen, has an excess of the molar amount of hydrazine hydrate in a polar inert organic solvent such as a C 1 -C 3 alkanol, preferably ethanol, at room temperature for about 18-24 hours to form the intermediate of formula III.

The intermediate compound of formula (III) may be converted to the corresponding intermediate of formula (IIA) wherein R 1 is not a lower perfluoroalkyl group by treatment with an appropriate alkyl orthoalkanoate or alkyl orthobenzoate at about 80-120 ° C for about 1-24 ° C. clock. In the resulting compound of formula (IIA), the character of R 1 (hydrogen or alkyl) is given by the nature of the corresponding orthoalkanoate used in the synthesis. For example, when triethyl orthoformate is used, R 1 is hydrogen, triethyl orthopropionate means R1 is ethyl, and when triethyl orthoisobutyrate is used, R1 is isopropyl.

Intermediate. of formula III can also be converted into the corresponding general intermediate. Of formula ⁽ IIa) in which R 1 represents a lower perfluoroalkyl group and a hundred reactions with an excess of the molar amount corresponding to the peri-uoralkanoic acid, such as. This reaction is carried out in a conventional manner and obtains a corresponding amount of [1,2,4Hriazolo {4,3]. A quinoxaline which, following treatment with phosphorus oxychloride, in the presence of a tertiary amine. as · - tri-. ethylamine at elevated temperature gives the corresponding 4-chloro derivative

The intermediate of formula (IIA) (wherein Ru represents a hydrogen atom, a lower alkyl group, a lower perfluoroalkyl group, or a phenyl group). Then it is converted to the [1,2,4,4] hexyl-1,4-di-4 (-h) -h (): (4, 4-amino-4-amino derivative of the general formula) IA in which R2 and R1 have the same meaning as described above, with the exception of the alkanoyl group, in which the reactions are in excess: HNR 2 R 3 in an inert organic solvent, preferably in N, N-dimethylformamide, at a temperature between about 0 ° C and about 60 ° C. The reaction takes about 2 to 24 hours, for example preferred compounds of the general formula IA in which both symbols Ra.a. · Ethyl groups, at 2 4 8 711.

The reaction is carried out by reacting the corresponding compound of formula IIA with diethylamine in N, N-dimethylformamide at room temperature for 2-3 hours. Similarly, preferred compounds of formula IA are those wherein R? represents a hydrogen atom and represents an ethyl group, prepared by reacting a compound of formula IIA with monoethylamine in N, N-dimethylformamide at room temperature for 4 to 5 hours.

[1,2,4] triazolo [4,3-a] quinoxaline-4-amino derivatives of the formula IA in which at least one of R2 and R3 is a C2 -C5 alkanoyl group are prepared from the corresponding compounds of the formula IA, wherein at least one of R 2 and R 3 is hydrogen, by reacting the compound with the corresponding alkanoic anhydride under virtually anhydrous conditions. This reaction can be carried out in the presence of an organic base such as a tertiary amine catalyst (although the presence of this base is not necessarily necessary) at a temperature ranging from about 20 ° C to 140 ° C. The reaction time is about 0.5 to 24 hours. The molar ratio of acid anhydride to the starting 4-amino derivative should be at least 1: 1, but preferably from about 4: 1 to 25: 1, with the tertiary amine normally being used in an amount of about 25 to 150% by weight of the above acylating agent. When an excess of this tertiary amine is used, the reagent can also serve as the reaction solvent. While it is quite possible and in some cases even very desirable to carry out the reaction in the absence of a solvent, there may be instances where the use of a suitable inert organic solvent is desirable. Suitable organic solvents for use herein include neutral, inert, anhydrous organic solvents such as acetone, methylethylketone, benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride, chloroform, ethylene dichloride, tetrachloroethane, methylate, ethyl acetate, isopropyl acetate, methylpropionate, ethylpropionate, diethyl propionate, diethyl propionate, diisopropyl ether, di-n-propyl ether and the like. However, as mentioned above, however, the reaction is usually carried out in the absence of such a solvent only with an excess of acid anhydride. Similarly, an excess of the aforementioned tertiary amine may serve as a solvent. Preferred tertiary amines that can serve as solvents and / or catalysts in the above reaction are triethylamine, dimethylaniline, pyridine, picoline, lutidine, collidine, and quinoline.

Starting materials of formula IV wherein X а X ¹ are hydrogen, they are known in the art. Compounds of formula IV wherein X ¹ is methoxy may be prepared according to the method described by GWH Cheeseman [J. Chem. Soc., P. 1170 (1962)] and wherein 4-methoxy-o-phenylenediamine hydrochloride is treated with at least an equimolar amount of dlethyloxalate and diethylamine under an inert gas atmosphere, preferably nitrogen, at reflux for about 2 to 3 hours, followed by reaction with phosphorus oxychloride in a tertiary amine, preferably diethylaniline, at reflux for 1-2 hours.

Another treatment of the starting material of formula IV is described in Reaction Scheme II below.

Scheme II

(Vi) (vi)

(Vlil)

2 ^ 3 (i)

^ Ж.248711

According to Scheme II, the .derivát quinoxaline of general formula IV in which X is fluorine, chlorine or bromine and methoxy, or • X ¹ is hydrogen, sodium -methoxidem operates in an alcoholic solvent medium at slightly elevated ^temperature! (e.g. 40 to 60 ° C) for about 6 to 18 hours to give the corresponding 2-chloro-3-methoxyquinoxaline derivative of formula V, which then reacts with hydrazine hydrate in an analogous manner to the above to give the corresponding 2-hydrazino-3. The latter intermediate of formula (VI) is then converted to the desired 7-substituted 4-methoxy [1,2,4] triazole by using the corresponding orthoester or perfluoroalkanoic acid as described above. The [4,3-a] quinoxaline derivative of formula (VII), which is then gradually converted to the corresponding compound in a conventional manner

4-hydroxy compound of formula VIII and then to the corresponding 4-chloro derivative. In this way, a compound of formula (IIB) is obtained in which X is as defined above (i.e. has a meaning other than hydrogen) and χΐ represents a hydrogen atom. From this intermediate of formula (IIB), the corresponding novel final products of formula (IB) in which R 1, R 2 and R ³ have all the meanings given above and X are prepared by merely applying the reaction procedures described above in connection with the discussion of the last reaction steps in Scheme I. χΐ is as defined above.

The invention also relates to pharmaceutically acceptable addition salts of the novel compounds of formula (I). These salts are readily prepared by contacting the free base with the corresponding mineral or organic acid in either an aqueous solution or a suitable organic solvent. The solid salt can then be isolated by precipitation or evaporation of the solvent. Pharmaceutically acceptable acid addition salts of the invention include, but are not limited to, 4-hydrosulphides, sulfates, hydrogensulfates, mesylates, tosylates, nitrates, phosphates, acetates, lactates, maleates, fumarates, citrates, tartrates, succinates, gluconates and the like. are mesylates. If desired, the compounds of the formula I can be obtained from the acid addition salts by treatment with a suitable base in the form of the free base, which can be isolated by extraction with a suitable organic solvent.

The compounds of formula I and their pharmaceutically acceptable acid addition salts have activity as antidepressants and anti-fatigue agents and accordingly can be used to treat symptoms associated with depression and fatigue.

This efficacy is demonstrated by the following rat test, which is a modification of the method described by R. D. Porsolt et al. in European

Journal of Pharmacology, 47, p. 379 (1978) and utilizes the subjective observation method developed for mice by Wallach and Hedley [Comm. Psychopharm., 3, p.35 (1979)]. In accordance with the original Porsolt method, male rats (Charles River) weighing 280 to 325 g are placed in individual plastic cylinders (height 45 cm, diameter 22 cm) filled up to 25 cm with water at 25 ° C. On day 1, rats were placed in this vessel for 15 minutes. During the first 10 minutes, rats typically float around the walls of the container and look for a leak. Towards the end of the aforementioned 15-minute interval, the rats recognized that the escape was hopeless, immobilized, and floated without movement in the vessel until the time they were removed from the vessel. 24 hours after this initial experiment - rats were orally administered either vehicle or test compound and after 1 hour the rats were reinserted into individual water cylinders. For this purpose, a mixture of 90% by volume physiological saline solution (0.9% aqueous sodium chloride solution), 5% by volume ethanol and 5% by volume Emulphor is used as vehicle. Dissolve or suspend in ethanol and emulsifier, and then dilute the resulting solution or suspension with physiological saline solution. A total of 10. If the rat remains motionless and only floats passively in the water, it is denoted as "1." If the rat is trying to escape the war (intensive swimming and jumping), it is denoted as "0". The behavior of all rats is evaluated every 30 seconds, since these evaluations are performed in total of 10, the resulting value is for the rat. , which remains stationary for the entire test period, "10", while the rat, which for some time seemed to be trying to escape, has a lower value.

Generally, it has been found that rats treated with vehicle only have a final value of 8 to 9, while treatment with an antidepressant drug results in a reduction in this immobility (i.e. counteracts feelings of "despair" or "helplessness"). This efficacy depends on the dose administered and on whether the treatment has been performed once or repeatedly. Within these ranges, the test compound is considered to be active if the difference in response of the animals treated with the active substance and the animals treated with the vehicle alone (control group) is considered statistically significant in observation with the results obtained in known standard antidepressant efficacy tests. such as sleep deprivation (REM) and electrosevulsive shock (ECS). In other words, the test compound is laid.

24В711 is effective if a statistically significant reduction in immobility is observed.

The 4-amino- [1,2,4] triazolo [4,3-a] quinoxaline derivatives listed below were examined for rapid onset antidepressant activity in rats as described above. These compounds were found to be effective when administered orally at the dosages listed below. The compound mentioned in this review first (a compound corresponding to the general formula I in which X, X ¹ , R ¹ , R 2 and R 3 are hydrogen atoms) was described by BA Dreikorn et al. No. 4,008,322 as a fungicidal agent for combating fungal diseases of rice.

X xl Rl R2 R3 Dose (mg / kg) H H H н н 32 Cl H H н н 32 *) H Cl H н н 10 F H H н н 32 *) H F H н н 32 *) ОСНз H H н н 32 *) H H H н СОСНз 32 F H H н СОСНз 32 H F H н СОСНз 32 ОСНз H H н СОСНз 32 H H H н СНз 32 H H H н С2Н5 3.2 F H H н С2Н5 32 *) H F H н С2Н5 3.2 F F H н С2Н5 32 H H H н ISSO-C3H7 10 H Cl H н ISSO-C3H7 10 Cl Cl H н ISSO-C3H7 10 H F H н ISSO-C3H7 3.2 F F H н ISSO-C3H7 3.2 ОСНз H H н ISSO-C3H7 32 H H H СОСНз СОСНз 32 H Cl H СОСНз СОСНз 32 H H H СНз СНз 32 H H H С2Н5 С2Н5 10 Cl H H С2Н5 С2Н5 32 *) H F H С2Н5 С2Н5 10 F F H С2Н5 С2Н5 32 *) H Cl H ISSO-C3H7 СОСНз 32 H Cl СНз Н н 32 *) H Cl СНз Н СОСНз 32 H H СНз Н ISSO-C3H7 32 H Cl СНз Н ISSO-C3H7 3,2 *) H H СНз С2Н5 С2Н5 10 H Cl СНз С2Н5 С2Н5 32 *) H H С2Н5 н н 10 Cl H С? Нз н н 3,2 *) H Cl С2Н5 н н 3.2 Cl Cl С2Н5 н н 10 F H С2Н5 н н 32 H H С2Н5 н СОСНз 1.0 Cl H С2Н5 н СОСНз 32 H Cl С2Н5 н СОСНз 3.2 Cl Cl С2Н5 н СОСНз 3.2

14

X X ¹ Ri Rž Rš Dose (mg / kg) F H C2H5 H СОСНз 3.2 Η F C2H5 H СОСНз 3.2 Η Cl C2H5 H COC2H5 3.2 Η Cl C2H5 H СОСзН7 (п) 32 Η Cl C2H5 H СОС (СНз) з 32 Η H C2H5 H СНз 10 Η H C2H5 H С2Н5 3.2 NO. 1 H C2H5 H С2Н5 32 *) Η Cl C2H5 H С2Н5 32 *) F H C2H5 H С.2Н5 32 *) Η F C2H5 H С2Н5 32 Η H C2H5 H ISO-C 3 H 7 32 Η Cl C2H5 H iso-СзН? 3.2 NO. 1 Cl G2H5 H 1SO-C3H7 32 Η F C2H5 H ISSO-C3H7 10 F F C2H5 H ISSO-C3H7 32 *) Η H C2H5 СОСНз СОСНз 10 Η H C2H5 C2H5 СОСНз 32 Η H C2H5 СНз СНЗ 3.2 NO. 1 H C2H5 СНз СНз 32 *) Η Cl C2H5 C2H5 С2Н5 32 NO. 1 Cl C2H5. C2H5 С2Н5 10 Η F C2H5 C2H5 С2Н5 32 F F C2H5 G2H5 С2Н5 32 Η ОСНз C2H5 C2H5 С2Н5 32 NO. 1 Cl C2H5 —CH2CH2NCH2CH2— 32 *) Η H ISSO-C3H7 C2H5 С2Н5 32 Η H ISSO-C3H7 Η С2Н5 32 Η Cl C2H5 ISSO-C3H7 СОСНз 10 Η Cl CFs Η Н 3,2 *) Η F CFs Η Н 3.2 Η Cl CFs Η СОСНз 3.2 Η F CFs Η СОСНз 3.2 Η H CFs Η С2Н5 32 Η Cl CFs Η С2Н5 32 Η F CFs Η С2Н5 32 *) Η H CFs Η 1SO-C3H7 10 Η Cl CFs Η ISSO-C3H7 3,2 *) Η F CF3 Η ISSO-C3H7 3,2 *) Η H CFs С.2Н5 С2Н5 32 Η Cl CFs СгН5 С2Н5 32 Η Cl C2F5 Η ISSO-C3H7 32 Η Cl СбН5 Η ISSO-C3H7 32 Η H СбН5 СгН5 С2Н5 32 NO. 1 Cl C2H5 СНз СНз 32 *) Η H C? H5 С2Н5 С2Н5 10 NO. 1 H C2H5 C2H5 С2Н5 32 *) Legend: *) The compound was tested in the form of methanesulfonate (mesylate) The compound described is maybe patient- and the particular compound used to those requiring treatment served by a series of course, there will be deviations from these common application paths including administration benefits. oral and parenteral. Preferably Compounds produced by the process of mentioned the compounds are administered orally. Village- finding them can be applied alone or in The substances according to the invention are used orally combination with pharmaceutically acceptable in one or several doses range- carriers or diluents »in either jednorazo- between about 0.1 and 100 mg / kg body weight. vé »neboi multiple dose. Among the appropriate weight of treated patient daily, pharmaceutical carriers pertaining inert re- preferably from about 0.5 to about 0.5 10 mg / kg day- sensing agents or fillers, sterile aqueous and solutions No. If: desirable parenteral or intrave- various organic solvents. Farmaceu- For example, the compounds described herein may be used technical means produced by combining do not give in daily doses moving of the novel compounds of the formula I or from about 0.1 to 10 mg / kg body mass- their salts with pharmaceutically acceptable patient. According state of pa-

the carriers are conveniently administered in the form of a variety of dosage forms such as tablets, powders, capsules, lozenges, syrups and the like. These pharmaceutical compositions may optionally contain other ingredients such as flavoring agents, binders, excipients and the like. For example, tablets for oral administration may contain various excipients such as sodium citrate together with various disintegrants, starch, alginic acid and certain more complex silicates, and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

The invention is illustrated by the following non-limiting examples.

Preparation

4-Chloro-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline aj Preparation of 2-chloro-6-fluoro-3-methoxyquinoxaline

To a flame-dried reaction flask containing a suspension of 52 g (0.24 mol)

2,3-dichloro-6-fluoroquinoxaline in 500 ml of methanol is slowly added dropwise a solution of 6.6 g (0.29 mol) of sodium in 650 ml of methanol under a dry nitrogen atmosphere at 50 ° C. The reaction mixture was heated at 50 ° C overnight (i.e. about 16 hours) and the resulting clear solution was allowed to cool to room temperature (ca. 20 ° C). The reaction mixture is then concentrated in vacuo, the residue is dissolved in chloroform, the solution is washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent is evaporated under reduced pressure and the liquid residue is chromatographed on a 1000 ml silica gel column using toluene as the eluent. Fractions containing only the desired product were combined to give 48.3 g (95 percent) of pure 2-chloro-6-fluoro-3-methoxyquinoxaline, m.p. 93-95 ° C.

Mass spectrum:

m / e = 212 (P), 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-methoxyquinnoxaline 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 16 hours at about 20 ° C), then an additional 9.0 mL of hydrazine hydrate was added and the mixture was stirred at room temperature for 4 hours. The precipitate formed is filtered off and washed with ethanol to give 43.3 g (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxalide melting at 170-174 ° C with decomposition,

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 was heated to 100 DEG C. in a preheated oil bath overnight with a mechanical stirrer (ca. 16 hours). The reaction mixture is cooled to room temperature, the precipitate formed is filtered off with suction and washed with ethanol. 11.3 g (72 percent) of pure 7-fluoro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline melting at 245-246 ° C are obtained.

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

A mixture of 11.3 g (0.52 mol) of 7-fluoro-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, 115 ml of 1N hydrochloric acid and 345 ml of glacial acetic acid was added for 3 hours. heats to reflux. Upon completion of this heating, the reaction mixture was cooled to room temperature and poured into ice-water. The resulting mixture was stirred for 30 minutes, then the precipitate was filtered off, washed with water and air dried. 8.9 g (84%) of pure 7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline, melting above 300 ° C, are obtained.

Mass spectrum:

m / e = 204 (P).

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

A flame-dried flask was charged with 8.9 g (0.044 mol) of 7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline and 160 ml of phosphorus oxychloride under an atmosphere of dry nitrogen. 8.9 ml of tri-n-propylamine. The reaction mixture was heated to reflux for about 16 hours (overnight), then cooled to room temperature and poured into ice-water with stirring with a mechanical stirrer. The resulting aqueous mixture was stirred at room temperature for 30 minutes, filtered, the solid product was washed with cold water and triturated with ethyl acetate. 7.0 g (71%) of pure 4-chloro-7-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 305 DEG-308 DEG C. are obtained.

Mass spectrum:

m / e = 222 (P), 224 (P + 2).

Preparation В

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

a) Preparation of 1-ethyl-7-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 [product of Preparation Ab) J and 250 ml of triethyl orthopropionate was heated in a preheated oil bath overnight with a mechanical stirrer (ca. 16 hours). to 100 ° C. The resulting mixture was cooled to room temperature (20 ° C), the precipitate formed was filtered off and washed with ethanol to give 11.3 g. (64%): pure 1-ethyl 1-7-fluoro-4-methoxy- 1,2,4] triazolo [4,3-a] quinoxaline, melting at 200-202 ° C with decomposition.

and

b) Preparation of 1-ethyl-7-fluoro-4-hydroxy-

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

A mixture of 11.3 g (0.046 mol) of 1-ethyl-7-fluoro-4-methoxy- [1,2,4] triazolo] 4,3-a] quinoxaline, 115 ml of 1 N hydrochloric acid and 345 ml of glacial acetic acid was refluxed for 3 hours. After heating, the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was stirred for 30 minutes, then filtered and the solid product was air dried after washing with water. 6.6 g (62%) of pure 1-ethyl-7-fluoro-4-hydroxy- [1,2,4] triazolo [4,3a] quinoxaline melting above 300 ° C are obtained.

Mass spectrum:

m / e = 232 (P), 231 (P -1).

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

6.6 g (0.028 mole) of 1-ethyl-7-ethanone were charged to a flame-dried reaction flask under a dry nitrogen atmosphere ^. Flu: OT-4'hydroxy- [1,2,4] triazole-10 '(4', 3-a] chtaoxa (110) and 120 ml of phosphorus oxychloride together with

6.6 ml of tri-n-propylamine. The reaction mixture was refluxed overnight (ca. 1 hour), then cooled to room temperature and poured into ice-water with stirring with a mechanical stirrer. The resulting aqueous mixture was stirred at room temperature for 30 minutes, filtered ^. and the solid product was dissolved in ethyl acetate after washing with cold water. The organic solution was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated under reduced pressure. A reddish-brown solid was obtained, which was triturated with diethyl ether to give 4 g (57 percent) of pure 4-chloro-1-ethyl-7-fluoro [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 203 mp 205 ° C.

Mass spectrum:

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

Preparation; С

4,7-Dichloro- [1,2,4] triazolo [4,3, -a] Quinoxaline

a) i Preparation of 2,3-dihydroxy-6-chloro-quinoxaline

A mixture of 100 g (0.07 mol) of 4-chloro-1,2-phenylenediamine and 750 ml of diethyl oxalate is refluxed overnight and for about 16 hours. After completion of the heating, the reaction mixture was cooled to room temperature (ca. 20 ° C), filtered and the product on the filter was washed with ethanol and air dried. After drying to constant weight, 140 g of pure 2,3-dihydroxy-6-chloroquinoxaline melting above 260 ^DEG C. are obtained.

b) Preparation of 2,3,6-trichinoquininoxaline

A mixture of 140 g (0.70 mol) of 2 _y 3-dihydro-6-chloro-orchinoxalinu- and 326 ml (3 "50 moles) of phosphorus oxychloride overnight (about 16 hours) к heated under reflux and then poured on ice. The aqueous mixture was filtered and the filter residue was air dried after washing with water. The dried material was dissolved in chloroform, the organic solution was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, a thick suspension is obtained which, after recrystallization from a mixture of chloroform and ethanol, yields 120 g. (74%) of pure 2,3,6-trichloroquinoxaline, m.p. 139-142 ° C.

Mass spectrum:

m / e = 232 (P), 234. (P + 2), 230 (P + 4).

c) Preparation of 2,6> dichlQr ^{3'-in.ethOxyehi,} quinoxaline

A suspension of 11.7 g (0.05 mol): 2.3 _in 6-tuichloroquinoxaline in 140 ml of methanol is heated to 50 ° C and a solution of 1.4 g (0.06 mol) is added dropwise over 6 hours. of sodium dissolved in 140 ml of methanol. The resulting mixture was heated at 50 ° C overnight (ca. 16 hours), then an additional 140 mg of sodium in 20 mL of methanol was added over 1 hour, and the reaction mixture was heated at 50 ° C for 2 hours. The organic phase is separated and stored, and the aqueous phase is further extracted with chloroform, the chloroform extracts are combined and washed successively with fresh water and saturated sodium chloride solution, dried over anhydrous water. MgSO4, the drying agent was filtered off and the solvent was evaporated under reduced pressure and the residue was chromatographed on a 250 ml silica gel column using toluene as the eluent to give the desired product fractions, 9.8 g (86%). white solid product consisting of pure 2,6-dichloro-3-methoxyquinoxaline, m.p. 92-95 ° C.

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

A mixture of 4.9 (0.02 mol) 2,6-dichloro-3-methoxyquinoxaline and 2.7 g (0.053 mol) hydrazine hydrate (2.6 ml) in 75 ml ethanol was stirred overnight at room temperature (i.e. about 16 hours at about 20 ° C), the resulting mixture was filtered and the precipitate was washed with ethanol to give 4.4 g (98%) of pure.

6-Coior-2-hydrazine-3-methoxy-quinoxaline melting at 175-179 ° C with decomposition.

Mass spectrum:

m / e = 224 (P), 226 (P 1 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 6-621or-r-hydrazino-3-methoxyquizoxalin and 20 ml of triethyl ortho-formate was heated to 100 DEG C. in a preheated oil bath overnight with a mechanical stirrer (ca. 16 hours). The resulting mixture was cooled to room temperature, the precipitate formed was filtered off with suction and washed with ethanol. 1.0 g (69%) of pure 7-chloro-4-methoxy [1,2,4] triazolo [4,3-a] quinoxaline was obtained. mp 250-252 ° C.

f) Preparation of 7-chloro-4-hydroxy- [1,4,4] 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 hydrochloric acid and 105 ml of glacial acetic acid was added for 2.5 hours. heated to reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice-water. The resulting mixture was stirred for 20 minutes, then filtered, the isolated solid product was washed with water and air dried to constant weight. 2.6 g (87%) of pure 7-chloro-4-hydroxy- [1,2,4] triazolo [4,3-a] cinoxaline melting above 300 ° C is obtained.

g) Preparation of 4,7-dichloro-or- [1,4,4] triaro-10-ol

- [4,3-a] quinoxalm

To a flame-dried reaction flask was charged 2.6 g (0.012 mol) of l-chloro-α-hydroxy- [1,4,4] triazolo [4,3-a] cisoxalm and 40 ml of phosphorus oxychloride together under a dry nitrogen atmosphere. with 2.6 ml of tri-h-p-propyl amine. The reaction mixture was refluxed overnight (about 16 hours), then cooled to room temperature and poured slowly into ice water. The aqueous mixture was extracted with ethyl acetate, the extract was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the drying agent was filtered off and the solvent was evaporated under reduced pressure. A yellowish solid residue is obtained, which is subjected to chromatography on a column of 200 ml of silica gel using a 9: 1 mixture of chloroform and methanol as the eluent. Fractions containing the same product were combined and concentrated in vacuo to give an orange-colored solid residue consisting of 1.89 g (66%) of pure 4,7-dlchloro- [1,4,4] triazolo [4,3- α] 6hmoxaldehyde melting at 253 to 256 ° C with decomposition.

Mass spectrum:

m / e - 238 (P), 240 (P + 2)

242 (P-J-4).

Preparation of 1,2-triazolo [4,3-a] c2ihoxaline [1,2,4] triazolo [4,3-a]

a] Preparation of 7-chloro-1-ethyl-4-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline

A mixture consisting of 5.1 g (0.022 mol) of 6-6-chloro-r-hydrazi-3-methoxy-62-isoxaliz [product of preparation C (d]] and 60 ml of triethyl orthopropionate is heated with stirring overnight (ca. 16 hours). The mixture was cooled to room temperature (ca. 20 ° C) and the precipitate was filtered off with suction and washed with diethyl ether to give 4.3 g (75%) of pure 7-chloro-1. 221 DEG-223 DEG C .; ethyl 4-methoxy- [1,2,4] triazolo [4,3-a] chromnoxaline;

b] Preparation of 7-chloro-1-ethyl-4-2-hydroxy-

[1,2,4] triazolo] 4,3-a] 62inoxaline

A mixture consisting of 4.3 g (0.0072 mol) of 7-chloro-1-ethyl-4-2-hydroxy- [1,2,4] triazolo [4,3-a] quinoxaline, 40 ml of 1N hydrochloric acid and 60 ml of methanol is passed through The mixture was heated at reflux overnight and then cooled to room temperature. The precipitate formed is filtered off with suction and washed with methanol. 3.7 g (94%) of pure 7-chloro-1-ethyl-4-2-hydroxy- [1,4,4] -triolo [4,3-a] quinoxaline, melting above 300 ° C, are thus obtained.

c] Preparation of .alpha .- < 4 > -R < 4 > N-ethyl-1,2,4] triazolo. [4,3-a] quinoxaline

A flame-dried flask was charged with 5.1 g (0.02 mol) of 7-C21-l-ethyl-4-hydroxy- [1,4,4] triarolo [4,3-a] quinoxaline and a dry nitrogen atmosphere. ml of phosphorus oxychloride together with 5 .mu.l of tri-n-propylamine. The reaction mixture is refluxed overnight (about 16 hours), then cooled to room temperature and poured slowly into ice water. The resulting aqueous mixture was stirred at room temperature for 15 minutes, filtered, the solid product was washed with cold water and air-dried to dryness. constant weight. 4.2 g (79%) of pure 4,7-dichloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, melting at 217-220 ° C, decomposed.

Mass spectrum:

m / e = 266 (P), 268 (P + 2)

2'65- (P-1),

P - p a r a E.

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

a) Preparation of 2,3- (4-hydroxy-6-methoxy-6-ethoxyquinoline)

A mixture of 20 g [0.114 mol] of 4-methoxy-o-phenylenediamine and 11 g of [0.114 mol) of triothylamine- dissolved in 20 ml of diethyl oxalate overnight (about 16 hours); Heat to reflux. Upon completion of this heating, the reaction mixture was cooled to room temperature (20 ° C) and the desired product was filtered off. After washing with ethanol, 14.8 g (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline are obtained, m.p. above 300 ° C.

Mass spectrum:

m / e = 192 ' (P).

b) Preparation of 2-methyl-6-methyl-biphenyl-quinine-xalin

14.8 g (0.077 mol) -2.3, 3-dihydroxy- (- »- methoxyclainoxaline) and 75 ml of phosphorus oxychloride are added to the over-flame-dried reaction flask under a dry nitrogen atmosphere. 15 ml of tri-n-piopylammate were exothermic and the mixture was stirred at room temperature (20 ^° C) for 1 hour and then heated at reflux overnight (about 1 hour). After completion of the reaction, the reaction mixture was again cooled to room temperature and finally poured slowly into ice-water, and the resulting aqueous mixture was stirred at room temperature for 20 minutes, filtered and the precipitate collected. The precipitate is dissolved in chloroform, the solution is freed from insoluble matter by filtration, and the filtrate is washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. ethanol. 14.2 g (80%) of pure are obtained

M.p. 156-159 ° C; 2,3-dihloro-6-methoxyquinoxaline, m.p.

Mass spectrum:

mte = 228 (ip). 230 (₽ + 2), 232 (P + - 4).

c) - Preparation of 2-chloro-3,6-drmethoxy-quinoxaline

To a suspension of 77.1 g (S) of chloro-ε-methoxy-quinoxaline in 60 ml of methanol, submitted? in a flask-dried-over-flame reaction flask, a solution of 850 was slowly added over a period of 7 hours at 5-0 ° C under a dry nitrogen atmosphere; - mg. ' of sodium in 80 ml of methanol. The resulting mixture was heated to 50 ° C overnight and then cooled to room temperature, then concentrated in vacuo. The residue is dissolved in chloroform solution; Wash with water and dry over anhydrous magnesium sulphate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue is chromatographed on a column of 400 ml of silica gel using toluene as the eluent. The fractions containing the desired product were combined and concentrated in vacuo to give 6.1 g (88%) of _: 2-chloro-3% 6-methoxy-quinoxaline as a white solid, m.p. m.p. to 81 ° C.

Analysis calculated for C 10 H 15 ClN 2 OH ·:

% C, 4.04%;% N, 12.47%.

53-29% · C, 4.05-% H, - 12.28% N.

d) - Preparation of S-Di-Methoxy-2-Hydrazino-Chloro-oxal-1-ol.

Mixture 5- g; (0.022 mole-2-chloro-3,6-dimethoxyhine) 2.8-g (0.056 mole) hydrazine hydrate (2.7 ml) was heated to 50 ° C overnight in 75 ml of ethanol. Upon completion of this heating, an additional 1.0 mL of hydrazine hydrate was added, the mixture was heated at 50 ° C for 6 hours, then an additional 1.0 mL of hydrazine hydrate was added thereto. Heating at 50 ° C was continued overnight The reaction mixture was cooled to room temperature, filtered and the precipitate on the filter washed with ethanol to give 4.1 g (85%) of pure 3 & lt _; 16 > 1-dimethoxy-2H-hydrazinoquinoxaline melting at 128-130 ° C with decomposition.

e) Preparation of 4,7-dimethoxy- [1,2,4] triazolo [N-a] quinoxaline

A mixture of 1.5 g (0.068 mol) -3,6,6-di-ethoxy-2-hydrogenazoline-quinine-xaline. and 20 ml of triethyl orthoformate were heated in a preheated oil bath at -100 DEG C. with stirring with a mechanical stirrer overnight. The reaction mixture is cooled to room temperature, the precipitate formed is filtered off with suction and washed with ethanol. 1.8 g of pure 4,7-dimethoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

Mass spectrum:

m / e = 230 (P), 231 (P 4 - 1), 232 (P + 2).

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

A mixture of 1.6 g (0.0069 mol) of 4,7-dimethoxy- [1,2,4] triazolo [4,3-a] quinoxaline, 16 ml of 1N hydrochloric acid and 48 ml of glacial acetic acid is heated for 3 hours. After completion of the heating, the reaction mixture was poured onto ice and filtered, and the product collected on the filter was washed with diethyl ether to give 1.19 g (80%) of pure 4-hydroxy-7-methoxy- [1, m.p. 2,4] triazolo [4,3-a] quinoxaline, m.p. > 300 ° C.

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

A flame-dried reaction flask was charged with 1.1 g (0.0055 mol) of 4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline and 15 ml of oxychloride under a dry nitrogen atmosphere. phosphoric acid along with 1.0 ml of tri-n-propylamine. The reaction mixture was refluxed overnight (about 16 hours), then cooled to room temperature and finally poured into ice water. The aqueous mixture is extracted with ethyl acetate, the extract is washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, the drying agent is filtered off and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a 150 ml silica gel column using a 95: 5 (v / v) mixture of chloroform and methanol as eluent. Identical fractions containing the desired product were combined and concentrated in vacuo. The residue was recrystallized from chloroform / diethyl ether to give 400 mg (31%) of pure 4-chloro-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, melting at 266-268 ° C with decomposition. .

Mass spectrum:

m / e 234 (P), 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-hydrazinoquinoxaline [product of Preparation E (d)] and 50 ml of triethyl orthopropionate is heated in a preheated oil bath overnight with a mechanical stirrer (ca. 16 hours). at 100 ° C. The reaction mixture is cooled to room temperature (ca. 20 ° C), the precipitate formed is filtered off with suction and washed with ethanol. 3.3 g (72 percent) of pure 4,7-dimethoxy-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 184-188 ° C.

Mass spectrum:

m / e = 258 (P), 228 (P 30).

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

A mixture of 3.3 g (0.013 mol) of 4,7-dimethoxy-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, 33 ml of 1 N hydrochloric acid and 99 ml of glacial acetic acid with 2 heated to reflux for hours. After completion of this heating, the reaction mixture was cooled to room temperature and poured into ice water. The aqueous mixture was stirred for 20 minutes and then extracted with ethyl acetate. The extract was washed first with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Filtration of the drying agent and evaporation of the solvent under reduced pressure gave a yellowish solid which, after washing with water and air-drying to constant weight, yielded 1.87 g (67%) of pure 1-ethyl-4-hydroxy-7-methoxy- [ 1,2,4] triazolo [4,3-a] quinoxaline melting above 250 ° C.

c) Preparation of 4-chloro-1-ethyl-7-methoxy-

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

A flame-dried flask was charged with 1.87 g (0.0076 mol) of 1-ethyl-4-hydroxy-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline under a dry nitrogen atmosphere and 25 ml of phosphorus oxychloride together with 1.8 ml of tri-n-propylamine. The reaction mixture was heated at reflux overnight (ca. 16 hours), then cooled to room temperature and finally poured slowly into ice water. The aqueous mixture was stirred at room temperature for 30 minutes, filtered, and the solid product was washed with cold water and dissolved in chloroform. The organic solution was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was evaporated under reduced pressure to give a yellow solid which, after trituration with diethyl ether and filtration, gave 1.6 g (80%) of pure 4-chloro-1-ethyl-7-methoxy- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 173-175 ° C.

Mass spectrum:

m / e = 262 (P), 264 (P 4-2), 261 (P-1).

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-phenylenediamine [Journal of the American Chemical Society, Vol. 75, 1294 (1953)] and 150 ml of diethyl oxalate were refluxed under nitrogen for 18 hours. Upon completion of this heating, the reaction mixture was cooled to room temperature (ca. 20 ° C), filtered, the isolated product was washed successively with ethanol (4 x 100 ml) and air-dried. constant weight. 19.3 g (80 percent) of pure 2,3-dihydroxy-6-fluoroquinoxaline melting above 300 ° C are obtained (melting point 387 to 390 ° C in the literature - see U.S. Pat. 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 mol) of 2,3-dihydroxy-6-fluoroquinoxaline and 50 ml of phosphorus oxychloride is heated at reflux overnight (ca. 16 hours), then cooled to room temperature and poured into 200 ml with vigorous stirring. g of ice. The resulting aqueous mixture was filtered and the isolated product was washed several times with water. There were obtained 28.2 g of 2,3-dichloro-6-fluoroquinoxaline, m.p. 148-152 ° C.

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

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

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

A mixture of 10 g (0.047 mole) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml (0.47 mole) of triethyl orthoformate was heated in a preheated oil bath under nitrogen for overnight (about 16 hours). Mp 100 ° C. The resulting mixture was cooled to room temperature, the precipitate formed was filtered off with suction and, after washing three times with 50 ml of ethanol each time, air-dried to constant weight. 9.42 g (91%) of pure 4-chloro-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline, melting at 310-312 ° C, decomposed.

Mass spectrum:

m / e = 224,223,222 (P +).

Preparation Η

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

Mixture. 10.0 g (0.047 mol) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline [product of preparation G (c)] and 95 ml (0.47 mol) of triethyl orthopropionate are stirred overnight with a mechanical stirrer (approx. Heat in a preheated oil bath at 100 ° C. The resulting mixture is cooled to room temperature (ca. 20 ° C), the precipitate formed is filtered off with suction and, after washing three times with 50 ml of ethanol each time, air-dried to constant weight. 7.5 g (65%) of pure 4-chloro-1-ethyl-8-fluoro- [1,2,4] triazolo [4,3-a] quinoxaline melting at 160-163 ° C are obtained.

Mass spectrum:

m / e = 249,250,251,252 [P + J.

Preparation

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-hydrazinocino-quinoxaline and 50 ml (0.65 mol) of trifluoroacetic acid is stirred under a dry nitrogen atmosphere for 24 hours under mechanical stirring. · 120 ° C, which makes it a homogeneous solution. The reaction mixture was poured into ice-water with stirring, stirred for a further 30 minutes, then filtered. The product was washed successively with three portions of water and dried under vacuum at 80 ° C. 12.58 g (77%) of pure 8-fluoro-4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline are obtained, m.p. 298-302 ° C. .

Mass spectrum:

m / e = 272- (P < + >).

b) Preparation of 4-chloro-7-fluoro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline

In a 250 ml three-necked reaction flask, dried over a flame, 12.5 g (0.046 mol) of 8-fluoro-4- (4-fluorophenol) was charged under a dry nitrogen atmosphere. 5'-1'-4'-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline and 85 ml of phosphorus oxychloride · together with

17.5 ml of tri-n-propylamine. The reaction mixture is refluxed overnight (about 16 hours), then cooled to room temperature (about 20 cc) and slowly stirred with a mechanical stirrer.

Pour into 1,000 ml of ice-water. The resulting aqueous mixture was stirred for an additional 30 minutes at room temperature and then extracted three times with 300 ml of chloroform each. The combined chloroform layers were washed successively with saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated under reduced pressure. This gives a yellow solid, 10.47 g (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 138 [deg.] C.

Mass spectrum:

m / e = 292/290 (P < + >).

A nd J J

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

a) Preparation of 2,3-dihydroxy-6,7-difluoroquinoxaline

A mixture of 11.3 g (0.0784) of 4,5-difluoro-o-phenylenediamine (see U.S. Pat. No. 4,264,600) and 80 ml (0.589) mol) of diethyl oxalate is refluxed for 4 hours. condenser to form a thick product precipitate. The reaction mixture was allowed to cool to room temperature (20 ° C) overnight, filtered, and the solid product was air dried to constant weight after several washes with diethyl ether. 15.5 g of pure 2,3-dihydroxy-6,7-difluoroquinoxaline, melting above 310 ° C, are obtained.

Mass spectrum:

m / e = 198 (P < + >).

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

A mixture of 15.4 g (0.078 mol) of 2,3-dihydroxy-6,7-difluoroquinoxaline, 39 g (0.187 mol) of phosphorus pentachloride and 20 ml (0.22 mol) of phosphorus oxychloride is stirred and refluxed for 4 hours. 20 ml of phosphorus oxychloride are added thereto to facilitate the reaction (the reaction mixture becomes homogeneous within 30 minutes). After completion of the reaction, the reaction mixture was stirred at room temperature overnight (16 hours), whereupon a yellowish precipitate formed. The resulting mixture was poured into 200 g of ice water and stirred with further cooling. There was obtained 20.9 g of a reddish-brown solid of 2,3-dichloro-6,7-difluoroquinoxaline, m.p. 162 DEG-164 DEG C. (decomposition).

Mass spectrum:

m / e = 238/236/234 (P < + >).

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

A mixture of 10 g (0.0426 mol) of 2,3-dichloro-6,7-difluoroquinoxaline and 5 ml (0.03 mol) of hydrazine hydrate in 200 ml of ethanol was stirred at room temperature for 24 hours, leaving rust free of it. red precipitate. The resulting thick suspension is filtered and the isolated product is washed twice with 20 ml of ethanol each followed by drying to constant weight. 5.99 g (67%) of pure 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline are obtained, melting at 212-215 ° C with decomposition.

Mass spectrum:

m / e = 230 (P), 232 (P h).

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-hydriazinoquinoxaline and 30 ml (0.18 mole) of triethyl orthoformate was heated at 100 ° C for 24 hours to give a reddish brown solid. product. The resulting suspension was cooled to room temperature, filtered, and the isolated product was washed with diethyl ether. 5.15 g (82%) of pure 4-chloro-7,8-difluoro- [1,2,4] triazolo [4,3-a] quinoxaline, melting with decomposition above 210 ^DEG C., is obtained.

Mass spectrum:

m / e = 242/240 (P +).

Preparation К

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 [product of Preparation J (c)] and 60 ml (0.30 mol) of triethyb Orthopropionate is stirred with a mechanical stirrer Heat in a preheated oil bath at 100 ° C for 24 hours. The resulting mixture was cooled to room temperature (ca. 20 ^° C), the precipitated red precipitate was isolated by suction, washed twice with diethyl ether and air-dried to constant weight. 4.15 g (52%) of pure 4-chloro-6,7-difluoro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, melting with decomposition at 185 to 186 °, is obtained. C.

Preparation L

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

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

A mixture of 23.6 g (0.10 mol) of 2,3,6-trichloro-248,711 noxaline and 11 g (0.22 mol) of hydrazine hydrate in 500 ml of ethanol is stirred at room temperature (ca. 20 ° C) overnight (about 16 hours). ). The precipitate formed is filtered and washed with ethanol to give

22.2 g (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline melting at> 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 mol) of 2,6-dichloro-3-hydrazinoquinoxaline and 160 ml (0.87 mol) of triethyl orthoacetate is stirred under heating in a preheated oil bath at 100 [deg.] With a mechanical stirrer for 20 hours. C. The resulting yellow suspension was cooled to room temperature, filtered, and the isolated solid was washed with ethanol and air dried to constant weight. The yield is 10.2 g (46%) of pure · 4,8-dichloro-l-methyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 280 ^C C.

Mass spectrum:

m / e = 254/252 (P +).

Preparation M

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

a) Preparation of 8-chloro-hydroxy-4-oxo-0,1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline

In a 500 ml three-necked, flame-dried reaction flask equipped with a mechanical stirrer, nitrogen inlet and reflux condenser was charged 67 ml (0.77 mol) of trifluoroacetic acid, stirred and 20 g (0.087 mol) were added. 6-dichloro-3-hydrazinoquinoxaline [product of Preparation L (a)]. The reaction mixture was heated on a steam bath for 24 hours, then cooled to room temperature (ca. 20 ° C) and poured into 200 g ice water. The aqueous mixture thus obtained is stirred for 30 minutes, filtered, the isolated product is washed several times with water and air-dried to constant weight (which takes about 18 hours). 14.3 g (57%) of pure 8-chloro-4-hydroxy-O-trifluoromethyl- [1,2,4] triazolo [4,3-a] chmaxaline, melting at 253 to 255 ° C.

Mass spectrum:

m / e · = 290/288 (P @ +).

b) Preparation of 4,8-dichloro-1-trifluoromethyl-

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

To a 250 ml three-necked reaction flask, dried over a flame and equipped with a mechanical stirrer, dropping funnel and reflux condenser, was charged, under a nitrogen atmosphere, 14.3 g (0.05 mol) of 8-chloro-4-hydroxy-1-trifluoromethyl [1,2,4] triazolo [4,3-a] chmaxalm in 100 ml of phosphorus oxychloride. 19 ml (0.10 mol) of tri-n-proipylaimine was added dropwise over 5 minutes and the reaction mixture was heated under reflux for 20 hours, resulting in a clear, dark burgundy solution. After heating, the resulting clear solution was cooled to room temperature and poured into 1000 ml of ice-water with vigorous stirring with a mechanical stirrer. The aqueous mixture was stirred at room temperature for 30 minutes and then extracted three times with 500 ml of chloroform each. The organic extracts were combined, washed successively with water, saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Filtration of the drying agent and evaporation of the solvent under reduced pressure gave a yellow solid residue consisting of 11.4 g (75%) of pure 4,8-dichloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] chmoxaline, m.p. 133-135 ° C.

Mass spectrum:

m / e = 308 (P + 2), 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 a mechanical stirrer and a reflux condenser, 50.0 g (0.274 mol) of trimethyl crobenzocate were charged and preheated to about 70 ° C. Stirring is initiated and 10.0 g [0.0437 moles] of 2,6-dichloro (cr-3-hydrazinoquinoxaline [product of Preparation L (a) J] are added to the flask. 120 ° C, then cooled to room temperature (20 ° C) and stirred overnight (about 16 hours), the resulting yellow suspension was filtered, the isolated solid was washed twice with 50 ml of ethanol each time and air dried to constant weight. 9.8 g (72%) of crude 4,8-dichloro-1-phenyl- [1,2,4] triazolopropyl-1H-ajchrnoxaline, m.p.

Mass spectrum:

m / e · = 316/314 (P +).

Example 1

2-chloro-3-hydazazincchincxaИn

33.5 g (0.168 mol) of 2,3- 4-chloro (ncxaИ248711 nu) are mixed with 18.5 g (0.369 mol) of hydrazine hydrate in 500 ml of ethanol overnight at room temperature (i.e. about 16 hours at a temperature of ca. The resulting thick yellow suspension was filtered and the precipitate was washed with ethanol, and the precipitated material was recrystallized from hot methanol to give 13.5 g (41%) of 2-chloro-3-hydrazinoquinoxaline melting at 181 ° C with decomposition.

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

Example 2

4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline

9.0 g (0.046 mol) of 2-chloro-3-hydrazinoquinoxaline (the product of Example 1) was stirred with 100 ml of triethyl orthoformate for 1 hour at 100 ° C. The mixture is cooled to room temperature, the precipitate formed is filtered off, washed with cyclohexane and dried. 8.8 g (94% yield) are obtained.

4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. with decomposition at 287 ° C.

Mass spectrum: m / e = 204 (P).

Example 3

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

15.5 g (0.080 mol) of 2-chloro-3-hydrazinoquinoxaline (the product of Example 1) were stirred together with triethyl orthoacetate at 100 ° C for 3 hours. The mixture was cooled to room temperature, the solid precipitate was filtered off, washed with ethanol and air dried. 11.4 g (yield 65%) are obtained.

4-chloro-1-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

4.5 g (0.023 mol) of 2-chloro-3-hydrazinoquinoxaline (the product of Example 1) was stirred at 100 ° C with 50 ml of triethyl orthopropionate for 1 hour. The reaction mixture was cooled to room temperature, the white precipitate was filtered off and washed with cyclohexane. 4.5 g (85% yield) of 4-chloro-1-ethyl- [1,2,4] triazolo] 4,3-a] quinoxaline are obtained, m.p. 158-160 ° C.

Mass spectrum:

m / e = 232 (P).

Example 5

4-chloro-1-n-propyl- [1,2,4] triazolo [4,3-a] quinoxaline

3.0 g (0.015 mol) of 2-chloro-3-hydrazinoquinoxaline (product of Example 1) was stirred at 100 ° C with 27 ml of triethyl orthobutyrate for 2 hours. The mixture was cooled to room temperature, the precipitate formed was filtered off and washed with cyclohexane. The crude solid was taken up in chloroform and the solution was filtered to remove insoluble material. The chloroform solution is concentrated in vacuo to give a solid which, after recrystallization from chloroform, yields 1.96 g (53% yield) of 4-chloro-1'-propyl- [1,2,4] triazolo [4,3] 173 DEG-175 DEG.

Mass spectrum:

m / e = 246 (P).

Example 6

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

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

Mass spectrum:

m / e = 246 (P).

Example 7

4-methylamino- [1,2,4] triazolo [4,3-a] quinoxaline

2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-aquininoxaline (product of Example 2) in 30 ml of Ν, Ν-dimethylformamide are saturated with gaseous monomethylamine, the solution is stirred for 3 hours After stirring at room temperature, the monomethylamine gas was re-introduced and the resulting solution was stirred at room temperature for a further 2 hours. The precipitate formed is filtered off and washed with N, N-dimethylformamide. Recrystallization from Ν, Ν-dimethylformamide gave 1.37 g (69% yield) of 4-methylamino- [1,2,4] triazolo [4,3-a] quinoxaline, melting above 300 ° C.

Mass spectrum:

m / e = 199 (P).

Calcd for C10H9N5:

60.29% С, 4.55% Η, 35.15% Ν, found:

59.99% С, 4.47% Η, 35.11% Ν.

Example 8

4-dimethylamino- [1,2,4] triazolo [4,3-a] quinoxaline

A suspension of 2.0 g (0.01 mol) of 4-chloro- [1,2,41-triazolof4,3-a] quinoxaline (product of Example 2) in 30 ml of N, Nd, dimethylformamide is saturated with gaseous dimethylamine and stirred overnight at room temperature. room temperature. The reaction mixture is poured onto ice and the precipitate formed is filtered off. 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);

For C11H11N5, calculated:

% C, 61.96;% H, 5.20;% N, 32.84.

% C, 62.26;% H, 5.43;% N, 32.92.

Example 9

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

A suspension of 2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 2) in 30 ml of N, N-dimethylformamide was saturated with gaseous monoethylamine and was stirred for 2 hours. Stir at room temperature. The gaseous monoethylamine is then reintroduced into the mixture and stirring is continued for 2 hours. The precipitate formed is filtered off 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);

For C11H11N5, calculated:

% C, 61.96;% H, 5.20;% N, 32.84.

% C, 61.93;% H, 5.09;% N, 32.72.

Example 10

4-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline

4.4 g [0.021 mol] of 4-chloro- [1,2,4] triazolo [4,3-ajquininoxaline (product of Example 2) were stirred together with 6.5 ml (0.063 mol) of diethylamine in 100 ml for 2 hours Of N, N-dimethylformamide at room temperature. The reaction mixture was poured into ice water, the precipitated crude solid product was filtered off and washed with water. Recrystallization from isopropanol 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 / s 241 (P).

Example 11

4-di-n-pr-opylamino- [1,2,4] triazolo [4,3-a] quinoxaline

2.0 g (0.01 mol) of 4-chloro- [1,2,4] triazolo [4,3-ajinoxaline (product of Example 2) and 3.0 g (0.03 mol) of di-n-propylamine in 50 ml of N, N-dimethylformamide were stirred at room temperature for 3 hours and the reaction solution was poured onto ice. The precipitate formed is filtered off and air-dried. Recrystallization from 250 ml of cyclohexane 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: C10H19N5:

% H, 7.11;% N, 26.00. Found:

% C, 66.68;% H, 6.97;% N, 26.12.

Example 1 a d 12

4-isopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline

2.0 g [0.01 mol] of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 2) together with 1.77 g (0.03 mol) of isopropylamine in 30 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight, the resulting dark colored solution was poured onto ice, the precipitate formed was filtered off and washed with water. 2 g (53% yield) of 4-isopropylamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 133-135 ° C.

Mass spectrum:

m / e = 222 (P).

For C12H13N5.1 / 3 H2O calculated:

% C, 61.79;% H, 5.90;% N, 30.02;

36

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 according to the procedure of Example 11 using 4-chloro-1-methyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 3) as the starting material instead of '4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 2) adiethylamine as; of a reagent instead of di-n-propylamine. The resulting crude product was recrystallized first from chloroform and then from cyclohexane to give 7.2 g (54 percent yield) of pure 4-diethylamino-1-methyl- [1,2,4] triazolo [4,3- a] quinoxaline, m.p. 123-125 ° C.

Example 14

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

To a solution of 1.2 g (0.005 mol) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 4) in 20 ml of N, N-dimethylformamide was added at at 0 ° C for about 2 minutes reported ammonia gas. The resulting solution was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour, then poured onto ice and stirred for 20 minutes. The precipitate formed is filtered off, 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: for C 11 H 15 N 5. 1/6 HzO calculated:

% C, 61.10;% H, 5.28;% N, 32.39.

% H, 5.14;% N, 31.96.

Example 15

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

To a solution of 1.2 g (0.005 mol) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline [product of Example 4] in 50 ml of N, N-dimethylformamide was added at at 0 ° C for 2 minutes shows monomethylamine gas. The reaction mixture was stirred at 0 ° C for 30 minutes, then at room temperature for 2 hours, then poured onto ice and stirred for an additional 20 minutes. The precipitate formed is filtered off and air-dried after washing with water. 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).

Analysis: for C 18 H 13 N 5. 1/8 H2O calculated:

62.80 ·% · C, · 5.82% · H, 30.51% N, found:

% H, 5.86;% N, 30.62.

Example 1 a d 16

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

A mixture of 1.2 g (0.005 mole) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 4) and 676 mg (0.015 mole) of anhydrous dimethylamine was added. in 50 ml of N, N-dimethylformamide was stirred first at 0 ° C for 30 minutes and then at room temperature for 2 hours. The reaction mixture is poured onto ice, stirred for 20 minutes, the precipitate formed is filtered off and, after washing with water, air-dried. Recrystallization first from chloroform and then from chloroform / cyclohexane gave 510 mg (42% yield) of 4-dimethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 158 ° C.

Mass spectrum ·:

m / e = 241 (P).

Calcd for C13H15N5:

64.71% · C, 6.27% H, 29.02% · N, found:

% C, 64.69;% H, 6.27;

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

To a solution of 1.2 g (0.005 mol) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 4) in 50 ml of N, N-dimethylformamide The resulting clear solution is stirred for 30 minutes at 0 ° C and then for 2 hours at room temperature, and the reaction mixture is poured onto ice, the precipitate formed. filtered and washed with water and air-dried to give 1.0 g after recrystallization from ethanol.

243711 (yield 83%) · pure 1-ethyl-4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline in Torre white solid, m.p.

238 [deg.] C.

Mass spectrum:

m / e = 241 (P).

Analysis calculated for C 18 H 18 N 5:

% C, 64.71;% H, 6.27;% N, 29.02.

H, 6.20; N, 29.15.

Example 18

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

The title compound was prepared according to the procedure in Example 11, substituting 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 4) instead of 4- chloro- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 2) and diethylamine as reagent instead of di-n-propylamine The crude product obtained after recrystallization from cyclohexane gave 3.54 g (yield). 69%) of pure 4-diethylamino-1-ethyl [1,2,4] triazololo [4,3-a] quinoxaline as a white solid, m.p. 98-100 ° C.

Mass spectrum:

m / e = 269 (P).

Example 19

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

To a solution of 2.3 g (0.01 mol) of 4-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 4) in 30 ml of N, N-climethylformamide 1.77 g (0.03 mol) of isopropylamine are added. A precipitate formed from the reaction mixture within 30 minutes. The mixture was stirred at room temperature overnight, then 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. 222-224 ° C.

Mass spectrum:

m / e = 255 (P).

For C14H17N5, calculated:

% C, 65.86;% H, 6.71;% N, 27.43.

% C, 65.32;% H, 6.76;% N, 27.25.

Example 20

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

A suspension of 1.0 g (0.004 mol) of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaliline (product of Example 6) in 15 ml of N, N dimethylformamide was saturated with gaseous Noethylamine and stirred at room temperature for 4 hours. The precipitate formed is filtered off and washed with N, N-dimethylformamide. 220 mg (yield 22%) of 4-ethylamino-1-isopropyl-1- [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

Mass spectrum:

m / e = 255 (P).

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

For C14H17N5, calculated:

% C, 65.86;% H, 6.71;% N, 27.43.

H, 6.58; N, 27.29.

Example 21

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

A mixture of 1.0 g (0.004 mol) of 4-chloro-1-isopropyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 6) and 900 mg (0.012 mol) of diethylamine in 15 ml The N, N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture is poured onto ice, the precipitate formed is filtered off, washed with water and applied to a column of 175 ml of silica gel eluting with chloroform. 2,4,4] triazolo [4,3-a] quinoxaline as a white solid, m.p. 93-95 ° C.

Mass spectrum:

m / e = 283 (P).

Distillation of 100 mg of the pure product under a vacuum of 13 Pa at 140-150 ° C gave an analytical sample of the product, m.p. 94-96 ° C.

Analysis calculated for: C18H20N5:

% H, 7.47;% N, 24.71.

% C, 67.56;% H, 7.20;

Example. 22nd

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

A mixture of 1.23 g (0.005 mol) of 4-chloro-1-n-propyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 5). and 1.1 g (0.015 mol) of diethylamine in 15 ml of N, N-dimethylformamide were stirred at room temperature for 2 hours. The reaction mixture is poured onto ice, the precipitate is filtered off and, after washing with water, air-dried. After recrystallization twice from ethanol. and water to give 1.1 g (78% 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 calculated for: C16H21N5.1 / 8 H2O:

% C, 67.28;% H, 7.50;% N, 24.52.

67.38% C, 7.45 ° / o H, 24.73% N.

Example 23

8-chloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

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

1.0 g (0.0044 mol) of 2,6-dichloro-3-hydrazinoquinoxaline (the product of Preparation L (a) [was heated to reflux with 15 ml of triethyl orthopropionate for 4 hours, after which time the reaction mixture was cooled. The precipitate formed is filtered and washed with cyclohexane and air dried to give 730 mg (yield (62%)) of 4,8-dichloro-1-ethyl- [1,2,4] triazolo [4]. 3-a] quinoxaline melting above 250 ° C.

Mass spectrum:

m / e = 266 (P), 268 (P + 2).

b) Preparation of 8-chloro-4-diethylamino-1-ethyl-

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

A mixture of 7.4 g (0.028 mol) of 4,8-d-chloro-1-ethyl- [1,2,4] triazoio [4,3-a] quinoxaine and 6 grams (0.082 mol) of diethylamine in 140 ml

The Ν, Ν-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture is filtered, the filtrate is poured onto ice, the precipitate formed is filtered off and taken up. with chloroform. The chloroform phase was dried over anhydrous magnesium sulfate and, after filtration, evaporated in vacuo. Recrystallized from diethyl ether / petroleum ether to give 1.6 g of pure 8-chloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] of quinoxaline melting at 105-108 ° C with decomposition.

Mass spectrum:

m / e = 303 (P), 305 (P + 2).

For C 18 H 18 ClN 5 calculated:

% C, 59.30;% H, 5.97;% N, 23.05.

% C, 58.92;% H, 5.85;% N, 22.81.

Example 24 d, 8-dichloro-4-diethoiamine-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

a) Preparation of 2,6,6-trichloro-3-hydrazinoquinoxaline

4.4. g (0.016 mol) of 2,3,6,7-tetrachloroquinoxaline and 1.76 g (0.035 mol) of hydrazine hydrate in ethanol (60 ml) were stirred at room temperature overnight. The resulting thick suspension is filtered and the residue retained on the filter is washed with ethanol. It is obtained

4.9 g of crude · 2,6,7-trichloro-3-hydrazinoquinoxaline melting above 260 ° C.

Mass spectrum:

m / e = 262 (P 1, 264 '(P 1 + 2)).

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

4.9 g (0.018 mol) of 2,6,7-trichloro-3-hydrazinoquinoxaline in 50 ml of triethyl orthopropionate were heated at 100 ° C for 2 hours. The resulting precipitate was filtered off at room temperature and washed with cyclohexane. Recrystallization twice from chloroform-cyclohexane gave 2.9 g (54%) of pure 1,7,8-trichloro-1-ethyl- [1,2,4] triazolo) 4,3-a] quinoxaline as pink solid, m.p. 198 DEG-201 DEG.

Mass spectrum:

m / e = 300 (P), 302 (P + 2), 304 (P + 4).

306 (P + 6).

c) Preparation of 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline

2.9 g (0.0096 mol) of 4,7,8-γϊο1ι1-γ-1-β-1- [1,2,4] triazolo [4,3-a] quinoxaline and 2.1 g (0 Diethylamine in 50 ml of N, N248711

42

-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture is poured onto ice, stirred for 15 minutes, the precipitate formed is filtered off and, after washing with water, air-dried. Recrystallization three times from isopropanol gave 500 mg (16% yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl- [1,2,41 triazolo [4,3-a] quinoxaline, m.p. Mp 149 ° C.

Mass spectrum:

m / e = 337 (P), 339 (P + 2).

Calcd for C15H17Cl2N5:

% C, 53.26;% H, 5.07;% N, 20.70;

% H, 5.13;% N, 20.75.

Example 25

4-Diethylamino-1-ethyl-8-methoxy-

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

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

4.2 g [0.018 mol] of 2,3-dichloro-6-methoxyquinoxaline [product of Preparation E (B)] and

2.7 ml of hydrazine hydrate was refluxed in 100 ml of ethanol for 4 hours and then stirred at room temperature overnight. The precipitate was filtered off and washed with ethanol to give 3.9 g (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline melting above 250 ° C.

Mass spectrum:

m / e = 224 (P), 226 ([beta] - [-2]).

b) Preparation of 4-chloro-1-e'h-iyl'-8-methioxy- [1,2,4] triazolo [4,3-a] quinoxaline

1.3 g (0.0058 mol) of 2-chloro-3-hydrazino-6-methoxyquinoline and 25 ml of triethyl orthopropionate were first heated to 100 ° C for 4 hours and then stirred at room temperature for 60 hours. The precipitate formed is filtered off and washed with ethanol. Recrystallization from ethanol gave 530 mg (35% yield) of pure 4-chloro-1-ethyl-8-methoxy-

[1,2,4] triazolo [4,3-a] quinoxaline melting at 196-198 ° C.

Mass spectrum:

m / e = 262 (P), 264 (P + 2).

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

520 mg of 4-chloro-1-ethyl-8-methoxy- [1,2,4] triazolof 4,3-a] quinoxaline (0.002 mol) and

673 mg (0.008 mol) of diethylamine were stirred at room temperature overnight in 10 ml of N, N-dimethylformamide. The reaction mixture is poured onto ice, the precipitate formed is filtered off and, after washing with water, air-dried. Recrystallization from 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. 138 [deg.] C.

Mass spectrum:

m / e = 299 (P).

Analysis: for C16H21N5O. 1/8 H2O calculated:

% C, 63.71;% H, 7.10;% N, 23.22.

% C, 63.63;% H, 6.88;% N, 23.37.

Example 26

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

a) Preparation of 4-chloro-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline

2.2 g (0.011 mol) of 2-chloro-3-hydrazinoquinoxaline are treated with 6 ml of triethyl orthobenzoate and the mixture is heated at 100 ° C for 30 minutes. After cooling the orange-colored reaction mixture to room temperature, ethanol was added and the precipitate formed was filtered off. 2.1 g of crude product are obtained, which is further purified by trituration with warm methanol. After filtration and air-drying, 1.58 g (51%) of pure 4-chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline was obtained as an orange solid.

b) Preparation of 4-diethylamino-1-phenyl-

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

To a solution of 1.58 g (0.00563 mol) of 4-chloro-1-phenyl- [1,2,4] triazolo [4,3-a] quinoxaline in 15 ml of Ν, Ν-dimethylformamide was added 1.738 ml of diethylamine. . The mixture is stirred at room temperature overnight, the precipitate formed is filtered off and, after washing with N, N-dimethylformamide, it is recrystallized twice from a mixture of hexane and ethyl acetate (3: 1 by volume). 555 mg of pure 4-diethylamino-1-phenyl [1,2,4] triazolo [4,3-] quinoxaline are obtained in the form of white needle crystals, m.p. 166-168 ° C.

For C19H19N5, calculated:

% C, 71.60;% H, 5.99;% N, 22.06.

% C, 71.86;% H, 5.86;% N, 22.09.

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

Example 27

a) Preparation of 4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline

To 15.4 ml of cold trifluoroacetic acid (22.8 g, 0.20 mole), presented in a flame-dried reaction flask and immersed in an ice bath, under a dry nitrogen atmosphere, add 3.89 g (0). 0.02 mol) of 2-chloro-3-hydrazinoquinoxaline (product of Example 1). The reaction mixture is heated at 100 ° C for 3 hours, then poured onto ice, the product is filtered off with suction and, after washing with water, air-dried to constant weight. 3.0 g (60%) of pure 4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo] 4,3-a] quinoxaline, m.p.

Mass spectrum: m / e = 254 (P).

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

To a flame-dried reaction flask was charged with 3.0 g (0.0118 mol) of 4-hydroxy-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline and a dry nitrogen atmosphere. ml of phosphorus oxychloride in

2.38 g (0.0236 mol) of triethylamine (3.3 ml). The reaction mixture is heated at 100 ° C for about 16 hours (ie overnight), then cooled to room temperature, concentrated in vacuo, shaken with ice, water and ethanol and extracted with ethyl acetate. The ethyl acetate extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and evaporation of the solvent under reduced pressure gave a residue which was dissolved in hot chloroform. The solution was filtered, the filtrate was allowed to stand overnight at room temperature and filtered again. The last filtrate was concentrated in vacuo to give 1.4 g of 4-chloro-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline as a brownish solid.

Preparation of 4-diethylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-quinoxaline]

A mixture of 700 mg (0.0025 mol) of 4 - [(1 H) <1 H] -1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline (prepared as described above) and 560 mg ( 0.0075 mol) of diethylamine (0.8 ml) in 10 ml was stirred overnight, then poured onto a filter, washed with water and dissolved in ethyl acetate.

The organic solution was washed with saturated sodium chloride solution and dried without N, N-dimethylformamide at room temperature and ice. The resulting mixture was a solid product with anhydrous magnesium sulfate. Removal of the desiccant by filtration and solvent evaporation under reduced pressure gave a yellowish solid which, after recrystallization from diethyl ether, gave pure 4-diethylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline . The first crop yielded 260 mg (34%) of the product with a melting point of 155-157 ° C; the second crop yielded 170 mg (22%) of the product with a melting point of 153-156 ° C.

For C14H14F3N5, calculated:

% C, 54.37;% H, 4.56;% N, 22.64.

% 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-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 27b) and 443 mg (0.0075 mol) of isopropylamine (0.64 ml) in 10 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight and then poured onto ice. The resulting mixture was filtered, the isolated solid was washed with water and dissolved in diethyl ether. The ethereal solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, the drying agent was filtered off and the solvent was evaporated under reduced pressure. A white powder product was obtained which, after recrystallization from diethyl ether, gave 550 mg (74%) of pure 4-isopropylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 187 ° C.

Calcd for C13H12F3N5:

% C, 52.88;% H, 4.10;% N, 23.72.

% 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 mol) of 1-ethyl-4-ethylamino- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 17) and 2.5 g (0.025 mol) of acetic anhydride ( 2.5 ml), presented in a flame-dried reaction flask, was heated to reflux (140 ° C) for 3 hours under a dry nitrogen atmosphere and then allowed to cool to room temperature, avoiding precipitation of 24871 at. The mixture was poured into water and extracted with chloroform. The chloroform extracts were combined and, after washing with water, dried over anhydrous magnesium sulfate. 57%) 1-ethyl-4- (N-ethylacetylamino) - [1,2,4] triazolo (4,3-a) quinoxaline, m.p. 185-187 ° C.

Analysis calculated for: C15H17N5O:

% C, 63.59;% H, 6.05;% N, 24.72.

% C, 63.17;% H, 6.05;% N, 24.39.

Example 30

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

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

For C13H13N5O, calculated:

% C, 61.16;% H, 5.13;% N, 27.43.

% C, 60.90;% H, 5.26;% N, 27.66.

Example 31

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

A mixture of 5.5 g (0.0258 mol) of 4-amino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 14) and 25 g (0.25 mol) of of acetic anhydride (25 ml) in 60 ml of pyridine containing 100 mg of p-dimethylaminopyridine is stirred at room temperature overnight (ca. 18 hours). The resulting suspension was filtered to remove insoluble material by filtration and the orange-red filtrate was evaporated under high vacuum to a dark resinous residue. Upon addition of water, white, pinkish crystals are obtained, which are suctioned off and, after washing with plenty of water, are dried under vacuum at 50 ° C. 2.9 g (38%) of 4-di-acetylamino-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 157 DEG-159 DEG C., are obtained, which, after recrystallization, are obtained. ethyl acetate and diethyl ether gave an analytically pure sample, mp 158-160 ⁰ C. In addition to elemental analysis, this pure product is further characterized by mass spectroscopy and NMR spectroscopy.

Mass spectrum: m / e = 297 (P).

Analysis: Calculated for C15M15N5O2 ^1:

% C, 60.59;% H, 5.09;% N, 23.56.

% H, 5.09;% N, 23.41.

Example 32

Using the procedures described in the above Preparations and Examples, the following [1,2,4] triazolo [4,3-a] quincxalia-4-amine derivatives were prepared from readily available starting materials:

d] -benzamino [1,2,4] triazolo (4,3-a) quinoxaline, m.p. 199 DEG-201 DEG C.,

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

223 DEG-225 DEG C. 4-ethylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 234 DEG-237 DEG C., [.alpha.] - [1,2,4] triazolo [4,3-a] quinoxaline, m.p.

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

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

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

8-chloro-4- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 253-256 ° C;

8-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;

4-Amino-7,8-dichloro-1-ethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline, melting above 260 ° C,

4-Amino-1 - [(1 R)] - (1 R) - (1-ethyl-) -

- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 248-253 ° C,

4-iacetylamino-7, [eta] &lt; 1 &gt; -1,3-di-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-

- [1,2,41 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] quinoxaline, m.p. 208-211 ° C,

4-Diethylamino-8-fluoro-

- [1,2,4. ] triazolo · (4,3-a) quinoxaline, m.p. 151-153 ° C,

4-Diethylamino-1-ethyl-8-fluoro-

- [1,2,4] triazolo · [4,3-a] quinoxaline, m.p. 94-97 ° C,

7-Coior-d-dimethammino-e-ethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate (mesylate), m.p. 214-217 ° C,

7-chloro-1-diethyl-amino-ol-ethyl-[1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 172-175 ^c ,

7,8-dicelor-O-ethyl-1- (N-piperazino) - [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 252-255 ° C;

7.8-Dichloro-r-dimethyylamino-O-ethyl-

- [1,2,4] triazolo · [4,3-a] quinoxaline, m.p. 168-171 ° C,

7.8- diohror-4- · dimethdlamino-e-e-yl-

- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 216-219 ° C, n-acetylamino-1-ethyl-8-fluoro-

- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 203-205 ° C, n-amino-7-chloro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 240-243 ° C,

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

7-Cellular-r-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline ethanesulfonate, m.p. 205-207% r-diethylamino-7,8-difluoro- [1,2] 4] triazolo [4,3-a] cemoxaline methanesulfonate, m.p. 220-223 ° C; r-acetylamino-7-chloro-1-ethyl- [1,2,4] triazolo [4,3- a] quinoxalm-methanesulfonate, m.p. 210-212 ° C;

8-Celo-1,1-ethyl-1-ethylamino- [1,2,4] trlazolo [4,3-a] ceinoxaline methanesulfonate, m.p. 235-238 ° C, r-amino-7-cellular- [1] 2,4,4] triazolo [4,3-a] 7-quinoxaline methanesulonate, m.p. 279-282 ° C; r-amino-8-chloro-1-methyl- [1,2,4] triazolo [4,3-a] -a] 7-quinoxaline methanesulfonate, m.p. 213-215 ° C,

8-chloro-4-sopropylamino-1-trifluoromethyl- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 183-185 ° C;

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

4-diacety lamino- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 211-214 cc, r-dia7ethylamino-8-7-chloro- [1,2,4] triazolo [1,3-] a] ceinoxaline, melting point

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,

8-chloro-1-ethyl-4-trimethylacetylamino-

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

7,8-Difluoro-1-ethyl-4-isopropylamino-

- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 151-152 ° C,

4-n-butyrylamino-8-chloro-1-ethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 185-187 ° C,

8-chloro-4-diethylamino-1-trifluoromethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline hydrate, m.p. 135-136 ^° C,

4-Amino-8-chloro-1-trifluoromethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 259-261 ° C,

4-ethylamino-8-fluoro-1-trifluoromethyl-

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

8-fluoro-4-isopropylamino-1-trifluoromethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline methane-sulfonate, m.p. 180-183 ° C,

8-fluoro-4-isopropylamino-1-trifluoromethyl-

- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate, m.p. 185-188 ° C,

4-diethylamino-7,8-difluoro-1-ethyl- [1,2,4] triazolo [4,3-a] quinoxaline, m.p. 109-11 ° C; 1-ethyl-4-ethylamino-7- Fluorotriazolo [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 ° C;

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

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,

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 methane sulfonate, m.p. 178-181 ° C,

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

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

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

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

4-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 1.25 g (0.005 mol) of 4-amino-8-chloro-1-ethyl-1- [1,2,4] triazolo [4,3-a] quinoxaline (m.p. 248 to 253 ^Q C, the product described in of Example 32) and 15 ml of propionic anhydride with about. Heat at reflux for 16 hours, then cool to room temperature (ca. 20 ^° C), filter, and dissolve the isolated precipitate in chloroform. The organic solution was filtered, washed successively with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated under reduced pressure. The residue is chromatographed on 150 ml of silica gel using a 95: 5 by volume mixture of chloroform and methanol as eluent. The fractions containing the desired product were combined and concentrated in vacuo to give a crystalline material which, after recrystallization from chloroform-ethyl ether, gave 540 mg (36%) of pure 8-chloro-1-ethyl-4-propionylamino- [1]. M.p. 212-215 ° C, 2,4] triazolo [4,3-a] quinoxaline.

Analysis: for CuHidClN5O found:

% C, 54.91;% H, 4.59;% N, 22.76.

Example 34

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

556 g (2.7 mol) of 4-chloro- [1,2,4] triazolo [4,3-a] quinoxaline (product of Example 2), 830 ml (8.1 mol) of diethylamine and 3 liters of Ν, Ν- The dimethylformamide was stirred at room temperature (ca. 20 ° C) using a mechanical stirrer. The temperature of the reaction mixture gradually rose to 58 ° C and the mixture turned to a dark green solution, which was then stirred at room temperature for 4 days. The reaction mixture is poured onto. ice to precipitate the crude product. The precipitate is filtered off with suction and washed thoroughly with water. The crude product was dissolved in chloroform, the solution was filtered, the filtrate was concentrated in vacuo and the residue was applied to a 1.5 kg silica gel column which was then eluted with chloroform. Fractions containing the desired product are combined and rotary vacuum pump vacuumed. thicken. 310.2 g of pure 4-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline is obtained as an off-white solid. The product is; in all respects; identical to the product prepared in Example 10.

410.2 g (1.7 mol) of the above-prepared 4-diethylamino- [1,2,4] triazolo [4,3-a] quinoxaline are dissolved in 4100 ml of hot ethanol. The heating was discontinued and 192.2 g (2.0 mol) of methanesulfonic acid was added to the ethanol solution. The resulting mixture was stirred at room temperature overnight (ca. 16 hours). The precipitated product is filtered off, washed with fresh ethanol and air-dried to constant weight. 503 g of crude salt are obtained, which after recrystallization from 4000 ml of ethanol yields 412 g (49%) of pure 4-dimethylamino- [1,2,4] triazolo [4,3-a] quinoxaline methanesulfonate (mesylate). mp 211-214 ° C.

calculated:

% C, 55.36;% H, 4.64;% N, 23.06.

Claims (11)

A process for the preparation of [1,2,4] triazolo [4,3-a] quinoxalin-4-amine derivatives of the general formula I in which: А X X ¹ are independently selected from the group comprising hydrogen, fluorine, chlorine and bromine, and methoxy; R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 perfluoroalkyl group, or a phenyl group; and R 2 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 3 phenylalkyl, and C 2 -C 5 alkanoyl, provided that> ') X (I) when X and X ^{1 have} hydrogen atoms and R 1 represents a hydrogen atom or a methyl group, at least one of R 2 and R 3 is not a hydrogen atom, or R 2 and R 3 together form the piperazine ring, and their pharmaceutically acceptable acid addition salts, characterized in that the corresponding 4-chloro derivative of the general formula II rif T X (n) in which X, X ¹ and R 1 are as defined above, reacted with an amine of the formula ^T HNR2 R3 wherein R 2 and R 2 are as defined above except for the alkanoyl group, to give the corresponding 4-amino derivative, and the 4-amino derivative in which at least one of R 2 'and R 5' is hydrogen is optionally reacted with the corresponding alkanoic anhydride to give the desired compound of formula (I) containing an alkanoyl residue as defined above, optionally converting the resulting compound of formula (I) into a pharmaceutically acceptable acid addition salt thereof. 2. Method according to claim 1, characterized in that the reaction with the amine of formula HNRzR3 ^T carried out using an excess of amine of formula HNR2 R3 ^t 'in an inert organic solvent. 3. A process according to claim 2 wherein the inert organic solvent is dimethylformamide. 4. A method according to claim 2, characterized in that the reaction with the amine of formula R 3 ^t HNRz carried out at 0-60 ° C for a time ranging from 2-24 hours. 5. The process of claim 1 wherein the acylation of the 4-amino compound is carried out under anhydrous conditions using at least an equimolar amount of the anhydride of the corresponding alkanoic acid. 6. The process of claim 5, wherein the acid anhydride and the starting 4-amino derivative are used in a molar ratio of from 1: 1 to 25: 1. 7. The process of claim 1 wherein the acylation of the 4-amino compound is carried out at a temperature of from 20 to 140 [deg.] C. for a period of from 0.5 to 24 hours. 8. The process of claim 1 wherein the acylation of the 4-amino compound is carried out in the presence of a neutral inert anhydrous organic solvent. 9. The process of claim 8 wherein the neutral inert organic solvent is a halogenated hydrocarbon. 10. A process according to any one of Claims 1 to 9, wherein the corresponding starting materials are used to form compounds of formula (I) in which: А X X ¹ independently represent hydrogen, chlorine or methoxy, R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a trifluoromethyl group or a phenyl group; R2 and R3 independently are hydrogen, alkyl having 1 to 4 carbon atoms or acetyl group, demonstrating that when X а X ¹ are hydrogen and R is hydrogen or methyl then at least one of R2 and R 3 is not a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof. 11. The process of claim 10, wherein the corresponding starting materials are used to give 1-ethyl-4-ethylamino- [1,2,4] trlazolo [4,3-a] quinoxaline.