DD236931A5 - PROCESS FOR THE PREPARATION OF TRIAZOLOCHINAZOLIN COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of novel (1,2,4) triazolo (1,5-c) quinazoline compounds. The invention provides a process for the preparation of novel (1,2,4) triazolo (1,5-c) quinazoline compounds and their pharmaceutically acceptable salts which can be used as benzodiazepine antagonists, analiomodulators, as antiasthmic agents, adenosine antagonists, etc. The object of the invention is to produce novel compounds which have valuable pharmaceutical properties. According to the invention, the object is achieved by preparing compounds of general formula I, wherein the substituents have the meaning given in the description, by, for example, treating a compound of formula II wherein the substituents are as defined in the description with a Base.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel [1,2,4] triazolo [1,5-c] quinazoline compounds, salt and tautomers of these compounds, to pharmaceutical compositions containing these compounds and to the use of such compounds and pharmaceutical compositions containing them Contain connections.

Characteristic of the known technical solutions

The triazoloquinazoline compounds can be prepared in a manner known per se.

Object of the invention

The invention provides a process for the preparation of novel [1,2,4] triazolo [1,5-c] quinazoline compounds and their pharmaceutically acceptable salts. These compounds are benzodiazepine antagonists and analiomodulators, as well as anti-asthmatic agents and central nervous system stimulants that can enhance memory.

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of novel compounds which have valuable pharmaceutical properties.

According to the invention, novel [1,2,4] triazolo [1,5-c] quinazoline compounds of the formula I

H - . R

H "

-4- 812

/ VV

vyv

wherein R ^{1 is} phenyl or lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl substituted phenyl, or a 5-membered aromatic or partially or fully saturated heterocyclic ring containing 1 to 3 heteroatoms from the group N, O and S or a 6-membered aromatic or partially or fully saturated heterocyclic ring containing 1 to 4 heteroatoms from the group consisting of N, O and S, this heterocyclic ring being bonded to the trialzoloquinazoline nucleus via a carbon atom, and wherein said heterocyclic ring is unsubstituted or lower alkyl, hydroxy, amino, halogen R ^{2 is} unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, nitro, amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or aryl and wherein X is oxygen, sulfur or NR ³ , wherein R ^{3 is} hydrogen, lower alkyl, aryl-lower alkyl, cycloalkyl, lower alkenyl wherein the double bond is separated from the nitrogen atom by at least one saturated hydrocarbon atom, lower alkynyl wherein the triple bond is from the nitrogen atom at least one saturated carbon atom is separate, aryl, amino-lower alkyl, lower-alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or hydroxy-lower alkyl.

When R ^{2 is} hydrogen, the compounds of formula I may exist in a tautomeric form, as shown in formula I ':

K-. - R ¹

Il

IM I

The term "lower" in combination with organic groups and substituents means groups and substituents of up to 7 carbon atoms, and preferably those of up to 4 carbon atoms.

Cycloalkyl contains 3 to 20, preferably 5 to 8 and in particular 6 ring members and may for example be cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cycloalkyl groups may be substituted by one or more additional groups such as lower alkyl or aryl groups.

Aryl groups may be substituted by one or more additional groups, such as lower alkyl, halo, hydroxy, nitro, amino, amino substituted by one or more lower alkyl groups, or aryl.

A lower alkyl group may be unsubstituted or substituted and. For example, methyl, ethyl, propyl, isopropyl, η-butyl, t-butyl, pentyl, neopentyl, isopentyl or heptyl. The preferred group is methyl.

Suitable substituents for lower alkyl groups include halo and hydroxy. Substituted lower alkyl groups are, for example, chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl and hydroxymethyl.

Lower alkoxy is z. For example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, pentoxy, isopentoxy, hexyloxy and heptyloxy.

Preference is given to methoxy.

Halogen is z. As fluorine or bromine or preferably chlorine.

A 5-membered heterocyclic ring containing 1 to 3 heteroatoms from the group consisting of N, O and S preferably contains 1 or heteroatoms from the group consisting of N, O and S. In particular, the rings contain 1 to 3 nitrogen atoms; an oxygen atom; a sulfur atom; or a nitrogen atom and an oxygen or a sulfur atom.

Corresponding heterocyclic rings may be aromatic, typical representatives are, for example, thienyl, furyl, pyrroly !, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, 1,2,3- or 1,2,4-triazolyl.

Further, a 5-membered heterocyclic ring containing heteroatoms as defined above may be partially or completely saturated, such ring being, for example, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, thiazolinyl, oxazolinyl and triazolinyl.

A 6-membered heterocyclic ring containing 1 to 4 heteroatoms from the group N, O and S may contain heteroatoms as defined above for the 5-membered rings. It can be aromatic, z. Pyridyl, or non-aromatic, e.g. B.

Pyranyl, piperidinyl, morpholinyl and O-ribofuranosyr.

Aryl means an aromatic heterocyclic ring as defined above, or e.g. Phenyl.

Aryl-lower alkyl is e.g. Benzyl, phenylethyl, thenyl, thienylethyl, furfuryl, furylethyl, pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, piperidinylmethyl and piperidinylethyl.

Arylniederalkenyl is z. Cinnamyl, 3- (2- or 3-furyl) -2-propene-1-yl, 3- (2- or 3-pyrrolyl) -2-propene-1-yl or 3- (2-, 3- or 4-pyridyl) -2-propen-1-yl.

-5-81220

Lower alkylthio is ζ. As methylthio, ethylthio or isopropylthio.

Lower alkylsulfinyl is z. As methylsulfinyl or ethylsulfinyl.

Lower alkylsulfonyl is z. As methylsulfonyl or ethylsulfonyl.

Lower alkenyl may, for. As ethenyl, propenyl or butenyl.

Lower alkynyl may, for. Example, ethynyl or propynyl.

Amino-lower alkyl may e.g. B. 2-aminoethyl or 2- or 3-aminopropyl. Lower alkylamino lower alkyl may be e.g. B. 2- (N-methylamino) -ethyl or 2- (N-ethylamino) -ethyl. Diniederalkylaminoloweralkyl may, for. B. 2- (N, N-dimethylamino) -ethyl or 2- (N, N-diethylamino) -ethyl.

The claimed compounds can form acid addition salts, especially pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts are acid addition salts which are preferably formed from therapeutically acceptable inorganic or organic acids, such as strong mineral acids, e.g. B.

Hydrohalic acids, such as hydrochloric or hydrobromic acid; Sulfuric acid, phosphoric or nitric acid; aliphatic or aromatic carboxylic acids or sulfonic acids, e.g. Formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, cinnamic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, Pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid or ascorbic acid.

The compounds of formula I and their pharmaceutically acceptable salts are benzodiazepine antagonists and analiomodulators. Furthermore, these compounds are adenosine antagonists and may be antiasthmic and central nervous system stimulants and may improve memory. These beneficial properties can be demonstrated in mammals such as humans when the compounds are administered orally, intraperitoneally or by inhalation at doses of 0.01 mg / kg to 500 mg / kg body weight, preferably 0.1 to 100 mg / kg and more preferably 10 to 30 mg / kg body weight.

The invention particularly relates to compounds of formula I wherein R ^{1 is} phenyl or phenyl substituted by 1 to 3 radicals of the type lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; or R ^{1 represents} an O-lower aromatic or partially or fully saturated heterocyclic ring containing 1 to 3 heteroatoms from the group N, O and S or a 6-membered aromatic or partially or fully saturated heterocyclic ring containing 1 to 4 heteroatoms from the group N , O and S, said heterocyclic ring being bonded to the triazoloquinazoline nucleus via a carbon atom, and wherein said heterocyclic ring may be unsubstituted or substituted by lower alkyl, hydroxy or halogen; wherein R ^{2 is} hydrogen, lower alkyl, aryl-lower alkyl, lower alkenyl, aryl-lower alkenyl or aryl wherein X is O, S or NR ³ , wherein R ^{3 is} hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl or lower-alkylamino-lower alkyl; and wherein Ring A is unsubstituted or substituted by one to three lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl groups; and pharmaceutically acceptable salts thereof.

The invention relates in particular to compounds of the formula I in which R ^{1 is} phenyl or phenyl which is substituted by one to three radicals of the type lower alkyl, for. Methyl or ethyl, lower alkoxy, e.g. For example, methoxy, hydroxy, halogen, e.g. Fluorine or chlorine, and trifluoromethyl; or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms from the group consisting of N, O and S or a 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms from the group consisting of N, O and S, such a heterocyclic ring bonded via a carbon atom; z. 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl; 3- or 4-pyrazolyl or 2- or 4-imidazolyl; wherein said aromatic heterocyclic ring is unsubstituted or substituted by hydroxy, lower alkyl, e.g. Methyl or ethyl, or halogen, e.g. B.

Fluorine or chlorine, may be substituted; wherein R ^{2 is} hydrogen or lower alkyl, for example methyl; wherein X is oxygen, especially when R ^{1 is} phenyl or substituted phenyl; or wherein X is NR ³ , wherein R ^{3 is} hydrogen or lower alkyl, e.g. Methyl or ethyl, especially when R ^{1 represents} an aromatic heterocyclic ring or a substituted aromatic heterocyclic ring;

and wherein Ring A is unsubstituted or substituted by 1 to 3 halogen groups, e.g. B. 8- or 9-fluoro, 8- or 9-chloro, or 7,9-dichloro; or lower alkyl, e.g. 8- or 9-methyl, as well as pharmaceutically acceptable salts thereof.

The invention more particularly relates to compounds of the formula I in which R ^{1 is} phenyl or halogen-substituted phenyl, in particular in the ortho or meta position, in particular by fluorine or chlorine; or furyl especially 2-furyl; wherein R ^{2 is} hydrogen; wherein X is oxygen, especially when R ^{1 is} phenyl substituted by halogen, e.g. Fluorine in the ortho or meta position; or wherein X is NH, in particular when R ^{1 is} 2-furyl; and wherein Ring A is substituted by halogen in the 8- or 9-position, especially by chlorine in the 9-position, and pharmaceutically acceptable salts thereof.

The invention more particularly relates to the compounds specifically mentioned in the examples.

The compounds of the formula I can be prepared in a manner known per se, for. B.

-6- 812 20

a) by treating a compound of formula II, ^{Wl = <} f " ^Rl

(II)

wherein R ¹ , R ² , X and ring A are as defined above, one of the two radicals W ¹ and W ^{2 is} NH and the other of the two radicals W ¹ and W ^{2 is} O or NH, with a base, or b ) by treating a compound of formula III,

wherein R ¹ , R ² and ring A are as defined above, with a reactive derivative of carbonic acid, or c) by treating a compound of formula IV,

I A

.CN

αν)

wherein ring A is as defined above and Z is the radical of a carbonic acid derivative which is bonded via a nitrogen atom, with a hydrazide of the formula V

CR ¹

H ₂ I

ord) to obtain a compound of formula I wherein R ^{2 is} hydrogen and X is oxygen, by treating a compound of formula VI,

/ \ / V / IA Il J

V \ »

wherein Y is a group which can be converted by an oxidizing agent in the group -N = C = O, with such an oxidizing agent followed by a ring closure, or

e) to obtain a compound of formula I wherein R ^{2 is} hydrogen by reacting the group L in a compound of formula VII,

r ~ ir ^Rl / v IA Il

wherein L is selected from the group halogen, lower alkoxy, aryl-lower alkoxy, mercapto, lower alkylthio and isothiocyanato, in the group XH, or,

f) to obtain a compound of formula I wherein R ^{2 is} hydrogen by treating a compound of formula VIII

-7- 812 20

ϊ A Π T (VIII)

ν * γ \

with a reactive derivative of a carboxylic acid of formula R'-COOH, and if desired, by converting a compound obtained into another compound of the invention and / or by converting a salt obtained into the free compound or other salt and / or by conversion an obtained free compound having a salt-forming group in a salt.

Method a): The base is z. Example, an organic base, preferably a tertiary amine, for. As pyridine or triethylamine, but may also be ammonia.

The ammonia source may, for. A carbamate, such as a lower alkyl carbamate, e.g. As methyl or ethyl carbamate or ammonium carbonate. The reactions may be carried out with or without inert solvent, at atmospheric or elevated pressure, e.g. In an autoclave.

Compounds of the formula II can be prepared by reacting a compound of the formula IX,

(IX)

wherein W ¹ and W ^{2 are} independently O or NH, are reacted with ammonia and / or with a reactive derivative of carbonic acid.

The reactive derivatives of carbonic acid include esters, amides and carbonic acid anhydrides, as well as the corresponding thio or imino compounds, e.g. As phosgene, diethyl carbonate, thiophosgene, Chlororkohlensäuretrichlormethylester, O-ethylurethane, urea, cyanamide or guanidine.

The source of ammonia can also serve as a reactive derivative of carbonic acid, such as. As an O-Niederalkylurethan, such as O-ethylurethane.

When W ¹ and W ^{2 are} oxygen, the compound of formula IX is prepared from an anthranilic acid ester and a hydrazide of formula V (R ¹ CONHNH ₂ ). When W ¹ and W ^{2 are} NH, the compound of formula IX is prepared from an anthranilonitrile and a hydrazide of the formula

R ¹ CNHNH ₂ NH

or a hydrazide of anthranilic acid and a nitrile of the formula R ¹ CN. When W ^{1 is} NH and W ^{2 is} O, the compound of Formula IX is prepared from an anthranilic acid hydrazide and a nitrile of the formula R ¹ CN. When W ^{1 is} oxygen and W ^{2 is} NH, the compound of formula IX is prepared from a hydrazide of anthranilic acid and a reactive derivative of the acid of formula R ¹ COOH, e.g. B. a halide thereof, such as R ¹ COCI or R ¹ COBr or an anhydride of the formula (R ¹ CO) ₂ O prepared.

Process b): The reactive derivative of carbonic acid and the general reaction conditions are the same as those described under process a). As a reactive derivative, furthermore, a cyanogen halide, e.g. As cyanogen chloride or preferably cyanogen bromide, suitable. A suitable base such as triethylamine, pyridine or sodium hydroxide may be added to neutralize the hydrohalic acid formed during the reaction. The cyclization is especially in situ and can be effected by acid such as mineral acid, e.g. Hydrochloric acid, or base, such as a trialkylamine catalyzed. The compounds of formula III can be prepared by the method of Potts et al., J. Org. Chem. 35, 3448 (1970). These compounds can also be prepared by reacting a reactive precursor of anthranilic acid, such as isatoic anhydride, with a hydrazide of the formula

R ¹ CNi

: no ₂

is reacted, or by a thioamide of the formula

R ¹ C-NH ₂

is reacted with a Anthranilsäurehydrazid.

Process c): The remainder of a carbonic acid derivative Z is z. Isocyanato or isothiocyanato; -NHC (= O) O-lower alkyl or -NHC (= S) O-lower alkyl; or -NHC (= O) N-di-lower alkyl or -NHC (= S) N-di-lower alkyl or a corresponding imido derivative, such as cyanimido (-NH-) CN).

The reaction is preferably carried out in a solvent such as an ether, e.g. As dioxane or an alcohol, for. B.

2-methoxyethanol, or a liquid amide, ζ. B. dimethylacetamide.

-8- 812

When Z is isocyanato or isothiocyanates) or NHC (= O) O-lower alkyl or -NHC (= S) O-lower alkyl, the reaction is advantageously carried out in the presence of a base such as a tertiary amine, e.g. Trimethylamine, triethylamine, and especially tripropylamine. The compounds of formula IV in which Z is isocyanato and isothiocyanato can be converted into the corresponding compounds in which Z is -NHC (= O) O-lower alkyl and -NHC (= S) O-lower alkyl by reacting with a lower alkanol, such as ethanol.

The compounds of formula IV in which Z represents -NHC (= O) O-lower alkyl or -NHC (= S) O-lower alkyl may also be prepared by reacting an o-aminobenzonitrile with chlorocarbonyl lower alkyl ester or chlorothiocarbonyl lower alkyl ester, e.g. B. with chloroformate or Chlorthiokohlensäureethylester.

The compounds of formula IV in which Z is -NHC (= O) N-di-lower alkyl or -NHC (= S) N -di-lower alkyl can be prepared by reacting the appropriate o-isocyanatobenzonitrile or o-isothiocyanatobenzonitrile with a di-lower alkylamine such as diethylamine , is implemented.

The preferred solvents when Z is isocyanato or isothiocyanato are ethers, especially dioxane, and more particularly amides such as 1-methyl-2-pyrrolidone. The preferred solvents when Z is -NHC (= O) O-lower alkyl or -NHC (= S) O-lower alkyl or -NHC (= O) N-di-lower alkyl-NHC (= S) N-di-lower alkyl are alcohols, in particular 2-methoxyethanol and more particularly amides, such as 1-methyl-2-pyrrolidinone or dimethylacetamide. The reaction is preferably carried out at temperatures of 0 to 250 ° C, in particular between 20 and 150 ⁰ C. For compounds in which X is NH, are required as starting compounds, for example, o-cyanimidobenzonitriles. Such compounds are described by Wentrup in Tetrahedron 27, 367 (1971) and by Bedford et al. in J. Chem. Soc., 1633 (1959). Presumably, the compound of formula X is

wherein R ¹ , R ² , R ³ and Ring A are as defined above, an intermediate in the cyclization described above.

The double cyclization starting from a compound of the formula X is an integral part of the process described above.

Method d): A group which can be converted by an oxidizing agent into the group -N = C =O can be any group which is of importance for rearrangement reactions such as Hofmann, Curtius or Lossen, and is e.g. Carbamoyl, N-hydroxycarbamoyl or azidocarbonyl.

The oxidizing agent may, for. As lead tetraacetate or a hypohalite. The hypohalite is preferably an alkali metal hypohalite, such as sodium hypochlorite or sodium hypobromite. The said group probably goes through the first stage z. Hofmann reaction (Ber. 14, 2725 [1881]) to form the isocyanate, which then reacts with the free NH of the triazole.

Processed): A compound of formula VII, wherein L represents halogen, lower alkoxy or aryl-lower alkoxy, may be hydrolyzed. The hydrolysis is preferably carried out by base, e.g. B. by sodium hydroxide solution.

The 5-halogeno compounds can be prepared by reacting a compound of formula I in which X is oxygen with a reactive halide such as phosphoryl chloride, Ρ, Ρ-dichlorophenylphosphine oxide or phosphorus pentachloride, with or without inert solvent.

The 5-lower alkoxy or 5-arylalkoxy compounds can be prepared from the 5-halo compounds by treatment with the appropriate alcohol in the presence of base.

Further, a 5-halo, 5-mercapto or δ-alkylmercapto-substituted-ti ^ ltriazoloti ^ -clquinazoline can be substituted by ammonia or substituted ammonia to give compounds of formula I wherein X is NR ³ .

The mercapto group can be replaced by lower alkyl, e.g. Methyl, by replacing the 5-mercapto compound with e.g.

Methyl chloride is reacted in the presence of a base such as sodium hydride.

The compound of formula VII, wherein L represents SCN, may be treated with ammonia or an amine H _? NR ³ are reacted in a polar aprotic solvent, preferably at about room temperature. Dieo-SCN compounds can be prepared from the corresponding 5-thiones by reacting such 5-thione with cyanogen bromide in the presence of a base such as

Sodium hydride is treated.

Method (f): A reactive derivative of a carboxylic acid of the formula R'-COOH may be a corresponding acid halide, e.g.

an acid chloride, an ester such as a lower alkyl ester, an imino ether or thioether, a thioamide or, preferably, an amidine.

The reaction can be carried out with or without solvent, as in the presence of an amide, ζ. Β. of dimethylacetamide, preferably with heating.

The starting materials of formula VIII can be prepared by reacting a compound of formula IV wherein ring A is as defined above and Z is one of the groups -N = C = S, -N = C = O, -NH-CN or -N = C = NR ³ , is reacted with hydrazine or a reactive derivative thereof, e.g. At room temperature in an inert solvent such as an ether, e.g. B.

Tetrahydrofuran. This process is preferred in the preparation of compounds of the formula I, in which X is oxygen and, in particular, sulfur.

Furthermore, a compound obtained can be converted into another compound of the invention. For example, the 5-thione compounds can be converted to the 5-oxo compounds by treating with a hypohalite salt, such as sodium hypochlorite or sodium hypobromite. The 5-imino or substituted imino compounds can be hydrolyzed with aqueous acid to the corresponding 5-oxo compounds. Compounds of formula I wherein R ^{2 is} hydrogen and X is oxygen can be converted to compounds wherein R ^{2 is} lower alkyl, e.g. B.

-9- 812

by reacting with an alkyl halide in the presence of a base such as sodium alkoxide in an inert solvent such as dimethyl sulfoxide.

In the preparation processes for the compounds of the invention described above, the reactions are carried out under standard conditions. For example, the batches may be cooled or heated to suitable temperatures, suitable solvents and catalysts may be added, and the reaction may be conducted under an inert gas atmosphere.

The claimed salts and free compounds are interconvertible. For example, acid addition salts can be converted to free compounds by treating them with a suitable base, and free compounds can be converted to the corresponding acid addition salts by treating with the appropriate acid.

The starting materials for the preparation of the compounds of the invention are either known or can be prepared in a manner known per se.

The compounds of formula I can be used to prepare pharmaceutical compositions containing an effective amount of the triazoloquinazoline compounds of formula I or a salt thereof, in combination with conventional adjunctive or parenteral, oral, bronchial, rectal or intravenous carriers or carriers Administration are suitable. Preference is given to tablets, dragees and gelatine capsules which share the active component with

a) diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, calcium phosphate and / or glycine, b) lubricants, e.g. Silica, talc, stearic acid, their magnesium or calcium salts and / or polyethylene glycol, for tablets also c) binders, e.g. Magnesium aluminum silicate, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, if desired. D) disintegrants, e.g. As starches, agar, alginic acid or sodium alginate, or foaming mixtures, and / or e) absorbents, dyes, flavorings and sweeteners. Dragees or tablet cores may be provided with suitable coatings which may be enteric-coated. Coating solutions are z. B. concentrated aqueous sugar solutions, the gum arabic. Polyvinylpyrrolidone, polyethylene glycol, talc and / or titanium dioxide may contain. Resistant coatings are obtained with paint solutions in organic solvents such as shellac, acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate in ethanol and the like. Dyes or pigments may be added to identify the name and dose.

Capsules are either made of hard gelatin or are soft closed capsules of gelatin and a plasticizer, e.g. As glycerol or sorbitol. The hard capsules contain either unpressed powder mixtures z. B. such as below

a) and b), or granules similar to those used for tablets. In the soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquids, such as in fatty oils, paraffins or polyethylene glycols.

Suppositories are preferably solid fat emulsions or suspensions containing the active ingredient e.g. in natural or synthetic triglycerides, paraffins, waxes and / or polyethylene glycols.

Compositions for parenteral administration are preferably aqueous solutions or suspensions of these compounds, but also oily solutions or suspensions thereof, e.g. B. in natural or synthetic fatty oils, such as sesame oil or ethyl oleate, in suitable ampoules.

Bronchial compositions are preferably aerosol sprays and may be administered from a dispenser as described in U.S. Patents 4,292,966, 4,174,712 and 4,137,914. The active ingredient is mixed with a blowing agent such as a hydrocarbon, a chlorofluorocarbon mixture or carbon dioxide.

These compositions may be sterilized and / or contain additives such as preservatives, stabilizers, moistening or emulsifying agents, solubilizers, salts for regulating osmotic pressure and / or buffers.

They may also contain other therapeutically valuable substances and are produced by conventional techniques such as mixing, granulation or appropriate coating methods. They may contain between 10 and 95%, preferably between 20 and 70% of the active compound. Individual unit doses for a nipple of about 50 to 70 kg in weight may preferably contain between 10 and 200 mg, especially between 20 and 100 mg of said active ingredients.

embodiments

Having described the invention in general terms as follows, specific examples are given below for a more detailed understanding, for illustrative purposes only, and are not intended to limit the scope of the invention in any way, such as to the scope of the examples. Temperatures are given in degrees centigrade, reduced pressure evaporations unless otherwise stated are carried out at 1 to 13kpa.

example 1

7 g of 3- (2-carbamoylphenyl) -5- (4-chlorophenyl) -1H-1,2,4-triazole are dissolved at 50 ° in 180 ml of dry dimethylformamide. 10.4 g of lead tetraacetate are added while stirring, and the batch is stirred for a further 10 minutes under nitrogen. The mixture is added to a mixture of 500 ml of crushed ice and 50 ml of concentrated hydrochloric acid. The white solid which precipitates is isolated, washed thoroughly with cold water and recrystallized from 2-methoxyethanol. There is thus obtained 2- (4-chloropheriyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, m.p.315-318 ° C.

The starting material is prepared as follows: A mixture of 61 g of 1-hydrazinophthalazine hydrochloride, 43.4 g of p-chlorobenzaldehyde and 200 ml of methanol is refluxed for 18 hours under nitrogen. The mixture is concentrated under aspirator vacuum, stirred for a few minutes and filtered. The yellow solid obtained is washed with ether (3 × 300 ml), the p-chlorophenylhydrazone is isolated and used directly in the following reaction: 120 g of this p-chlorophenylhydrazone are dissolved in a mixture of 2300 ml of glacial acetic acid and 160.1 g of anhydrous sodium acetate at room temperature for several minutes stirred under nitrogen. 26.2 ml of bromine in 150 ml of glacial acetic acid are added dropwise, then the mixture is stirred for 12 hours at 90 ⁰ C, cooled and filtered. The filtrate is concentrated to dryness under reduced pressure. The solid obtained is stirred into 800 ml of water, neutralized with sodium hydroxide solution and stirred for 18 hours. The product, 3- (4-chlorophenyl) -1,2,4-triazolo [3,4-a] phthalazine; mp. 222-225 ⁰ C, is further used without purification. The pure compound melts after recrystallization from ethanol at 224-225 ⁰ C.

-10- 81220

To a mixture of 12.7 g of sodium methylate and 1 500 ml of ethanol are added 66 g of the described triazolophthalazine. The batch is heated under nitrogen for 6 days under nitrogen. The mixture is concentrated under reduced pressure to 100 ml, diluted with 1000 ml of water, stirred for 2 hours, filtered and adjusted to pH 5 with cooling with hydrochloric acid. The solid 3- (4-chlorophenyl) -5- (2-cyanophenyl) -1H-1,2,4-triazole is isolated, washed with water and air-dried The material is sufficiently clean for the next step. but can also be further purified by recrystallization from a mixture of ethanol 'and isopropanol to give a white solid, mp 236-238 ° C. 5 g of the described crude nitrile are dissolved in 20 ml of 85% sulfuric acid, 90 minutes at stirred 80 ⁰ C and 400 ml of ice water. the precipitate is isolated, washed with water, pressed dry on the filter and washed with ether. the product, 3- (2-carbamoylphenyl) -5- (4-chlorophenyl) -1H-1 , 2,4-triazole is recrystallized from 2-methoxyethanol to give the pure amide, mp. 234-237 ⁰ C.

Example 2: Following the procedure of Example 1, 3- (2-carbamoylphenyl) -5-phenyl-1H-1,2,4-triazole is converted into the 2-phenyl-1-triazolo-1-ol-quinazoline oil, m.p. .311-313 ° C after recrystallization from ethanol. The reaction takes place for one hour at 80.degree. The carbamoyl-compound, mp. 222-225 ⁰ C., after Druey, Fungier, Helv. Chim. Acta 34, 195-210 (1951) starting from 3-phenyl-1,2,4-triazolo [3,4-a] phthalazine over the nitrile, as described in Example 1.

Example 3: To a solution of 20.5 g of 3- (2-carbamoylphenyl) -5- (3-pyridyl) -1H-1,2,4-triazole in 600 ml of dry dimethylformamide, 9.4 g of glacial acetic acid are added, with stirring 4O ⁰ C 35g lead tetraacetate are added. The dark red mixture is stirred at 85 ^° C. under nitrogen for 66 hours, poured into 2,000 ml of ice-water and cooled. After 20 hours, the precipitated solid is isolated, dissolved in hot ethanol and filtered through diatomaceous earth. The ethanolic filtrate is treated with 4.7 g of p-toluenesulfonic acid hydrate. Addition of dry ether gives the tosylate of 2- (3-pyridyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, mp. 268-271 ⁰ C. Concentration of the aqueous mother liquor and continuous extraction with ether gives a further amount of less pure material.

The starting amide, mp. 248-250 ⁰ C after recrystallization from 2-methoxyethanol, is of 3- (3-pyridyl) -1,2,4-triazolo [3,4-a] phthalazine [Haase, Biniecki, Chem. Abstracts 61,3103b (1964)] on the nitrile as described in Example 1, except that the nitrile and amide are isolated at neutral pH.

Example 4: To a mixture of 6 g of 2- (4-chlorophenyl [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) on and 150 ml of dry dimethylsulfoxide are added 1.3 g of sodium methylate is heated for one hour under nitrogen at 85 ^° C., and 1.3 ml of methyl iodide in 10 ml of dimethylsulfoxide are added, a white solid is formed rapidly, the batch is heated for a further 3 hours, cooled and poured into 800 ml of ice water The solid is washed with water, dried in air and recrystallised twice from dimethylacetamide to give pure 2- (4-chlorophenyl) -6-methyl [1,2,4] triazolo [1,5-c] quinazolin-5 (6H ) on, mp. 323-325 ⁰ C.

Example 5: By the same method as in Example 4, 2-phenyl [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one is quantitatively converted to the crude 6-methyl compound and then recrystallized Tetrahydrofuran, mp. 231-234 ° C.

Examples: A mixture of 10.4 g of 2-phenyl- [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one and 150 ml of dry dimethylformamide is mixed with 1.8 g of a 57% Treated dispersion of sodium hydride in mineral oil, heated under nitrogen to 100 ⁰ C and 10 minutes later added dropwise over 20 minutes with 7.7 g of trans-cinnamyl bromide in 75 ml of dimethylformamide. The mixture is stirred at 65 ^° C. under nitrogen for four hours, cooled and poured into ice-water. The crude precipitate is recrystallized from dimethylacetamide and then from dimethyl sulphoxide. This gives the pure 6-trans-Cinnamylderivat, mp 167-169 ° C.

Example 7: A mixture of 13 g of 2-phenyl [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) on and 100 ml of dry dimethylformamide is mixed with 2.05 g of a 57% dispersion of sodium hydride in Treated mineral oil and stirred under nitrogen for two hours. To the clear solution, 0.2 g of potassium iodide, then 2.05 g of the dispersion of sodium hydride in OeI and then 8.3 g / 3-3-picolyl chloride is added very gradually, the temperature increases to 50 ⁰ C. The mixture is stirred under nitrogen for 20 hours at 50 ⁰ C and added to 600 g of crushed ice. The white solid is washed in isolation with water and taken up in 400 ml of boiling ethanol. After filtration, the filtrate is adjusted to pH 2 with methanesulfonic acid. The crude salt is recrystallized from ethanol and suspended in 100 ml of a mixture of ether and 0.5N sodium hydroxide solution. The free base is isolated and purified by recrystallization from isopropanol. The pure 6- (3-picolyl) derivative is obtained, mp 202-204 ° C.

Example 8: A solution of 7,3 g of 2- (3-pyridyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) on p-toluenesulfonate in 60 ml of dry dimethyl sulfoxide is treated with 1 Treated 4g of a 57% dispersion of sodium hydride in mineral oil. The reaction is heated under nitrogen for ¹ hour at 6O ⁰ C and then treated with 2.4 g of methyl iodide. After stirring for 24 hours under nitrogen at 60 ⁰ C, the mixture is poured into 500 ml of ice water, the precipitate isolated, washed with water and dried in air. It is suspended in 400 ml of methanol, adjusted to pH 4 with p-toluenesulfonic acid, and the salt is precipitated by the addition of ether. The crude salt is suspended in 2 N sodium hydroxide solution, isolated, washed with aqueous sodium thiosulfate solution, then with water, ethanol and again converted into the tosylate. The salt is recrystallized from ethanol. The pure 6-methyl derivative is obtained as tosylate, mp. 217-219 ° C.

Examples: A mixture of 15 g of 1- (2-aminobenzoyl) -2- (isonicotin-imidoyl) hydrazine and 300g Ethylcarbamatwird four and a half hours under nitrogen at an external temperature of 210 ⁰ C stirred on a water separator. In this case, about 90 ml of liquid are obtained. The remaining material, which solidifies on cooling is stirred at 60 ⁰ C for one hour in 500 ml of water, isolated, stirred vigorously with 500 ml of ethyl acetate and re-isolated. The crude product is then dissolved in water, adjusted to pH 13 with sodium hydroxide, filtered and neutralized with acid. The precipitated product is dissolved in 200 ml of 2-

-11- 81220

Methoxyethanol suspended, acidified with p-toluenesulfonic acid and treated with ether. The precipitated salt is purified by transferring it to the free base, returning it to the tosylate and recrystallizing from methanol. This gives pure 2- (4-pyridyl) - [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) on p-toluenesulfonate, mp. 271-274 ° C.

The starting material is prepared as follows: 16 g of 4-pyridylhydrazidine are mixed with 16.3 g of isatoic anhydride, 200 ml of dry pyridine are added, and the reaction is stirred overnight at room temperature under nitrogen. The precipitate is isolated, washed with 50 ml of tetrahydrofuran and 500 ml of dry ether and dried in air. The product of mp. 231-235 ⁰ C is obtained. Mixture of the mother liquor with 1 000 ml of petroleum ether gives a further amount of mp. 221-224 ⁰ C.

Example 10: Following the procedure of Example 9, 3-pyridyl-hydrazidine is treated with 5-chloroisatoic anhydride. The product, mp. 189-193 ⁰ C is condensed with ethyl carbamate. This gives g-chloro-O-pyridylfi ^^ ltriazoloti.B-cJchinazolin-5 (6H) on as p-toluenesulfonate, mp. 320-322 ° C.

Example 11: A mixture of 6 g of 3- (2-amino-3,5-dichlorophenyl) -5-phenyl-1H-1,2,4-triazole and 50 g of ethyl carbamate is heated to 195 ^° C. under nitrogen for 6 hours, then it is heated Cooled 80 ⁰ C, poured into 1000mlWas stirred for 16 hours. The product is isolated, washed with water, then with 300 ml of methanol and dried in air. The crude material is recrystallized from 2-methoxyethanol / water (12: 1). Pure 7,9-dichloro-2-phenyl [1,2,4] triazolo [1,5-c] quinazoline is obtained.

5 (6H) on, m.p. 309-311 ° C.

The triazole used as starting material is prepared as follows: 25 g of benzamidine hydrochloride are dissolved in 100 ml of methanol and treated with 13 g of 50% sodium hydroxide solution. The salt is filtered off, the solution is added to 26 g of 2-amino-3,5-dichlorobenzoic acid hydrazide in 300 ml of toluene. The batch is refluxed under nitrogen for 60 hours in an apparatus with a water separator. The deposited liquid is removed, fresh toluene is added during this time. The mixture is concentrated under reduced pressure to 75 ml and treated with 300 ml of petroleum ether. The white product is isolated and recrystallized from methanol. The pure product is obtained, mp 235-238 ° C.

Example 12: Following the procedure of Example 11, 3- (2-amino-5-chlorophenyl) -3- (2-pyridyl) -1H-1,2,4-triazole in 9-chloro-2- (2-pyridyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, m.p.> 34O ⁰ C, converted. The triazole used as starting material is prepared as follows: A mixture of 12g of 5-chloroisatoic anhydride, 8.3 g 2-Pyridylhydrazidin and 150ml of pyridine was stirred 20 hours under nitrogen, 200 ml of ether are added, and the product, mp 230-232 ^0th C, is isolated. This intermediate, 1- (2-amino-5-chlorobenzoyl) -2-picolinimidoy! Hydrazine, in 150ml of a mixture of diphenyl ether / biphenyl (3: 1), stirred for 5 hours under nitrogen at 18O ⁰ C, cooled and washed with 200 ml of hexane. The product is isolated and is thus obtained, after recrystallisation from ethanol, said triazole, mp. 207-209 ⁰ C.

Example 13: A suspension of 7 g of 3- (2-amino-5-chlorophenyl) -5-phenyl-1H-1,2,4-triazole in 100 ml of dry dioxane is treated with 5.1 g of trichloromethyl chloroformate and added under nitrogen for 90 minutes Room temperature stirred. 2.62 g of triethylamine are added and stirring is continued for another 18 hours. The reaction is then refluxed for one hour and cooled, the solid is isolated, washed with ether, then with water and then suspended in water and stirred vigorously for 90 minutes. The product m.p.> 340 ° C is pure g-chloro-phenylti ^^ triazoloti.ö-cl-quinazoline Biei-llon. The triazole used as the starting material is prepared as follows: As described in Example 11, the free benzamidine base is prepared from 4.64 g of the hydrochloride in 110 ml of ethanol. It is added to a solution of 5 g of 2-amino-5-chlorobenzoic acid hydrazide in 200 ml of chlorobenzene / ethanol (9: 1) in an apparatus with a water separator. The batch is refluxed under nitrogen for four hours, during which time 130 ml of liquid are separated off, and further chlorobenzene is added in order to keep the amount of liquid approximately constant. The mixture is cooled, 200 ml of ether are added, the product is isolated, washed with ether and dried in air. The triazole, mp 254-255 ⁰ C, is analytically pure.

Examples 14-21: In a manner analogous to that described in Example 13, compounds of the formula I in which R ^{2 is} hydrogen and X is oxygen are selected from the corresponding 3- (2-aminophenyl) -5-substituted-1 H-1, 2,4-triazoles, which in turn can be prepared from the corresponding amidine and 2-amino-5-chlorobenzoic acid hydrazide:

R ¹

14 14 9-CI 4-methylphenyl

4-fluorophenyl 4-methoxyphenyl 3,4,5-trimethoxyphenyl 2-furyl 2-thienyl 3-fluorophenyl 4-trifluoromethylphenyl

Example 22: Analogously to Example 13, 3- (2-amino-5-chlorophenyl) -5- (2-fluorophenyl) -1H-1,2,4-triazole is converted into the 9-chloro-2- (2-fluorophenylHI) Itriazoloti ^ -clchinazolin-öieHlon, mp> ° C, converted.

The triazole is prepared as follows: A mixture of 6.0 g of 2-fluorobenzamide and 8.7 g of 2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1,3-dithia-2,4-diphosphetane ( Lawesson's reagent) in 100 ml of toluene is refluxed for three hours and stirred, concentrated to dryness under reduced pressure and triturated with dry ether. The solid thus obtained is washed again with ether. The combined ether phases are filtered through silica gel and concentrated. This gives the solid thioamide, which is used without further purification. The thioamide is used together with 7.9 g of 2-amino-5-chlorobenzoic acid hydrazide in

Number of the substituent example from ring A 14 9-Cl 15 9-Cl 16 9-Cl 17 9-Cl 18 9-Cl 19 9-Cl 20 9-Cl 21 9-Cl

Mp. Mp of the used product triazole > 320 ⁰ C > 300 ⁰ C > 320 ° C 254-257 ° C > 320 ⁰ C 217-219 ⁰ C > 290 ⁰ C 243-248 ° C > 340 ° C 236-237 ⁰ C > 330 ° C 250-251 ° C > 320 ⁰ C 260-263 ⁰ C 334-336 ⁰ C 215-217 ⁰ C

-12- 812

100 ml of a mixture of diphenyl ether / biphenyl (3: 1) and stirred under nitrogen at 180 ⁰ C for 20 hours. The cooled mixture is diluted with 200 ml of hexane and filtered. The precipitate is purified by high pressure liquid chromatography in 2- (2-amino-5-chlorophenyl) -5- (2-fluorophenyl) -1,3,4-oxadiazole, m.p. 168-170 ° C, and the desired triazole Fp.211- 213 ° C, separated.

Example 23: 1.36 g of benzoylhydrazine in 50 ml of dry dioxane with T, 44g o-lsocyanatobenzonitril in 20 ml of dioxane and kept for one hour at 80 ^c C under nitrogen. After cooling, 1.87 g of solid are isolated. Evaporation of the mother liquor and treatment with ether gives an additional amount of solid. The combined material, mp> 295 ⁰ C, is used directly in the next stage. It is added to a mixture of 30 ml of concentrated ammonium hydroxide solution and 120 ml of ethanol and refluxed for 2 hours under nitrogen. The solution is partially evaporated under reduced pressure to remove the ethanol and cooled. The precipitate is isolated and washed with water. The product, Fp.310-313 ⁰ C is identical to the 2-phenyl [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, is described Dasin Example 2. Fig.

Example 24: In an analogous manner as in Example 23, the intermediate with the Fp.300 ⁰ C, prepared from 2-isocyanatobenzonitrile and 2-fluorobenzoylhydrazine, in 2- (2-fluorophenyl) [1,2,4] triazole [1, 5-c] quinazolin-5- (6H) on, m.p. 326-329 ⁰ C, converted.

Example 25: The intermediate prepared from 6.1 g of 2-isocyanato-5-chlorobenzonitrile and 7.0 g of 4-hydroxybenzoylhydrazine as described in Example 23 is added to a mixture of 31 ml of triethylamine, 25 drops of methanesulfonic acid and 300 ml of ethanol and stirred under nitrogen for two hours under reflux. The mixture is concentrated to dryness under reduced pressure, taken up in ethanol and treated with water. The solid is isolated, washed with water and dried under high vacuum. Pure 9-chloro-2- (4-hydroxyphenyl) [1,2,4] triazolot1,5-c] quinazolin-5 (6H) one, m.p.> 350 ° C, is obtained.

Example 26: The intermediate of 2-tetrahydrofuroylhydrazine and 6-chloro-1-isocyanatobenzonitrile prepared analogously to the method described in Example 23 is, as described in Example 25, in 9-chloro-2- (2-tetrahydrofuryl) [1,2 , 4] triazolo [1,5-c] quinazolin-5 (6H) on, mp. 239-243 ° C, converted.

Example 27: The intermediate of N-methylpipecolic acid hydrazide and o-chloro-isocyanatobenzonitrile, prepared analogously to the method described in Example 23, is converted into 9-chloro-2- [2- (1-methylpiperidyl)] as described in Example 25. - [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) on and cleaned as a fumarate with mp. 274-276 ° C.

Example 28: A suspension of 3.8 g of 3- (2-amino-5-chlorophenyl) -5- (2-pyridyl) -1H-1,2,4-triazole, precursor for Example 12, in 100 ml of methanol is charged with 1 , 5g Bromcyän added and stirred under nitrogen for 18 hours under reflux. 1.43 g of triethylamine are added, it is stirred for a further hour under reflux. After filtration, the solid is washed with methanol and ether, it melts above 330 ⁰ C. It is suspended in 100 ml of methanol, an equimolar amount of methanesulfonic acid is added, allowed to stir overnight. The product is isolated, washed with methanol and dried in vacuo. This gives pure 9-chloro-5-imino-2- (2-pyridyl) -5,6-dihydro [1 _/ 2,4] triazolo [1,5-c] quinazolinemethanesulfonate, m.p. 248-250 ° C.

Examples 29-36: In a manner analogous to Example 28, the following compounds of formula I in which R ^{2 is} hydrogen and X is NH are prepared from the corresponding triazoles. In some examples, the free base is isolated, in others a different salt than the methanesulfonate (mesylate).

Number of the substituent R ¹ Type of salt Mp of the product example from ring A 29 9-Cl 4-methylphenyl mesylate 312-315 ⁰ C 30 9-Cl 4-fluorophenyl tosylate 310-312 ° C 31 9-Cl 3,4,5-trimethoxyphenyl mesylate 278-282 ⁰ C 32 9-Cl phenyl - 284-286 ° C 33 9-Cl 2-furyl mesylate 275-280 ° C 34 9-Cl 3-fluorophenyl - > 0 ⁰ E] ⁰ C 35 9-Cl 2-thienyl mesylate 247-252 ⁰ C 36 9-Cl 4-trifluoromethylphenyl mesylate 286-290 ⁰ C

Example 37: 1.41 g of 2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5-c] quinazoline are combined with 200 ml of ethanol and 100 ml of 70% aqueous ethylamine in an autoclave made of stainless steel at an external temperature of 150 ⁰ C heated. A pressure of 70OkPa is reached, the batch is kept for 16 hours under these conditions. After cooling, the material is concentrated to dryness under reduced pressure. The resulting solid is recrystallized from methanol. Pure 5-ethylimino-2- (2-furyl) -5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, m.p. 133-135 ° C, is obtained. The 5-methylthio compound used as starting material is prepared as follows: A mixture of 15.8 g of 2-furancarboxylic acid hydrazide, 20 g of 2-cyanophenylisothiocyanate and 600 ml of dry dioxane is stirred under nitrogen for one hour under nitrogen. The reaction is evaporated to dryness under reduced pressure, the residue is triturated with methanol and the solid is isolated. 32.6 g of this intermediate, mp> 300 ° C, are suspended in a mixture of 230 ml of triethylamine, 1800 ml of ethanol and 7 ml of methanesulfonic acid, stirred for two hours under nitrogen under reflux, concentrated under reduced pressure to a thick oil, in 300 ml of ethanol and stirred until complete crystallization is. The solid, crude 2- (2-furyl) -5-mercapto [1,2,4] triazolo [1,5-c] quinazoline, m.p.> 300 ° C, is used directly in the next step.

-13- 812 20

2.01 g of this mercapto compound are added to a solution of 0.83 g of sodium methylate in 20 ml of methanol, the mixture is stirred for a few minutes and then treated with 0.47 ml of methyl iodide. A solution is formed, and after one hour of heating at a bath temperature of 80 ⁰ C, a dense precipitate has formed, which is further diluted with methanol, cooled and dried in air. The solid, m.p. 188-190 ° C, is isolated, washed with methanol and dried in air.

Example 38: In a manner analogous to that described in Example 37, 2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5-c] quinazoline with 40% aqueous methylamine in ethanol in 2- ( 2-Furyl) -5-methylimino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, mp. After recrystallization from methanol 193-195 ⁰ C, converted.

Example 39: As in Example 37, 2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5-c] quinazoline is added with ammonium hydroxide solution saturated with ammonia at ⁰ ° C for 6 hours 15O ⁰ C and a pressure of 1.15 MPa implemented in a stainless steel autoclave. 2- (2-Furyl) -5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, mp 282-285 ° C., after recrystallization from methanol.

Example 40: A mixture of 4.8 g of 3- (2-methylaminophenyl) -5- (2-furyl) -1H-1,2,4-triazole, 2.17 g of cyanogen bromide and 150 ml of methanol is refluxed for 18 hours under nitrogen , The mixture is filtered hot to 600mg (2- (2-furyl) -6-methylli ltriazoloti ^^ ^ -clchinazolin-öieHion, Fp.238,5-214,5 ⁰ C to remove after recrystallization from 2-methoxyethanol. After Cooled, a white solid is obtained, which is taken up in methanol and treated with 2.8 ml of triethylamine, then refluxed for two hours, diluted with cold water and isolated by filtration The solid material is made from a 2-methoxyethanol / methanol mixture The salt is then taken up in 300 ml of water containing several drops of methanesulfonic acid, filtered for purification, concentrated to a small volume under reduced pressure and precipitated by the addition of isopropanol The product is dried under high vacuum at 100 ° C. for 18 hours, giving pure 2- (2-FuryD-S-imino-B-methyl-S) -dihydroH ^^ ltriazoloH ^ -c-quinazolinemethanesulfonate, mp. 263 ° C. The starting material is prepared as follows: 14.5 g of 2- (methylamino) benzoic acid hydrazide [Hetteretal, J. prakt. Chem. 111, 36-53 (1925)] are reacted with 2-furanamidine as described in Example 13 described from 12.9 g of the hydrochloride is treated; This gives the desired triazole, mp. 179-183 ⁰ C.

Example 41: In a stainless steel autoclave, 50 ml of concentrated ammonium hydroxide aqueous solution is saturated with ammonia gas at ⁰ ° C, and 1.22 g of 5,9-dichloro-2- (2-tetrahydrofuryl) [1,2,4] triazolo [1,5-c] quinazoline is added. The mixture is heated for 6 hours at an external temperature of 15O ⁰ C, cooled and filtered. The precipitate is washed with water and dried under high vacuum. This gives pure 9-chloro-5-imino-2- (2-tetrahydrofuryl) -5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, Fp.203-206 ⁰ C.

The starting material is prepared as follows: A mixture of 45 ml of phosphoryl chloride, 0.3 g of phosphorus pentachloride and 2.1 g of the product of Example 26 is stirred under nitrogen at room temperature. After five minutes, 1.2 ml of pyridine are added dropwise. The batch is gradually heated to 110 ^° C. for one hour, stirred at this temperature for 16 hours, filtered and concentrated to dryness under reduced pressure. The residue is taken up in ethyl acetate, washed with 2N hydrochloric acid, dried over sodium sulfate and concentrated to dryness. Recrystallization from Essigester yields the dichloro compound, melting at 150-152 ⁰ C.

Example 42 A mixture of 300 ml of concentrated aqueous ammonium hydroxide solution saturated with ammonia gas at ⁰ ° C. and 5.7 g of 9-chloro-2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5- c] quinazoline is heated in a stainless steel autoclave at an external temperature of 150 ⁰ C for 18 hours. At this time, the pressure rises to 1.7MPa. After cooling, the solid material is isolated, washed with water and dried in air. The thus-obtained 9-chloro-2- (2-furyl) -5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, m.p. 269-271 ° C, is converted to the methanesulfonate salt by dissolving in 150 ml of 2-methoxyethanol and adding 0.66 ml of methanesulfonic acid and 25 ml of dry ether. This gives the pure salt, which is identical to that of Example 32.

The starting material is prepared as follows: A suspension of 40.6 g of 2-amino-5-chlorobenzonitrile in 400 ml of water is added dropwise with 20.3 ml of thiophosgene under nitrogen and with vigorous stirring. After three hours of stirring, the isothiocyanate is isolated, washed with water, then twice with 100 ml of cyclohexane, and dried in vacuo. 18.5 g of isothiocyanate and 28.7 g of 2-furoylhydrazine in dioxane are heated under nitrogen for one hour under reflux. After cooling, 22.2 ml of triethylamine and 0.1 ml of methanesulfonic acid are added. After two more hours under reflux, the mixture is concentrated to dryness under reduced pressure, suspended in 300 ml of isopropanol and stirred vigorously for one hour. The solid is isolated and dried in air. The thus obtained 9-chloro-2- (2-furyl) -5-thiono ^j 5,6-dihyd> o [1,2,4] triazolo [1,5-c] quinazoline is used directly in the next step: A mixture of 17.7 g of 9-chloro-2- (2-furyl) -5-thiono-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, 200 ml of methanol and 31.4 g Sodium methoxide is stirred for five minutes at room temperature under nitrogen and then treated dropwise with 3.7 ml of methyl iodide. 200 ml of methanol are added, the mixture is stirred under nitrogen for 2 hours at a bath temperature of 8O ⁰ C, cooled, and the 9-chloro-2- (2-furyl) -5-methylthio [1,2,4] triazolo [ 1,5-c] quinazoline is isolated, washed with water and dried in air, mp 202-207 ⁰ C.

Example 43: Analogously to Example 42, 2- [2- (N-methylpiperidyl)] - 5-methylthio [1,2,4] triazolo [1,5-c] quinazoline is prepared in 5-imino-2- [2- (N-methylpiperidyDl-Se-dihydroIl Itriazoloti ^^ ^ -cJchinazolin, mp. 193-194 ⁰ C, placed. the methylthio compound, mp. 142 ° C, is prepared from the mercapto compound, which in turn from o- Cyanophenylisothiocyanat and N-Methylpipecolinsäurehydrazid, as described in Example 42, win.

Example 44: Analogously to Example 42, 2- [2- (N-methylpyrrolyl)] - 5-methylthio [1,2,4] triazolo [1,5-c] quinazoline in 5-imino-2- [2- (2- N-methylpyrrolylll-S ^ ^^ -dihydroII Itriazolofi ^ -clchinazolin, mp. 251-254 ⁰ C, placed. The starting material is prepared as described in example 42, prepared by reacting o-Cyanphenylisothiocyanat and N-methylpyrrole-2- starting from carboxylic acid hydrazide.

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Example 45: 4.28 g of 2- (2-pyrrolyl) -5-thiono-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, analogous to Example 39 prepared from S-chloro ^ -isothiocyanatobenzonitril and 2-Pyrrolcarbohydrazid, are added with 225 ml of a 40% aqueous solution of methylamine, which was saturated at 0 ⁰ C with methylamine gas, in a stainless steel autoclave and heated at an external temperature of 150 ° C for 6 hours. The batch is cooled to room temperature, the solid is isolated, washed with water and dried in air. Recrystallization from aqueous methanol then water gives pure 5-methylimino-5,6-dihydro-2- (2-pyrrolyl) - [1,2,4] triazolo [1,5-c] quinazoline, m.p. 220-221X ,

Example 46 Analogously to Example 39, 3-furancarboxylic acid hydrazide is reacted with δ-chloro-cyano-phenyl isothiocyanate. There is obtained 2- (3-furyl) -5-mercapto [1,2,4] triazolo [1,5-c] quinazoline, m.p.> 300 ° C, which is converted to the 5-methylthio compound and then in the 9-chloro-2- (3-furyl) -5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline which is purified as the methanesulfonate acid, m.p. 292 ⁰ C.

Example 47 Analogously to Example 13, 3- (amino-5-chlorophenyl) -5- (3-furyl) -1H-1,2,4-triazole, which is prepared by evaporation of the mother liquor from the preparation of the imino compound of the Example 46 is converted into the 9-chloro-2- (3-furyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, which, after recrystallization from dimethylacetamide-water has a mp> 350 ⁰ C.

Example 48: A mixture of 5.7 g of 9-chloro-2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5-c] quinazoline and 40 ml of cyclohexylamine is stirred for 6 hours under nitrogen heated to reflux. After cooling, the solid is isolated and recrystallized from ethanol. There is obtained pure 9-chloro-5-cyclohexylamino-2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazoline, mp. 158-160 ⁰ C.

Example 49: A mixture of 5,6g9-chloro-2- (2-furyl) -5-mercapto [1,2,4] triazolo [1,5-c] quinazoline and 40 ml of aniline is stirred under nitrogen for 66 hours at 150 ⁰ C stirred. The mixture is heated on a rotary evaporator under aspirator vacuum to remove residual aniline and recrystallized from aqueous ethanol. Pure 9-chloro-2- (2-furyl) -5-phenylimino

n, mp 231-233 ° C.

Example 50: Analogously to Example 37, 1.06 g of 9-chloro-2- (2-furyl) -5-methylthio [1,2,4] triazolo [1,5-c] quinazoline are placed in a 50 ml stainless steel autoclave Isopropylamine at 150 ⁰ C (ambient temperature) for 6 hours to react. 9-Chloro-2- (2-furyl) -5-isoporphylimino-5,6-dihydro [1,2,4] -triazolo [1,5-c] quinazoline, which after recrystallization from ethanol at 140-141 ⁰ C melts.

Example 51: A mixture of 1.9 g of N-carbethoxyanthranilonitrile, prepared according to Breukink and Verkade, Rec. Trav. Chim. 79,443 (1960) and 1.26 g of 2-furancarboxylic acid hydrazide, 50 ml of 2-methoxyethanol and 1 ml of tri-n-propylamine are heated under nitrogen for 20 hours under reflux. A portion of the solvent, 30 ml, is distilled off, allowed to cool the mixture. The white crystals are isolated, washed with methanol and dried in vacuo. Pure 2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one is obtained, mp 338-343 ° C.

Example 52 Analogously to Example 51, 9-chloro-2- (3-chlorophenyl) - [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one, m.p.> 350 ° C., prepared from 4.2 g of N-carbomethoxy-ö-chloro -aminobenzonitrile and 3.4 g of 3-chlorobenzhydrazide. The urethane starting material used is prepared by reacting 15.6 g of 2-amino-5-chlorobenzonitrile, 200 ml of ethyl methyl ketone and 10 g of sodium bicarbonate with 8.4 ml of methyl chlorocarbonate for 42 hours under nitrogen at 80 ° C. The mixture is cooled, freed by filtration of inorganic material, concentrated to dryness under reduced pressure and recrystallized from chlorobenzene-cyclohexane; the product thus obtained has a mp of 126-132 ⁰ C.

Example 53: In a manner analogous to Example 52, 4.2 g of N-carbonmethoxy-6-chloro -aminobenzonitrile with 3.1 g of 2-fluorobenzhydrazide in 100 ml of 2-methoxyethanol with 0.3 ml of tri-n-propylamine under nitrogen Heated under reflux for hours. This gives pure 9-chloro-2- (2-fluorophenyl) [1] itriazoloti.S-clchinazolin-ethylen which is identical to the material described in Example 22.

Example 54: A mixture of 3.0 g of N- (2-cyanophenyl) -0-ethylthiourethane, 1.83 g of 2-furancarboxylic acid hydrazide, 2 ml of tri-n-propylamine and 50 ml of 2-methoxyethanol is heated under nitrogen and reflux for 18 hours. The reaction is concentrated under reduced pressure to a viscous oil which crystallizes on treatment with methanol. The solid is identical to 2- (2-furyl) -5-mercapto [1,2,4] triazolo [1,5-c] quinazoline, the preparation of which is described in Example 37. The thiourethane is prepared by refluxing o-cyanophenyl isothiocyanate in excess absolute ethanol overnight under nitrogen. After filtration at room temperature, the filtrate is concentrated to dryness under reduced pressure. The residual solid is recrystallized ausCyclohexan, one obtains the thiourethane, mp. 87-89 ⁰ C.

Example 55. While cooling in an ice bath, ammonia gas is passed through a solution of 15 g of 9-chloro-2- (2-furyO-S-thiocyanato) -triazolone-cinquinazoline in 200 ml of 1,3-dimethylimidazolidone for 90 minutes, after an additional hour at ambient temperature, dilute the reaction with 500 ml of water, isolate the solid, and recrystallize from 2-methoxyethanol with a small amount of water, dried for 18 hours at 100 ° C / 26Pa, pure 9-chloro-2- (2-furyl) - S-imino-Be-dihydron-1-triazolo-ti-c-quinazoline, mp 279-280 ° C. The starting material is described in principle as described by Vlattas et al., J. Heterocyclic Chem., 20, 1287 (1983), prepared in a nitrogen atmosphere to a suspension of 790 mg of sodium hydride (50% in oil) in 40 ml of dry tetrahydrofuran 5 g of 9-chloro-2- (2-furyl) -5-thiono-5,6- dihydro- [1,2,4] triazolo [1,5-c] quinazoline in portions The mixture is stirred for two hours under nitrogen, externally a Cooled to ^{0 0} C and treated dropwise under nitrogen with a solution of 1.75 g of cyanogen bromide in 15 ml of tetrahydrofuran. It is stirred in an ice bath for 90 minutes, diluted with 100 ml of water and extracted three times with 100 ml of ethyl acetate. The combined organic extracts are filtered, dried over magnesium sulfate and concentrated to dryness under reduced pressure. This gives the desired thiocyanate compound in sufficient purity. Recrystallization from 2-methoxyethanol gives the pure material, mp 218-22O ⁰ C.

-15- 81220

Example 56: A mixture of 1.79 g of N, N-dimethyl-N '- (4-chloro-2-cyanophenyl) urea, 1.05 g of 2-furancarboxylic acid hydrazide and 25 ml of 2-methoxyethanol is refluxed for 20 hours under nitrogen. The mixture is cooled and the crystalline 9-chloro-2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6) one isolated, washed with water, then with methanol and dried in vacuo. The material is identical to the compound obtained according to Example 18. The urea used as the starting material is prepared by dissolving 2.7 g of 4-chloro-2-cyanophenyl isocyanate in 100 ml of warm toluene and treating with 20 ml of a 17.6% solution of dimethylamine in toluene for 20 hours at room temperature under nitrogen. The batch is concentrated to dryness under reduced pressure while allowing the temperature to rise to not more than 50 ⁰ C. A solid is obtained which is converted by recrystallization from cyclohexane to the pure urea, mp 95-97 ° C.

Example 57: A mixture of 2.15 g of N-carbethoxy-δ-nitroanthranilonitrile, 1.56 g of 2-fluorobenzhydrazide, 1 mL of tri-n-propylamine and 50 mL of (RS) -I-methoxy-2-propanol is allowed to sit under nitrogen for 20 hours Reflux heated. The mixture is cooled, treated with 50 ml of methanol and filtered. The white precipitate is washed with methanol and recrystallized from dimethylacetamide / ethanol. This gives pure 2- (2-fluorophenyl) -9-nitro [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) -one, which melts above 35O ⁰ C.

Example 58: A solution of 2 g of 9-chloro-2- (2-furyl) -5-thiocyanato [1,2,4] triazolo [1,5-c] quinazoline in 28 ml of 1,3-dimethylimidazolidone is added to 2 ml Tert-butylamine given. The mixture is stirred for 3 hours under nitrogen, diluted with 20 ml of ethanol and treated with 20 ml of water. The precipitate is isolated, recrystallized from 2-methoxyethanol and dried under high vacuum. This gives pure 5-tert-butylamino-9-chloro-2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazoline, mp> 330 ° C.

Example 59: When ethanolamine is used instead of tert-butylamine as in Example 58, 9-chloro-2- (2-furyO-B-hydroxyethylamino-tis-1-triazoloti) -c-quinazoline, m.p. 217 ⁰ C, received.

Example 60: To a solution of 1.45 g of 5,9-dichloro-2- (2-furyl) - [1,2,4] triazolo [1,5-c] quinazoline in 150 ml of dry tetrahydrofuran at 5O ⁰ C during Gassed for 40 minutes gaseous methylamine. The mixture is concentrated to dryness, treated with water and filtered. This gives a white solid, which is taken up to recrystallize in hot toluene. After heating for a few minutes to remove water by azeotropic distillation, cyclohexane is added on cooling. Pure 9-chloro-2- (2-furyl) -5-methylaminop [1,2,4] triazolo [1,5-c] quinazoline, mp 166-168 ° C, is thus obtained.

The starting material is obtained as follows: A mixture of 15 g of 9-chloro-2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one (Example 18) and 275 ml Ρ, Ρ-dichlorophenylphosphine oxide is heated at 182-187 ° C for 24 hours. Excess solvent is removed in vacuo, the residue is cooled and treated with 750 ml of dichloromethane. It is heated under reflux, residual starting material is filtered off. The filtrate is treated with charcoal, filtered through diatomaceous earth and concentrated under reduced pressure to a small volume. The dichloro compound crystallizes at OX, mp. 242-242.5 ° C (Z).

Example 61: When the above-described 5,9-dichloro compound is reacted with excess concentrated ammonium hydroxide solution under ice cooling and the reaction is diluted with water, 9-chloro-2- (2-furyl) -5-imino-5,6 -dihydro [1,2,4] triazolo [1,5-c] quinazoline, m.p. 276-278 ° C.

Example 62: To a solution of 4.9 g of 2- (5-bromo-2-furyl) -9-chloro-5-thiocyanato [1,2,4] triazolo [1,5-c] quinazoline in 80 ml of tetrahydrofuran is added during Gaseous ammonia under ice-cooling for 1.3 hours. The precipitate which forms is isolated, washed with tetrahydrofuran, recrystallized from Ν, Ν-dimethylacetamide and dried at 100 ^° C. under a high vacuum. This gives pure 2- (5-bromo-2-furyl) -9-chloro-5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline, mp 282 -283 ° C.

The starting material is prepared as follows: A mixture of 6 g of 5-bromo-2-furancarboxylic acid hydrazide (prepared according to Blomquist and Stevenson, J. Am. Chem. Soc. 56, 148 [1934]), 5.8 g of o-chloro-cyano-phenylisothiocyanate and 70 ml of N Methylpyrrolidone is stirred at 150 ⁰ C for 4 hours under nitrogen and added to a mixture of 100 ml of ice water and 100 ml of isopropanol. The precipitate is isolated and pressed dry on the filter as possible. It is dissolved in 150 ml of hot dioxane, filtered, concentrated to 20 ml, cooled and treated with 100 ml of methanol. This gives pure 2- (5-bromo-2-furyl) -9-chloro-5-mercapto [1,2,4] triazolo [1,5-c] quinazoline, m.p. 273-276 ° C. The 5-mercapto compound is then converted to the 5-thiocyanato compound as described in Example 55.

Example 63: To a mixture of 15.1 g of 3- (2-amino-5-chlorophenyl) -5- (2-furyl) -1,2,4-triazole (intermediate from Example 18) and 300 ml of isopropanol, 7 , 4ml of a 50% aqueous cyanamide solution, then a mixture of.,., 3.7g concentrated sulfuric acid and 4ml of water. The mixture is refluxed for 6 hours, cooled to room temperature, and the pH is adjusted to 7 by addition of 10% sodium hydroxide solution. The mixture is cooled in an ice bath and stirred at 5 ^° C. for half an hour. The precipitate is isolated, washed with cold anhydrous ethanol and dried in vacuo at 80 ⁰ C for 18 hours. The crude product is dissolved at 110-115 ⁰ C in 240 ml of glacial acetic acid, treated with charcoal and filtered hot through diatomaceous earth. The filtrate is cooled to room temperature, stirred for one hour, and the solid was isolated, washed with three 80 ml portions of water, then washed with 40 ml of anhydrous ethanol and dried in vacuo at 8O ⁰ C for 18 hours. Pure 9-chloro-2- (2-furyl) -5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline is thus obtained, identical to the product of Example 61.

The starting material can also be prepared as follows, in a manner deviating from the procedure described in Example 13: With vigorous stirring, a solution of 47.55 g of 2- (ethoxycarbonylamino) benzonitrile (see Example 51) in 100 ml of N, N-dimethylformamide is used to pass so much chlorine gas. that the internal temperature at 3O ⁰ C ± 2 ° C remains. If, according to HPLC analysis, no starting material is present, nitrogen is passed through the mixture with further stirring for one hour, then 200 ml of water are added dropwise with cooling. The product is isolated, washed with water and added

-16- 81220

50-60 ° C for 16 hours in a vacuum. The resulting o-chloro-1-ethoxycarbonylaminolbenzonitrile, mp. 126-129 ° C is recrystallized from aqueous ethanol to give pure material, mp. 131-133 ° C. 15 g of this urethane are stirred together with 8.42 g of 2-Furancarbonsäurehydrazid in 75 ml of N-methylpyrrolidone for 5 hours in an apparatus with a water at a bath temperature of 160 ⁰ C. Part of the solvent distils over, the solution is cooled, and 150 ml of water are added gradually as the temperature goes down. The product is isolated at room temperature, washed with 100 ml of water, then with 50 ml of isopropanol and dried for 16 hours in vacuo at 70-75 ⁰ C. The product, 9-chloro-2- (2-furyl) [1,2,4] triazolo [1,5-c] quinazolin-5- (6H) one, is identical to that of Example 18. 60g of this product stirred in 350 ml of ethylene glycol and treated with a solution of 17.1 g of sodium hydroxide in 55 ml of water. The reaction is stirred at reflux for 19 hours, cooled to room temperature and treated with 550 ml of water. The pH is then adjusted by the addition of glacial acetic acid to 6.5 to 7.0, it is stirred for a further 15 minutes, the solid is isolated, washed with three 50ml portions of water and 16 hours in vacuo at 80 ⁰ C dried. This gives pure 3- (2-amino-5-chlorophenyl) -5- (2-furyl) -1,2,4-triazole which is identical to the intermediate used in Example 18.

Example 64: Preparation of 10,000 tablets, each containing 50 mg of active ingredient, having the following composition:

2- (2-fluorophenyl) -9-chloro [1,2,4] triazolo [1,5-c] quinazoline 500 g

Milk sugar 707 g

Cornstarch 75 g

Polyethylene glycol 6000 75 g

Talc 75 g

Magnesium stearate 18 g

purified water q.s.

Procedure: All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water, and the suspension is added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powders and, optionally with the addition of a further amount of water, granulated. The granules are dried overnight at 35 ° C, driven through a sieve of 1.2 mm mesh size and pressed into tablets having a score line.

Example 65: Preparation of 10000 capsules containing in each case 20 mg of the active substance having the following composition:

2- (3-fluorophenyl) -9-chloro [1,2,4] triazolo [1,5-quinazoline 200 g

Lactose 1700 g

Modified starch 100 g

Procedure: All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is placed in a suitable mixer and mixed to homogeneity first with the starch, then with lactose. No. 3 gelatin capsules are filled with 200 mg each of this mixture, using a Kapseiabfüllmaschine.

In an analogous manner, capsules or tablets are prepared containing 10-200 mg of the other disclosed compounds mentioned in the Examples.

Claims (11)

-1- 812 Invention claim: 1. Process for the preparation of compounds of the formula I, _Ή -. -R ¹ Il j I ^A II ⁽ 2 ir wherein R ^{1 is} phenyl or phenyl substituted by lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or a 5-membered aromatic or partially or fully saturated heterocyclic ring containing 1 to 3 heteroatoms from the group consisting of N, O and S, or a 6-membered aromatic or partial or fully saturated heterocyclic ring containing 1 to 4 heteroatoms from the group consisting of N, O and S, said heterocyclic ring being bonded to the triazoloquinazoline nucleus via a carbon atom, said heterocyclic ring being unsubstituted or lower alkyl, hydroxy, amino, halogen or R ^{2 is} unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, nitro, amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or aryl lower alkoxy, and wherein X is oxygen, sulfur or NR ³ , wherein R ^{3 is} hydrogen, lower alkyl, aryl-lower alkyl, cycloalkyl, lower alkenyl wherein the double bond is separated from the nitrogen atom by at least one saturated carbon atom, lower alkynyl wherein the triple bond is from the nitrogen atom at least one saturated carbon atom is separate, aryl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or hydroxy-lower alkyl, salts and tautomers of these compounds, characterized in that
a) by treating a compound of formula II _o W ¹ = CR ¹
W ^ J II UH wherein R ¹ , R ² , X and ring A are as defined above, one of the two radicals W ¹ and W ^{2 is} NH and the other of the two radicals W ¹ and W ^{2 is} O or NH, with a base, or
b) by treating a compound of the formula III, H-/
U Il I a Il ^ (III) wherein R ¹ , R ² and ring A are as defined above, with a reactive derivative of carbonic acid, or c) by treating a compound of formula IV, -2- 812 20 ^(IV) wherein ring A is as defined above and Z is the radical of a carbonic acid derivative which is bonded via a nitrogen atom, with a hydrazide of the formula V O = GE ¹ KH (V) H ₂ H d) to obtain a compound of the formula I in which R ^{2 is} hydrogen and X is oxygen, by treating a compound of the formula V 1 R ¹ I A II H (VI) wherein Y is a group which can be converted by an oxidizing agent in the group -N = C = O, with such an oxidizing agent followed by a ring closure, or e) to obtain a compound of the formula I in which R ^{2 is} hydrogen by reacting the group L in a compound of the formula VII, U. R ¹ A j) I (711) wherein L is selected from the group halogen, lower alkoxy, Arylniederalkoxy, mercapto, lower alkylthio and isothiocyanato, in the group XH, or f) to obtain a compound of formula I wherein R ^{2 is} hydrogen by treating a compound of formula VIII HH I a II J (viii) with a reactive derivative of a carboxylic acid of the formula R ¹ -COOH and, if desired, by converting a compound obtained into another compound of the invention and / or by converting a salt obtained into the free compound or other salt and / or by conversion an obtained free compound having a salt-forming group, ineinSalz ,. _.._ ..... _ _ 2. Method according to item I, characterized in that compounds of the formula I are prepared in which R ^{1 is} phenyl or phenyl which is substituted by 1 to 3 radicals of the type lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; or R ^{1 represents} a 5-membered aromatic or partially or fully saturated heterocyclic ring which -3- 812 20 Contains 1 to 3 heteroatoms from the group N, O and S or a 6-membered aromatic or partially or fully saturated heterocyclic ring containing 1 to 4 heteroatoms from the group N, O and S, said heterocyclic ring on the Triazolochinazolinkern via a carbon atom and wherein said heterocyclic ring may be unsubstituted or substituted by lower alkyl, hydroxy or halogen; wherein R ^{2 is} hydrogen, lower alkyl, aryl-lower alkyl, lower alkenyl, aryl-lower alkenyl or aryl wherein X is O, S or NR ³ , wherein R ^{3 is} hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl or lower-alkylamino-lower alkyl; and wherein Ring A is unsubstituted or substituted by one to three lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl groups; and pharmaceutically acceptable salts thereof. 3. Process according to item 1, characterized in that compounds of the formula I are prepared in which R ^{1 is} phenyl or for phenyl which is substituted by one to three radicals of the type lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl; orfor a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms from the group N, O and S, or for a 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms from the group N, O and S, such heterocyclic ring being via a carbon atom is bonded; wherein said aromatic heterocyclic ring may be unsubstituted or substituted by hydroxy, lower alkyl or halogen; wherein R ^{2 is} hydrogen or lower alkyl; wherein X is oxygen or NR ³ , wherein R ^{3 is} hydrogen or lower alkyl, and wherein Ring A is unsubstituted or substituted by 1 to 3 halogen or lower alkyl groups, and pharmaceutically acceptable salts thereof. 4. The method according to item 1, characterized in that compounds of formula I are prepared wherein R ^{1 is} phenyl or phenyl which is substituted by one to three radicals of the type lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl, wherein R is ^{2 is} hydrogen or lower alkyl, X is oxygen, and ring A is unsubstituted or substituted by 1 to 3 halogen or lower alkyl groups, and pharmaceutically acceptable salts thereof. 5. Process according to item 1, characterized in that compounds of the formula I are prepared in which R ^{1 is} a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms from the group consisting of N, O and S or a 6-membered aromatic heterocyclic ring, which contains from 1 to 4 heteroatoms from the group consisting of N, O and S, one such heterocyclic ring being bonded via a carbon atom; wherein said aromatic heterocyclic ring may be unsubstituted or substituted by hydroxy, lower alkyl or halogen; wherein R ^{2 is} hydrogen or lower alkyl; X is NR ³ , wherein R ^{3 is} hydrogen or lower alkyl, and wherein Ring A is unsubstituted or substituted by 1 to 3 halogen or lower alkyl groups, as well as pharmaceutically acceptable salts thereof. 6. The method according to item 1, characterized in that one produces compounds of formula I wherein R ^{1 is} phenyl or substituted by halogen phenyl, or for Fu ryl; wherein R ^{2 is} hydrogen; wherein X is oxygen or NH, and wherein Ring A is substituted by halogen in the 8 or 9 position, and pharmaceutically acceptable salts thereof. Process according to item 1, characterized in that compounds of formula I are prepared in which R ^{1 is} phenyl substituted by halogen, R ^{2 is} hydrogen, X is oxygen and ring A is substituted in the 8 or 9 position by halogen , and pharmaceutically acceptable salts thereof. 8. Process according to item 1, characterized in that compounds of the formula I are prepared in which R ^{1 is} furyl, R ^{2 is} hydrogen, X is NH and ring A in the 8 or 9 position is substituted by halogen, and pharmaceutically acceptable salts thereof. 9. The method according to item 1, characterized in that 9-chloro-2- (2-fluorophenyl) [1,2,4] triazolo [1,5-c] quinazolin-5 (6H) one and its pharmaceutically acceptable Salts produces. 10. The method according to item 1, characterized in that one produces g-chloro-P-fluorophenylMI ^ Altriazolot ^ S-cl-quinazolin-5 (6H) on and its pharmaceutically acceptable salts. 11. The method according to item 1, characterized in that 9-chloro-2- (2-furyl) -5-imino-5,6-dihydro [1,2,4] triazolo [1,5-c] quinazoline and its pharmaceutically acceptable salts.