NO823132L - PROCEDURE FOR THE PREPARATION OF NEW POLYCYCLIC POLYAZAHETEROCYCLES. - Google Patents

Description

The invention relates to a process for the production of new polycyclic polyaza heterocycles and their acid addition salts with valuable pharmacological properties.

According to the invention, produce only new compounds corresponding to the general formula I

in which R-| and independently mean hydrogen, lower-

alkyl or hydroxyl lower alkyl, or together means lower-

alkyl or ethyleneoxyethylene, ethyleneazaethylene or N-lower-

alkyl- or N-(2-hydroxylower alkyl)-ethyleneazal lower ethylene,

R^ means hydrogen or a lower-'aliphatic or saturated lower cycloaliphatic hydrocarbon residue or unsubstituted or substituted vphenyl, R^ and R^ means hydrogen or lower alkyl, and Ar means an unsubstituted or substituted benzo- or pyri-

most A benzo or pyrido residue is understood to mean a divalent residue which, together with the two adjacent carbon atoms, forms a benzene or pyridine ring. Furthermore, the object of the invention is the preparation of the acid addition salts of the compounds of the general formula I, especially the pharmaceutically acceptable acid? . addition salts of compounds of the general formula I.

When nothing else is noted, it is understood in the

following and the following with lower residues such as contain a maximum of 7 and preferably a maximum of 4 carbon atoms. Due to the close relationship between the compounds of the general formula I in the form of free bases and in the form of acid addition ion salts,

in what follows, bases and their acid addition salts also possibly mean the corresponding acid addition salts resp.

free bases.

Lower alkyl R-j and/or Rg is e.g. ethyl, propyl, isopropyl, butyl or isobutyl, and above all methyl. In hydroxyl lower ealkyl R-| and/or R2, hydroxy is in a position higher than 1, correspondingly, such residues are e.g.

2- or 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl and above all 2-hydroxyethyl. As lower alkyl one, R-j and R2 together mean e.g. ethylene, trimethylene, hexamethylene and above

all tetramethylene or pentamethylene, or similarly branched, i.e. lower alkylated, especially methylated residues,

like for example. 1,4-dimethyltetramethylene or 3,3-dimethylpentamethylene. Lower alkyl in ethylene azaethylene is e.g. ethyl, propyl, isopropyl and above all methyl, and 2-hydroxy lower alkyl, e.g. 2-hydroxypropyl and above all 2-hydroxyethyl.

As lower aliphatic hydrocarbon residue, R-j is lower alkyl, lower alkenyl or lower alkynyl with a maximum of each 7

and preferably at most every k carbon atoms. As lower alkyl R 1 , e.g. methylethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, pentyl, isopentyl, neopentyl, 1-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, heptyl, iso-heptyl, 1-methylhexyl or 1-propylbutyl, such as lower alkenyl, especially those with 3 to k carbon atoms, e.g. allyl, 1-methylallyl, 2-methylallyl, 2-butenyl or 3-butenyl, and as lower alkynyl e.g. 2-propynyl or 2-butynyl. As a saturated lower cycloaliphatic hydrocarbon residue, R is in particular cycloalkyl, lower alkylcycloalkyl or cycloalkyllower alkyl each time with a maximum of 7 carbon atoms, such as e.g. cyclopentyl. cyclohexyl, cycloheptyl or 2- or 4--methyl cyclohexyl, resp. cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, or cyclohexylmethyl.

Substituted phenyl R^ is e.g. phenyl substituted one or more times by halogen, up to atomic number 35" lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano, and/or nitro.

In a pyrido residue Ar, the ring nitrogen atom can be in each of the four possible positions, in particular they are in

4-position and above all in 2-position to the ring carbon atom,

which is connected by it with substituted nitrogen atom of pyrazine ring. As pyrido residue, Ar is thus referred to the central pyrazine ring, especially pyrido/ 4->3-e7- and above all pyrido-^/ 2, 3-.e_7-residue. Substituents of the benzo or pyrido residue Ar are e.g. halogen up to atomic number 35, lower alkyl,-. lower alkoxy, lower alkylthio, trifluoromethyl, cyano or nitro.

As a substituent of phenyl and/or as a substituent Ar present halogen is fluorine, bromine, or above all

chlorine, lower alkyl, e.g. ethyl, propyl, isopropyl, butyl or tert.-butyl and especially methyl, lower alkoxy e.g. ethoxy, propoxy, isopropoxy, butoxy or isobutoxy, and especially methoxy, and lower alkylthio, e.g. ethylthio, propylthio, isopropylthio, butylthio, especially methylthio. Lower alkyl R^ is e.g. isopropyl or preferably primarily lower alkyl,

such as ethyl, propyl, isobutyl and above all methyl and lower alkyl, R₂ is preferably one of the aforementioned primary lower alkyls, above all methyl next to methyl R₂.

As acid addition salts of compound of formula

In particular, pharmaceutical acceptances are taken into account

only acid addition salts. Such can possibly be used as

the free compounds of the general formula I, as active substances for pharmaceutical preparations. As an example, mention should be made of addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandslic acid and embonic acid.

The compounds of the general formula I and their

.acid addition salts have valuable psychopharmacological properties. In particular, they seem antagonistic towards the wood

using reserpine induced hypothermia, e.g. by intra-peritoneal or peroral application in rats ]_ sml. Benz and Waser, Arzneimittelforsch, 21 (5) 654- (1 971 J_/ i dosis-

range from 10 to 100 mg/kg, and against the ptosis induced by tetrabenazine by intraperitoneal or peroral application in rats / sml. Rubin et al. J. Pharmacol. exptl. Ther. 120, 125 (195727 in the dose range from 3 to 100 mg/kg. For example, the ED^q of 4-, 5-dihydro-2-/(dimethylamino)-methyl7-5-phenyl-1, 2, 4.-triazol ,/ 1 , 5i-α7quinoxaline hydrochloride in the second mentioned sample 3-10 mg/kg per os, and 1 0 mg/

kg i.p.. In the social conflict test on rats, the compound with the general formula I as the above-mentioned shows an anxiolytic effect

ning after oral administration of doses from 1 mg/kg. In contrast to the negative inotropic and positive chronotropic effect of many known antidepressants such as imipramine, the compounds of the general formula I as those mentioned above in isolated guinea pigs show a weak positive inotropic and weak negative chronotropic effect. The toxicity of the compounds of the general formula I is low compared to the desired pharmacological effects. These properties characterize the compounds of the general formula I as antidepressant anxiolytics, which may find application in the treatment of depression.

The invention relates in particular to a compound of the general formula I in which R-j and R2 have the meaning given under formula I, R^ means a lower aliphatic or a saturated lower cycloaliphatic hydrocarbon residue or unsubstituted phenyl, or phenyl substituted with halogen up to atomic number 35t lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano or nitro, and Ar means an unsubstituted benzo- or pyrido]_ 2,3-_e7-residue or benzo- or pyrido/~~2,3-_e7~-residue substituted with substituents of the above-mentioned group, and R^ and R^ has the meaning given under formula I, as well as their acid addition salts, especially the pharmaceutically acceptable acid addition salts.

The invention relates in particular to compounds of the general formula I in which R-| means lower alkyl, R2 means lower hydrogen or lower alkyl, or R-j and R2 together mean lower alkylene, R^ means unsubstituted phenyl or phenyl substituted with halogen up to atomic number 35» or lower cycloalkyl and Ar means an unsubstituted or with halogen up to atomic number 35 substituted benzo- or pyrido / 2,3-e_7-

residue, and R^ and R^ have the meaning given under formula I,

and their acid addition salts, especially the pharmaceutically acceptable acid addition salts.

The invention relates above all to compounds of the general formula I in which R-j means lower alkyl, especially methyl, R£ means hydrogen or lower alkyl, especially methyl or R1 and R2 mean the lower alkyl, especially tetramethylene,

R^ means unsubstituted or with halogen up to atomic number 35» especially chlorine, substituted -phenyl and Ar means an unsubstituted or with halogen up to atomic number 35, especially chlorine, substituted benzo residue or pyrido/ 2,3-e_7rr est en, R^ has it under formula I meaning given, and R^ means hydrogen or methyl,

and their acid addition salts, especially the pharmaceutically acceptable acid addition salts.

The invention primarily relates to compounds of the general formula I in which R-j means methyl, R2 means hydrogen or methyl, R3 means phenyl, R^ means hydrogen or methyl R<- means methyl or above all hydrogen, and Ar means benzo- or pyrido/ 2, 3- ej- the residue, their acid addition salts especially the pharmaceutically acceptable acid addition salts.

The new compounds are produced in a manner known per se, as e.g.

a) a reactive ester of a compound of the general formula II

wherein Rj, R^, R^ and Ar have the meaning given under formula I, are reacted with a compound of the general formula

III

in which R-j and Rg have the meaning given under formula I, or is b) in a connection with the general formula IV

where n means 0 or 1 and X means oxygen, or if h

means one, can also mean. two hydrogen atoms, R^ has alone and together with R2 the meaning of R-|, or if n means 1, also

can mean lower alkoxy, and R2, R^>R,°g R^°g Ar has the meaning given under formula I, is reduced by means of a hydride-reducing agent the carbonyl group ( ene) resp. the optionally present lower alkoxycarbonyl groups, or

c) in a compound with the general formula I, in which R-j means hydrogen, and R-j, R2>R^iR^ and Ar has the meaning given under formula I, introduces a residue different from the hydrogen, R^at if the bonding carbon atom is also located at least one hydrogen atom, or

fd) in a compound of the general formula I, in which one or both of the symbols R-^ and R2 are hydrogen, and R^»R^>

R^j and Ar have the meaning given under formula I, one or two residues R^ and/or R2 different from hydrogen are introduced,

and if desired, a formed connection is transferred with the general one

formula I to an addition salt, an inorganic or organic acid, or from a formed acid addition salt the base is released,

and the latter is transferred, if desired, again in an acid addition salt.

For the reaction according to a), suitable as reactive esters of compounds with the - general formula II are, for example, esters of organic sulphonic acids such as lower alkanesulphonic acid esters or arenesulphonic acid esters, e.g. methanesulfonic acid esters, resp. benzenesulfonic acid or p-toluenesulfonic acid esters, or halides, especially bromides, chlorides or iodides. The reactions are carried out, for example, in an inert organic solvent at temperatures from* approx.

0°C to approx. 100°C, resp. the boiling point of the solvent used, if this is lower than 100°C, in the presence of an excess of the compound to be reacted, with the general formula III, or a tertiary organic or an inorganic base,

e.g. triethylamine, ethyldiisopropylamine or pyridine, resp.

an alkali metal carbonate or bicarbonate, such as potassium carbonate or sodium bicarbonate, as an acid scavenger.

The reduction of the compound with the general formula IV according to b) can, for example, be carried out using a lower alkylaluminum hydride, such as diisobutylaluminum hydride,

e.g. in an aromatic hydrocarbon, such as toluene, at temperatures between approx. -10°C and room temperature, or by means of lithium aluminum hydride or diborane in an ethereal solvent, such as diethyl ether or tetrahydrofuran, e.g. at temperatures between room temperature and approx. 55°C, resp. the solvent's boiling temperature if this is below 55°C

The introduction of a from hydrogen different wood

• the bonding carbon atom also contains at least one hydrogen atom and thus is neither aromatic nor over a quaternary carbon atom bonded residue R^ in a compound of the general formula I

in which Ro is hydrogen, according to c) takes place in particular by reacting one of the latter compounds with a reactive

ester of a secondary or preferably primary lower alkanol, lower alkenol or lower alkynol, or a cycloalkanol with 5 to 7 carbon atoms or a preferably primary cycloalkyl lower alkanol with 4 to 7 carbon atoms. If you use e.g. as correspondingly reactive ester halohydrogen acid ester, such as chlorides or especially bromides or iodides or esters with organic sulphonic acids, such as lower alkanesulphonic acid or arenesulphonic acid esters, e.g. methanesulfonic acid ester or benzenesulfonic acid or p-toluenesulfonic acid ester, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, allyl alcohol, 2-methylallyl alcohol, 2-propynol, cyclopentanol, cyclohexanol, cycloheptanol, cyclopropyl-, cyclobutyl cyclopentyl- or cyclohexylmethanol or 2-cyclopentylethanol. The reaction can take place in an inert organic solvent or diluent, for example at temperatures ■between approx. 0°C

and 100°C, especially between room temperature and approx. 80°C, resp. the solvent's boiling point ::when this is below 80°C in the presence of a basic condensing agent, e.g. an alkali metal, alkali metal amide or hydride or an alkali metal lower alkoxide, such as sodium or potassium methoxide, ethoxide or tert.-butoxide.

A primary residue R^ can e.g. wood is also introduced

a three-step reaction sequence in which the compound with the general formula I is acylated in the first place to corresponding compounds with the acyl residue of a lower alkanoic acid or cyclo-alkyl lower alkanoic acid with a maximum of 7 carbon atoms in the 5-position and reducing the latter compounds with the aid of a hydride reducing agent analogous to method b) .

The introduction of a resp. two hydrogen-different residues R-j and/or R£i a compound of the general formula I, in which at least one of the symbols R^ and R2 means hydrogen,

can, for example, take place by reacting a corresponding compound with the general formula I with the equimolar -- or possibly at least double molar amount of a reactive ester, e.g. echhalohydrogen ester, as a chloride

or especially bromide or iodide, or an ester with an organic sulphonic acid, e.g. a lower alkanesulphonic acid or arenesulphonic acid ester, as of methanesulphonic acid ester, resp. of benzenesulfonic acid or p-toluenesulfonic acid ester of a non-tertiary lower alkanol or a corresponding mono- or di-

ester of a lower alkanediol, e.g. a corresponding ester of methanol, ethanol, propanol, isopropanol, or butanol of

a corresponding monoester of 1,2-ethanediol or 1,2- or 1,3-propanediol, or a corresponding mono- or diester of 1,4-butanediol or 1,5-pentanediol, essentially analogous

to the reaction conditions specified for method a).

A further possibility for the introduction of the remains

R. and/or R. which is different from hydrogen in suitable compounds with the general formula I consists in the reaction of such compounds with oxolave alkanes such as e.g. formaldehyde, acetaldehyde, acetone, 2-butanone or 3-pentanone under reducing conditions, e.g. in the presence of formic acid at temperatures from approx. 60°C to approx. 100°C, or is in an inert organic solvent in the presence of hydrogen and a common hydrogenation catalyst, e.g. a noble metal catalyst, such as palladium charcoal or an alkaline earth metal carbonate or platinum oxide or of Raney nickel at room temperature or normal pressure under slightly elevated temperatures and pressures. When using aldehydes, especially formaldehyde, above all in the presence of formic acid, all hydrogen atoms present are replaced by lower alkyl, e.g. methyl, while by using ketones in the presence of hydrogen and hydrogenation catalysts a compound of the general formula I with secondary lower alkyl as R^ and hydrogen as Rg can also be obtained.

The compounds with the general formula II are likewise new substances. For the preparation of such compounds 'in which Ar means a benzo residue and R^ means hydrogen, while and

If R has the meanings given under formula I, one can e.g. start from in the amino group possibly corresponding to the definition for R^, and optionally in the benzene ring substituted o-nitro-alkylenes. In their amino groups, one is introduced in the first place

suitable protecting group, such as a lower alkoxycarbonyl group,

e.g. ethoxycarbonyl group by successive action of sodium hydride and chloroformate ethyl ester is in dimethylformamide, and in the product formed reduce the nitro group in the usual way, e.g. using hydrogen in the presence of Raney nickel to the amino group. The reduction product over-

is carried by dissolving in a hydrochloric acid-acetic acid mixture and adding sodium nitrite solution to the corresponding diazonium chloride, and the latter is connected by a (2-chlorolaverealcanamido)-malonic acid dilaverealkyl ester as diethyl esters to the corresponding azo compound, e.g. the corresponding £~ 2-(N-Alkoxycarbon<y>l-N-R^-amino)-phen<y>laz£7~(2-chlorolaVere-alkanamido)-malonic acid diethyl ester. When treating the latter with aqueous sodium hydroxide solution at room temperature and acidifying e.g. with hydrochloric acid cold, occurs during hydrolysis decarboxylation and subsequent condensation, the corresponding 1-/~2-(N-ethoxycarbonyl-N-R^-amino)-phenyl7~5-(1 - chlorolower alkyl)-1 H-1 , 2 , 4-triazole-3-carboxylic acid, which in turn by splitting off the ethoxycarbonyl group, e.g. by

help of conc. hydrobromic acid hot, e.g. at approx. 90°C is cyclized to the corresponding 4-R4-5-R3-4, 5-dihydro-/_ 1,2,47-triazolo/~1 , 5-a7quinoxaline-2-carboxylic acid". This can in the benzene ring, i.e. in a of positions 5, V, 8 or 9, contain substituents if it was assumed that a corresponding benzene ring substituted N-R^-2-nitroaniline. The carboxylic acid formed can finally be directly reduced or esterified,

e.g. transfer into the methyl ester by boiling with methanol and hydrochloric acid, using a hydride reducing agent, e.g. treatment with sodium borohydride or a mixture of methanol and tetrahydrofuran, to the corresponding 4--R^-5-R^-4, 5-dihydro-/1,2,47-»triazolo/1,5-a7quinoxaline-2-methanol with the general formula II. The latter can be transferred to it in the usual way. for reaction according to a) desired reactive esters, e.g. by reaction with methanol sulfonyl chloride in the presence of a suitable base, e.g. triethylamine, in an inert organic solvent to

the corresponding methanesulphonic acid ester is, or by reaction with phosphorus tribromide in an inert organic solvent to the corresponding bromide, i.e. the corresponding 2-(bromomethyl) compound.

Compound of the general formula II, wherein

Ar means a pyrido residue, can be prepared analogously, however such compounds are obtained in which Ar is a pyrido/2,3-_e7_residue, and which is neither substituted in the 7- nor in the 9-position with chlorine or bromine, most advantageously by the following reaction -sion consequence, assuming that 3-amino-2-chloro-pyridine is optionally substituted, however, not with chlorine or preferably bromine in the i- or 6-position. The aforementioned amino compound is transferred in the usual way into the corresponding diazonium chloride and the latter is coupled with a (2-chlorolaverealcanamido)-malonic acid dilaverealkyl ester such as diethyl ester or the dimethyl ester of the corresponding (2-chlorolaverealcanamido)-(2-chloro-3-pyr -dylazo)-malonic dilave alkyl ester is. This is transferred by subsequent treatment with ordinary alkanol sodium hydroxide solution at room temperature and with cold hydrochloric acid to the corresponding 1-(2-chloro-3-pyridyl)-5-(1-chloro-lower alkyl)-1H-1,2, 4-triazole-3-carboxylic acid. The latter is transferred by reaction with ammonia or a primary amine of formula R^-NJ^, optionally in the presence of a catalytic to double molar amount of an alkali metal iodide to the corresponding 4--R^-5-R^-4-, 5-dihydro -pyrido/ 2;:3-b7-/ 1 , 2,_4_7triazolo J_ 1 , 5-d7pyrazine-2-carboxylic acid and the latter is reduced analogously to the above reaction sequence, preferably after esterification to corresponding compounds with the general formula II, and this is transferred to a suitable reactive ester.

Compound of the general formula II, wherein

• as well as R^ which also R^ means lower alkyl, especially methyl, get

one, for example, by not immediately reducing an ester formed in the above-mentioned reaction sequence that is immediately preferred to the hydroxy compound with the general formula II,

e.g. methyl ester, wherein R^ is lower alkyl, especially methyl,

but first e.g. by means of lithium diisopropylamide over-

is introduced into a corresponding alkali metal compound, and reacts the latter with a lower alkyl halide such as methyl iodide, and only then reduces the ester group to the hydroxymethyl group.

Starting substance f is of the general formula IV in which

X-| means oxygen, and n is 0, because the reduction according to b) is also new. They can be prepared from the corresponding above-mentioned carboxylic acids or their functional derivatives,

e.g. the likewise already mentioned lower alkyl esters, or e.g. also the corresponding acid chlorides by reaction with amines of the general formula III in a manner known per se. Such starting substances of the general formula IV,

wherein and R^ each means lower alkyl, especially methyl, is preferably prepared from corresponding compounds with lower alkyl as R^ and hydrogen as R^ by introducing lower alkyl Rg analogously to the above-mentioned introduction of lower alkyl R^

in those of the amides* of the general formula IV corresponding esters. Compounds with the general formula IV in which X means two hydrogen atoms and n means one, are obtained from a compound with the general formula I in which R-j and optionally also R£ means hydrogen, by introducing a lower ealkanoyl - hydroxyl lower alkanoyl or lower alkoxycarbonyl residue, e.g. e.g. by reaction with a lower alkyl ester of the corresponding lower alkanoic acid of hydroxyl lower alkanoic acid, or with a lower alkanoyl chloride or chlorformic acid lower alkyl ester.

Depending on the choice of starting materials and working methods, the new compounds can exist in the form of one of the possible stereoisomers or as mixtures of these, e.g. depending on the number of asymmetry centers as pure optical isomers, i.e. optical antipodes or as racemates, or in the case of diastereo-isomerism also as racemate mixtures.

Formed racemate mixtures can, due to the physical-chemical differences of the components, be separated into the pure racemates in a known manner, for example by chromatography and/or

fractional crystallization.

Formed racemates can be separated into the optical antipodes by known methods, for example by recrystallization from an optically active solvent with the help of micro-organisms, or by reaction of an end product with the racemic base salt-forming optically active acid, and separation of the salts formed in this way, e.g

due to their different solubilities, in the diastereomers, of which the antipodes can be released by the action of

suitable means. The most effective one is preferably isolated

of the two antipodes.

Formed free compounds of formula I can be transferred -in a manner known per se, in acid addition ion salts, e.g. a.

by treatment with the corresponding acid, usually in the presence of a solvent or diluent.

Formed acid addition salts can be converted in a manner known per se into the free compounds, e.g. by treatment with a base such as an alkali metal hydroxide or a basic earth exchanger.

The compounds including their salts can also be obtained in the form of their hydrates, or contain the solvent used after crystallization.

The invention also relates to the embodiments

of the method according to which amn starts from a .-.at one or another step of the method as an intermediate product up-

connection reached, and completes the missing steps, or

as a starting material instead of a racemate, an optical antipode is used, and/or a starting material in the form of a salt, or in particular forms the starting material under the reaction conditions.

In the method according to the invention, starting materials are preferably used which belong to the compounds mentioned at the outset as particularly valuable. New starting materials and methods for their production are also covered by the invention.

The pharmaceutical preparations contain e.g.

from approx. 10% to approx. 95%, preferably from approx. 20% to approx. 90%

of at least one active substance produced according to the invention together with at least one pharmaceutical carrier or auxiliary substance. Pharmaceutical preparations are e.g. such dosage unit forms as dragees, tablets, capsules or suppositories, further ampoules. Per dose units, such preparations contain e.g.

10 to 500 mg, and preferably 25 to 250 mg of active substance.

The pharmaceutical preparations are prepared in a manner known per se, e.g. by usual mixing, granulation, coating, dissolution or lyophilization methods.

Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture,

and processes the mixture or the granulate if desired or necessary after adding a suitable excipient for tablets or dragon cores. Suitable carriers are especially fillers such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate are, e.g. tricalcium phosphate is or calcium hydrogen phosphate, further binders such as starch pastes, e.g. of corn, wheat, rice or potato starch, gelatins, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, and/or if desired explosives such as the above-mentioned starches, further carboxymethyl starch, - cross-linking a polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow control and lubricants,

e.g. silicic acid, talc, stearic acid or salts thereof,

such as magnesium or calcium stearate and/or polyethylene glycol. Kite cores are equipped with a suitable, possibly stomach-proof, cover, as one e.g. uses concentrated sugar solutions, which may contain gum arabic, talc,

.polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions in suitable organic solvents or in emulsifiers or mixtures, or for the production of gastric juice resistent e coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methylcellulose phthalate. For the tablets or kite covers

dyes or pigments can be added, e.g. for the identification or characterization of different effects

some drug doses.

Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Stick capsules can contain the active substance in the form of a granule, e.g. mixed with fillers,

such as lactose, binders such as starches, and/or slip-

agents, such as talc or magnesium stearate, and optionally stabilizers. The soft capsules are preferably the active substance dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil and others. are liquid polyethylene glycols, since stabilizers may also be added.

As rectally usable pharmaceutical preparations, there are e.g. considering suppositories, which consist of a combination of the active substance with a suppository base. Natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols are suitable as suppository base material. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active substance with a base mass; as base material there is e.g. namely liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, using suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate, or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran and possibly also stabilizers.

The invention likewise relates to the use of compounds of the general formula I and their pharmaceutically acceptable acid addition salts as medicine, especially as antidepressants or anxiolytics, preferably in the form of pharmaceutical preparations. The dosage depends on the type of warm blood, age and the individual condition of the person to be treated, as well as on the method of application. The per daily administered dose is between approx. 1 and approx. 100 mg/kg, and preferably e.g. on warm-blooded animals of approx. 70 kg body weight,

between approx. 3 and approx. 50 mg/kg.

The invention will be explained in more detail with the help of some examples.

Example 1

To the suspension of 5.00 g (0.018 mol) of 5-phenyl-4, 5-dihydro-/— 1 , 2,47-triazolo/ 1 , 5-α7-quinoxaline-2-methanol in 180 ml of abs. methyl chloride and 3.64 g (0.036 mol) triethyl

amine is added dropwise under nitrogen at -10°C to 3.10 g. (0.027 mol) of methanesulfonic acid chloride over the course of 5 minutes. After stirring for 1 hour at 0°C, 0.70 g of triethylamine and 0.60

g of methanesulfonic chloride, stirs for a further 30 minutes at 0°C, and evaporates the clear reaction solution in vacuo completely at 35°C, obtaining the methanesulfonic acid ester of 5-phenyl-4-,5-dihydro-/1,2,47~triazolo / 15-α7quinoxaline-2-methanols as colorless, crystalline residue (contains triethylamine hydrochloride). The methanesulfonic acid ester thus formed is further reacted at once without further purification by adding an ice-cold mixture of 15.0 ml (Q.11 mol) of 33 µg ethanolic dimethylamine solution and 15 ml of ethanol and stirring the reaction mixture closed for 1 hour. It is then evaporated in vacuo and the residue dissolved in ethyl acetate and 1N potassium bicarbonate solution. The aqueous phase is separated and extracted once or twice with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution, and dried over sodium sulfate. After the desiccant has been filtered off, the filtrate is mixed well

stirring dropwise with ethereal hydrogen chloride solution until the pH value 4 is reached. After three hours of stirring in an ice bath, the crude hydrochloride formed is filtered off and washed with ethyl acetate. It is then dissolved in 70 ml methylene chloride and 100 ml isopropanol. After evaporation of methylene chloride in a vacuum at 40°C, the desired hydrochloride crystallizes out again. Leave it for approx. 15 hours in an icebox, filter off the crystals, and wash it with isopropanol. After drying in high vacuum at 120°C, the formed 2-/"(dimethylamino )-methyl7^5-phenyl-4, 5-dihydrob-/-1 , 2,_47-triazolo/-1 , 5i-a_7-quinoxaline melts -hydro-clofid with formula

The necessary starting material 5-phenyl-4'5-dihydro-'/1,2,47-triazolo/1,5-a7quinoxaline-2-methanol is prepared as follows: a) To a suspension of 19'60 g (approx. 0.4-1 mol) of sodium hydride/mineral oil in 100 ml of dimethylformamide is added dropwise

at 10 - 15°C under nitrogen a solution of 79.40 g (0.371 mol) o-nitrodiphenylamine ]_ sml. F. Kehrmann and E. Havas, Ber,

46, 341 (1913/7) in 500 ml of dimethylformamide during one hour with good stirring. The reaction mixture is stirred for a further

three hours at room temperature and then add dropwise 45.0 ml (0.4-72 mol) chloroformic acid and ethyl ester at 20°C. After stirring for one hour at room temperature, the reaction mixture is cooled

.to 0°C, and slowly add 15 ml of glacial acetic acid, with the pH value at the end reaching 5. The reaction mixture is then poured onto an ice-water mixture and extracted three times with ethyl acetate. The extract is washed three times with water and twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated

to dryness in vacuo. The residue is stirred with 200 ml of hexane and 100 ml of water over the course of 3 hours. The crystallized crude product is filtered off and washed well with water and hexane. After recrystallization from isopropanol, you get: (2-nitrophenyl)-phenylcarbamic acid ethyl ester of m.p. 53~56°C.

b) A solution of 35.15 g (0.123 mol) (2-nitro-phenyl)-phenylcarbamic acid ethyl ester in 350 ml of ethanol is hydrogenated with the addition of 8.0 g of Raney nickel at normal

press for 25 hours at 15-20°C. One is to filter off the catalyst, evaporate the filtrate in vacuum at a maximum of 40°C and recrystallize the residue from methylene chloride/hexane. After drying in vacuum, the formed N-(2-aminophenyl)-phenylcarbamic acid ethyl ester melts at 87-90°C.

c) A solution of 34.00 g (0.133 mol) (2-amino-phenyl)-phenylcarbamic acid ethyl ester is in 31 g of glacial acetic acid and 80 ml

conc. hydrochloric acid is diazotized at 0-5°C with 27 ml' (0.133 mol) of a 5-molar sodium nitrite solution. The formed diazonium salt solution is mixed with 80 g of ice, and dropwise rapidly with a solution of 33.4-0 g (0.133 mol) (2-chloroacetamido)-malonic acid diethyl ester/ml. Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-1 10 )1 954-J.7t in 330 ml of acetone. 610 ml of a saturated potassium carbonate solution is then added dropwise at 0 - 5°C over the course of 30 minutes, with the pH value of the reaction mixture reaching 6 at the end. After adding 50 ml of ether, stirring for 90 minutes

in an ice bath, and then filter the already crystallized reaction product, the crystals are washed well with water and

some ether. After drying over calcium chloride in a desiccator, the formed ]_ 2-(N-ethoxycarbonyl-phenylaminep)-phenylaz£7-(2-chloroacetamido)-malonic acid diethyl ester melts at 102-

>104°C. To recover additional reaction product, the combined filtrates are extracted with 500 ml of ethyl acetate. The separated organic phase is separated, washed four times with water and once with saturated sodium chloride solution, dried over sodium sulfate

and evaporated in a vacuum. The residue is dissolved in 50 ml of ether,

and let it stand for crystallization for two days at room temperature. Then the formed crystals are filtered out and washed with a little ether and a lot of hexane. After drying, a quantity is obtained that surpasses directly produced from the same product and m.p. 102-104°C.

d) Add 84.8 ml (0.848 mol) of a 1N sodium hydroxide solution precooled to 0°C with good stirring

within 5 minutes a solution of 14-6.6 g (0.283 mol)

of the azof orbindel prepared according to c) se in 14-66 ml of methanol. It is stirred for 90 minutes at room temperature, and then 4-50 ml of 2N hydrochloric acid is added dropwise while cooling with a water mixture until the Congo acid reaction. The free carboxylic acid crystallizes out after inoculation and rubbing with a glass rod. The formed crystal slurry is stirred for three hours at 0°C, then suctioned off, washed with water to pH 5" and dried over calcium chloride in a vacuum at 80°C. The formed 1-]_ 2-(N-ethoxycarbonyl-phenyl-amino)-phenyl7-5~(chloromethyl)-1H-1,2,4-triazole-4-carboxylic acid sinters at 158°C and melts with decomposition at 167-170°C. e) A suspension of 53.80 g (0.134-mol) of the according

d) prepared carboxylic acids in 280 ml of 48% hydrogen bromide

acid is stirred for 22 hours at a bath temperature of 105°C below

nitrogen, -as a clear solution first occurs, and after two hours a crystalline precipitate gradually appears. The reaction mixture is then cooled to room temperature, and 300 ml of water is added while stirring. After three hours of cooling to 0°G, the carboxylic acid is sucked off, washed with a total of 800 ml of water to pH 5" and dried in vacuum, first over calcium chloride and then over phosphorus pentoxide. The 5-phenyl-4,5-dihydro-/1,2,_47~triazolo/1,5-a7quinoxaline-2-carboxylic acid formed melts during cleavage at 205-207°C.

f) A suspension of 74" 90 g (0.256 mol) of the according

e) prepared carboxylic acid in 1500 ml methanol and 300 ml 6N

methanolic hydrochloric acid solution is stirred under nitrogen for 17 hours

under reflux, since after 1 hour there is a clear

resolution. The reaction mixture is then stirred for 4 hours at 0°C, the formed crystals are filtered off with suction and washed with a total of 250 ml of methanol. After drying over calcium chloride and potassium hydroxide in vacuo, the formed 5-phenyl-4,5-dihydro-/1,2,/7-triazolo-]_1,5-a7quinoxaline-2-carboxylic acid methyl ester sintered at 140°C and melts at 1 50-1 54-°C.

g) A suspension of 87.0 g (0.285 mol) of the acc

f) prepared ester in 870 ml of methanol and 870 ml of tetrahydro-

furan, is mixed under stirring and nitrogen at room temperature during 15 minutes with a total of 30.0 g (0.795 mol) of sodium borohydride, divided into three portions. During strong foaming, the temperature of the reaction mixture thus rises* to 30°C, and is kept there by cooling with cold water. Man about-

stir for two hours at room temperature, and after adding 1750 ml of ice-water mixture for a further three hours at 0°C. The precipitated alcohol is sucked off and washed with water to pH 6. After drying over calcium chloride in vacuum, the formed 5-phenyl-4»5-dihydrob-/-1 , 2, 4;7-triazolo/ 1 melts , 5-α7quinoxaline-2-methanol at 180-185°C

Example 2

That of 8.70 g (0.0313 mol) of 5-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline-2-methanol and 5.92 g (0.051 mol) of methanesulfonic acid chloride crude methanesulfonic acid ester prepared according to example 1 is stirred after adding 24 ml (0.188 mol) of 33% in g ethanolic methylamine solution, and 24 ml of ethanol for one hour at room temperature. The reaction mixture is then evaporated in vacuo, and the residue is dissolved in ethyl acetate and 1N potassium bicarbonate solution. The aqueous phase is separated and extracted twice more with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to dryness.

The residue of 9.20 g is dissolved in methylene chloride-methanol. (9:1) and chromatograph the solution on a column of 900 g silica gel. Methylene chloride-methanol (9:1) is also used as an eluent. The fractions containing the desired crude product of Rf value 0.4 _/ System: methyl enchloride-methanol (9:1_)_/ are evaporated to dryness, dissolved in 30 ml of acetone, mixed with a solution of oxalic acid in acetone until there is reached the pH value of 6. The solution is left for approx. 15 hours at room temperature, the formed crystals are filtered off,

and wash it with acetone. After drying in high vacuum at 90°G, the formed 2-/ (methylamino)-methyl7-5-phenyl-4, 5-dihydro-_/_ 1, 2, 47~triazolo/ 1 , 5-a7c&inoxaline oxalate sinters at 190°C and melts at 210-213°C.

Example 3

A suspension of 22.50 g (0.66 mol) 2-(bromo-methyl)-5-phenyl-4,5-dihydro-/1,2,4-triazolo/1,5-α7quinoxaline in 225 ml of isopropanol and 45.30 ml (0.33 mol) of 33% ethanolic dimethylamine solution is stirred under nitrogen at room temperature for 2 hours. The mixture is then evaporated in a vacuum, and the residue is dissolved in ethyl acetate and 1N potassium bicarbonate solution.

The aqueous phase is separated and extracted twice more with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution and dried over sodium sulfate. The desiccant is filtered off and the filtrate is mixed with good stirring dropwise with ethereal chlorine-hydrogen solution until the pH value 4 is reached - After three hours of stirring in an ice bath, the crude hydrochloride formed is filtered off and washed with ethyl acetate. Recrystallization as discussed in Example 1 gives 2-N-(dimethylamine)-methyl-7-5-phenyl-4-5-dihydro-1,2,7-triazolo1,5-a7quinoxaline hydrochloride of m.p. . 232-235 during cleavage.

Analogously, from 10.0 g (0.029 mol) of the same bromomethyl compound with 10.70 g (0.146 mol) diethylamine, 2" J_ (diethylamino )-methyl7-5"phenyl^4, 5-dihydro-/ 1 , 2 ,_47-triazolo J_ 1 , 5-α7quinoxaline hydrochloride of m.p. 192-195°C (under decomposition) after crystallization from methylene chloride/ethyl acetate and with 12.4-0 g (0.14.6 mol) piperidine obtain 2-/~(piperidino)-methyl7-5-phenyl-4., 5 -dihydro -/~~ 1 , 2,.47-triazolo-/- 1, 5-α7quinoxaline hydrochloride of m.p. 240-25Q°C (under decomposition) after crystallization from methylene chloride/ethyl acetate.

The necessary starting material 2-(bromomethyl)-5-phenyl-4, 5-dihydro-[1,2,47-triazolo]1,5-a7quinoxaline is prepared as follows: a) In the suspension of 44.30 g (0.159 mol ) of the 5-phenyl-4, 5-dihydro-</>1,2,47-tria- prepared according to example 1 g). zolo/ 1, 5-α7quinoxaline-2"methanol in 660 ml abs. methylene chloride, 43.00 g (0.159 mol) phosphorus tribromide is added dropwise at 20°C under nitrogen over the course of 30 minutes, and stirred for 4 hours at room temperature. It then evaporates in vacuo at 40°C to dryness, and dissolve the residue in 1200 ml ethyl acetate and 200 ml ice-water mixture. The aqueous phase is separated and extracted once more with ethyl acetate. The combined organic extracts are washed 4 times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue is dissolved in 200 ml of methylene chloride and 500 ml of isopropanol. After evaporation of the methylene chloride in vacuum at 40°C, the desired compound crystallizes out. The crystal slurry is allowed to stand for approximately 15 hours in ice-box, filter off the crystals and wash them with isopropanol. After drying over casium chloride in a vacuum desiccator, the formed 2-(bromoethyl)-5-phenyl-.4,5-dihydro-/ 1,2,47-triazolo/ 1, 5-a7quinoxaline of 115°C and melts at 122-130°C.

Example 4

In the suspension of 1.20 g (0.0037 mol) of N,N-dimethyl-5-phenyl-4-, 5-dihydro-[~~ 1, 2, 47-triazolo/ 1 , 5-α7quinoxaline-2-carboxamide in 180 ml abs. toluene, 940 ml (0.011 mol) of a 1.2-molar solution of diisobutylaluminum hydride in toluene is added dropwise at 2°C under nitrogen over the course of 15 minutes. The clear yellow solution formed is stirred for a further 1 hour at 5°C, then 5 ml isopropanol is added dropwise to the reaction mixture and poured onto an ice-water mixture. The organic phase is separated, washed twice with ice water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The honey-like residue is dissolved in 20 ml of ethyl acetate, and, with good stirring, ethereal hydrochloric acid is slowly added dropwise until the pH value 4 is reached. After approx.

After 15 hours' rest in an ice cabinet, the raw hydro-

chloride and washed with ethyl acetate. Recrystallization as discussed in Example 1 gives 2-(dimethylamino)methyl7-5-phenyl-4.,5-dihydro-/1,2,4,7-triazolo/1,5-α7-quinoxaline hydrochloride of

sm.p. 232-235°C during decomposition.

The carboxamide required as starting material is prepared as follows: a) The mixture of 7.00 g (0.023 mol) of the 5-phenyl-4,5-dihydro-/1,2,47-triazolo/1 ,5-α7quinoxaline-2-carboxylic acid methyl ester is in 300 ml of methanol and 62.6 ml (0.4-57 mol) of 33 µg ethanolic dimethylamine solution is heated in an autoclave for 16 hours at 100°C. There-

then the reaction mixture is evaporated in a vacuum and the residue is dissolved in methylene chloride and an ice-water mixture. The organic

phase is washed twice with cold 5% potassium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The. amorphous residue crystallizes by expulsion with 300 ml of ether. After filtration and drying in a high vacuum, one obtains N,N-dimethyl-5-phenyl-4,5-dihydro-/1,2,£J-triazolo/1,5-a7quinoxaline-2-carboxa-

mid, which sinters from 125°C and gradually melts at 150-165°C

Example 5

Analogous to example 1, it is obtained from 9.30 g (0.0297 mol) of 5-(4-chlorophenyl)-4,5-dihydro-[1,2,4,7-triazolo]-1,5- α7-quinoxaline-2-methanol over its crude methanesulfonic acid ester using 40.7 ml (0.297 mol) of 33 µg ethanolic dimethylamine solution give 2-(dimethylamino)-methyl7-5-(4--chlorophenyl)-4,5 -dihydro-/ 1 , 2,_47~triazolo/ 1, 5-a7quinoxaline- hydrochloride,. which after recrystallization from methylene chloride/ isopropanol sinters at 230°C and melts during cleavage at 24-8-25l°C.

Analogous to example 1, starting from 20.30 g (0.059 mol) 5-[3-(trifluoromethyl)-phenyl]-4-, 5-dihydro-[1,2,47-triazolo]-1 ,5-α7-quinoxaline-2-methanol over its crude methanesulfonic acid ester using 4-8.2 ml (0.35 mol) of 33% ethanolic dimethylamine solution obtain 2-/ (dimethylamino )-methyl7_5-/ 3- (trifluoromethyl )-phenyl7_4,5-dihydro-/1,2,'47-triazolo/1,5_α7quinoxaline which for purification is chromatographed on basic alumina of activity stage I with the eluent methylene chloride-methanol (99:1) and then recrystallized from hexane. The product (free base) then melts at 115-118°C.

Analogous to example 1, starting from 35.05 g (0.144 mol) 5-(2,3-dimethylphenyl)-4, 5-dihydro-/1,2,47-triazolo/1,5-α7quinoxaline -2-methanol over its crude methanesulfonic acid ester using 198 ml (1.4-4 mol)

33 $~ig ethanolic dimethylamine solution obtain 2-/ (dimethylamino)-methyl7-5-(2, 3-dimethylphenyl)-4, 5-dihydro-/-1,2,/7-triazolo/-1 , 5-a7 -quinoxaline hydrochloride, which after recrystallization from methylene chloride/isopropanol sinters at 250°C and melts with decomposition at 257-259°C

Analogous to example 1, one wants when it is assumed

8.0 g (0.026 mol) of 7-chloro-5-phenyl-4,5-dihydro-[<->1,2,47-triazolo/1,5-a7quinoxaline-2-methanol over its crude methanesulfonic acid ester using 25.6 ml (0.218 mol) 33% ethanolic dimethylamine solution obtain 7-chloro-2-/ (dimethylamino)-methyl7-5-phenyl-4-, 5-dihydro-/ 1, 2, Ø-triazolo/- 1, 5-α7-quinoxaline hydrochloride, which after recrystallization from methylene chloride/ethyl acetate sinters from 220°C and melts on cleavage at 228-232°C.

Analogously to example 1, starting from 16.50 g (0.0432 mol) of 8-chloro-2-(2,4-dichlorophenyl)-4,5-dihydro-/"1,2,47-triazolo/ 1,5-α7-quinoxaline-2-methanol over the crude methane sulfonic acid ester using 59.0 ml (0.432 mol) of 33% ethanolic dimethylamine solution give 8-chloro-2-(dimethylamino)-methyl7-5~( 2,4-dichloro-phenyl)-4-,5-dihydro,2,47-triazolo/~1,5-α7quinoxaline hydrochloride, which after recrystallization from methylene chloride/isopropanol sinters under decomposition from 282°C.

The methanol derivatives required as starting materials are prepared - as follows: a) Analogously to example 1 a) using 26.2 g (0.105 mol) of 4.-chloro-N-(2-nitrophenyl)-aniline /"sml .

V.C. Barry et al., Proe. Roy. Irish Acad., 55 B, 160 (1953/7

obtain (4-chlorophenyl)-(2-nitrophenyl)-carbamic acid ethyl ester of

sm.p. 90-93°C after recrystallization from methylene chloride/hexane;

using 95.08 g (0.337 mol) of 2-nitro-N-[-3-(trifluoromethyl)-phenyl-7-aniline/ml. the following section h/7 obtain (2-nitrophenyl)-/-3-(trifluoromethyl)-phenyl7-carbamic acid ethyl ester of m.p. 45-4-8°C after recrystallization from hexane: using 65.0 g (0.268 mol) of 2,3-dimethyl-N-(2-nitrophenyl)-aniline/ml. the following paragraph h/7 few

(2,3-Dimethylphenyl)-(2-nitrophenyl)-carbamic acid ethyl ester is of m.p. 105-106°C after recrystallization from isopropanol;

using 43.00 g (0.173 mol) of 5-chloro-2-nitro-N-phenylaniline / ml. A. P. Kottenhahn et al. J. Org. Chem. 28, 3117 (l963/7) after chromatography of the crude product on silica gel with the eluent toluene obtain (5-chloro-2-nitro-phenyl)-phenyl-carbamic acid ethyl ester as a brown oil, which becomes solid after some time and then melts at 71-73 °C;

using 56.55 g (0.178 mol) of 2,4-di-chloro-N-(2-nitrophenyl)-aniline/ml. V.C. Barry and J.G. Belton, Proe. Roy. Irish Acad., 57B 14-4 (1955/7) after chromatography of the crude product on silica gel with eluent toluene obtain (4-chloro-2-nitrophenyl)-(2,4-dichlorophenyl)-carbamic acid ethyl ester of sm.

m. 93-96°C after recrystallization from isopropanol.

b) Analogous to example 1 b) one would, using

41.20 g (0.128 mol) (4-chlorophenyl)-2-nitrogenyl)-carbamic acid ethyl ester obtain (2-aminophenyl)-(4-chlorophenyl)-carbamic acid ethyl ester of m.p. 112-115°C after recrystallization from methylene chloride/hexane;

using 81.50 g (0.230 mol) of 2-nitro-phenyl-N-(trifluoromethyl)-phenyl-7-carbamic acid ethyl ester obtain

(2-Aminophenyl)-(3-(trifluoromethyl)-phenyl-7-carbamic acid ethyl ester of m.p. 105-108°C after recrystallization from methylene chloride/hexane;

using 71.90 g (0.229 mol) (2,3-dimethylphenyl)-(2-nitrophenyl)-carbamic acid ethyl ester, (o-aminophenyl)-(2,3-dimethylphenyl)-carbamic acid ethyl ester is obtained - of sm.p. 95-97°C after recrystallization from methylene chloride/hexane;

using 4-3.20 g (0.135 mol) of 5~chloro-2-nitrophenyl-phenyl-carbamic acid ethyl ester obtain (2-amino-5-chloro-phenyl)-phenylcarbamic acid ethyl ester of m.p. 98-101°C after recrystallization from methylene chloride/hexane;

using 39.85 g (0.102 mol) (2,4-dichloro-phenyl)-(4--chloro-2-nitrophenyl)-carbamic acid ethyl ester are few

(2-amino-4-chloro-phenyl)-(2,4-dichloro-phenyl)-carbamic acid ethyl ester of m.p. 137-139°C after recrystallization from methylene chloride/hexane.

c) Analogous to example 1 c), using 38.60 g (0.133 mol) (2-amino-phenyl)-(4-chlorophenyl)-carbamic acid ethyl ester, / 2-(N-ethoxycarbonyl-4--chlorof enylamino)-phenylazo7"

(2-chloro-acetamido)-malonic acid diethyl ester of m.p. 80-85°C

after recrystallization from ether/hexane;

using 61.20 g (0.189 mol) of (2-amino-phenyl)-[3-(trifluoromethyl)-phenyl-7-carbamic acid ethyl ester is obtained (2-£~N-ethoxycarbonyl-3-(trifluoromethyl ) - f enylamine£7_f enylazo_7~

•(2-chloroacetamido)-malonic acid-dimethyl ester is of m.p. 76-79°C

after recrystallization from ether/hexane;

Using 56.60 g (1.199 mol) of (2-amino-phenyl)-(2,3-dimethylphenyl)-carbamic acid ethyl ester obtain / 2-(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenylaz£7 -(2-chloroacetamido)-rahalonic acid diethyl ester of m.p. 120-122UC one is recrystallization from ether/hexane,

using 31.60 (0.109 mol) (2-amino-5-chloro-phenyl)-phenylcarbamic acid ethyl ester get / 2-(N-ethoxy-carbonyl-phenyl-amino)-4--chloro-phenylaz £7~ (2-chloroacetamido)-malonic acid diethyl ester, which after crystallization from ether sinters at 90°C and melts at 105-110°C;

Using 33.30 g (0.093 mol) of (2-amino-4-chlorophenyl)-(2,4-dichlorophenyl)-carbamic acid ethyl ester obtain amorphous / 2-(N-ethoxycarbonyl-2,4-dichloro-phenylamino) -5-chloro-phenylaz£7~

(2-Chloroacetamido)-malonic acid diethyl ester. This crude malonic ester can be used for cyclization analogously to example 1d).

d) Analogously to example 1d), using 36.90 g (0.067 mol) of 2-(N-ethoxycarbonyl-4-chloro-phenylamino)-phenylaz[7-(2-chloroacetamido)-malonic acid diethyl ester, crude 1-/2-(N-ethoxycarbonyl-4-chloro-phenylamino)-phenyl7-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid, which sinters at 185°C and melts at 190-192°G during cleavage; using 98.50 g (0.168 mol) of /~2-(N-ethoxycarbonyl-3-(trifluoromethyl)-denylamino)-phenylaz£7-(2-chloro-acetamido)-malonic acid diethyl ester and the crude 1-/ 2-/_ N-Ethoxycarbonyl -3 -(trifluoromethyl)-phenylamine£7"phenyl7~5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid, which sinters at 88°C and melts with cleavage at 100-108°C; using 91.10 g (0.166 mol) of 2-(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenylaz£7~(2-chloroacetamido)-malonic acid diethyl ester, the crude 1-/ 2 -(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenyl7~5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid, which melts with decomposition at 188-190°C: Using 53 .70 g (0.097 mol) /~2-(N-ethoxycarbonylphenylamino)-4-chlorophenylaz£7J-(2-chloroacetamido)-malonic acid diethyl ester and the crude 1-_/ 2-(N-ethoxycarbonyl-phenylamino )-4-chlorophenyl/-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid which sinters at 105°C and melts with decomposition at 115-117°C; using 59.53 g (0.0957 mol) crude J_ 2-(N-ethoxycarbonyl-2,4-dichlorophenylamino)-5-chloro-phenylazc/-(2-chloroacetamido)-malonic acid diethyl ester obtain the crude 1 -/ 2-(N-ethoxycarbonyl-2,4-dichlorophenylamino)-5-chlorophenyl/ -5-(chloromethyl)-1H-1,2,4~triazole-3-carboxylic acid, which melts at 186 C and is decomposed. e) Analogous to example 1e), using 50.00 g (0.115 mol) crude 1-/2-(N-ethoxycarbonyl-4-chlorophenylamino)-phenyl7-5-(chloromethyl)-1H-1,2, 4-triazole-3-carboxylic acid obtain the crude 5~(4"chlorophenyl)-4,5-dihydro-/ 1,2, CJriazolo/ 1,5-a/-quinoxaline-2~ carboxylic acid which sinters at 191°C and melts from 196°C with decomposition;

using 77.50 g (0.165 mol) of crude 1-/2-/N-ethoxycarbonyl-3-(trifluoromethyl)-phenylamino/-phenyl/-5-(chloromethyl)-1H-1,2,4-triazole-3- carboxylic acid obtain the crude 5-/ 3-(trifluoromethyl)-phenyl7~4, 5-dihydro-/ 1 , 2, 4_7-triazolo/ 1 , 5-a/ quinoxaline-2-carboxylic acid, which melts during cleavage at 204 -206°C;

using 69.70 g (0.163 mol) of crude 1-(2-(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenyl)-5-(chloromethyl-1H-1,2,4-triazole-3-carboxylic acid obtain the crude 5~(2,3-dimethylphenyl)-4, 5-dihydro-/ 1, 2,_4/_triazolo/ 1 , 5-a7quinoxaline-2-carboxylic acid which sinters at 178°C under red coloration, melts at 195- 197°C during decomposition;

using 42.20 g (0.097 mol) of crude 1-[2-(N-ethoxycarbonyl-phenylamino)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid obtain the crude 7-chloro-5-phenyl-4,5-dihydro-/ 1,2,4-triazolo-/ 1,5-a/quinoxaline-2-carboxylic acid,

which sinters with browning at 178°C and melts with cleavage at 205-210<0>C;

using 33.30 g (0.066 mol) of crude 1-(2-(N-ethoxycarbonyl-1,2,4-dichlorophenylamino)-5-chlorophenyl)-5-(chloromethyl)-1H-1,2,4- triazole-3-carboxylic acid obtain the crude 8-chloro-5-(2,4-dichlorophenyl)-4?5-dihydro-/~1,2, 47-triazolo/-1,5-aZ quinoxaline-2-carboxylic acid as melts during the splitting of wood

218-222°C. f) Analogous to example 1f), using 43.4-0 g (0.133 mol) of crude (5-(4-chlorophenyl)-4, 5-dihydro-/-1;, 2, 47-triazolo-/ 1,5-α7quinoxaline-2-carboxylic acid obtain 5-(4-chlorophenyl)-4,5-dihydro-/~1,2,47~triazolo/ 1,5_α7quinoxaline-2-carboxylic acid methyl ester, which after recrystallization from methylene chloride/ isopropanol sinters at 143°C and gradually melts during decomposition at 155 - 212°C; using 54.10 g (0.150 mol) of crude -5-(3-(trifluoromethyl)-phenyl7~4,5-dihydro-/—1,2,47-triazolo/<->1,5-α7 quinoxaline- 2-carboxylic acid get 5-/ 3-(trifluoromethyl)-phenyl7~ 4,5-dihydro-/-1,2,47-triazolo-/ 1,5-a7quinoxaline-2-carboxylic acid methyl ester is as after recrystallization from methylene chloride /methanol melts at 204-206°C; using 58.1 ug (0.181 mol) of crude 5-(2,3-dimethylphenyl)-4,5-dihydro-/1,2,47"triazolo/1,5-α7quinoxaline-2-carboxylic acid obtain 5-( 2,3-dimethylphenyl)-4,5-dihydro-[1,2,47-triazolo]1,5-a7quinoxaline-2-carboxylic acid methyl ester, which after recrystallization from methylene chloride/methanol melts at 170-172°C; using 26.60g (0.0815 mol) crude 7-chloro-5-phenyl-4,5-dihydro-/1,2,47-triazolo/1,5-a7quinoxal in-2-carboxylic acid get 7- chloro-5~phenyl-4,5-dihydro-/~1,2,47-triazolo /~~ 1 , 5-a7quinoxaline-2-carboxylic acid methyl ester is, which after recrystallization from methylene chloride/isopropanol sinters at 165°C and melts at 190-194°C; using 25.40 g (0.0642 mol) of crude 8-chloro-5-(2,4-dichlorophenyl)-4',5-dihydro-β-1,2,47-triazoloβ-1,5 -α7 quinoxaline-2-carboxylic acid get 8-chloro-5"(2,4-dichlorophenyl)-4, 5-dihydro/ 1 , 2, 4_7-triazolo/-1 , 5-α7-quinoxaline-2-carboxylic acid methyl ester , which after recrystallization from methylene chloride/isopropanol melts at 264-266° C. g) Analogous to example 1g), using 38-50 g (0.113 mol) of 5-(4-chlorophenyl)-4,'5-dihydro- /-1, 2,47-triazolo/ 1,5-α7~quinoxaline-2-carboxylic acid methyl ester get 5-(4-chloro phenyl)-4, 5-dihydro -/ 1 , 2, 47-triazolo/ 1 ,5-α7quinoxaline-2-methanol, which after recrystallization from methylene chloride/isopropanol melts at 1 90-1 95°C;

using 26.65 g (0.0712 mol) of 5-(3-trifluoromethyl)-phenyl7-4,5-dihydro-(1,2,47-triazolo)-1,5-a7quinoxaline-2-carboxylic acid methyl ester obtain 5 -/ 3-(trifluoromethyl)-phenyl7-4, 5-dihydro-/ 1 , 2,47-tri ia zolo -/ 1,5-a7quinoxaline-2-methanol which after recrystallization from methylene chloride/isopropanol melts at 168- 171°C.

using 39.84 g (0.119 mol) of 5-(2,3-dimethylphenyl)-4-,5-dihydro-/1,2,4_7-triazolo/1,5~a7quinoxaline-2-carboxylic acid methyl ester obtain 5 -(2, 3-dimethylphenyl)-4-, 5-hydro-/1,2,47-triazolo/1,5-α7-quinoxaline-2-methanol, which after recrystallization from methylene chloride/isopropanol sinters at 165°C and.melts at 186-194°C;

Using 20.80 g (0.061 mol) of 7-chloro-5~phenyl-4,5-dihydro-/ 1,2,47-triazolo/ 1,5-a7quinoxaline-2-carboxylic acid methyl ester obtain 7-chloro- 5~phenyl-4,5-dihydro-/~1,2,47-triazolo/1,5-α7quinoxaline-2-methanol, which after recrystallization from methylene chloride/isopropanol sinters at 191°C and melts at 204-206°C;

using 19.80 g (0.0483 mol) of 8-chloro-5-(2,4-dichlorophenyl)-4,5-dihydro-/~1,2,47-triazolo/1,5-α7quinoxaline- 2-carboxylic acid methyl ester obtain 8-chloro-5~ (2, 4--dichlorophenyl)-4, 5-dihydro-/ 1 , 2, 47-triazolo/ 1 , 5-a7quinoxaline-2-methanol of sm.p . 229-231°C.

The two necessary substituted 2-nitro-N-phenylanilines not mentioned in the literature for step a) are prepared as follows: h) A solution of 80.00 g (0.567 mol) 1-fluoro-2-nitrobenzene and 182 .72 g (1.133 mol) of 3-(trifluoromethyl)-aniline i

4-00 ml of dimethylsulfoxide is stirred for 68 hours at 130°0. After cooling, the reaction mixture is poured into 1000 ml of water and extracted twice with 500 ml of ethyl acetate. The combined organic extracts are washed 5 times with 1N hydrochloric acid, 5 times with water and once with saturated sodium chloride solution, dried over

sodium sulfate and evaporated in vacuo. The oily residue is dissolved in 200 ml of toluene, and the solution is filtered through an inlet beaker filled with 610 g of silica gel and the filling is washed afterwards with 1000 ml of toluene. The filtrate is evaporated in vacuo to dryness, and the residue is crystallized from methylene chloride/hexane.

After drying in vacuum, the 2-nitro-N-(3-trifluoromethyl)-phenyl7-aniline formed melts at 69-70°C.

In a completely analogous way, starting from 117-00 g (0.830 mol) 1-fluoro-2-nitrobenzene and 222.00 g (1.826

mol) 2,3-dimethylaniline in 585 ml of dimethylsulfoxide obtain N-(2,3-dimethylphenyl)-2-nitroaniline of m.p. 118-120°C after recrystallization from methylene chloride/hexane.

Example 6

To the suspension of 10.00 g (0.0358 mol) of 5-phenyl-4,5-dihydro-pyrido/2,3-e_7/ 1 , 2,^/triazolo/-1 , 5-α7pyrazine-2-meta -

zero in 350 ml abs. methylene chloride and 7.24 g (0.072 mol) triethylamine are added dropwise at -8 to -5°C 6.15 g (0.054 mol) methanesulfonic acid chloride over 10 minutes. The clear, yellow reaction solution is stirred for 90 minutes at room temperature, and then washed three times. times with ice water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated in vacuo to dryness.

The methanesulfonic acid ester of 5-phenyl-4»5-dihydro-pyrido[-2,3-e7-/-1,2,ijt riazolo]1,5-a7pyrazine-2-methanol is obtained as a pale yellow crystalline residue and reacted without further purification with once, adding an ice-cold mixture of 35.4 ml (0.26 mol) of 33% ethanolic dimethylamine solution and 35 ml of ethanol, the reaction mixture is stirred closed for three hours. It is then evaporated in a vacuum, and the residue is dissolved in ethyl acetate and 1N potassium bicarbonate solution. The aqueous phase is separated and extracted a further 2 times with ethyl acetate. The combined extracts are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and

evaporated in vacuum. After recrystallization of the residue from methylene chloride/isopropanol, 2-/(dimethylamino)-methyl7"-5-phenyl -

4-, 5-dihydro-pyrido/ 2, 3- eJ/_ 1, 2, 4-71riazolo/ 1,5-α7pyrazine, m.p. 135-139°C, corresponding formula

The necessary starting material 5-phenyl-4,5-dihydro-pyrido/2,3-e_7~/1,2,47triazolo/1,5-a/pyrazine-2-.methanol~ is prepared as follows: a) a solution of 56.80 g (0.4-41 mol) 3-amino-2-chloro-pyridine (purum) in 440 ml glacial acetic acid and 110 ml conc. hydrochloric acid is diazotized at 0-5°C with 88.3 ml (0.441 mol) of a 5-molar sodium nitrite solution. The cold diazonium salt solution formed is added dropwise over the course of 20 minutes with good stirring to a solution of 88.50 g (0.353 mol) (2-chloroacetamido)-malonic acid diethyl ester/ml. Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-110 (1954/7 in 1760 ml of methanol, while at the same time 2400 ml of saturated potassium bicarbonate solution is dripped from another dropping funnel under slight cooling so rapidly that the pH value of the reaction mixture is constantly approx. 6, and the reaction temperature remains between 20 and 23°C. Then 400 ml of saturated potassium bicarbonate solution is added dropwise (the pH value reaches 7, stirring for 1 hour at 20°C and then 2 hours at 0-5°C. The light yellow crystals formed are filtered off with suction and washed with water, a little ether and end with hexane. After drying in air, the formed (2-chloro-acetamido)-(2-chloro-3-pyridylazo)-malonic acid diethyl ester, which contains varying amounts of crystal water, melts at 60-72°C. b) To 817 ml (0.817 mol) of a 1N sodium hydroxide solution precooled to 0°C, with good stirring,

during 5 minutes 1 to 2°C cooled solution of 118.30 g (approx. 0.27 mol) of the crude azo compound prepared according to a) in

1060 ml of methanol. During heating to 18 to 20°C, a clear reddish-brown solution is formed, which is stirred for one hour at room temperature. You then add 10 g of activated charcoal, stir for 5 minutes at room temperature, and filter the mixture over diatomaceous earth. and post-wash with a little methanol/water (1:1). The clear yellow filtrate is mixed while stirring with 2N hydrochloric acid until a pH value of 3 is reached. After stirring for three hours in an ice bath, it is suctioned off. crystallized e acid, and wash well with water and hexane. After drying over calcium chloride in vacuum, the formed 1-(2-chloro-3-pyridyl)-5~(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid melts at 203-205°C with decomposition.

c) A mixture of 50.00 g (0.183 mol) of the diazolecarboxylic acid prepared according to b), 59.60 g (0.64-2 mol) aniline and

0.05 g of potassium iodide in 1000 ml of ethanol is boiled for 24 hours under reflux. The reaction mixture is then evaporated in vacuo to dryness, and the residue is dissolved in 200 ml of ether and 500 ml of 1N sodium hydroxide solution. The alkaline aqueous phase is separated,

washed three times with each time 150 ml of ether, and then adjusted by adding conc. hydrochloric acid congo acid. 150 ml of methylene chloride is also added, stirred for 1 hour at 0°C and the carboxylic acid formed is filtered off. After washing with water and methylene chloride, the product is dried in vacuum over calcium chloride. The 5-phenyl-4,5-dihydro-pyrido/2,3-b// 1,2,47 triazolo/<->1,5-a7pyrazine-2-carboxylic acid thus formed melts at 208-213°C during decomposition .

By evaporating the methylene chloride phase of the mother liquor, a further amount of the same carboxylic acid is obtained.

d) A suspension of 49.20 g (0.168 mol) of the acc

c) prepared carboxylic acid in 490 ml of methanol and 100 ml of 6n methanolic hydrochloric acid solution is boiled for 16 hours under reflux while

a clear, yellow solution is formed. It is then evaporated in vacuo and the residue dissolved in methylene chloride and ice-cold potassium bicarbonate solution. The separated organic phase is washed 1 time with cold 1N potassium bicarbonate solution and 1 time with saturated sodium chloride solution, dried over sodium sulfate and evaporated

in vacuum. After recrystallization of the residue from methylene chloride/isopropanol, 5-phenyl-4, 5-dihydro-pyrido/2,3-e_7-/T,2,47triazolo/1,5-a7ipyrazine-2-carboxylic acid methyl ester of m.p. . 198-201°C.

e) A suspension of 38.50 g (0.125 mol) of it. according to

d) prepared ester in 1250 ml of methanol and 1250 ml of tetrahydrofuran is distributed while stirring at room temperature with 23.6 g

(0.625 mol) of sodium borohydride, distributed over three portions. During vigorous foaming, the temperature of the reaction mixture thereby increases to 33 to 35°C and is maintained there by slight cooling. The mixture is then stirred for 90 minutes at room temperature and after adding 1250 ml of ice water for a further 2 hours at 0-5°C. The precipitated product is filtered off with suction, washed with water to pH 6, and ether. After drying over calcium chloride in vacuo, the 5-phenyl-4-, 5-dihydro-pyrido-/ 2, 3-eJ£ 1,2,47triazolo/ 1 , 5-§7pyrazine-2-methanol formed melts at 233-237 °C.

Example 7

That of 10.00 g (0.036 mol) 5-phenyl-4,5-dihydro-pyrido-/ 2,3~e_7/ 1 , 2, 47triazolo/ 1 , 5-α7pyrazine-2-methanol and 6.15 g ( 0.054-methanesulfonic acid chloride according to example 6 prepared

crude methanesulfonic acid ester is stirred after adding 88 ml (0.934 mol) of 33% ethanolic methylamine solution and 20 ml of ethanol overnight at room temperature. The reaction mixture is then evaporated in vacuo and the solid residue is dissolved in ethyl acetate and 1N potassium bicarbonate solution. The aqueous phase is separated and extracted once more with ethyl acetate. The combined extracts are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 200 ml of ethanol and mixed with a saturated ethanolic fumaric acid solution until the pH value of a sample mixed with water is 4. After 5 hours, the precipitated crystal is filtered off and recrystallized twice from ethanol.

After drying, the formed 2-J_ (methylamino)-methyl7-5-phenyl-4,5-dihydro-pyrido/~2,3-e7/~1,2,47triazolo/~1,5-a7 melts

pyrazine-fumarate-(1:1) at 180-183°C with cleavage.

Analogously, when starting from 5.00 g (0.018 mol) 5-phenyl-4-»5-dihydro-pyrido/2,3-£7j_ 1»2,_4_7triazolo/1,5~a7pyrazine-2-methanol- over its crude methanesulfonic acid ester using 12.70 g (0.179 mol) of pyrrolidine obtain 2-(1-pyrrolidinyl)-methyl7-5-phenyl-4,5-dihydro-pyrido/2,3-eTV 1 , 2,_4_7triazolo/ 1,5-a7pyrazine of m.p. 110-113°C after recrystallization from methylene chloride/isopropanol.

Example 8

Analogous to example 6, starting from 12.20 g (0.039 mol) 5-(2-chlorophenyl)-4,5-dihydro-pyrido/~2,3-e7/~1,2,47-triazolo/ 1,5-α7pyrazine-2-methanol over its crude methanesulfonic acid ester using 53 mL (0.390 mol) of 33% ethanolic dimethylamine solution give 2-(dimethylamino)-methyl7-5-(2-chloro-phenyl)- 4, 5-dihydro-pyrido/ 2, 3- eJ/_ 1, 2,_47triazolo/ 1,5_a7pyrazine, if in ethyl acetate prepared hydrochloride after recrystallization from isopropanol melts at 224-228°C with decomposition;

starting from 3.46 g (0.011 mol) 5~(3-chloro-phenyl)-4,5-dihydro-pyrido-/2,3-ε_7/1 ,2,47triazolo/1,5-α7pyrazine- 2-methanol over its methanesulfonic acid ester using 11 ml (0.08 mol) of 33% ethanolic dimethylamine solution give 2-/ (dimethylamino)-methyl7~5-(3-chlorophenyl)-4,5-dihydro-pyrido/ 2,3-eTV 1, 2, 47triazolo/ 1 , 5-a7p_yrazin of m.p. 97-100°C after crystallization from methylene chloride/isopropanol;

starting from 6.85 g (0.022 mol) 5"(4-chlorophenyl)-4,5-dihydro-pyrido/2,-3-e7/1,2,4_7triazolo/1,5-a7pyra- zin-2-methanol over its methanesulfonic acid ester using 39 mL (0.218 mol) of 33 µg ethanolic dimethylamine solution give 2-(dimethylamino)-methyl 7''5-(4-chlorophenyl)-4,5-dihydro-pyrido / 2,3-e_7/ 1 , 2, 4_7triazolo/ 1 , 5-a7-pyrazine of m.p. 185-188°C after crystallization from methylene chloride/isopropanol;

starting from 6.30 g (0.020 mol) 5-(4-methoxyphenyl)-4,5-dihydro-pyrido[2,3-eJJ_ 1 ,2,47triazolo[—1 ,5~a7pyrazine-2- methanol over its crude methanesulfonic acid ester using 21 ml (0.12 mol) of 33 µg ethanolic dimethylamine solution get

2-/ (dimethylamino ) -methyl7_5-(4-methoxyphenyl)-4, 5-dihydro-pyrido / 2,3-e7/ 1 , 2,_^7triazolo/ 1 , 5-a7pyrazine, the hydrochloride of which prepared in ethyl acetate after recrystallization from isopropanol melts at 215-222°C during cleavage and

starting from 20.20 g (0.071 mol) of 5-cyclohexyl-4-,5-dihydro-pyrido-[2,3-eJj_ 1 ,2,4_7triazolo[1],5-a7pyrazine-2-methanol over its crude methanesulfonic acid methyl ester is, using 97 ml (0.71 mol) of 33% ethanolic dimethylamine solution, obtain 2-(dimeth<y>lamino)-meth<y>l7-5-c<y>clohex<y> l-4>5-dihydro-pyrido/ 2, 3- £JL-^» 2, 4.7^riazolo/ 1, 5-a7-pyrazine, whose hydrochloride prepared in ethyl acetate after recrystallization from methylene chloride/ isopropanol melts at 278-28l° C during cleavage.

The necessary starting materials are prepared as follows: a) Analogous to example 6c) and 6d) using 31.40 g (0.115 mol) 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H -1,2,4-triazole-3-carboxylic acid and 206.00 g (1.61 mol) of 2-chloroaniline give 5-(2-chlorophenyl)-4,5-dihydro-pyrido/~2,3-e7/ ~1,2,47triazolo/1,5-α7pyrazine-2-carboxylic acid and its methyl ester, which after recrystallization from methylene chloride/isopropanol melts at 155-163°C; using 7.36 g (0.027 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 48.10 g (0.378 mol) 3-chloroaniline get 5-(3-chlorophenyl)-4»5-dihydro-pyrido/2,3-_e7/ 1 , 2, 4_7triazolo/ 1 , 5-a7pyrazine-3-carboxylic acid and its methyl ester which after recrystallization from methylene chloride/isopropanol melt at 213-216°C: using 8.91 g (0.033 mol) 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole- 3-carboxylic acid and 20, 90 g (0.164 mol) p-chloroaniline get 5-(4-chlorophenyl)-4,5-dihydro-pyrido/ 2,3-e7/ 1,2, 4/triazolo-/ 1, 5-α7pyrazine-2-carboxylic acid and its methyl ester which, after recrystallization from methylene chloride/ethyl acetate, melts at 234-237 C during decomposition;

using 10.00 g (0.037 mol) 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 15.80 g (0.128 mol ) 4-methoxy-aniline get 5"(4-methoxy-phenyl)-4,5-dihydro-

pyrido/ 2, 3- ε7-/_ 1,2,47triazolo/ 1 , 5-α7pyrazine-2-carboxylic acid and its methyl ester, which after recrystallization from -methylene chloride/isopropanol melts at 1 90-1 96°C;

using 21.80 g (0.080 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 35.70 g (0.360 mol ) cyclohexylamine obtain 5-cyclohexyl-4, 5-dihydro-pyrido/ 2,3-eTY 1, 2, 47triazolo/ 1,5-a7pyrazine-2-carboxylic acid and its methyl ester which, after recrystallization from methylene chloride/isopropanol, melts at 170-176 °C.

b) Analogous to example 6e), using 15.00 g (0.044 mol) 5-(2-chlorophenyl)-4,5-dihydro-pyrido/~2,3-e7

/~1 , 2,4-7triazolo/~1 , 5~a7 -pyrazine-2-carboxylic acid-methyl ester and 8.28 g (0.219 mol) of sodium borohydride obtain 5"(2-chlorophenyl)-4,5 -dihydro-pyrido/ 2, 3- eJ/_ 1, 2, 4_7triazolo-/ 1,5-a7pyrazine-2-methanol of sm.

mp 193-196°C;

using 3.80 g (0.011 mol) 5'(3-chlorophenyl)-4,5-dihydro-pyrido/2,3-_ε7/1,2,47triazolo/1,5-α7pyrazine-2-carboxylic acid methyl ester and 4.20 g (0.112 mol) sodium borohydride obtain 5-(3-chlorophenyl)-4, 5-dihydro-pyrido/2,3-e7/_ 1,2,47triazolo/—1,5-a7pyrazine-2- ethanol of m.p. 204-206°C;

using 7.90 g (0.023 mol) 5-(4-chlorophenyl)-4,5-dihydro-pyrido/2,3-_triazolo/1,5-a7pyrazine-2-carboxylic acid methyl ester and 4.37 g (0.116 mol) sodium boron-

hydride get 5-(4-chlorophenyl)-4, 5-dihydro-pyrido/~2,3-e7/~1,2,^7 triazolo/ 1,5-a7pyrazine-2-methanol of m.p. 240-245°C during cleavage;

using 8.10 g (0.024 mol) of 5-(4-methoxyphenyl)-4,5-dihydro-pyrido[2,3-eJJ_1,2,47triazolo]1,5-a7pyrazine-2-carboxylic acid methyl ester oe 4.50 g (0.120 mol) sodium borohydride obtain 5~(4-methoxy-phenyl)-4,5-dihydro-pyrido/ 2, 3- eJ / f 1 , 2, 47triazolo/ 1,5-a7pyrazine-2- methanol of m.p. 226-230°C, and

using 29.80 g (0.095 mol) of 5-cyclohexyl-4,5-dihydro-pyrido/2,3-_e7/1,2,47triazolo/~1,5~α7pyrazine-2-carboxylic acid methyl ester and 18, 00 g (0.476 mol) of sodium borohydride after evaporation of the reaction mixture and extractive work-up with methylene chloride obtain 5-cyclohexyl-A. 5-dihydro-pyrido/-2,3-ε7/_1»2,47triazolo/1,5-α7pyrazine-2-methanol,

which after recrystallization from methylene chloride/isopropanol melts at 1 90-1 94°C.

Example 9

To the solution of 8.00 g (0.027 mol) of 4-methyl-5-phenyl-4»5-dihydro-/—1,2,£J-triazolo/1,5-α7quinoxaline-2-

methanol in 270 ml abs. methylene chloride and 5.50 g (0.055 mol) triethylamine are added dropwise under hydrogen at 0°C 4»70 g (0.041 mol) methanesulfonic acid chloride over the course of 5 minutes. After stirring for three hours at 0 to 4°C, the clear reaction mixture is poured onto an ice-water mixture, the organic phase is separated, extra-

triturate the aqueous phase once more with methylene chloride. The extracts are washed twice with ice-cold water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.

The methanesulfonic acid formed as a residue of honey-like consistency from 4-methyl-5-phenyl-4,5-dihydro-/1,2,47-triazolo-/1,5-a7quinoxaline-2-methanols is reacted without further purification by adding a cold mixture of 37.5 ml (0.274 mol) of 33 µg ethanolic-dimethylamine solution, and 37.5 ml of ethanol, and leave the reaction mixture closed for 1 hour. The mixture is then evaporated in vacuo, and the residue is dissolved in ethyl acetate and 1N potassium bicarbonate solution. The aqueous phase is separated and extracted once more with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution and dried over sodium sulfate. After filtering off the desiccant, the filtrate is mixed

with good stirring drop by drop with ethereal hydrogen chloride solution until the pH value 3 is reached. After standing for 5 hours at room temperature, the crude hydrochloride formed is filtered off and washed with ethyl acetate. It is then dissolved in 50 ml of methylene chloride and 100 ml of ethyl acetate. After evaporation of the methylene chloride in vacuum at 40°C, the desired hydrochloride crystallizes out again. The mixture is allowed to stand for two hours in the refrigerator, then filtered

the crystals and wash them with ethyl acetate. After drying in high vacuum at 120°C, the formed 2-(dimethylamino)-methyl-7~4-methyl-5-phenyl-4 melts. 5-Dihydro-(1,2,47-triazolo)1,5-α7quinoxaline hydrochloride at 195-198°C.

The 4-methyl-5-phenyl-4,5-dihydro-/1,2,47-triazolo/1,5_a7quinoxaline-2-methanol required as starting material is prepared as follows: a) To the suspension of 50.0 g (0.272 mol ) aminomalonic acid dimethyl ester hydrochloride in 250 ml abs. methylene chloride is added dropwise over the course of 1 hour to 30.0 ml (0.30 mol) of 2-chloropropionic acid chloride. After 4 hours of boiling under reflux, chlorine-hydrogen evolution has ended. The suspension is cooled to room temperature, 100 ml of ice-cold water is added, the organic phase is separated and washed three times with water and once with saturated sodium chloride solution. After evaporation in a vacuum, the residue is dissolved in 100 ml of methylene chloride, slowly adds 400 ml of hexane, and leaves the mixture for 2 hours at room temperature. Then the formed crystals are filtered off, and washed with methylene chloride-hexane (1:4)" After drying in a vacuum, the formed (2-chloropropionamido)-malonic acid-dimethyl-

ester at 100 to 102°C.

b) A solution of 26.20 g (0.102 mol) of the (2-aminophenyl)-phenyl-carbamic acid ethyl ester prepared according to example 1b) in 246 ml of glacial acetic acid and 62 ml of conc. hydrochloric acid diazo-

tered at 0-5°C with 20.4 ml (0.102 mol) of a 5-molar sodium nitrite solution during 20 minutes. The resulting diazonium salt solution is mixed with 60 g of ice, and 24.23 g (0.102 mol) of (2-chloro-propionamido)-malonic acid dimethyl ester in 243 ml of acetone is quickly added. 500 ml of a saturated potassium carbonate solution is then added drop by drop at 0-5°C over the course of 30 minutes, with the pH value eventually reaching 6. After 1 hour of stirring at 0^5°C, 300 ml of ethyl acetate is added, the organic phase and extract the aqueous one more time with ethyl acetate. The combined organic extracts are washed .4 times with water and twice with saturated sodium chloride solution. be dried

over sodium sulfate and evaporated in vacuo as the orange colored /2-(N-ethoxycarbonyl-phenylamino)-phenylazo/-. (2-chloro-propionamido)-malonic acid dimethyl ester of a honey-like consistency is obtained. It can be used for the next step without further purification.

c) Add 316 ml (0.316 mol) of a 1N sodium hydroxide solution precooled to 0°C with good stirring

within 3 minutes a solution of 53.0 g (approx. 0.102 mol) of the azo compound prepared according to b) in 530 ml of methanol. Stir for a further 90 minutes at room temperature and then add glacial acetic acid drop by drop until a pH value of 5 is reached.

The clear solution is mixed with 2N hydrochloric acid for a Congo acid reaction. 350 ml of water is then added dropwise to the reaction mixture over the course of 3 hours, with crystallization gradually taking place. After stirring for 6 hours at 0°C, the formed crystals are filtered off and washed well with water. After dry-

over calcium chloride in vacuo melts the formed 1-/2-(N-ethoxy-carbonyl-phenylamino)-phenyl7~5-(1-chloroethyl-)-1H-A~1 ,2, ^/-triazole ^-carboxylic acid at 153 to 156°C.

d) A suspension of 37.90 g (0.091 mol) of the carboxylic acid prepared according to c) in 210 ml of 4-8% hydrobromic acid

stirred for 12 hours at a bath temperature of 105°C under nitrogen, as a clear green solution is formed. It is then cooled. the reaction mixture to room temperature and add dropwise over 90 minutes under nitrogen 530 ml of water. After three hours of cooling at 0°C, the carboxylic acid is sucked off, washed with a total of 600 ml of water to pH 4, and dried in a vacuum desiccator over calcium chloride. The 4-methyl-5-phenyl-4, 5-dihydro-/-1,2,47-triazolo/1,5-α-quinoxaline-2-carboxylic acid formed sinters at 176°C and melts from 181°C with decomposition.

e) A suspension of 26.70 (0.087 mol) of the carboxylic acid prepared according to d) in 535 ml methanol and 1-06 ml 6n methanolic hydrochloric acid solution, is stirred under nitrogen for 16 hours at boiling temperature under reflux, as a clear light yellow solution quickly forms . The reaction mixture is then evaporated in vacuo to dryness. The residue is dissolved in methylene chloride and ice water, the organic phase is separated, and the aqueous phase is extracted once more with methylene chloride. The combined organic extracts are washed twice with ice-cold 1N potassium bicarbonate solution and twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.

Add 60 ml of ether to the residue of a honey-like consistency

and then 60 ml of hexane. After 4 hours from filtration, the formed crystals are filtered off and washed with ether-hexane (1:1). After drying in vacuum, the formed 4--'methyl-5-phenyl-4, 5-dihydro1,2,47 triazolo/1,5-α7-quinoxaline-2-carboxylic acid methyl ester sinters at 134°C and melts at 139 to U1 °C.f) A solution of 16.60 g (0.052 mol) of the ester prepared according to e) in 166 ml of methanol and 166 ml of tetrahydrofuran

distributed under stirring and nitrogen at room temperature i

within 10 minutes with. a total of 5.48 g (0.145 mol) sodium borohydride, divided into three portions. During strong foaming, the temperature of the reaction mixture thereby increases to 29°C. The mixture is stirred for 3 hours at room temperature and after adding 335 ml of ice-water mixture for a further two hours at 0°C. The precipitated alcohol is sucked off and washed with water to pH 6. After drying over calcium chloride in a vacuum desiccator, the formed 4-methyl-5-phenyl-4, 5-dihydro-/ 1, 2, 47-triazolo-_/-1 sinters, 5-α7quinoxaline-3-methanol at 150°C and melts at 157-160°C.

Example 10

To the solution of 7.70 g (0.022 mol) N,N,4,4-tetramethyl-5-phenyl-4,5-dihydro-/1,2,47-triazolo/-1,5-a/quinoxaline-2 -carboxamide in 1100 ml abs. toluene, 45.40 ml (0.066 mol) of a 1.2-molar solution of diisobutylaluminum hydride in toluene are added dropwise at 0 to 2°C under nitrogen over the course of 20 minutes. The reaction mixture is stirred for a further 1 hour at 5°C, then 15 ml of isopropanol is added dropwise, and then 160 ml of ice-cold water and as much conc. caustic soda until a pH value of 11 is reached. The organic phase is separated and the aqueous phase is extracted once more with toluene. The combined organic extracts are washed twice with 2N caustic soda, twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, and evaporated in vacuo. The residue of a honey-like consistency is dissolved in ethyl acetate, the solution is chromatographed on a column of 180 g silica gel, first with 2 1 ethyl acetate and then with 3 1 methylene chloride-methanol (95:5).

The fractions containing the desired products are evaporated

in vacuum, dissolve in ethyl acetate, and mix while stirring with ethereal hydrogen chloride solution until a pH value of 4 is reached. After 1 hour of stirring in an ice bath, the pure hydrochloride formed is filtered off and washed with ethyl acetate. After drying in high vacuum at 80°C over potassium hydroxide, the formed 4,4-d melts in methyl -2-(dimethylamino)-methyl7'-5-phenyl-4,5-dihydro -/~1 , 2 , 47-triazolo/-1 , 5-a7c.quinoxaline hydrochloride at 206-207°C.

The starting material required N,N,4,4-tetramethyl-5-phenyl-4>5-dihydro-/1,2,47-triazolo/1,5»a7quinoxaline-2-carboxamide is prepared as follows: a) A solution of 18.0 g (.0.056 mol) of the 4-methyl-5-phenyl-4,5-dihydro-[1,2,47-triazolo]1,5-a7quinoxal in- 2-carboxylic acid methyl ester in 900 ml of methanol and 154 ml (1.12 mol) of 33% ethanolic dimethylamine solution is stirred closed for 24 hours. The reaction mixture is then evaporated in a vacuum, and the residue is dissolved in methylene chloride and an ice-water mixture. The organic phase is washed twice with cold, 5% potassium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After recrystallization of the residue from 100 ml of isopropanol and drying in a vacuum desiccator over calcium chloride, the formed N,N,4-trimethyl-5-phenyl-4,5-dihydro-/—1,2, lj - triazolo-/ 1,5- α7quinoxaline-2-carboxamide at 150 to 152°G. b) To a solution cooled to -70°C of 3.60 ml (0.026 mol) of diisopropylamine in 78 ml of abs. tetrahydrofuran is dripped in

over 15 minutes under nitrogen by syringe 16 ml (0.026 mol) of a 1.6 molar solution of butyllithium in hexane. The clear, yellow reaction solution is stirred for 5 minutes at -10°C. After

renewed cooling to -7Q°C is added dropwise over the course of 30 minutes to a solution of 7.80 g (0.023 mol) of the carboxylic acid amide prepared according to example 1Q b) in 4.5 ml of hexamethylphosphoric acid triamide and 3 1 ml of tetrahydrofuran. The deep brown-red solution is stirred for 1$ minutes at -70°C, and after the addition of 3.20 ml (0.051 mol) of methyl iodide a further 90 minutes at -70°C. The reaction solution is then allowed to warm up to 0°C, poured onto an ice-water mixture and extracted twice with ethyl acetate. The organic extracts are washed twice with ice-cold 2N hydrochloric acid, twice with 1N potassium bicarbonate solution,

and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to dryness. The residue of a honey-like consistency which slowly begins to crystallize is dissolved in ethyl acetate and the solution is chromatographed on a column of 200 g silica gel with the eluent ethyl acetate. The fractions containing the desired product are combined and recrystallized from isopropanol. After drying in a vacuum desiccator over calcium chloride, the formed N,N,4,4-tetramethyl-5-phenyl-4,5-dihydro-/~"1,2,4-7-triazolo/~1,5-α7quinoxaline- 2-carboxamide at- 147-U9°C.

Example 11'

Tablets containing 1.00 mg 2-[(dimethylamino)-methyl7-5-phenyl-4, 5-dihydro-/~1 , 2, 4,7-triazolo/"" 1 , 5-a7quinoxaline dihydrochloride as active substance can, for example is produced in the following composition.

Mainly Uling:

The active substance is mixed with milk sugar, part of the wheat starch and with colloidal silicic acid and the mixture is passed through a sieve. A further part of the wheat starch is pasted with 5 times the amount of water in a water bath and the powder mixture is crushed with this paste, until a slightly plastic mass is formed. The mass is driven through a sieve of approx.

3 mm mesh size, is dried, and the dry granules are run through a sieve again. A remaining wheat starch, talc and magnesium stearate are then mixed in. The resulting mixture is pressed

tablets of 250 mg with fracture.rill e.

Example 12

Analogous to example 11, tablets can be prepared

with a content of each time. 50 mg of active substance during each use of 50 mg of 2-/(dimethylamino)-methyl7-5-phenyl-4,5-dihydro-/-1 , 2, 4;7-triazolo-/"~1, 5- a7quinoxaline and each time 100 mg of milk sugar per tablet.

Example 13

To prepare 1000 capsules each time containing 100 mg of active substance, 1.00 g of 2-/(dimethylamino)-methyl7-5-phenyl-4,5-dihydro-/"!,2,^7-triazolo/ are mixed ~1,5-α7quinoxaline hydrochloride with 173.0 g of laetose, moisten the mixture evenly with an aqueous solution of 2.0 g of gelatin, and granulate it through a separate sieve, (e.g. sieve III according to Ph. Heiv. V).The granulate is mixed with 10.0 g of dry corn starch and 15.0 g of talc, and filled evenly into 1000 hard gelatin capsules of size 1.

Instead of 2-/(dimethylamino)-methyl7-5-phenyl-4,5-dihydro-/1,2,47-triazolo/1,5~a7quinoxaline hydrochloride, in the above-mentioned examples 11, 12 and 13, one can also using a pharmaceutically acceptable acid addition salt of another compound of the general formula I.

>

Claims (18)

1. Process for the preparation of new polycyclic polyazaheterocycles of the general formula I wherein R-j and Rg independently mean hydrogen, lower alkyl, or hydroxy lower alkyl, or together mean lower alkylene or ethyleneoxyethylene, ethylene aza ethylene or N-lower alkyl- or N-(hydroxy lower alkyl)-ethylene aza lower ethylene, R^ means hydrogen or a lower aliphatic or saturated lower cycloaliphatic hydrocarbon residue or unsubstituted or substituted phenyl, R^ and R^ means hydrogen or lower alkyl and Ar means an unsubstituted or substituted benzo or pyrido residue, their acid addition salts, characterized in that a) a reactive ester of a compound with it general formula - II whereinR^» R^» Rr; and Ar has the above meaning, is reacted with a compound of the general formula III in which R-j and R^ have the above meaning, orb) in a connection with the general formula IV in which n means 0 or 1, and.X means oxygen, or if n means 1. can also mean.two hydrogen atoms, R^ alone or together with R^ has the meaning of R-j , or if n means 1, can also mean lower alkoxy, and R^ , R^ , R^ , R^ and Ar have the above meaning, are reduced by means of et. hydride reducing agent the carbonyl group(s) resp. an optionally present lower alkoxycarbonyl group, or c ) in a compound with the general formula I, in which R^ means hydrogen and R-j , R2» R^» R^ and Ar have the above meaning, a residue R^ different from hydrogen is introduced, if the bonding carbon atom also has at least one hydrogen atom, or d ) in a connection with the general formula I, wherein one or both symbols R-| and R^ means hydrogen, and R^ , R^ , Rcj and Ar have the above meaning, one or two residues R^ and/or R^ different from hydrogen are introduced and, if desired, a formed compound of the general formula I is transferred to a addition salt with an inorganic or organic acid, or from a formed acid addition salt, the base is released, and the latter is transferred, if desired, back into an acid addition salt. 2. Process according to claim 1, characterized in that for the reaction according to a) esters of organic sulfonic acids or halides are used as the reactive ester of the compound with the general formula II. 3. Method according to claim 1, characterized in that the reaction according to a) is carried out in the presence of an acid-binding agent. shelter. Process according to claim 1, characterized in that the reduction according to b) is carried out using a lower alkyl aluminum hydride in an aromatic hydrocarbon, or using lithium aluminum hydride or diborane in an ethereal solvent. 5 . Method according to claim 1, characterized in that the introduction of a different from hydrogen at the bonding carbon atom also showed a hydrogen atom-containing residue R^ in a compound of the general formula I according to c) is completed by reacting one of the latter compounds with a reactive ester of a primary or secondary lower alkanol, lower alkenol, a cycloalkahol of 5 to 7 carbon atoms, or a primary cycloalkyl lower alkanol of 1 to 7 carbon atoms. 6. Method according to claim 5, characterized in that the reactive ester used is a halogenated hydrogen ester or an ester with an organic sulphonic acid. 7. Method according to claim 5, characterized in that the reaction is carried out in the presence of a basic condensing agent. 8. Method according to claim 1, characterized in that the introduction of a resp. two residues R^ and/or Rg different from hydrogen, according to d) are carried out by reaction of a compound with the general formula I, in which at least one of the symbols R-j and R2 means hydrogen with the equimolar or possibly at least double molar amount of a reactive ester of a lower alkanol or a reactive monoester of a lower alkanediol. 9. Process according to claim 8, characterized in that an ester with an organic sulphonic acid or a halogenated hydrogen ester is used as the reactive ester. 10. Method according to claim 8, characterized in that the reaction is carried out in the presence of an acid-binding agent. 11. Method according to claim 1, characterized in that the introduction of a resp. two residues R., and/or R.sup., different from hydrogen according to d) are carried out by reacting a compound of the general formula I, in which at least one of the symbols R-j and R.sup. means hydrogen, with an oxolave alkane under reducing conditions. 12. Method according to claim 11, characterized in that formaldehyde in the presence of formic acid is used as oxolave alkane. 13. Method according to claim 1, characterized in that a compound is prepared with the general formula I specified in claim 1, in which R-j and R^ have the meaning specified in claim 1, R^ means a lower aliphatic or a saturated lower cycloaliphatic hydrocarbon residue, or unsubstituted or with halogen to atomic number 35 lower alkyl, lower alkoxy, lower alkylthio, trifluoromethylcyano, or highly substituted phenyl, and Ar means an unsubstituted or with substituents a <y> of the above-mentioned type substituted benzo- or pyrido / 2,3-e7 residue, and R^ and R^ have the meaning specified in claim 1, as well as their acid addition salts. 14-. Method according to claim 1, characterized in that a compound of the general formula I stated in claim 1 is prepared, in which R-| means lower alkyl, R 1 means hydrogen or lower alkyl, or R 1 and R^ together means lower alkyl one, R^ means unsubstituted or with halogen up to atomic number 35 substituted phenyl, or lower cycloalkyl, and Ar means an unsubstituted or with halogen up to atomic number 35 substituted benzo- or pyrido/ 2, 3- eT residue, and R^ and R^ have the meaning stated in claim 1 and their acid addition ion salts. 15. Process according to claim 1, characterized in that a compound of the general formula I specified in claim 1 is prepared, in which R-, means lower alkyl, R 2 means hydrogen or lower alkyl, or R-j and R 2 means lower alkylene, R 2 means unsubstituted or with halogen up to atomic number 35" substituted phenyl,_ and Ar means an unsubstituted or with halogen up to atomic number 35 substituted benzo residue, or Pyrido/2,3-j|7 residue, R^ has the meaning specified in claim 1, and R 1 is hydrogen or methyl, and their acid addition salt is . 16. Process according to claim 1, characterized in that a compound is prepared with the general formula I stated in claim 1, in which R^ means methyl, R^ means hydrogen, or R-| and R2 means tetramethyl en, R^ means unsubstituted or chlorine-substituted phenyl, and Ar means enu-substituted or chlorine-substituted benzo residue, or pyrido/^, 3-e7r est en, R^ means hydrogen or methyl and R^ means hydrogen or methyl , as well as their acid addition salts. 17. Process according to claim 1, characterized in that a compound is prepared with the general formula I specified in claim 1, in which R^ means methyl, R^ means hydrogen, or methyl, R^ means phenyl, R^ means hydrogen or methyl, R^ means hydrogen or methyl, and Ar means benzo- or pyrido/ 2, 3- eJ the residue, as well as their acid eaddition salt is. 18 . Process according to claim 1, characterized in that 2-(dimethylamino)methyl7-5-phenyl-4,5-dihydro-1,2,47-triazolo-1,5-a7quinoxaline and its acid addition salts are produced.