DE3326118A1 - Pyridopyrimidinetriones, processes for their preparation, their use and medicaments containing them - Google Patents

Abstract

Pyridopyrimidinetriones of the general formula I <IMAGE> in which R<1> denotes a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R<2> denotes an alkyl group having 1 to 5 carbon atoms, R<3> denotes a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R<4> denotes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a trifluoromethyl group, R<5> denotes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, their N-oxides and their acid addition salts are novel compounds. They have a hypotensive action. Processes for the preparation thereof and of the intermediates are given.

Description

The invention relates to pyridopyrimidinetriones, processes for their preparation, their use and medicaments containing them.

The compounds according to the invention are used in the pharmaceutical industry as intermediates and for the production of medicaments.

The preparation of substituted pyrido [2,3-d] pyrimidinetriones is described by Ogura et al. [Chem. Letters, 8, 657-58 (1972); Chem. Pharm. Bull 21 (1973) 2014-18], Hirota et al. [Heterocycles 14 (1980) 407-10; J. Org. Chem. 46 846-51 (1981)] and Broom et al. [J. Org. Chem. 41 (1976) 1095-99]. A mixture of 1,3-dimethyl-6-hydroxy-2,4-dioxopyrido [2,3-d] pyrimidine and 1,3-dimethyl-2,4,7-trioxopyrido [2,3-d ] pyrimidine was obtained in the treatment of 1,3-dimethyl-2,4-dioxopyrido [2,3-d] pyrimidine-8-N-oxide with trifluoroacetic anhydride in trifluoroacetic acid [Bartholomew DG, Dissertation Abstr. Intern. B 35, No. 8, 3845-46 (1975)]. Antibacterial piperazinyl pyrido [2,3-d] pyrimidinones and processes for their preparation are described in U.S. Patent 3,887,557, U.S. Patent 3,962,443, British Patent 14 84 138 and British Patent 14 82 853, among others.

The invention relates to pyridopyrimidinetriones of the general formula I (I), wherein

R [high] 1 denotes a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

R [high] 2 denotes an alkyl group with 1 to 5 carbon atoms,

R [high] 3 denotes a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R [high] 4 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a trifluoromethyl group,

R [high] 5 denotes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms,

their N-oxides and their acid addition salts.

Alkyl groups can be straight-chain or branched. For example, the methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl and tert-pentyl groups may be mentioned as alkyl groups. The methyl group is preferred. Alkoxy groups contain the abovementioned alkyl groups; the methoxy group is preferred.

Halogen atoms are bromine, chlorine and preferably fluorine.

Any acid addition salts can be used as salts. Special mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts are converted into pharmacologically compatible salts by methods known to the person skilled in the art. Water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate (2- (4-hydroxybenzoyl) benzoate), fendizoate (o- [ (2'-Hydroxy-4-biphenylyl) carbonyl] benzoate), propionate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate,

Tartrate, amsonate (4,4'-diamino-stilbene-2,2'-disulfonate), embonate [4,4'-methylene-bis- (3-hydroxy-2-naphthoate)], metembonate [4,4'- Methylene bis (3-methoxy-2-naphthoate)], stearate, tosilate (p-toluenesulphonate), 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, mesylate (methanesulphonate), also salts with bumetanide ( 3-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid), furosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilic acid), besunide (4-benzyl-3-butylamino-5-sulfamoyl-benzoic acid), piretanide [4 -Phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid], etacrynic acid ([2,3-dichloro-4- (2-methylenebutyryl) phenoxy] acetic acid), tienilic acid ([2,3- Dichloro-4- (2-thenoyl) phenoxy] acetic acid), azosemide [5- (4-chloro-5-sulfamoyl] -2-thenylaminophenyl) tetrazole], galosemide (N- [4- (3-trifluoromethylanilino) -3-pyridylsulfonyl] propionamide), 4-chloro-3-sulfamoyl-benzoic acid.

One embodiment of the invention are pyridopyrimidinetriones of the general formula I * (I *),

wherein

R [high] 1 * denotes a hydrogen atom or a methyl group,

R [high] 2 * means a methyl group,

R [high] 3 * denotes a hydrogen atom or a methyl group,

R [high] 4 * denotes a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group,

R [high] 5 * denotes a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a methoxy group,

and their acid addition salts.

A preferred embodiment of the invention are pyridopyrimidinetriones of the general formula I ** (I **),

wherein

R [high] 1 ** means a methyl group,

R [high] 2 ** means a methyl group,

R [high] 3 ** means a hydrogen atom,

R [high] 4 ** denotes a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group,

R [high] 5 ** denotes a hydrogen atom or a methoxy group,

and their pharmacologically acceptable acid addition salts.

Representatives of the compounds according to the invention are

8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -1-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

8- [3- (4- [2-Chlorophenyl] -1-piperazinyl) propyl] -1-methyl-3-isopropyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1-Ethyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -3-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1-Methyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

3-Isopropyl-1-methyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

8- [3- (4- [2-Methoxyphenyl] -1-piperazinyl) propyl] -1-methyl-3-neopentyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -3-ethyl-1-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1-tert-Butyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -3-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1-Isopropyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

3-Ethyl-1-methyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -1-methyl-3-pentyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1-Ethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

3-n -Butyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -1-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidintrione,

1-Methyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

1-Isobutyl-3-methyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

1,3-Diethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione,

1-sec-Butyl-3-methyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione,

8- [3- (4- [2-Methoxyphenyl] -1-piperazinyl) propyl] -1-methyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3 -d] pyrimidintrione,

1,3-Dimethyl-8- [3- (4- [3-chloro-4-fluorophenyl) -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidintrione,

in particular

1,3-Dimethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione,

8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione,

1,3-Dimethyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione,

1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione,

1,3-Dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione

and their pharmacologically acceptable acid addition salts.

The pyridopyrimidinetriones of the general formula I or the configurations I * and I **, their N-oxides and their acid addition salts have valuable properties which make them commercially useful. On the one hand, the pyridopyrimidinetriones, their N-oxides and their pharmacologically, i.e. biologically compatible, acid addition salts bring about a marked reduction in blood pressure in mammals. On the other hand, some pyridopyrimidinetriones and the pharmacologically unacceptable acid addition salts are intermediates for the preparation of pyridopyrimidinetriones and their pharmacologically acceptable acid addition salts.

The antihypertensive effect of the compounds according to the invention is expressed in a strong and sustained lowering of blood pressure in normotensive and genetically hypertonic rats. In addition, the compounds according to the invention are distinguished by favorable compatibility.

The excellent effectiveness of the pharmacologically active compounds I, I *, I ** according to the invention, their preferred representatives, their N-oxides and their acid addition salts permit their use in human and veterinary medicine, the indications being hypertension of all degrees of severity, especially primary and secondary hypertension , be considered.

The invention therefore also relates to a method for treating mammals suffering from one of the abovementioned diseases. The method is characterized in that the diseased mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the general formulas I, I *, I **, their preferred representatives, their N-oxides and / or their salts. The invention also relates to the use of the pharmacologically active compounds according to the invention in combating the diseases indicated above. The invention also encompasses the use of these compounds for the production of medicaments which are employed for combating the diseases mentioned.

The invention therefore also relates to medicaments which contain one or more pyridopyrimidinetriones of the general formula I ', their N-oxides and / or their pharmacologically acceptable acid addition salts.

Refinements of the medicaments are those which contain pyridopyrimidinetriones of the formula I *, I ** or their preferred representatives and / or their pharmacologically acceptable acid addition salts with inorganic or organic acids.

The medicaments are produced by processes known per se, the new compounds being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.

In accordance with the invention, the active ingredients are used in any suitable formulation, provided that the formation or maintenance of adequate blood levels is ensured. This can be achieved, for example, by oral or parenteral administration in suitable doses. The pharmaceutical preparation of the active ingredient is advantageously in the form of unit doses which are tailored to the desired administration. A unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, granulate, solution, emulsion or suspension.

"Unit dose" in the context of the present invention is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or a multiple of a therapeutic single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a full, half, third or quarter daily dose. If only a fraction, such as half or a quarter of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, for example in the form of a tablet with a score line.

The pharmaceutical preparations according to the invention, if they are in unit doses and are intended for administration to humans, for example, can contain about 0.1 to 500 mg, advantageously 0.5 to 100 mg and in particular 1 to 30 mg of active ingredient.

In general, it has proven to be advantageous in human medicine to use the active ingredient (s) when administered orally in a daily dose of about 0.001 to about 5, preferably 0.01 to 2, in particular 0.05 to 1 mg / kg of body weight, optionally in the form to administer several, preferably 1 to 3, single doses to achieve the desired results. A single dose contains the active ingredient (s) in amounts of about 0.001 to about 2.5, preferably 0.01 to 1.0, in particular 0.05 to 0.5 mg / kg of body weight. Similar dosages may be used for parenteral, e.g., intravenous, treatment.

The therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, e.g. after meals and / or in the evening. However, it may be necessary to deviate from the dosages mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and application of the drug and the period of time or the interval within which the administration takes place. So it can be in In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. If the dosage is creeping in, a lower dose is administered at the beginning of the treatment, then slowly switched to a higher dose. Once the desired blood pressure reduction has been achieved, the lower dose is used again.

Any person skilled in the art can easily determine the required optimal dosage and type of application of the active ingredients on the basis of his specialist knowledge.

The pharmaceutical preparations usually consist of the active ingredients according to the invention and non-toxic, pharmaceutically acceptable drug carriers, which are used as admixtures or diluents in solid, semi-solid or liquid form or as envelopes, for example in the form of a capsule, a tablet coating, a bag or another container, come into use for the therapeutically active ingredient. A carrier substance can serve, for example, as a mediator for the absorption of drugs by the body, as a formulation aid, as a sweetener, as a flavor corrector, as a colorant or as a preservative.

Tablets, dragees, hard and soft capsules, e.g. made of gelatine, dispersible powders, granulates, aqueous and oily suspensions, emulsions, solutions or syrups are used for oral use.

Tablets can contain inert diluents, e.g., calcium carbonate, calcium phosphate, sodium phosphate, or lactose; Granulating and distributing agents, e.g., corn starch or alginates; Binders such as starch, gelatin or acacia gum; and lubricants such as aluminum or magnesium stearate, talc or silicone oil. They can also be provided with a coating, which can also be designed in such a way that it causes delayed dissolution and absorption of the drug in the gastrointestinal tract, so that, for example, better tolerability, retention or retardation is achieved. Gelatin capsules can contain the drug mixed with a solid, e.g. calcium carbonate or kaolin, or an oily, e.g. olive, peanut or paraffin oil, diluent.

Aqueous suspensions can include suspending agents, e.g., sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth or acacia; Dispersing and wetting agents, e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g., methyl or propyl hydroxybenzoates; Flavoring agents; Contains sweeteners, e.g. sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.

Oily suspensions can contain, for example, peanut, olive, sesame, coconut or paraffin oil and thickening agents such as beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavorings and antioxidants.

Water-dispersible powders and granules can contain the active ingredients as a mixture with dispersants, wetting agents and suspending agents, e.g. those mentioned above, as well as with sweeteners, flavoring agents and coloring agents.

Emulsions can contain e.g. olive, peanut or paraffin oil in addition to emulsifying agents such as acacia gum, tragacanth gum, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.

Sterile injectable aqueous suspensions, isotonic saline solutions or other solutions containing dispersants or wetting agents and / or pharmacologically acceptable diluents, e.g. propylene or butylene glycol, are used for parenteral administration of the medicinal substances.

The active ingredient (s) can optionally also be formulated in microencapsulated form with one or more of the specified carriers or additives.

If the pyridopyrimidinetriones according to the invention, their N-oxides and / or their acid addition salts are to be used for the treatment of hypertension, the pharmaceutical preparations can also contain one or more pharmacologically active components of other drug groups, such as other antihypertensives, small beta-receptor blockers, diuretics, saluretics, alkaloids , etc., e.g. dihydralazine, propranolol, labetalol, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinamine, Rauwolfia total alkaloids.

The invention also relates to a process for the preparation of pyridopyrimidinetrions of the general formula I, their N-oxides and their acid addition salts, which is characterized in that one

a) a uracil derivative of the general formula II (II),

wherein

R [high] 1, R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 6 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms means, cyclized and, if appropriate, then converted the base obtained into an acid addition salt or into the N-oxide or a obtained acid addition salt into the free base or another acid addition salt or into the N-oxide; or

b) an alkyl compound of the general formula III (III), in which R [high] 1 and R [high] 2 have the meaning given above and X represents a leaving group, with a phenylpiperazine of the general formula IV (IV),

wherein R [high] 4 and R [high] 5 have the meaning given above, or converts its acid addition salt and optionally then converting the base obtained into an acid addition salt or into the N-oxide or an acid addition salt obtained into the free base or another acid addition salt or converted to the N-oxide; or

c) for the preparation of pyridopyrimidinetrions of the general formula Ia (Ia),

wherein R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 1a denotes an alkyl group having 1 to 5 carbon atoms, a pyridopyrimidinetrione of the general formula Ib (Ib), in which R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 1b denotes a hydrogen atom, with an alkyl derivative of the general formula V

R [high] 1a - X (V),

wherein R [high] 1a and X have the meaning given above, reacts and optionally then converts the base obtained into an acid addition salt or into the N-oxide or an acid addition salt obtained into the free base or another acid addition salt or into the N-oxide; or

d) for the preparation of pyridopyrimidinetrions of the general formula Ic (Ic),

wherein R [high] 1, R [high] 2, R [high] 3 and R [high] 5 have the meaning given above and R [high] 4c denotes a halogen atom, a pyridopyrimidinetrione of the general formula Id (Id),

wherein R [high] 1, R [high] 2, R [high] 3 and R [high] 5 have the meaning given above and R [high] 4d denotes a hydrogen atom, halogenated and optionally then the base obtained into an acid addition salt or converted into the N-oxide or a obtained acid addition salt into the free base or another acid addition salt or into the N-oxide; or e) for the preparation of pyridopyrimidinetrionen of the general formula I, in which R [high] 3 denotes a hydrogen atom, an aminoalkyl compound of the general formula VI (VI),

wherein R [high] 1, R [high] 2 and X have the meaning given above, with an aniline of the general formula VII (VII),

wherein R [high] 4 and R [high] 5 have the meaning given above, or converts its acid addition salt and optionally then converting the base obtained into an acid addition salt or into the N-oxide or an acid addition salt obtained into the free base or another acid addition salt or converted into the N-oxide.

The reaction according to process variants a) to e) are carried out by methods known per se to the person skilled in the art. The reactions take place both in the absence and in the presence of solvents. Leaving groups known to the person skilled in the art, such as alkylsulfonyloxy, e.g. mesyloxy, arylsulfonyloxy, e.g. p-toluenesulfonyloxy or, preferably, halogen, e.g. iodine, bromine, especially chlorine, come into consideration as leaving groups.

The cyclization according to process variant a) is carried out, for example, by heating the uracil derivatives II (R [high] 6 = -H) to temperatures between 100 and 200 ° C, optionally with the addition of a water- removing solvent or catalyst, e.g. acetic anhydride, or using reduced pressure (vacuum) to accelerate the reaction. The cyclization of the uracil derivatives II (R [high] 6 = alkyl) is carried out, for example, in the presence of a basic catalyst such as sodium hydroxide, with solvents such as methanol or ethanol being added if necessary.

The reaction according to process variant b) is generally carried out at an elevated temperature, preferably between 50 and 200 ° C., an inert solvent such as chloroform, benzene, xylene, dichlorobenzene, acetonitrile or dimethylformamide being used if appropriate. It is also advantageous to add an equivalent amount of an organic or inorganic auxiliary base, such as triethylamine or potassium carbonate, or to use an excess of the phenylpiperazine IV. In the absence of a solvent, it is expedient to use an excess of auxiliary base.

The alkylation according to process variant c) is expediently carried out with alkylating agents, e.g. alkyl halides or sulfuric acid alkyl esters, in the presence of suitable bases, e.g. potassium carbonate or sodium hydride, optionally with the addition of solvents, e.g. acetone, dimethylformamide, at temperatures between 20 and 150 ° C.

The halogenation according to process variant d) is preferably carried out at low temperature, e.g. between -78 and 20 ° C, in an inert solvent such as chlorinated hydrocarbons or their mixtures, e.g. dichloromethane or trichloroethane. Chlorine or bromine are used as halogenating agents.

The reaction according to process variant e) is generally carried out at temperatures between 80 and 200.degree. C., preferably between 100 and 170.degree. Appropriately, in a solvent such as alkanols whose boiling point is above 100 ° C, for example C [deep] 1 -C [deep] 4-alkanols, or aromatic hydrocarbons, for example toluene, xylenes, chlorobenzene or dichlorobenzenes, optionally in the presence of a base , for example triethylamine or excess VII worked. The reaction in the reflux is preferred temperature of the solvent carried out, since the reaction time can be kept short.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. acetone, water, a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, precipitating with a nonsolvent for the addition salt, or by evaporating the solvent.

Salts obtained, for example the hydrochlorides, can be converted into the free base by adding excess sodium or potassium hydroxide, which is then converted into the free base by solvent extraction with a suitable, water-immiscible solvent such as chloroform, dichloromethane, diethyl ether, benzene, toluene, cyclohexane, etc. ., is won. The free bases can also be obtained by neutralizing an acid addition salt with sodium methylate in methanol and isolating the base by known processes. Pharmacologically incompatible acid addition salts are converted into pharmacologically acceptable acid addition salts by converting them into the base and reacting them with a corresponding acid.

The conversion of the resulting pyridopyrimidinetriones of the general formula I into the N-oxides is preferably carried out with hydrogen peroxide or equivalent oxidizing agents, such as monopersulfuric acid, perbenzoic acid, monoperphthalic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, or complexes with hydrogen peroxide, such as boron trifluoride etherate, with temperatures between Room temperature and boiling point of the solvent, expediently above 50 ° C., are maintained. The usual inert solvents, e.g. water, or solvent mixtures, e.g. acetone / water, in suitable mixing ratios are used as solvents. On the other hand, the oxidation can also be carried out in pure organic solvents such as alcohols, ketones, acids or acid anhydrides, e.g. ethanol, acetone, glacial acetic acid, acetic anhydride, etc.

The uracil derivatives of the general formula II are new compounds which are interesting intermediates for the preparation of the pyridopyrimidinetriones and can therefore be used commercially. The uracil derivatives II, their preparation and use are therefore a further subject of the invention.

The uracil derivatives of the general formula II are prepared by adding substituted uracils of the general formula VIII (VIII),

wherein R [high] 1, R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above, with an acrylic acid ester of the general formula IX

CH [low] 2 = CH - CO - O - R [high] 6 (IX),

in which R [high] 6 denotes an alkyl group having 1 to 5 carbon atoms, reacts and, if appropriate, then hydrolyzes the ester obtained.

The addition of the acrylic ester IX to the uracil VIII is generally carried out in inert solvents, such as open-chain or cyclic ethers, e.g. diisopropyl ether, dioxane, tetrahydrofuran, at temperatures between 0 ° and 100 ° C, preferably in the presence of a base such as sodium hydroxide, potassium hydroxide, Potassium carbonate.

Any subsequent hydrolysis is carried out in a manner known per se by saponification with the equivalent amount of alkali, for example sodium hydroxide solution, potassium hydroxide solution, in polar solvents such as water, alcohols, for example methanol or ethanol, at temperatures from 0 ° C. to the boiling point of the solvent .

Alkyl compounds of the general formula III are prepared by adding uracils of the general formula X (X),

wherein R [high] 1, R [high] 2, R [high] 6 and X are as defined above, cyclized. The cyclization is carried out analogously to process variant a).

The phenylpiperazines IV are known or are prepared by processes known per se, for example by reacting bis (2-chloroethyl) amine with corresponding anilines.

Uracils of the general formula X are prepared by using compounds of the general formula XI (XI),

in which R [high] 1, R [high] 2 and X have the meaning given above, are reacted with an acrylic acid ester IX and, if appropriate, then hydrolyzed. Acrylic ester addition and, if appropriate, subsequent saponification take place analogously to the above-described preparation of II from VIII and IX.

The aminoalkyl compounds VI are obtained by reacting alkyl compounds III with bis (2-hydroxyethyl) amine, and then introducing the leaving group (e.g. by reacting with thionyl halides or alkyl or aryl sulfonic acid halides).

The anilines VII are known or are produced by known processes. The uracils VIII and the compounds XI are known or are prepared analogously to DE-OS 19 42 405.

To prepare pyridopyrimidinetrionen of the general formulas I * and I **, corresponding

a) uracil derivatives (II *), (II **),

wherein

R [up] 1 *, R [up] 2 *, R [up] 3 *, R [up] 4 * and R [up] 5 * or R [up] 1 **, R [up] 2 * *, R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above, R [high] 6 * is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms or R [high] 6 ** represent a hydrogen atom or a methyl or ethyl group, cyclized;

b) alkyl compounds <formula>

(III *) (III **)

wherein

R [high] 1 * and R [high] 2 * or R [high] 1 ** and R [high] 2 ** have the meaning given above, X * a mesyloxy group, a tosyloxy group, an iodine atom, a bromine atom or a chlorine atom or X ** a bromine atom or a chlorine atom, with phenylpiperazines

<formula>

(IV *) (IV **)

wherein

R [high] 3 *, R [high] 4 * and R [high] 5 * or R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above , implemented;

c) pyridopyrimidinetriones (Ib *), (Ib **),

wherein

R [up] 2 *, R [up] 3 *, R [up] 4 * and R [up] 5 * or R [up] 2 **, R [up] 3 **, R [up] 4 ** and R [high] 5 ** have the meaning given above and R [high] 1b * or R [high] 1b ** denote a hydrogen atom,

with alkyl derivatives

R [high] 1a * - X * (V *) R [high] 1a ** - X ** (V **)

in which R [high] 1a * or R [high] 1a ** denote a methyl group and X * and X ** have the meaning given above, reacted; or d) pyridopyrimidinetriones (Id *) (Id **)

where R [high] 1 *, R [high] 2 *, R [high] 3 * and R [high] 5 * or R [high] 1 **, R [high] 2 **, R [high] 3 ** and R [high] 5 ** have the meaning given above and R [high] 4d * or R [high] 4d ** denote a hydrogen atom, chlorinated;

e) aminoalkyl compounds (VI *) (VI **) where R [high] 1 *, R [high] 2 * and X * or R [high] 1 **, R [high] 2 ** and X ** have the meaning given above, with Anilines <formula>

(VII *) (VII **)

wherein R [high] 4 * and R [high] 5 * or R [high] 4 ** and R [high] 5 ** have the meaning given above.

The following examples serve to illustrate the invention. F .: melting point, boiling point: boiling point, decomposition: with decomposition.

Temperatures are given in ° C.

Examples

example 1

1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione

a) 1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

6.7 g (14.6 mmol) 5- (2-carboxyethyl) -1,3-dimethyl-6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino) -uracil are at a Pressure of 12-15 mbar (1200-1500 Pa) heated to 140 ° for 1 hour. The melt is dissolved in 15 ml of a mixture of ethyl acetate / methanol (4: 1) and purified by column chromatography; Yield 4 g (62%), mp 120-121 ° (from isopropanol).

The title compound is obtained alternatively by treating 1,3-dimethyl-5- (2-ethoxycarbonylethyl) -6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino) -uracil (5 g, 10 mmol) with 0.4 g of sodium hydroxide in 100 ml of methanol (stir for 12 hours at 22 ° C.), yield 69%.

b) 5- (2-carboxyethyl) -1,3-dimethyl-6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamino) uracil

17.9 g (36.7 mmol) 1,3-dimethyl-5- (2-ethoxycarbonylethyl) -6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino) -uracil are dissolved in 150 ml of methanol dissolved and, after the addition of 36.7 ml of 2N sodium hydroxide solution, stirred at 40 ° for 1 hour. The solvent is distilled off in vacuo; the residue is neutralized with 36.7 ml of 2N hydrochloric acid and extracted several times with dichloromethane. After evaporation of the organic phase, 14.8 g of 5- (2-carboxyethyl) -1,3-dimethyl-6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamine) uracil (88 %), M.p. 100-103 ° (from acetone).

c) 1,3-Dimethyl-5- (2-ethoxycarbonylethyl) -6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino) -uracil

4.0 g (10.3 mmol) of 1,3-dimethyl-6- (3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamino) uracil are mixed with 1.7 g (17 mmol) of ethyl acrylate and

400 mg of solid sodium hydroxide in 25 ml of anhydrous dioxane heated to 60 ° for 3 hours. After all volatile components have been distilled off in vacuo, the residue is worked up by column chromatography (neutral silica gel, mobile phase: ethyl acetate / methanol 8: 1); Yield 2.5 g (50%), colorless oil.

Example 2

8- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidinetrione

a) 8- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H , 8H] pyrido [2,3-d] pyrimidintrione

4.9 g (10 mmol) of 5- (2-carboxyethyl) -1,3-dimethyl-6- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] -propylamino) -uracil become heated in 15 ml of acetic anhydride to 140 ° for 0.5 hours and then evaporated in vacuo. The residue is dissolved in dichloromethane, washed with saturated sodium carbonate solution and dried, and the solvent is distilled off. The residue is recrystallized from methanol; Yield 3.6 g (76%), mp 143-145 °.

b) 5- (2-carboxyethyl) -1,3-dimethyl-6- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propylamino) uracil

1 g (2 mmol) 6- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] -propylamino) -1,3-dimethyl-5- (2-ethoxycarbonylethyl) -uracil are in 30 ml of methanol dissolved and, after the addition of 22 ml of 0.1 N sodium hydroxide solution, heated to 60 ° for 4 hours. The solvent is distilled off in vacuo, the residue is brought to pH 7 with 22 ml of 0.1 N hydrochloric acid and extracted several times with dichloromethane. The combined extracts are evaporated. The residue is recrystallized from acetone; Yield 0.6 g (61%), m.p. from 100 ° (decomp.).

c) 6- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propylamino) -1,3-dimethyl-5- (2-ethoxycarbonylethyl) uracil

3.3 g (10 mmol) 6- (3-chloropropylamino) -1,3-dimethyl-5- (2-ethoxycarbonylethyl) uracil are mixed with 4.5 g (20 mmol) 1- (4-chloro-2- methoxyphenyl) piperazine in 40 ml of xylene heated to 140 ° for 12 hours and after cooling filtered. The filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel (mobile phase: ethyl acetate); Yield 3.2 g (61%), colorless oil.

d) 6- (3-chloropropylamino) -1,3-dimethyl-5- (2-ethoxycarbonylethyl) uracil

23.1 g (0.1 mol) 6- (3-chloropropylamino) -1,3-dimethyluracil are mixed with 33 ml (0.3 mol) ethyl acrylate and 13.8 g (0.1 mol) ground potassium carbonate in 1 liter Acetone refluxed for 12 hours. The solution is filtered and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate. Then undissolved starting material is filtered off (4 g). The filtrate is purified by column chromatography (silica gel, mobile phase: ethyl acetate); Yield 14.9 g (54%), mp 66-68 ° (diethyl ether).

e) 1- (4-chloro-2-methoxyphenyl) piperazine is obtained by chlorinating 1- (2-methoxyphenyl) piperazine in dichloromethane at -70 ° with the stoichiometric amount of chlorine; Yield 53%, mp of the monohydrochloride 213-215 °, mp of the dihydrochloride 225-226 °, mp of the free base 102-104 °. Alternatively, 1- (4-chloro-2-methoxyphenyl) piperazine is obtained by heating 4-chloro-2-methoxyaniline and bis- (2-chloroethyl) amine in xylene at 140 ° for 4 hours -225 °.

Example 3

8- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidinetrione

a) 8- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H , 8H] pyrido [2,3-d] pyrimidintrione

1.6 g (5.6 mmol) of 8- (3-chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d ] pyrimidintrione are heated to 140 ° with 2.7 g (12 mmol) of 1- (4-chloro-2-methoxyphenyl) piperazine in 30 ml of xylene for 24 hours, cooled and filtered. The filtrate is evaporated in vacuo, the residue is purified by column chromatography (silica gel, mobile phase: ethyl acetate / methanol 20: 1); Yield 2.0 g (75%), mp 143-145 ° (from methanol). b) 8- (3-Chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

8.8 g (26.6 mmol) 5- (2-carboxyethyl) -6- (3-chloropropylamino) -1,3-dimethyluracil are stirred in 20 ml acetic anhydride at 140 ° for 1 hour. After cooling, the mixture is treated with 50 ml of ethyl acetate and filtered; Yield - after working up the mother liquor as well - 6.6 g (87%), mp 175-177 ° (from ethyl acetate).

Alternatively, the compound is obtained by reacting 115.5 g (0.5 mol) of 6- (3-chloropropylamino) -1,3-dimethyluracil with 50 g (0.5 mol) of ethyl acrylate in 1.3 liters of acetone in the presence of 70 g (0.5 mol) of ground potassium carbonate, holding the mixture for 40 hours at 60 °, evaporating the filtered acetone solution, reaction of the reaction product with 0.6 g of sodium hydroxide in 500 ml of methanol at 23 ° for 15 hours, yield 88 g ( 62%), m.p. 176-178 °.

c) 5- (2-carboxyethyl) -6- (3-chloropropylamino) -1,3-dimethyluracil

10 g (30 mmol) 6- (3-chloropropylamino) -1,3-dimethyl-5- (2-ethoxycarbonylethyl) uracil are dissolved in 30 ml methanol and, after addition of 30 ml 1N sodium hydroxide solution, stirred at 22 ° for 3 hours . After the solvent has been removed in vacuo, the mixture is neutralized with approx. 3 ml of concentrated hydrochloric acid (approx. 36 mmol) and extracted several times with dichloromethane. Yield 8.8 g (89%), mp 118-120 ° (from acetone).

Example 4

8- (3- [4- (4-chloro-2-methoxyphenyl) -1-piperazinyl] propyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidinetrione

4.4 g (10 mmol) 1,3-dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H , 3H, 8H] pyrido [2,3-d] pyrimidintrione are dissolved in 700 ml of dichloromethane and cooled to -70 °. The amount of chlorine (0.7 g = 0.5 ml) previously measured at -70 ° in the liquid state is introduced into this solution with stirring. The mixture is allowed to warm to 22 ° over the course of an hour, washed with aqueous sodium hydrogen carbonate solution and water, the solvent is removed in vacuo and the

Residue by column chromatography (silica gel, mobile phase: ethyl acetate / methanol 20: 1); Yield 2.1 g (45%), mp 143-145 ° (from methanol).

Example 5

1,3-Dimethyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione

5.7 g (20 mmol) of 8- (3-chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidinetrione are heated with 3.6 g (20 mmol) 1- (4-fluorophenyl) piperazine and 3 g (30 mmol) triethylamine in 50 ml xylene at 140 ° for 15 hours. After cooling, it is extracted with 50 ml of 2N hydrochloric acid, the acidic extract is extracted twice with 50 ml of toluene, the aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted 4 times with 100 ml of toluene each time. After the combined toluene extracts have been dried over sodium sulfate, the solvent is distilled off in vacuo and the residue is recrystallized from 50 ml of ethyl acetate. Yield 4.4 g (51%), mp 155-157 °.

Analog are obtained

1,3-Dimethyl-8- [3- (4-phenyl-1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d ] pyrimidintrione (yield 19.5%, mp 166-168 °);

1,3-Dimethyl-8- [3- (4- [2-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione (yield 52%, mp 116-118 °);

1,3-Dimethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 62%, mp 131-133 °);

1,3-Dimethyl-8- [3- (4- [4-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 52%, mp 142-144 °);

8- [3- (4- [2-Chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 44%, mp 114-117 °);

8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 57%, mp 119-121 °);

8- [3- (4- [4-chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 37%, mp 147-149 °);

1,3-Dimethyl-8- [3- (4- [3-fluorophenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione (yield 50%, 156-158 °);

1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 46%, 120-121 °);

1,3-Dimethyl-8- [3- (4- [3-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione (yield 58%, 100-102 °);

1,3-Dimethyl-8- [3- (4- [4-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 45%, mp 185-187 °);

1,3-Dimethyl-8- [3- (4- [2-ethoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 50%, mp 155-158 °);

1,3-Dimethyl-8- [3- (4- [3-ethoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 47%, mp 119-121 °);

1,3-Dimethyl-8- [3- (4- [4-ethoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione (yield 63%, mp 166-168 °);

8- [3- (4- [4-chloro-2-methoxyphenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidintrione (yield 60%; mp 143-145 °);

8- [3- (4- [2,4-Dimethoxyphenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidinetrione (yield 53%, mp 124-126 °);

1,3-Dimethyl-8- [3- (4- [2-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidinetrione (yield 41%, mp 117-119 °); respectively.

1,3-Dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione (yield 40%, mp 92-95 °)

by reacting 8- (3-chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidinetrione with 1-phenyl- piperazine, 1- (2-methylphenyl) piperazine, 1- (3-methylphenyl) piperazine, 1- (4-methylphenyl) piperazine, 1- (2-chlorophenyl) piperazine, 1- (3-chlorophenyl) - piperazine, 1- (4-chlorophenyl) piperazine, 1- (3-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1- (3-methoxyphenyl) piperazine, 1- (4-methoxyphenyl) - piperazine, 1- (2-ethoxyphenyl) -piperazine, 1- (3-ethoxyphenyl) -piperazine, 1- (4-ethoxyphenyl) -piperazine, 1- (4-chloro-2-methoxyphenyl) -piperazine, 1- (2 , 4-Dimethoxyphenyl) piperazine, 1- (2-trifluoromethylphenyl) piperazine or 1- (3-trifluoromethylphenyl) piperazine.

Example 6

Analogously to example 5 are obtained

1,3-Dimethyl-8- [3- (4- [4-methylphenyl] -3-methyl-1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidinetrione (yield 52%, mp 135-137 °);

1,3-Dimethyl-8- [3- (4- [3-methylphenyl] -3-methyl-1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidintrione (yield 64%, mp 141-143 °) or

8- [3- (4- [4-chlorophenyl] -3-methyl-1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H ] pyrido [2,3-d] pyrimidintrione (yield 59%, mp 127-129 °)

by reacting 8- (3-chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione with 2-methyl- 1- (4-methylphenyl) piperazine, 2-methyl-1- (3-methylphenyl) piperazine or

1- (4-chlorophenyl) -2-methylpiperazine.

Example 7

1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione is analogous to Example 5 by reacting 8- (3-chloropropyl) -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2, 3-d] pyrimidintrione obtained with 1- (2-methoxyphenyl) piperazine, the reaction being carried out in place of xylene in

Acetonitrile / triethylamine (20 hours at 90 °), yield 44%;

Dimethylformamide / potassium carbonate (6 hours at 120 °), yield 34%;

Dimethyl
<nonreadable>

Hours at 90 °), yield 36%;

Ethanol / triethylamine (12 hours at 90 °), yield 45%.

Example 8

1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl- N [high] 1-oxide) propyl] -5,6-dihydro-2,4,7- [1H , 3H, 8H] pyrido [2,3-d] pyrimidintrione

4.4 g (10 mmol) 1,3-dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H , 3H, 8H] pyrido [2,3-d] pyrimidintrione are stirred in 20 ml of acetone with 2.5 ml of 30% strength aqueous hydrogen peroxide solution for 60 hours at 22 °. The solvent is distilled off in vacuo and the residue is recrystallized from ethyl acetate / methanol 50: 1. Yield 2.5 g (51%), dec. from 153 °.

Example 9

1,3-Dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione hydrochloride

0.7 g (1.44 mmol) 1,3-dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione are mixed with 14.4 ml of 0.1 N hydrochloric acid. The water is distilled off in vacuo. The residue is recrystallized from 80 ml of ethanol. 0.5 g of the title compound is obtained, yield 67%, melting point 245 ° -247 °.

Example 10

Ampoules with an active ingredient content of 25 mg

5 g of 1,3-dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione are suspended in 500 ml of double-distilled water and then admixed with 115 ml of 0.1 N hydrochloric acid, whereupon the active ingredient dissolves. Then 7.5 g of sodium chloride are added and the volume is made up to 1 liter with double-distilled water. The solution is filtered through a membrane filter and filled into 5 ml ampoules, which are then sterilized at 100 ° for 1 hour.

Example 11

Tablets with an active ingredient content of 20 mg

10 kg of 1,3-dimethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione, 45 kg calcium sulfate dihydrate, 31 kg corn starch and 3 kg polyvinylpyrrolidone are moistened with 20 liters of water and granulated through a sieve (mesh size 1.25 mm). The granulate is dried in a fluidized bed dryer to a relative humidity of 50 to 60% and then 8 kg of sodium carboxymethyl cellulose, 2 kg of talc and 1 kg of magnesium stearate are added. The finished granules are compressed into tablets of 200 mg and 8 mm in diameter.

Example 12

250,000 retard capsules with an active ingredient content of 30 mg

8.25 kg 1,3-dimethyl-8- [3- (4-fluorophenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [ 2,3-d] pyrimidinetrione and 3.1 kg of hydroxypropylmethylcellulose are dissolved in a mixture of 24 liters of 96% ethanol and 16 liters of water (+ HCl). 1.1 kg of talc is suspended in this solution. 16 kg of sugar pellets are sprayed with the active ingredient solution in a fluidized bed device. The active ingredient pellets obtained are sprayed in a fluidized bed device with a solution of 0.6 kg of ethyl cellulose, 0.3 kg of hydroxypropylmethyl cellulose and 0.12 kg of stearic acid in 14.8 liters of methylene chloride and 4.0 liters of 96% ethanol. After the coated active ingredient pellets have dried, they are filled into size 4 hard gelatine capsules.

Analogously to Examples 10 to 12, 8- [3- (4- [3-chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H , 8H] pyrido [2,3-d] pyrimidinetrione or 1,3-dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4 , 7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione formulated in ampoule, tablet or capsule form.

pharmacology

To determine the antihypertensive effect, the substances to be examined are administered intravenously once per 6 male, normotonic rats (= NR, weight 310-390 g) or male, spontaneously hypertensive rats (= SHR, weight 360-440 g). 80 mg / kg of chloralose are given intraperitoneally for anesthesia. The mean arterial pressure is measured in the aortic arch via a catheter in the carotid artery. dex. The heart rate is derived from the blood pressure amplitude or from the EKG. The intravenous application of 10 µmol / kg per test substance takes place in 1 ml / kg 0.9% sodium chloride solution with an injection time of 0.2 ml / min. The results of the experiments are time-effect curves for an observation period of 1 hour (mean values +/- standard deviation from N = 6 for 11 points in time / curve).

The toxicity studies are carried out on female NMRI mice (body weight 22-26 g). The animals (5 animals per dose) receive food and water ad libitum. Different doses of the substances are administered i.v. applied. The observation period is 14 days. The LD [low] 50, i.e. the dose at which 50% of the animals die, is determined graphically from the dose-effect curve.

In the tables below, the compounds examined are identified by a serial number assigned as follows

No. Name of the connection

_______________________________________________________________________________

1 8- [3- (4- [4-chloro-2-methoxyphenyl] -1-piperazinyl) propyl] -1,3-

dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidine-

trion

2 1,3-dimethyl-8- [3- (4-phenyl-1-piperazinyl) propyl] -5,6-dihydro-

2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

3 8- [3- (4- [2-chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione No. Name of the connection

_______________________________________________________________________________

4 1,3-dimethyl-8- [3- (4- [2-ethoxyphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

5 1,3-dimethyl-8- [2- (4- [3-ethoxyphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

6 1,3-dimethyl-8- [3- (4- [2-methylphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

7 1,3-dimethyl-8- [3- (4- [4-methylphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

8 8- [3- (4- [4-chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

9 1,3-dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

10 1,3-dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) -

propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

11 1,3-dimethyl-8- [3- (4- [3-fluorophenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

12 1,3-dimethyl-8- [3- (4- [3-methoxyphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

13 1,3-dimethyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -5,6-

dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

14 1,3-dimethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

15 8- [3- (4- [3-chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-

5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidintrione

16 1,3-dimethyl-8- [3- (4- [2-trifluoromethylphenyl] -1-piperazinyl) -

propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidine-

trion

17 1,3-dimethyl-8- [3- (4- [3-methylphenyl] -3-methyl-1-piperazinyl) -

propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2,3-d] pyrimidine-

trion

Table I shows the influence of compounds according to the invention (10 μmol / kg i.v.) on the blood pressure of normotonic and spontaneously hypertonic rats as well as the toxicity in the mouse.

Table I.

NR = normotonic rat, SHR = spontaneously hypertonic rat

The compounds listed show reductions in blood pressure of over 10% of the initial value. After the maximum lowering effect has been reached over time, they can be divided into two groups. In one group (connections 1 - 8) the maximum is briefly reached within 1 to 5 minutes p.a., whereupon a setting to a slightly higher plateau and a slow return to the starting value takes place. In the other group, the maximum reduction in blood pressure is only achieved 10 to 30 minutes p.a., i.e. with a significant delay. The heart rate is increased slightly to significantly decreased in both groups.

The delayed setting of the maximum reduction in blood pressure, which is considered to be advantageous from a medical point of view, is reproduced again for some representative representatives in Table II.

Table II

Time dependence of blood pressure with i.v. Application of 10 µmol / kg to normotonic rats.

Claims (10)

1. Pyrimidintriones of the general formula I (I), wherein R [high] 1 denotes a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R [high] 2 denotes an alkyl group with 1 to 5 carbon atoms, R [high] 3 denotes a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R [high] 4 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a trifluoromethyl group, R [high] 5 denotes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, their N-oxides and their acid addition salts. 2. Pyridopyrimidintrione of the general formula I * (I *), where R [high] 1 * denotes a hydrogen atom or a methyl group, R [high] 2 * means a methyl group, R [high] 3 * denotes a hydrogen atom or a methyl group, R [high] 4 * denotes a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group, R [high] 5 * denotes a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a methoxy group, and their acid addition salts. 3. Pyridopyrimidintrione of the general formula I ** (I **), wherein R [high] 1 ** means a methyl group, R [high] 2 ** means a methyl group, R [high] 3 ** means a hydrogen atom, R [high] 4 ** denotes a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group, R [high] 5 ** denotes a hydrogen atom or a methoxy group, and their pharmacologically acceptable acid addition salts. 4. Pyridopyrimidintrione according to claim 3, selected from the group 1,3-Dimethyl-8- [3- (4- [3-methylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione, 8- [3- (4- [3-Chlorophenyl] -1-piperazinyl) propyl] -1,3-dimethyl-5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione, 1,3-Dimethyl-8- [3- (4- [4-fluorophenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione, 1,3-Dimethyl-8- [3- (4- [2-methoxyphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione, 1,3-Dimethyl-8- [3- (4- [3-trifluoromethylphenyl] -1-piperazinyl) propyl] -5,6-dihydro-2,4,7- [1H, 3H, 8H] pyrido [2 , 3-d] pyrimidintrione. 5. pyridopyrimidinetrione according to any one of claims 1 to 4 for use in combating hypertension. 6. Medicaments containing one or more pyridopyrimidinetriones according to one of claims 1 to 4. 7. Process for the preparation of pyridopyrimidinetrions of the general formula I, their N-oxides and their acid addition salts, characterized in that one a) a uracil derivative of the general formula II (II), wherein R [high] 1, R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 6 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms means, cyclized and, if appropriate, then converted the base obtained into an acid addition salt or into the N-oxide or a obtained acid addition salt into the free base or another acid addition salt or into the N-oxide; or b) an alkyl compound of the general formula III (III), wherein R [high] 1 and R [high] 2 have the meaning given above and X represents a leaving group with a phenylpiperazine of the general formula IV (IV), wherein R [high] 4 and R [high] 5 have the meaning given above, or converts its acid addition salt and optionally then converting the base obtained into an acid addition salt or into the N-oxide or an acid addition salt obtained into the free base or another acid addition salt or converted to the N-oxide; or c) for the preparation of pyridopyrimidinetrions of the general formula Ia (Ia), wherein R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 1a denotes an alkyl group having 1 to 5 carbon atoms, a pyridopyrimidinetrione of the general formula Ib (Ib), wherein R [high] 2, R [high] 3, R [high] 4 and R [high] 5 have the meaning given above and R [high] 1b denotes a hydrogen atom, with an alkyl derivative of the general formula V R [high] 1a - X (V), wherein R [high] 1a and X have the meaning given above, reacts and optionally then converts the base obtained into an acid addition salt or into the N-oxide or an acid addition salt obtained into the free base or another acid addition salt or into the N-oxide; or d) for the preparation of pyridopyrimidinetrions of the general formula Ic (Ic), wherein R [high] 1, R [high] 2, R [high] 3 and R [high] 5 have the meaning given above and R [high] 4c denotes a halogen atom, a pyridopyrimidinetrione of the general formula Id (Id), wherein R [high] 1, R [high] 2, R [high] 3 and R [high] 5 have the meaning given above and R [high] 4d denotes a hydrogen atom, halogenated and optionally then the base obtained into an acid addition salt or converted into the N-oxide or a obtained acid addition salt into the free base or another acid addition salt or into the N-oxide; or e) for the preparation of pyridopyrimidinetrionen of the general formula I, in which R [high] 3 denotes a hydrogen atom, an aminoalkyl compound of the general formula VI (VI), wherein R [high] 1, R [high] 2 and X have the meaning given above, with an aniline of the general formula VII (VII), wherein R [high] 4 and R [high] 5 have the meaning given above, or its acid addition salt reacts and optionally then the Holding base is converted into an acid addition salt or into the N-oxide or a obtained acid addition salt is converted into the free base or another acid addition salt or into the N-oxide. 8. Process for the preparation of pyridopyrimidinetrionen of the general formula I * and their acid addition salts, characterized in that one a) a uracil derivative of the general formula II * (II *), wherein R [high] 1 *, R [high] 2 *, R [high] 3 *, R [high] 4 * and R [high] 5 * have the meaning given above and R [high] 6 * is a hydrogen atom or a Alkyl group with 1 to 3 carbon atoms means, cyclized, or b) an alkyl compound of the general formula III * (III *), where R [high] 1 * and R [high] 2 * have the meaning given above and X * denotes a mesyloxy group, a tosyloxy group, an iodine atom, a bromine atom or a chlorine atom, with a phenylpiperazine of the general formula IV * (IV *), in which R [high] 3 *, R [high] 4 * and R [high] 5 * have the meaning given above; or c) for the preparation of pyridopyrimidinetrions of the general formula Ia * (Ia *), where R [high] 2 *, R [high] 3 *, R [high] 4 * and R [high] 5 * have the meaning given above and R [high] 1a * denotes a methyl group, a pyridopyrimidinetrione of the general formula Ib * (Ib *), wherein R [high] 2 *, R [high] 3 *, R [high] 4 * and R [high] 5 * have the meaning given above and R [high] 1b * denotes a hydrogen atom, with an alkyl derivative of the general formula V * R [high] 1a * - X * (V *), wherein R [high] 1a * and X * have the meaning given above, converts; or d) for the preparation of pyridopyrimidinetrions of the general formula Ic * (Ic *), where R [high] 1 *, R [high] 2 *, R [high] 3 * and R [high] 5 * have the meaning given above and R [high] 4c * denotes a chlorine atom, a pyridopyrimidinetrione of the general formula Id * (Id *), wherein R [high] 1 *, R [high] 2 *, R [high] 3 * and R [high] 5 * have the meaning given above and R [high] 4d * denotes a hydrogen atom, chlorinated; or e) for the preparation of pyridopyrimidinetrionen of the general formula I *, in which R [high] 3 * denotes a hydrogen atom, an aminoalkyl compound of the general formula VI * (VI *), wherein R [high] 1 *, R [high] 2 * and X * have the meaning given above, with an aniline of the general formula VII * (VII *), wherein R [high] 4 * and R [high] 5 * have the meaning given above, converts; and in each case then, if appropriate, the base obtained is converted into an acid addition salt or a obtained acid addition salt is converted into the free base or another acid addition salt. 9. Process for the preparation of pyridopyrimidinetrions of the general formula I ** and their pharmacologically acceptable acid addition salts, characterized in that one a) a uracil derivative of the general formula II ** (II **), wherein R [high] 1 **, R [high] 2 **, R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above and R [high] 6 ** represents a hydrogen atom or a methyl or ethyl group, cyclized; or b) an alkyl compound of the general formula III ** (III **), in which R [high] 1 ** and R [high] 2 ** have the meaning given above and X ** represents a bromine or chlorine atom, with a phenylpiperazine of the general formula IV ** (IV **), wherein R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above; or c) for the preparation of pyridopyrimidinetrions of the general formula Ia ** (Ia **), wherein R [high] 2 **, R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above and R [high] 1a ** denotes a methyl group Pyridopyrimidintrione of the general formula Ib ** (Ib **), wherein R [high] 2 **, R [high] 3 **, R [high] 4 ** and R [high] 5 ** have the meaning given above and R [high] 1b ** denotes a hydrogen atom, with an alkyl derivative of the general formula V ** R [high] 1a ** - X ** (V **) wherein R [high] 1a ** and X ** have the meaning given above, converts; or d) for the preparation of pyridopyrimidinetrions of the general formula Ic ** (Ic **), wherein R [high] 1 **, R [high] 2 **, R [high] 3 ** and R [high] 5 ** have the meaning given above and R [high] 4c ** means a chlorine atom Pyridopyrimidintrione of the general formula Id ** (Id **), where R [high] 1 **, R [high] 2 **, R [high] 3 ** and R [high] 5 ** have the meaning given above and R [high] 4d ** denotes a hydrogen atom, chlorinated ; or e) for the preparation of pyridopyrimidinetrionen of the general formula I **, in which R [high] 3 ** denotes a hydrogen atom, an aminoalkyl compound of the general formula VI ** (VI **), in which R [high] 1 **, R [high] 2 ** and X ** have the meaning given above, with an aniline of the general formula VII ** (VII **), wherein R [high] 4 ** and R [high] 5 ** are as defined above; and in each case then, if appropriate, the base obtained is converted into a pharmacologically acceptable acid addition salt or a obtained acid addition salt is converted into a pharmacologically acceptable acid addition salt. 10. A process for the preparation of a medicament according to claim 6, characterized in that one or more pyridopyrimidinetriones according to one of claims 1 to 4 are mixed with a pharmacologically acceptable carrier and optionally further additives or auxiliaries.