CS219898B2 - Method of making the pyrimidylchinazoline - Google Patents

Abstract

The pyrimidylquinazolines of the formula I <IMAGE> in which R<1> and R<2> are hydrogen, alkyl with 1 to 6 C atoms, alkenyl with 2 to 6 C atoms, cycloalkyl with 5 to 7 C atoms, R<3> is hydrogen, alkyl with 1 to 6 C atoms, alkenyl with 2 to 6 C atoms, phenyl, phenylalkyl with 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino with 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl, are prepared by a) reacting a compound of the formula II <IMAGE> where X is a mercapto radical or a halogen atom, with a compound of the formula III <IMAGE> or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a compound of the formula V <IMAGE> in which Hal is a halogen atom, or c) in a compound of the formula VI.

Description

The present invention relates to a process for the preparation of pharmacologically valuable pyrimidyl quinazoles of the formula I

and the addition - solí.s acid, wherein ^R1 and ^R2 are water-alkyl group having 1-6 carbon atoms, alkenyl having 2 to 6 carbon atoms, cycloalkyl having SKUs ^pi Nou ^5-7 atom uhUk ^y ^ ^f enyl or a benzyl group,

R3 is hydrogen, alkyl having 1-6 carbon atoms, alkenyl with 2 -group .When 6 carbon atoms, phenyl, fenylalikylovou group having 1 to 4 carbon atoms in the alkyl to ^be a ^{ha l ogen,} nhroskuph well, amino, alkylkarbonylaminosku yne with ^{p is from 1 to 6} carbon atoms, ^{plurality of projections} catching VA ^E m residues not tonylkarbonylamlnostopinu ^b oformylovou group.

Compounds of general formula R in which ^{R 1} = ^{R 2} , as ^well as addition salts, of these compounds with acids are particularly preferred. The alkyl and alkenyl groups in the meaning of the syimbols ^R1 , ^R2 and ^R3 may have a p-nm or branched chain. Cycloalkyl radicals represented symbotá ^R1 and ^R2 is preferably the residue ^of cyclopentyl and cyclohexyl radical. In the case of the phenylalkyl radical, benzyl and phenylethyl are preferred. Halogen means especially chlorine, fluorine or bromine. In an alkylcarioonylamino group, acetylamino is preferred.

Examples of suitable alkyl -a alkenyl radicals are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, allyl, methyl ^t ha.llyl . ^{for R3} , methyl, n-propyl, n-butyl, bromo or amino are preferred. Very particularly preferred are compounds ^No. enyne L ^y Formula wherein ^R1 = ^R2 = methyl and ^R3 = ^{l water-IC,} or nitгo skuρina ^as well as their addition salts with acids.

Compounds of formula I may, if it is at least en ^d of subsUtuentů. ^{R 1, R 2} or ^{R 3} is hydrogen, also occurring in other tautomeric forms.

The compounds of formula (I) are prepared by reacting ^pi perazine of formula (I ⁾ (II) with 4-amino-6,7-dimethoxyquinazoline of formula (III ₎ :

CH ₃ O

(III) in which:

X represents a mercapto group or, in particular, a halogen atom, preferably chlorine or bromine, and with 6'-halogen-2,4-dloxopyrimidine of the formula IV

in which

Hal represents a halogen atom, preferably chlorine, and

R ¹ , R ² and R ³ have the meanings given above, wherein the reaction of piperazine with compounds of formulas III and IV can be carried out in any order.

Thus, it is possible to react the plperaizine first with a compound of formula IV to form an intermediate of formula V

in which

R ¹ , R ² and R ³ have the meanings given above, and this intermediate of formula V is then reacted with a compound of formula III to form a compound of formula I.

However, the piperazine of formula II can also be reacted first with a compound of formula III to form an intermediate of formula VI

NH,

CHfi CH _b O

and then reacting the compound of formula VI with a compound of formula IV to form a compound of formula I.

The reaction of the piperazine of formula II with the compound of formula IV is generally carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended, such as in a hydrocarbon, e.g. benzene, toluene, xylene, halogenated hydrocarbon such as chloroform, methylene chloride, tetrachloromethane. chlorobenzene, an ether such as dioxane, diethyl ether, tetrahydrofuran, further in water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol such as methanol, ethanol, amyl alcohol, isbamyl alcohol etc. Mixtures of various solvents or dispersants may also be used. The reaction may be carried out at normal temperature or at elevated temperature, for example at 20 to 180 ° C. Normally, the reaction temperature is 80 to 120 ° C. At the lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between the pyrimidine of formula IV and the piperazine may be 1: 1 to 10 and optionally even more. When equimolar amounts are used, it is advisable to work in the presence of at least an equimolar amount of an acid binding agent such as potassium carbonate, sodium carbonate, triethylamine, etc. Without using acid binding agents, the hydrohalides of the compounds of formula V are usually obtained.

The subsequent reaction of the compound of formula V with the compound of formula III is also carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended. Suitable solvents or suitable dispersants are, for example, those compounds mentioned above as solvents or dispersants for the reaction of piperazine with the compound of formula IV. The reaction may be carried out at normal temperature or at elevated temperature, for example at 20 to 160 ° C. Usually the reaction temperature is 80 to 140 ^° C. At the lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between compounds of formula III and V is generally 1: 1. If an equimolar amount is used, when using a compound of formula III in which X is halogen, it is recommended to work in the presence of at least an equimolar amount of an acid-binding agent such as potassium carbonate, sodium carbonate, triethylamine, etc. when a compound of formula III in which X is halogen is used, usually a hydrohalide of the compounds of formula I is obtained. If one of the compounds of formula III or V is used in excess of the molar amount, the excess compound can serve as an acid binding agent.

The reaction of the piperazine of formula (II) with the compound of formula (III) is also carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended. Suitable solvents or suitable dispersants are, for example, those already mentioned in the reaction of piperazine with the compound of formula IV. The reaction may be carried out at room temperature or at elevated temperature, for example at 20 to 160 ° C. Usually the reaction temperature is 80 to 140 ° C. At the lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between compounds of formulas III and II is generally 1: 1. When equimolar amounts are used, the use of a compound of formula III in which X is halogen is recommended to work in the presence of at least an equimolar amount of an acid-binding agent, as otherwise the hydrohalides of the compound of formula VI are usually obtained. Suitable acid binding agents are those already mentioned above for the reaction of a compound of formula II with a compound of formula V or an excess of compounds of formula II or ITI.

The subsequent reaction of the resulting intermediate of formula (VI) with the compound of formula (IV) is again carried out in the abovementioned solvents or dispersants at room temperature or at elevated temperature, for example at 20 to 160 ° C. Usually the reaction temperature is 80 to 140 ° C. At the lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel.

The molar ratio between compounds is generally 1: 1. If equimolar amounts are used, it may be advisable to work in the presence of at least equimolar amounts of any of the aforementioned acid-binding agents such as potassium carbonate, sodium carbonate, triethylamine, etc. Without the addition of acid-binding agents, the hydrohalides of the compounds of the formula I. When a molar excess of the compounds of formula (VI) is used, the excess may act as an acid binding agent.

The preparation of the starting compound of formula III can be carried out according to known regulations (for example Soc. 1948, p. 1764 or U.S. Pat. No. 3,511,836). The starting compound of formula III in which X is chlorine is known (cf. DOS 1,620,138, column 7 and U.S. Pat. No. 3,511,836, Example 1). The starting compounds of formula III, in which X has the meaning of halogen other than chlorine, can be prepared accordingly. Thus, for example, the known 2,4-dihydroxy-1-methoxymethyquinazoline can be converted to 2,4-dibrole by treatment with phosphorus oxybromide ^. m ₍ -6,7-dimethoxyc-quinazoline and then converted by treatment with anhydrous ammonia to 2-bromo-4-amino-6,7-drmethoxyquinazoline. The starting compound of formula III in which X is SCH 1 is also known (cf. DOS 1 620 138, columns 7 and 8) The starting compounds of formula IV are also known and can be prepared, for example, by the procedure given in Example 1 below.

Compounds of formula I in which R ³ is hydrogen can be used to introduce the radical R ³ into the 5-position of the pyrimidine ring known per se. Thus, for example, a compound of formula Ia can be added

introduce a formyl radical for R ³ by reaction with a mixture of acetic anhydride and formic acid, nitro careful nitration with nitric acid, amino acid and phenylcarbonylamino alkylcarbonyl or nitro group reduction and alkylation or acylation with acylating agents which create alkylcarbonyl or phenylcarbonyl radical 'Br careful bromination etc.

Inorganic and organic acids such as hydrogen chloride, bromine, water, phosphoric acid, nitric acid are suitable for the formation of acid addition salts of the compounds of formula (I). , sulfuric acid, oxalic acid, lactic acid, tartaric acid, acetic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, methanesuliphonic acid, p-toluenesulfonic acid, citric acid or adipic acid. Pharmaceutically useful acid addition salts are preferred. The acid addition salts can be obtained in a conventional manner by reacting the components, suitably in a suitable diluent or dispersant. Suitable diluents or dispersants are, for example, ethers, water, alcohols, hydrocarbons, etc.

The compounds of Formula I and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties. In particular, they have strongly marked blood pressure lowering effects and are therefore suitable for the treatment of hypertension. Surprisingly, the compounds of formula (I) clearly outperform known compounds of similar structure as described in U.S. Pat. No. 3,511,836. Consequently, the chazolylpyrimidines of formula (I) produced by the process of the invention can be administered to humans alone, mixed with one another or which contain, as an active ingredient, an effective dose of at least one quinazolylpyrimidine of the formula I or an acid addition salt thereof in addition to the usual pharmaceutically acceptable carriers and additives. Suitable carriers are, for example, water, vegetable oils, starch, gelatin, milk sugar, magnesium stearate, waxes, petrolatum, etc. As additives, for example, wetting agents, tablet disintegrating agents, preservatives, etc. can be used. in the form of tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. In addition to the compounds of formula I, the pharmaceutical preparations may also contain one or more other pharmaceutically active substances, for example tranquillizers such as Luminal, Meprobamat, Chlorpromazine and benzodizepine-based sedatives such as Diazepam or Chlorodiazepoxide, vasodilators such as glycerin- trinitrate, pentaerythrlt-tetranitrate and Carbochnomen, cardiac muscle toning agents such as digitalis preparations, β-blockers such as Propanolol, bronchodilators and sympathomimetic agents such as Isoprenaline, Orciprenaline etc., α-adrenergic blockers such as Phentolamine such as Furosemide.

The preparation of the compounds of formula I is illustrated by the following examples.

Example 1

To a solution of 5 g of anhydrous piperazine in 50 ml of dioxane was added 2.5 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and the mixture was heated at 95 ° C for 12 hours. The reaction mixture is then concentrated, the residue is dissolved in water and the pH is adjusted to 2.5 by addition of hydrochloric acid. The acidic aqueous solution was extracted with methylene chloride, then the aqueous phase was basified with sodium hydroxide. A precipitate is formed which is recrystallized from ethanol. There was thus obtained 2-piperazinyl-4-amino-6,7-di ⁱ methoxydhinazolin in 83% yield. Melting point 235 ° C.

2.9 g of 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline are mixed in 50 ml of ethanol with the addition of 4 g of potassium carbonate and 2,2 g, 3-dimethyl-5-nitro-6-chloropyrimidine-2,4 -dione for 24 hours at room temperature. The reaction mixture was then filtered and the residue digested in 20 ml of 0.5 N aqueous hydrochloric acid.

The reaction mixture is filtered again, the residue on. The product was suspended in aqueous sodium carbonate solution, the product was filtered off and recrystallized from aqueous dimethylformamide.

There was thus obtained 4- (4-amino-6,7-dimethoxy-chlorosolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) -piperazine of formula

Melting point 300 ° C.

Analysis for C20H24N8O6 calculated:

50.8% C, 5.1% H, 23.7 found:

% N, 20.3% O;

% N, 20.4% O.

C 50.9%, H 5.1%, 23.5

Yield: 87%.

The 1,3-dimethyl-5-nitro-6-chloropyrimidine-2,4-dione used as starting material can be prepared as follows:

To 50 ml of concentrated sulfuric acid is added in portions of 17 g of 1,3-dimethyl-6-chloropyrimidine-2,4-dione at 15 ° C. The reaction mixture was then cooled to 3-5 ° C and 17 ml of fuming nitric acid was slowly added dropwise with stirring. The solution is then poured onto ice with stirring, whereupon a semi-solid precipitate precipitates. The mixture is extracted with methylene chloride, the organic phase is dried over magnesium sulphate and the solution is concentrated in a water pump vacuum at 25 ° C. There is oil left to solidify after a short time. The material was recrystallized once from a mixture of ligroin and ethyl acetate. 1,3-dimethyl-5-nitro-6-chloropyrimidine-2,4-dione is obtained in a yield of 95% of theory. Melting point 92 ° C.

The 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline used as starting material can be prepared as follows:

Example 2

To a mixture of 30 g piperazine in 500 ml toluene was added 20 g 1,3-dimethyl-6-chloropyrimidine-2,4-dione and the mixture was refluxed for 3 hours. The filter is then filtered and the filtrate is concentrated in a water pump vacuum. The residue obtained after concentration is recrystallized from ethyl acetate. There was thus obtained 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione of formula

in 75% yield. Melting point 117 ° C.

2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline were heated together with 4.5 g of 1,3-dime219898 thyl-ε-piperazinylpyrimiclin-S-dione in 50 ml of ethanol in an autoclave for 8 hours at 130 ° C. The mixture was then cooled and concentrated in a water pump vacuum. The residue was digested with water and then recrystallized from dimethylformamide. There was thus obtained 4- (4-aimino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxopyriinidin-6-yl) piperazine of formula

Melting point 273 ° C,

Analysis for C 20 H 25 N 7 O 4 calculated:

56.2% C, 5.9% H, 23.0% N. 15.0% O; found:

% C, 56.0;% H, 6.0;% N, W; 14.7% O.

Yield 81%.

If instead of 2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, 6 g of 2-methylmercapto-4-amino-6,7-dimethoxyquinazoline are used and otherwise the above-described procedure is used. , then 4- (4-amino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxopyrimidin-6-yl) piperazine was obtained in 73% yield. O.

Example 1 a d 3

5.2 g of 4- (4-amino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dibutyl-2,4-dioxopyrimidin-6-yl) piperazine of the formula

Dissolve in 20 ml glacial acetic acid. A mixture of 1/7 g of bromine in 20 ml of glacial acetic acid is then added dropwise with stirring under ice-cooling. The mixture was then allowed to stir at room temperature for 2 hours. The product was then filtered off and recrystallized from ethanol. 1- (4-Amino-6,7-dimethoxy-pyridin-2-yl) -1- (1,3-dibutyl-2,4-droxo-5-ibromo-pyrimidin-6-yl) -piperazine hydrobromide of formula I is obtained.

Melting point above 300 ° C [decomposition].

Analysis for CveHjvBrgN / Od calculated:

C, 46.5; H, 5.5; Br, 23.8; N, 14.6.

9.5% O;

naježeno:

H, 5.3%; Br, 23.5%; N, 14.7%.

9.8% O.

Yield 61%.

Example 4

To a mixture of 24 ml of acetic anhydride and 12 ml of formic acid is added 5.6 g of 4- (4-amino-6,7-dimethoxyquinazolin-2-yl) -1-1,3-dicycohexyl-2,4-dioxopyrimidine-6. -yl) piperazine of formula

and the mixture was stirred at 80 ° C for 5 hours. It is then concentrated in a water pump vacuum. The residue was worked up by the addition of 0.5 N aqueous sodium hydroxide solution, the product was filtered off and recrystallized from dimethylformamide. 4- (4-Amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dicyclohexyl-2,4-dioxo-5-formyl-pyrimidin-6-yl) -piperazine is obtained.

Melting point 314 ° C (dec.).

Analysis calculated for C31H41N7O5:

H, 6.9%; N, 16.6; O, 13.5; found:

H, 6.6; N, 13.5; O, 13.2.

Yield 81%.

Example 5

4.7 g of 4- ^{(4-amino-6,7-dimethoxy-2-oxychinazolin} у1) -1- (1,3-й1гпе1Ьу1-2,4-81оХ'0 »5-п11гс> руrimidin-6-yl ) of a piperazine of formula

CHjO

CH ₅ O

was suspended in 100 ml of ethanol, treated with about ⁴ g of ^p and .The ^palladium and charcoal (10%) and the mixture was hydrogenated h ^y 20 h at room temperature and atmospheric pressure with hydrogen with shaking. The simes were then filtered, the residue immediately digested with dlmethylformamide while hot, and the solution in dimethylformamide was filtered while hot to separate the catalyst. Then, the solution in dimethylformamide is concentrated under a water pump vacuum and the residue is recrystallized from aqueous dimethylformamide. There was thus obtained N, N-amino-N, N-dimethoxyquinazalin-2-yl) -1- (1,1-trans-2,4-oxo-5-aminopyrimidin-6- ^yl ) piperazine of formula

127 ° C.

Analysis calculated for C20H2SN7O4:

^54, 1% C, ^5, 9% H ²⁵ N 14 ^1%, 5% ^O; · Found:

H, 6.1; N, 25.0; O, 14.7.

Yields ^{to 7} 8% of theory.

Analogous procedure. as described in Examples 1 and 2, the following compounds of the formula were prepared

CH _b O

CH ₅ O

O

R1 = R2 R3 melting temperature —CH3 —CH3 317 CHs / —CH —C4H9 125 \ CH3 H H 297 —CH3 —NH — CO — 22H5 114 --C3H7 -c ^ 111 CH2 = CH — CH2— -Ό 119 H n-C 5 H 13 122 —CH3 —CH2 —CH = CH2 128 -Ό H 116 -cmhQ H 124 —C2H5 H 111 —C4H9 H 109 cyclohexyl H 121 —C2H5 So what 118 —C3H7 CHO 111 -C3H7 H 314

СНзC? Hs

НC2H5

Η303

98298

The pharmacological activity of the compounds of the invention was tested as follows:

1. Measurement of blood pressure in anesthetized rat with normal blood pressure

Male rats (1VANOVAS) weighing 300-340 g of SIV 50 strain are anesthetized by applying 66 mg / kg α-chloralose (1.1% solution, 0.6 mL / 100 g) and 20 mg / kg Aprobarbital to the tail vein. The cannula is inserted into the trachei to facilitate spontaneous breathing. Blood pressure measurements are made in an open way in the usual way via a polyethylene hose inserted into the right A.

carotis. Using a three-way stopcock, this polyethylene hose could be used for intra-arterial administration of test substances, each injecting a volume of 0.1 ml. By washing with 0.9% sodium chloride, they are also passed through the Arteria vertebralis towards the central nervous system before they are separated into the general body circulation.

The maximum decrease in systolic and diastolic blood pressure as well as the maximum change in heart rate are numerically evaluated. The time from the onset of change to the initial value is considered to be the effect time. The values obtained are summarized in Table 1 below:

Preparation and dose (mg / kg) TABLE 1 HF As / min X BD _S AkPa X WD min X BD _d AkPa x 0.01 * —4.0 36 —3.6 +5 Prazosin 0.1 —2.67 60 —2.27 0

BD _S = systolic blood pressure BD _d = diastolic blood pressure WD = duration of action

HF = heart rate x = mean * = 4- (4-amino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dimethyl-2,4-dio-xo-5-nitropyrimidine- 6-yl) piperazine

Prazosin = comparative formulation according to U.S. Pat. No. 3,511,836

2. Effect on blood pressure on a normalized normotonic dog

The experiments were performed on bastard dogs of both sexes under pentobarbital anesthesia [30-40 mg / kg i.v.]. Breathing of animals is done with a “Bird-Mark-7” respirator. The end-exhaled carbon dioxide content (measured by "Uras") is between 4.5 and 5% by volume.

Throughout the experiment, animals receive a continuous infusion of Pentobarbital i. V .: 4 mg / kg / / 6 ml / h to ensure a constant depth of anesthesia,

Systolic and diastolic blood pressure are measured peripherally in A. femoralis with a "Statham-Druckaufnehmer".

Parameters are continuously registered through the appropriate preamplifier on the direct pen "Brush-Mark-6".

The test preparations are administered intravenously as a bolus.

The values obtained are summarized in Table 2 below:

TABLE 2

Preparation and dose (mg / kg)

BD _S

AkPa x

0,1 *

Prazosin 0.5 - 5.33 - 2.0

WD BD _d HF min. AkPa As / min xxx - 5.6 —17 — 1.33 0

BD _S = systolic blood pressure BD _d = diastolic blood pressure WD = duration of action

HT = heart rate x = mean * = 4- (4-amino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitropyrimidine) 6-yl) piperazine

Prazosin = comparative preparation known from U.S. Pat. No. 3,511,836

213898

The pharmaceutical preparations may contain, for example 1 ^to crowd at 0.1 to 50 mg, preferably between 0.5 ^{and 40} mg of ^substance úičmn ^Star Come ^{characterized} judgment. On. 1 kg ^of t LESN ^s weight ^off his e administered daily naipřMad ^0002-1 mg ^of ODN above ^{h 0} 0 ² -to ^0.5 m ^g tárnrá Шку.

Example 6

The production of pills may follow the following formula:

4- (4-amino-6,7-dimethoxy-quinazolin-2-yl -L- (S-dimethyl-2,4-dioxO'-5-nitro-6- Jpiperazm ^ ^k u ^k u ^s runaway šltrob mtéčný sugar secondaries ^No phosphate to ^p-n weighing enoate mg 100 mg 60 mg 30 mg soluble škrob2 mg magnesium stearate mg kyseliny2 kololdn ^s křemtéftá ^alkyl selina4 mg

200 mg

Example 7

Tablets can be made according to the following recipe:

4- (4-amino-6,7-dimethoxychma)

^{imidazoline-2-yl)} -1- (l, 3-dimethyl-L · ^y -2,4-dioxopprimidin-6-yl - piperazine 2 ^- mg lactose 66) mg cornstarch 30 mg soluble starch 4 mg magnesium stearic acid salt 4 mg

100 mg

Claims (11)

OBJECT OF THE INVENTION 1. A process for producing pyrimidylchinazolinů ·· general formula I wherein ^{R 1} and R ^{2 as} hydrogen .znamenaj aakylovou group having 1-6 -atomy atoms, alkenyl having 2 to 6 carbon atoms, cykdoaakylovou slku ^pi nu -s ^5-7 atom ^Y coal-phen ^yl nominal benzylthio or benzyl, ^R3 represents hydrogen, ^alkyl nominal al SKU ^p yne with 1-6 carbon atoms, alkenyl or benzylthio 2 -to-C6 alkyl, phenyl, phenylalkyl having 1 to 4 carbon atoms in the alkyl radical , halo, nitro, amino, alkýlkarbonylaminaskupinu containing 1-0 -atomů atoms in the alkyl or formyl fenylkarboinylaminoskupinu SKU ^p-well, and their addition SOH ^alkyl with digestible fats and further comprising tlim a piperazine of formula II (II) is reacted first with either with a compound of formula III wherein: X is mercapto or halogen, or with the compound of formula IV -A O NR ¹ % R @ ¹ (IV) ^{in some} M ^F Hal is halogen and ^{R1, R2} and ^R3 have the meanings given above ^, and the obtained intermediate is then reacted with a compound of the formula-obecného or-IV which has not yet been used for the reaction, whereupon the obtained compound of formula I is optionally converted acid salt. 2. Method of claim 1 fabricated from -k pyrimidin ^ · quinazoline of the formula therein ^{of R1} and ^{R2 R0} maj ^{i - y} importance Uve ^d en ^Star point 1, and their addition salts with acids, characterized in that - with a piperazine of formula II is reacted first either -with a compound of formula III wherein X is halogen, or obecného- -compound of the formula ^- in it ^{of R} 1, ^R2 'and. ^R3 have ^the meanings indicated in -point 1 and Hal represents halogen, and the resulting intermediate is then allowed rea210898 discriminate between a compound of 'the formula III or IV · which has not been used к reaction, whereupon the obtained compound of formula I optionally converted to an addition - acid salt. 3. The process of claim 1 wherein the reactions are carried out in a solvent or dispersant. 4. Process according to any one of claims 1 to 3, characterized in that the reactions are carried out at temperatures from 20 to 160 ° C. 5. A process according to any one of claims 1 to 4, wherein the reactions are carried out in the presence of an acid binding agent. 6. Process according to claims 1-5, characterized • in that the starting material used is a compound of formula IV wherein Hal is chlorine and R ¹ and R ² represent hydrogen, alkyl having 1-6 carbon atoms, alkenyl C 2 -C 6, C 5 -C 7 cycloalkyl, phenyl or benzyl, and R ³ is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, phenylalkyl C 1 -C 4 alkyl, halogen, nitro, amino, C 1 -C 6 alkylcarbonylamino, phenylcarbonylamino, or formyl. 7. A process according to any one of claims 1 to 6, wherein the starting material is a compound of formula III wherein X is bromo or chloro. 8. Process according to claims 1-7, characterized in that the starting material used is a compound of formula IV wherein R ² has the same meaning as R ^1, both of which radicals have the above meanings and R ³ represents hydrogen, C C 1 -C 6 alkenyl; C 6 -C 6 alkyl, phenyl, C 1 -C 4 phenylalkyl, halogen, nitro, amino, C 1 -C 6 alkylcarbonylamino, phenylcarbonylamino or formyl. 9. A process according to any one of claims 1 to 8, wherein the starting material is a compound of formula (IV) wherein R @ ¹ = R @ ² = R @ ² and R @ ³ is hydrogen, C1 -C6 alkyl, alkenyl. C 2 -C 6 alkyl, phenyl, C 1 -C 4 phenylalkyl, halogen, nitro, amino, C 1 -C 6 alkylcarbonylamino, phenylcarbonylamino, or formyl. 10. The method according to claims 1-9 characterized tíím that is used as starting material a compound of formula IV wherein R ³ is hydrogen and R ¹ and R ² represent hydrogen, alkyl having 1-6 carbon atoms, alkenyl C 2 -C 6 -cycloalkenyl, C 5 -C 7 -cycloalkenyl, phenyl or benzyl. 11. The method according to claims 1-9, characterized in that as starting material · uses · the compound of Formula IV wherein R ³ is nitro and R ¹ and R ² represent hydrogen, alkyl having 1-6 carbon atoms, alkenyl a C 2 -C 6 group, a C 5 -C 6 cycloalkyl group Or a benzyl group.