NO810870L - PROCEDURE FOR THE PREPARATION OF PYRIMIDYL CHINAZOLINES - Google Patents

Description

The invention relates to a process for the production of pharmacologically valuable pyrimidylquinazolines of formula I

as well as their acid addition compounds,

where R<1>and R<2>mean hydrogen, alkyl with 1-6 C atoms, alkenyl with 2-6 C atoms, cycloalkyl with 5-7 C atoms, R means hydrogen, alkyl with 1-6 C -atoms, alkenyl with

2-6 C atoms, phenyl, alkylphenyl with 1-4 C atoms in the alkyl residue, halogen, nitro, amino, alkylcarbonylamino with 1-6 C atoms in the alkyl residue, phenylcarbonylamino or formyl. 1 2 Compounds of formula I, in which R = R is as well as the acid addition salts of these compounds, 12 3

especially preferred. The alkyl and alkenyl groups standing for R , R and R can be linear or branched.

1 2

For the cycloalkyl residue standing before R and R, cyclopentyl and cyclohexyl are preferred. For the alkylphenyl residue, benzyl and phenethyl are preferred. Halogen means in particular chlorine, fluorine or bromine. For the alkylcarbonylamino residue, acetylamino is preferred.

Examples of suitable alkyl and alkenyl radicals are: methyl, ethyl, n-propyl, i-propyl, n-butyl, ■ i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, n-hexyl, allyl, methallyl. For R<3>, methyl, ethyl, n-propyl, n-butyl, bromine or amino are preferred. Particularly preferred are compounds of formula I or their acid addition salts,

12 3

where R = R = methyl and R = hydrogen or nitro.

The compounds of formula I can, if at least 12 3

one of the substituents R1, R or R means hydrogen, also occurring in other tautomeric forms.

For the preparation of compounds of formula I, one can react a compound of formula II, wherein formula II X means a mercaptor residue or in particular a halogen atom, preferably chlorine or bromine, with a compound of formula III

12 3

wherein formula III R , R and R have the already mentioned meaning. This reaction is normally carried out in a suitable solvent or dispersant, in which the reaction participants are dissolved or is suspended, such as a hydrocarbon, for example benzene, toluene, xylene, a halogenated hydrocarbon, such as e.g. chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether such as dioxane, diethyl ether, tetrahydrofuran, further water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol such as e.g. methanol, ethanol, amyl alcohol, isoamyl alcohol, etc. The reaction can be carried out at normal temperature or elevated temperature, e.g. 20-160°C. The reaction temperature is normally 80-140°C. At a low 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 formula II and III is usually 1:1. If equal molar amounts are used, when using a compound II with X = halogen it is recommended to work in the presence of at least equimolar amounts of an acid binding agent such as e.g. pot ash, soda, triethylamine, etc. Without an acid-binding agent

otherwise you usually get the hydrohalides of the compounds with the general formula I. If one of the compounds II or III is used in molar excess, the excess of the compound can act as an acid-binding agent.

The preparation of the starting compounds of formula II can take place according to known regulations (e.g. Soc. 1948, p. 1764 or US patent no. 3,511,836).

The starting compound of formula II with X = Cl is known, compare DE-OS No. 1,620,138, column 7, and US Patent No. 3,511,836, example 1. The starting compounds of formula II, where X means a halogen atom other than chlorine , can be produced accordingly. Thus, e.g. the known 2,4-dihydroxy-6,7-dimethoxyquinazoline is transferred with phosphorus oxybromide to 2,4-dibromo-6,7-dimethoxyquinazoline and this with anhydrous ammonia is transferred to 2-bromo-4-amino-6,7-dimethoxyquinazoline . The starting compound of formula II with X = -SCH^ is likewise known, compare DE-OS No. 1,620,138, column 7-8.

The starting compounds with formula III can be obtained by reacting the pyrimidine with formula V

wherein Hal means 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 reaction participants are dissolved or is suspended, such as a hydrocarbon, for example benzene, toluene, xylene, a halogenated hydrocarbon such as e.g. chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether such as dioxane, diethyl ether, tetrahydrofuran, further water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol such as e.g. methanol, ethanol, amyl alcohol, isoamyl alcohol, etc. The reaction can be carried out at normal temperature or elevated temperature, e.g. 20-160°C. Normally the reaction temperature is 80-120°C. With a lower boiling point of the solvent or dispersant used, the reaction is carried out in a closed pressure vessel. The molar ratio between pyrimidine of formula V and piperazine can amount to 1:(1-10) and possibly more. If equimolar amounts are used, then to recommend working in the presence of at least equimolar amounts of an acid-binding agent, such as pot ash, soda ash, triethylamine, etc. Without an acid-binding agent, the hydrohalides of the compounds of formula III are usually obtained. For the preparation of compounds of formula I, one can also react 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline of formula IV

with a compound of formula V. The reaction of the quinazoline derivative of formula IV with a pyrimidine of formula V is normally carried out in a suitable solvent or dispersant, in which the reaction participants are dissolved or is suspended, such as a hydrocarbon, for example benzene, toluene, xylene, a halogenated hydrocarbon such as e.g. chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, an ether such as dioxane, diethyl ether, tetrahydrofuran, further water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, an alcohol such as e.g. methanol, ethanol, amyl alcohol, isoamyl alcohol, etc. The reaction can be carried out at normal temperature or elevated temperature, e.g. 20-160°C. Normally the reaction temperature is 80-140°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 usually 1:1. If equimolar amounts are used, then it is

to recommend working in the presence of at least equimolar amounts of an acid-binding agent, e.g. pot ash, soda ash, triethylamine, etc. Without an acid-binding agent, you usually get the hydrohalides of the compounds of formula I. If you use a molar excess of formula IV, this excess can act as an acid-binding agent.

The quinazoline with formula IV can be prepared according to known regulations (e.g. DE-OS no. 1,620,138).. An additional production method for the compounds according to the invention with formula I, for those where R 3 is different from hydrogen, states that one starts from the unsubstituted compounds of formula VI in the preparation of the pyrimidine ring

and on. in a manner known per se, the substituents introduce R 3 in the 5-position, thus e.g. the formyl group by reaction of VI with acetic acid/formic anhydride, the nitro group by careful nitration with nitric acid, the amino and alkylcarbonyl or phenylcarbonylamino group by reduction of the nitro group and possible acylation with acylating agents that introduce alkylcarbonyl- or the phenylcarbonyl group, the bromine residue by careful bromination, etc.

For the formation of acid addition salts with the compounds of formula I, inorganic and organic acids are suitable, for example hydrogen chloride, hydrogen bromine, naphthalene disulfonic acid (1.5), phosphoric acid, nitric acid, 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, methanesulfonic acid, p-toluenesulfonic acid, citric acid or adipic acid. Pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be obtained as usual by combining the components, most expediently a suitable dilution or dispersant. Suitable dilution resp. dispersants are e.g. ethers, water, alcohols, hydrocarbons etc.

The compounds according to the invention of formula I and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties. In particular, they have highly pronounced blood pressure-lowering effects and are therefore suitable for the treatment of hypertension. Surprisingly, the compounds of formula I are clearly superior to the known similarly structured compounds according to US patent no. 3,511,836. The quinazoline pyrimidines according to the invention can therefore be administered to humans alone, in admixture with each other or in pharmaceutical preparations which, as an active ingredient, contain

an effective dose of at least one of the k.inazoline pyrimidines according to the invention or an acid addition salt thereof, in addition to usual pharmaceutically acceptable carriers and additives. Suitable carriers are e.g. water, vegetable oil, starch, gelatins, milk sugar, magnesium stearate, wax, vaseline, etc. As additives, there can be e.g. a wetting agent, blasting agent, preservative etc. are used. The pharmaceutical preparations can be in the form of e.g. tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol formulations. In addition to the compounds of formula I, the pharmaceutical preparations may also contain one or more other pharmacologically active substances, for example sedatives such as luminal, meproba-mat, chlorpromazine and benzodiazepine additives such as diazepam or chlordiazepoxide, vasodilators such as glycerin trinitrate, pentaerythritol trinitrate and carbochromes, cardiac tonics such as e.g. digitalis preparations, g-blockers such as propanolol, bronchodilators and sympathomimetic agents such as isoprenaline, orciprenaline, etc., α-adrenergic blocking agents such as pentolamine, diuretics such as furosemide.

The preparation of the compounds of formula I will be explained with the help of some examples.

Example_l

2.9 g of 2-piperazinyl-4-amino-6,7-dimethoxy-quinazoline are stirred in 50 ml of ethanol while adding 4 g of pot ash and 2.2 g of 1,3-dimethyl-5-nitro-6-chloro-pyrimidinedione -(2.4) for 24 hours at room temperature. It is then suctioned off and the residue is digested in 20 ml of 0.5 N aqueous hydrochloric acid.

It is suctioned off again, the residue is suspended in aqueous soda solution, suctioned off and recrystallized from aqueous dimethylformamide.

One thus obtains 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl)-piperazine with the formula

Melting point: 300°C Analysis: ^C20H24 N8°6^

Yield: 87% of the theoretical.

The 1,3-dimethyl-5-nitro-6-chloropyrimidinedione (2,4) used as starting product can be prepared as follows: To 50 ml of concentrated sulfuric acid, at 15°C, 17 g of 1,3-dimethyl-6 -chloro-pyrimidinedione(2,4). It is then cooled to 3-5°C and 17 ml fuming nitric acid is slowly added to the mixture while stirring. The solution is then poured onto ice with stirring, as a semi-solid precipitate falls out. The mixture is extracted with methylene chloride, the organic phase is dried with magnesium sulphate and the solution is evaporated in a water jet vacuum at 25°C. An oil is left behind which becomes solid after a short time. The substance is recrystallized once from ligroin/acetic ester. One thus obtains 1,3-dimethyl-5-nitro-6-chloro-pyrimidinedione (2,4) in a yield of 95% of the theoretical. Melting point: 92<Q>C.

The starting product 2-piperazinyl-4-amino-6,7-dimethoxy-quinazoline can be prepared as follows: To a solution of 5 g of anhydrous piperazine in 50 ml of dioxane, 2.5 g of 2-chloro-4-amino- 6,7-dimethoxyquinazoline and then heat the mixture for 12 hours at 95°C. It is then evaporated, the residue is 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 is made alkaline with caustic soda. A precipitate falls out which recrystallizes from ethanol. 2-piper-azinyl-4-amino-6,7-dimethoxy-quinazoline is thus obtained in a yield of 83% of the theoretical. Melting point: 235°C.

Example_2

2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline are heated together with 4.5 g of 1,3-dimethyl-6-piperazinyl-pyrimidine-dione-(2,4) together with 50 ml of ethanol in an autoclave for 8 hours at 130°C. The mixture is then cooled and evaporated in a water jet vacuum. The residue is digested with water and then recrystallized from dimethylformamide. 4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidin-6-yl)-piperazine is thus obtained

Melting point: 273°C. Analysis: (C20H25N7°4*

Yield: 81% of the theoretical.

The starting product 1,3-dimethyl-6-pyr-azinyl-pyrimidinedione (2,4) can be prepared as follows: To a mixture of 30 g of piperazine in 500 ml of toluene, 20 g of 1,3-dimethyl-6- chloropyrimidinedione (2,4) and boil the mixture for 3 hours under reflux. It is then suctioned off and the filtrate is evaporated in a water jet vacuum. The residue remaining after evaporation is recrystallized from acetic acid. One thus obtains 1,3-dimethyl-6-piperazinyl-pyrimidinedione (2,4)

in a yield of 75% of the theoretical. Melting point: 117°C. Eksemgel_3 5.2 g 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1- (1,3-dibutyl-2,4-dioxo-pyrimidin-6-yl)-piperazine

dissolve in 20 ml of glacial acetic acid. A mixture of 1.7 g of bromine in 20 ml of glacial acetic acid is then added dropwise while cooling and ice-cooling. It is then left to stir for 2 hours at room temperature. It is then suctioned off and recrystallized from ethanol. One thus obtains 1-(4-amino-6,7-dimethoxy-

quinazolin-2-yl)-1-(1,3-dibutyl-2,4-dioxo-5-bromo-pyriniidin-6-yl)-piperazine hydrobromide

Melting point: over 300°C during decomposition.

Analysis: (<C>^<H>^<B>^N-yC^)

Yield: 61% of the theoretical

Example_el_4

5.6 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dihexyl-2,4-dioxo-pyrimidine) are added to a mixture of 24 ml of acetic anhydride and 12 ml of formic acid -6-yl)-piperazine . and the mixture is stirred for 5 hours at 80°C. It is then evaporated in a water jet vacuum. The residue is worked through with 0.5 N aqueous caustic soda, filtered off with suction and recrystallized from dimethylformamide. This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dihexy1-2,4-dioxo-5-formyl-pyrimidin-6-yl)-piperazine

Melting point: 314°C during decomposition.

Analysis: ^C31H41<N>7°5^

Yield: 81% of the theoretical.

Example_5

4.7 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl) 1). -piperazine

is suspended in 300 ml ethanol, 0.4 g Pd/coal is added

(10%), and the mixture is hydrogenated for 20 hours at room temperature and normal pressure while shaking with hydrogen. It is then suctioned off, the residue is digested hot at once with dimethylformamide, and the dimethylformamide solution is filtered off from the catalyst while still hot. The dimethylformamide solution is then evaporated in a water jet vacuum and the residue is recrystallized from aqueous dimethylformamide. 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-amino-pyrimidin-6-yl)-piperazine is thus obtained

Melting point: 327°C. Analysis: (C2QH26N704)

Yield: 78% of the theoretical.

Analogous to examples 1-5, the following substances were produced:

The pharmacological effect of the compounds according to the invention was investigated in the following way: 1 • Male Ivanovas rats (300-340 g) of the strain SIV 50 were anesthetized by application of 66 mg/kg a-Chloralose (1.1% solution, 0 .6 ml/100 g) and 20 mg:kg Aprobarbital in the needle vein. The trachea was cannulated to facilitate spontaneous breathing. The measurement of the blood pressure took place in the usual way with blood over a PE tube connected to the right A. carotid artery. With the help of a three-way tap, this PS tube could be used for i.a. application of the test substance, as each time a volume of 0.1 ml was injected. When flushing with 0.9% NaCl, the substance came across the vertebral artery also in the direction of the central nervous system before distribution in the general circulation took place.

Numerically assessed was the maximum systolic and diastolic blood pressure reduction as well as the maximum change in heart rate. The duration of effect was the time from the entry into force of the change until the initial value was achieved. The following values indicated in Table 1 were obtained:

Prazosin = Comparative preparation according to US patent no.

3,511,836

The investigations were carried out on bastard dogs of both sexes under pentobarbital anesthesia (30-40 mg/kg i.v.). Ventilation of the animals took place with a Bird-Mark-7 respirator. The end-expiratory carbonic acid content (measured with Uras) was between 4.5 and 5% by volume.

During the overall experiment, the animals received a permanent infusion of pentobarbital i.v.: 4 mg/kg/6 ml/h to ensure a constant depth of anesthesia.

The systolic and diastolic blood pressure was measured peripherally in the A. femoralis over a Statham pressure recorder.

The parameters were recorded continuously on a Brush-Mark-6 direct recorder via an associated preamplifier.

The test preparations were injected i.v. as Bolus. The values given in the following table 2 are obtained:

Prazosin = Truth-equal preparation according to US patent no. 3,511,836

The pharmaceutical preparations can e.g. per dose contain 0.1-50 mg, preferably 0.5-40 mg, of the active substance according to the invention. Per kg of body weight, e.g. can be administered daily. 0.002-1 mg, preferably 0.02-0.5 mg of the active substance.

Example_6

When making pills, the following recipe can be used: 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1

(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl).

Example<e>l_7

Tablets can be prepared according to the following recipe: 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)

1-(1,3-dimethyl 1-2,4-dioxo-pyrimidin-6-yl). -

Claims (10)

1. Process for the preparation of pyrimidylquinazolines of formula I and their acid addition salts, wherein R 1 and R 2 mean hydrogen, alkyl of 1-6 C atoms, alkenyl of 2-6 C atoms, cycloalkyl of 5-7 C atoms, R <3> means hydrogen, alkyl of 1 -6 C atoms, alkenyl with 2-6 G atoms, phenyl, alkylphenyl with 1-4 C atoms in the alkyl residue, halogen, nitro, amino, alkylcarbonylamino with 1-6 C atoms in the alkyl residue, phenylcarbonylamino or formyl, characterized by ata) a compound of formula II where X means a mercaptor residue or a halogen atom, is reacted with a compound of formula III or b) 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline is reacted with a compound of formula V wherein Hal means a halogen atom, orc) in a compound of formula VI the substituent R 3 is introduced in the 5-position of the pyrimidinedione nucleus, and the formed compound of formula I is optionally transferred in an acid addition salt. 2. Method according to claim 1, characterized in that the reaction is carried out in a suitable solvent or dispersant. 3. Method according to claims 1-2, characterized in that the reaction is carried out at room temperature or elevated temperature. 4. Method according to claims 1-3, characterized in that the compound II is reacted with the compound III or 2-piperazinyl4-amino-6,7-dimethoxy-quinazoline with the compound V at temperatures from 80-140°C. 5. Method according to claims 1-4, characterized in that the reaction is carried out in the presence of an acid-binding agent. 6. Method according to claims 1-5, characterized in that output connections 1 2 are used with R = R . 7. Method according to claims 1-6, characterized in that output connections with 1 2 are used R = R = methyl. 8. Method according to claims 1-7, characterized in that output connections with 3 are used formula III or IV where R = nitro. 9. Method according to claims 1-8, characterized in that a compound of formula II with X = chlorine or bromine is used. 10. Method according to claims 1-8, characterized in that a compound of formula V with Hal = chlorine is used.