DD157614A5 - PROCESS FOR THE PREPARATION OF PYRIMIDYL CHINAZOLINES - Google Patents

Abstract

In the process for the preparation of pyrimidyl-quinazolines of the formula I and their acid addition salts, wherein R is high-1 and R is highly hydrogen, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, R 3 is hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, alkylphenyl having 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, Phenylcarbonylamino or formyl, is a) a compound of formula II, wherein X is a Merkaptorest or a halogen atom with a compound of formula III or b) the 2-piperazinyl-4-amino-6,7-dimethoxy-quinazoline with a compound of Formula V, wherein Hal represents a halogen atom, or c) is introduced into a compound of formula VI, the substituent R is high 3 in the 5-position of Pyrimidindion core.

Description

H. 7. 1981

AP C07D / 2.28 589/8

58 719/11

Process for the preparation of pyrimidyl-quinazolines

The invention relates to a process for the preparation of pyrimidyl-quinazolines

The compounds according to the invention have valuable pharmacological properties, in particular pronounced antihypertensive effect "they are used as medicaments, in particular for the treatment of hypertension"

Characteristic of the known technical solutions

US Pat. No. 3,511,836 discloses similarly constructed compounds whose pharmacological effects are clearly inferior to those of the compounds prepared according to the invention.

Aim of the invention

The aim of the invention is the provision of new pyrimidylquinazolines with valuable pharmacological properties, in particular hypotensive action,

Explanation of the essence of the invention

The invention has for its object to find new Pyrimidylchinazoline with the desired properties and processes for their preparation,

'Λ "f% A " 58 719/11

According to the invention, pyrimidyl quinazolines of the formula I

(D

and their acid addition compounds wherein R and R are hydrogen, alkyl of 1 to 6 C atoms,. Alkenyl having 2 to β C atoms, cycloalkyl having 5 to 7 (-A-atoms, Έ- hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, alkylphenyl having 1 to 4 C atoms Atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl mean «

12

Compounds of formula I wherein R = R are, as well as the acid addition salts of these compounds, particularly

12 3

prefers. The alkyl and alkenyl groups for R, R and R 1 can be straight-chain or branched. at

12

the cycloalkyl radical R and R is preferably cyclopentyl and cyclohexyl. Benzyl and phenethyl are preferred in the phen. Halogen is in particular chlorine, fluorine or bromine. In the alkylcarbonylamino radical, acetylamino is preferred

Examples of suitable alkyl and alkenyl radicals are σ methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, n-hexyl, allyl, methallyl "of R ³ is methyl, ethyl, n ~ propyl _s n-butyl, bromine or amino * preferred compounds is very preferably of the formula 1 *. ^;

228 5 8 9 8 '*'' ^Ref * ^{3181 B}

or their acid addition salts in which R = R = methyl and R ⁵ = hydrogen or nitro.

If at least one of the substituents R, R ² or B? Hydrogen also occurs in other tautomeric forms.

To prepare the compounds of the formula I, a compound of the formula II

^{ 2

yfJ- *

where in formula II X is a mercapto radical or in particular a halogen atom, preferably chlorine or bromine, with a compound of the formula III,

12 3

where in formula III R, R and R have the meaning already given, implement. This reaction is usually carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended, e.g. a hydrocarbon, for example benzene, toluene, xylene, a halogenated hydrocarbon, e.g. Chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether, e.g. Dioxane, diethyl ether, tetrahydrofuran, water, dimethylsulphoxide, dimethylformamide, N-methylpyrrolidone, an alcohol, e.g. Methanol, ethanol, amyl alcohol, isoamyl alcohol, etc. The reaction may be carried out at normal temperature or elevated temperature, e.g. 20 to 160 C are performed. The reaction temperature is usually 80 to 140 ° C. At a lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between the compounds of the formulas II and III is generally 1: 1. If one uses equimolar amounts, it is

H HHMo ^ Ref. 3181 B

when using a compound II with X =. Halogen is recommended in the presence of at least equimolar amounts of an acid-binding agent, e.g. Potash, soda, triethylamine, etc. work. Without acid-binding agents, the hydrohalides of the compounds of the general formula I are usually obtained otherwise. If one of the compounds II or III is employed in a molar excess, the excess of the compound can act as an acid-binding agent.

The preparation of the starting compound of formula II may be carried out according to known procedures (e.g., Soc., 1948, p. 17'6 ^, or U.S. Patent No. 3,511,836).

The starting compound of the formula II where X = Cl is known, cf. DE-OS 1 620 138, column 7 and US Pat. No. 3,511,836, example i. The starting compounds of formula II, wherein X is a halogen atom other than chlorine, can be prepared accordingly. Thus, for example, the known 2, ii-dihydroxy-6,7-dimethoxy-hinderazole with phosphoroxybroraid in the 2, k- dibromo-6 ₅ 7-dimethoxychinazolin and this with anhydrous ammonia in the 2-bromo - '' i-amino-6, 7-dimethoxyquinazoline über- 'leads. The parent compound of formula II with X - SCH ₃ is also known, cf. DE-OS 1 620 138, column

The 'starting compounds of the formula III can be prepared by reacting the pyrimidines of the formula V

O.

R ² , (V)

wherein Hal represents a halogen atom, preferably chlorine, with piperazine. The. Reaction of a pyrimidine of formula V with piperazine is normally carried out in a suitable solvent or dispersant, in which the reactants are dissolved or suspended, e.g.

s ' '

4 Ref. 3181 B

a hydrocarbon, for example benzene, toluene, xylene, a halogenated hydrocarbon, e.g. Chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether, e.g. Dioxane, diethyl ether, tetrahydrofuran, water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol, e.g. Methanol, ethanol, amyl alcohol, xamethyl alcohol, etc. The reaction may be carried out at normal temperature or elevated temperature, e.g. 20 to 160 ° C are performed. Normally, the reaction temperature is 80 to 12O ° C. At a 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 the formula V and piperazine can be 1: 1 to 10 and, if appropriate, even more. If it is used in the same amount, it is advisable in the presence of at least equimolar amounts of an acid-binding agent, such as potash, Soda, triethylamine, etc. Without acid-binding agents, the hydrohalides of the compounds of formula III are usually obtained.

For the preparation of compounds of 'formula I, one can also use the 2 ~ piperazinyl' ^! i ~ amino ~ 6 _> 7-diiuethoxychinazoliii of the formula IV

with a compound of formula V implement. The reaction of the quinazoline derivative of formula IV with a pyrimidine of formula V is also normally carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended, e.g. a hydrocarbon,. for example, benzene, toluene, xylene, a halogenated hydrocarbon, e.g. Chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether,

^Ref ·

such as dioxane, diethyl ether, tetrahydrofuran, water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol, e.g. Methanol, ethanol, amyl alcohol, isoamyl alcohol, etc. The reaction may be carried out at normal temperature or elevated temperature, e.g. 20 to 160 C are performed. Normally, the reaction temperature is from 80 to 140 ° C. At a lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between the two compounds is generally 1: 1. If equal molar amounts are used, it is advisable to work in the presence of at least equimolar amounts of an acid-binding agent, such as potash, soda, triethylamine, etc. Without acid-binding agents Otherwise, it is usual to obtain the hydrolyloids of the compounds of formula I. If a molar excess of formula IV is used, this excess can act as an acid-binding agent.

The quinazoline of formula IV may be prepared according to known procedures (e.g., DE-OS 1 620 138). A further preparation process for the compounds of the formula I according to the invention, for which R is other than hydrogen, is that 'of the compounds of the formula VI. Unsubstituted in the 5-position of the pyrimidine ring

NH,

(VI)

3 ' and in a conventional manner introduces the substituents R in the 5-position, such as the formyl group by j reaction of VI with acetic acid / formic anhydride, the J

   ι

Nitro group by careful nitration with nitric acid, the amino and alkyl carbonyl or Pheriylcarbonylaminogruppe by reduction of'Nitrogruppe and optionally acylation

.J U | U | JQQ · $. Re f. 3181 ^

with acylating agents which introduce the alkylcarbonyl or phenylcarbonyl group, the bromine radical by careful bromination, etc.

For the formation of acid addition salts with the compounds of the formula I, inorganic and organic acids are suitable, for example hydrogen chloride, hydrogen bromide, naphthalenedisulfonic acid (i, 5 ·), phosphoric, nitric, sulfuric, oxalic, lactic, Wine, vinegar, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic-5-malic, suflfarinic, phenylpropionic, glucone , Ascorbic isonicotinine, methanesulfonic, p-toluenesulfonic, citric or adipic acid. Pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be obtained as usual by combining the components, conveniently in a suitable diluent or dispersant. Suitable diluents or dispersants are e.g. Ethers, water, alcohols, hydrocarbons etc.

The compounds of the formula I according to the invention and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties. In particular, they have strong hypotensive effects and are therefore suitable for the treatment of hypertension. Surprisingly, the compounds of the formula I are clearly superior to the known similarly constructed compounds of US Pat. No. 3,511,836. The quinazolylpyrimidines according to the invention can therefore be used on humans alone, in mixtures with one another! or in pharmaceutical preparations containing as active ingredient an effective dose of at least one erfindungsge.mäßen quinazolylpyrimidine or an acid addition salt thereof in addition to conventional pharmaceutically acceptable carriers and additives. Suitable carriers are e.g. Water, vegetable oils, starch, gelatin,

58 719/11

Lactose _s, magnesium stearate, waxes, Vaseline, etc _e Suitable additives can include, "B" .netzmittel, disintegrants, preservatives USWE used "The pharmaceutical preparations may be in the form of," B, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. The pharmaceutical preparations may also have one or more other pharmacologically active substances, for example tranquillizers, such as a addition to the compounds of formula I, B · Luminal, meprobamate, chlorpromazine and Benzodiazepinsedativa _$ such "as diazepam or chlordiazepoxide, vasodilators such _o B ₀ glycerin trinitrate, pentaerythritol tetranitrate and carbochromes, the heart-ionizing agents such as B digitalis preparations, β-blockers such as propranolol, bronchodilators and sympathomimetic agents such as isoprenaline, orciprenaline, etc. , or - adrenergic blocking agents, such as, for example, phentolamine, diuretics, such as, for example, purosemide »

Ausführu ngsbeispiel

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

Example 1 · ... "

2.9 g of 2-piperazinyl-4-amino-6,7-'dimethoxy-quinazoline in 50 ml of ethanol with the addition of 4 g of potassium carbonate and 2 g 1 2 _{S i} 3 ~ dimethyl-5-nitro ~ 6 "" Chlorine -pyrimidinedione (2,4) stirred for 24 hours at room temperature «is then filtered off and the residue is digested in 20 ml of O _S 5 η aqueous hydrochloric acid ©

It is again filtered off with suction _f, the residue suspended in aqueous sodium carbonate solution, filtered off with suction and "omkristallisierte" from aqueous dimethylformamide.

Ref. 3181 B

This gives 4- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) -piperazine of formula

CH ₃ O

Mp: 300 ^° C analysis:

calculated found: Yield:

C 50.8

50.9

H 5.1

5.1

N 23,7

23.5

O 20.3

20.4

87% of theory.

The starting 1,3-dimethyl-5-nitro-6-chloropyrimidinedione (2,4) can be prepared as follows:

To 50 ml of concentrated sulfuric acid are added at 15 ° C in portions 17g l, 3-dimethyl-6-chloro-pyrimidinedione (2,4). It is then cooled to 3 to -5 ⁰ C and added dropwise to the mixture slowly with stirring 17 ml of fuming nitric acid. The solution is then poured onto ice while stirring, precipitating a semi-solid precipitate. The mixture is extracted with methylene chloride, the organic phase is dried with magnesium sulfate and the solution is concentrated in a water jet vacuum at 25 ° C. It leaves behind an oil, which solidifies after a short time. The substance is recrystallized once from ligroin / ethyl acetate. The 1,3-dimethyl-5-nitro-6-chloropyrimidinedione (2,4) is thus obtained in a yield of 95 % of theory. Mp: 92 ° C.

The starting 2-piperazinyl-4-amino-6,7-dimethoxy-quinazoline can be prepared as follows:

2.5 g of 2-chloro-4-amino-6,7-dimethoxyquinazo are added to a solution of 5 g of anhydrous piperazirf in 50 ml of dioxane.

O.

Then, heat the mixture to 95 C for 12 hours. Then

English:. ·. ·. · Ref. 3181B

is concentrated, the residue dissolved in water and adjusted to pH 2.5 with hydrochloric acid. The acidic aqueous solution is extracted with methylene chloride, then the aqueous phase made alkaline with sodium hydroxide solution. There is a precipitate

which is recrystallized from ethanol. This gives 2-piperazinyl-4-amino-6,7-dimethoxy-quinazoline in a yield of 83% of theory, mp 235 ° C.

Example 2,

2.4 g of 2-chloro-4-amino-6,7-dimethoxy-quinazoline are together with 4.5 g, 3-dimethyl-6-piperazinyl-pyrimidin-dione (2.4) together with 50 ml of ethanol in an autoclave 8 Hours to 130 ⁰ C .heated. Then the mixture is cooled and concentrated in a water-jet vacuum. The residue is digested with water and then recrystallized from dimethylformamide. This gives 4- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-pyrirnidin-6-yl) -piperazine

NH ₀ 0

Mp: 273 ° C. Analysis:

C HN O

calculated: 56.2 5.9 23.0 15.0 found: 56.0 6.0 23.0 14.7

Yield: 81 % of theory. -

The starting 1,3-dimethyl-6-piperazinylpyrimidinedione (2, 4) can be prepared as follows:

20 g of 1,3-dimethyl-6-chloropyrimidinedione (2 _> 4) are added to a mixture of 30 g of piperazine in 500 ml of toluene, and the mixture is refluxed for 3 hours, then it is filtered off with suction and the filtrate is concentrated in a water-jet vacuum. The remaining after concentration residue is from ethyl acetate

Ref. 3181 B

recrystallized. This gives the 1,3-dimethyl-6-piperazinyl-pyrimidinedione (2,4)

-V

N-CH.

CH,

in a yield of 75% of theory. Mp: 117 ° C.

Example 3 '

5.2 g of 4- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dibutyl-2,4-dioxo-pyrimidin-6-yl) -piperazine.

are dissolved in 20 ml of glacial acetic acid. Then, while cooling and cooling with ice, a mixture of 1.7 g of bromine in 20 ml of glacial acetic acid is added dropwise. Then allowed to stir for 2 hours at room temperature. Then it is filtered off and recrystallized from ethanol. This gives the 1- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dibutyl-2,4-dioxo-5-bromopyrimidin-6-yl) -piperazine hydrobromide

C.H

49

HBr

Fp: over

Analysis:

C H.Br

calculated: '46.5 5.5 23.8

Found: 46.7 5.3 23.5 Yield: 61% of theory

14.6 14.7

9.5 9.8

• IV '

, Ref. 3181 B

Example 4

To a mixture of 24 ml of acetic anhydride and 12 ml of formic acid are added 5.6 g of 4- (4-amino-6,7-dimethoxy-quinazoline-2-yl).

i ~ * ² »4 ~ dioxo ™ pyr: lrniciin-6-yl) piperazine

C ₆ H ₁₁

^C 6 ^H 11.

added and the mixture stirred at 80 ° C for 5 hours. It is then concentrated in a water-jet vacuum. The residue is worked up with 0.5 N aqueous sodium hydroxide solution, filtered off with suction and recrystallised from dimethylformamide. There are thus obtained 4- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -l-1,3-trichloro-cyano-yyi, -2,4-dioxo-5-fluoromethylpyrimidine-6 yl) - piperazine

OHC

Mp: 314 ° C dec. Analysis: (C ₃₁ H ₄₁ N ₇ O ₅₎

CH N 0

calculated: 62.9 6.9 16.6 13.5

Found: 62.8 6.6 16.5 13.2 Yield: 81 % of theory

Example 5

4.7 4- (4-Amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) -piperazine

are suspended in 300 ml of ethanol, 0.4 g of Pd / charcoal

IJ

Ref. 3181 B

(10%) and the mixture hydrogenated for 20 hours at room temperature and atmospheric pressure while shaking with hydrogen. The mixture is then filtered off with suction, the residue is immediately digested with dimethylformamide hot and the dimethylformamide solution is filtered while still hot from the catalyst. Subsequently, the Dimethylformarnidlösung is concentrated in a water-jet vacuum and the residue recrystallized from aqueous dimethylformamide. 4 (4-amino-6,7-dimethoxy) -oxy- (4-amino-2-yl) -l- (1,3-dimethyl-2,4-dioxo-5-aminopyrimidine-6 is thus obtained ~ yl) ~ piperazine

N-CH.

CH ₃ O

Mp: 327 "C. Analysis

C H

Calculated: 54.3 5.9 Found: 54.0 6.1 Yield: 78% of theory.

N 3 0 5 25 0 14 7 25 14

The following substances were prepared analogously to Examples 1 to 5:

3 0

W * ²

-V ^

Ref. 3181 B

fp;

-CH

-CH-

CH,

CH,

CH,

~ ^C 4 ^H 9

317 ° C

325 ° c

H -CH

297 ° C 3I4 ° C

- ^C 3 ^H 7

331 ° C

319 ⁰ C

H -CH.

^η - ^C 6 ^H 13 -CH ₀ -CH = CH,

32 2 ⁰ C 328 ⁰ C

316 ° C

^C 2 ^H 5

^C 2 ^H 5 ^C 3 ^H 7 ^C 3 ^H 7

H H H H

CHO

R '

324 ^U C 311 ° C 309 ⁰ C 323 ° C 318 ° C 331 ° C 314 ° C

CH, H

° 2 ^H 5 ^C 2 ^H 5

H H

303 ⁰ C 298 ° C

Ref. 3181 B

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

1. Blood pressure measurement on the nqrmotonen anesthetized rat

Male IVANOVAS rats (300-340 g) of the strain SIV 50 were anesthetized into the tail vein by application of 66 mg / kg oc-chloralose (1.1 % solution, 0.6 ml / 100 g) and 20 mg: kg apprbarbital , The trachea was cannulated to facilitate spontaneous breathing. The measurement of blood pressure was carried out in a conventional manner using a PE tube embedded in the right of the carotid artery. By means of a three-way stopcock, this PE tube could be used for the ia application of the test substances, in each case - a volume of 0.1 ml was injected. By rinsing with 0.9% NaCl, the substances also reached the central nervous system via the vertebral artery before being distributed in the general circulation.

The maximum systolic and diastolic blood pressure reduction and the maximum change in heart rate were evaluated numerically. The duration of action was the time from the beginning of the change until the initial value was reached. The values indicated in Table 1 below were obtained: Tab

Preparation and dose (mg / kg) BD _s Δ mmHg X WD min "x BD _d Δ mmHg Ic HF As / min "x   # 12:01 - 30 36 - 27 + 5 prazosin 0.1 - 20 60. - 17 0

BD _s "blood pressure systolic BD _d " diastolic pressure WD »duration of action

Ref. 3181 B

HF = heart rate.

χ- Mittelwerf

4-Amino-6,7-dimethoxy-quinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) -piperazine

Prazosin = comparative preparation according to US Pat

3511836

2. Blood pressure effect on the anesthetized normotensive dog

The investigations were carried out on bastard dogs of both sexes in pentobarbital anesthesia (30-40 mg / kg i.v.). The animals were ventilated with a Bird Mark 7 respirator. The end-expiratory carbon dioxide content (measured with the ura) was between 4.5 and 5% by volume.

Throughout the experiment the animals received one

Duration of infusion of pentobarbital i.v .: 4 mg / kg / 6 ml / h, »-rf '.

to ensure a constant depth of anesthesia.

Systolic and diastolic blood pressure was measured peripherally in the femoral artery via a Statham pressure transducer.

The parameters were continuously registered on a Brush Mark 6 direct writer via associated preamplifiers.

The investigational medicinal products were administered i.v. injected as a bolus. The values indicated in Table 2 below were obtained: Table 2

Preparation and dose (mg / kg). ^BD s mmHg X min X BD _d mmHg X HF s / min X 0.1 · ~ 40 60 ~ 42 - 17 prazosin 0.5 - 15 10. .. - 10 0

Ref. 3161

BD f blood pressure systolic ·

 'S *

BD, = diastolic blood pressure. WD = duration of action ·

Εψ = heart rate. · Χ * = mean "^ s 4" (4-amino-6,7-dimethoxyquinazolin-2-yl) -1- (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidine-6- yl) -piperazine

Prazosin = comparison preparation according to US Pat. No. 3,511,836

The pharmaceutical preparations may e.g. per dose "" 0.1 to 50 mg, preferably 0.5 to 40 mg of the active compound according to the invention per kg body weight daily, for example 0.002 to 1 mg, preferably 0.02 to 0.5 mg of the active ingredient can be administered.

Example 6

The following recipe can be used in the preparation of pills:

4- (4-amino-6,7-dimethoxy-quinazolin-2-yl) -l (1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) piperazine corn starch lactose

Sec. Calcium phosphate Soluble starch Magnesium stearate Colloidal silica

200 mg

Example 7

Tablets can be prepared according to the following recipe:

4 ~ (4-amino-6,7-dimethoxy-chiiiazolin ~ 2-yl) ~ i- (1,3-dimethyl-2,4-dioxo-pyrimidin-6-yl) -

piperazine.

Lactose grain starch Soluble starch Magnesium stearate

100 mg

2 mg 100 mg 60 mg 30 mg 2 mg 2 mg 4 mg

2 mg 60 mg 30 mg 4 mg 4 mg

Claims (1)

58 719/11 Process for the preparation of clay pyrimidyl-quinazolines of the formula I (D 12 and their acid addition salts, wherein R and R are hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms _? B? Hydrogen, alkyl. "having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, 'phenyl, T ^ i citkyL ¹¹ ^ t 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C Atoms in the alkyl radical, phenylcarbonylamino or formyl], characterized in that a) a compound of the formula II (ID, CH, NR ^£ (III) where Σ is a mercapto radical or a halogen atom, with a compound of formula III 3 ° -X J, 0 R ¹ or b) the 2-piperazine 5'-l-4-amino-6- _i- 7-dimethoxy-y-quinazoline with a compound of the formula V HN N 58 719/11 wherein Hal represents a halogen atom, is reacted, or c) into a compound of formula VI CH (VI) the substituent R is introduced at the 5-position of the pyrimidinedione nucleus and the resulting compound of the formula I is optionally converted into an acid addition salt, 2 «Method according to item 1 *, characterized in that the reaction is carried out in a suitable solvent or dispersing agent * ....... 3 «method according to the points 1 to 2, characterized'dadurch that the reaction is carried out at room temperature or elevated temperature. , 4 · Process according to items 1 to 3, characterized in that the compound II with the compound III, or 2-Piperazinyi-4 "a ^r Aino-6,7-dimethoxy ~ quinazoline with the compound V at temperatures of 80 to 140 C is implemented · · · \ J CQQ β AO- - 58719/11 5 "" Process according to the items 1 to 4, characterized in that the reaction is carried out in the presence of an acid-binding agent. " 6 _e method according to the points 1 to 5 »characterized by
become 1 2 in that starting compounds with R = R are used 7 · Method according to points 1 to 6, characterized in that 1 2 by that starting compounds with R = R = methyl be used « 8, "Process according to items 1 to 7», characterized in that starting compounds of the formula III or IV with Έ. ~ Hitro be used · 9 * Process according to points 1 to 8, characterized in that a compound of formula II with X = chlorine or bromine is used. • 1O _e method according to the items 1 to 8 _f, characterized in that a compound of formula V with Hai = chlorine is used.