SK116893A3 - Alcoxymethylsubstituted pyridonebiphenyles - Google Patents

Abstract

Alkoxymethyl-substituted pyridone biphenyls of the general formula <IMAGE> in which R<1> stands for a carboxyl group, or stands for a C1-C8-alkoxycarbonyl group, R<2> stands for C1-C10-alkyl (straight-chain or branched) which is optionally substituted by phenyl, R<3> stands for halogen, hydrogen, C1-C6-alkyl, hydroxyl, C1-C8-alkoxy, trifluoromethyl or trifluoromethoxy, R<4> stands for carboxyl or for tetrazolyl and X stands for oxygen or sulphur, and their salts. Alkoxymethyl-substituted pyridone biphenyls are prepared by reacting appropriate pyridones with biphenylmethyl halogen compounds. The alkoxy methyl-substituted pyridone biphenyls can be employed as active ingredients in medicaments, in particular for the treatment of high blood pressure and atherosclerosis.

Description

Alkoxymethyl-substituted pyridone biphenyls

Technical field

The invention relates to alkoxymethyl-substituted pyridone biphenyls, a process for their preparation and their use in medicaments, in particular as blood pressure lowering agents and antiatherosclerotic agents.

BACKGROUND OF THE INVENTION

Renin, a proteolytic enzyme, is known to cleave in vivo from angiotensinogen the decapeptide angiotensin I, which is again degraded in the lungs, kidneys or other tissues to the blood pressure-increasing octapeptide angiotensin II. The various effects of angiotensin II, such as vasoconstriction, sodium ion retention in the kidneys, aldosterone release in the adrenal gland, and an increase in the sympathetic nervous system tone, act synergistically to increase blood pressure.

In addition, angiotensin II has the property of promoting the growth and multiplication of cells, such as cardiac muscle and smooth muscle cells, which in many disease states (e.g., hypertonia, atherosclerosis and cardiac insufficiency) increase and proliferate.

A possible intervention in the renin-angiotensin system (RAS) is, besides inhibiting renin activity, inhibiting angiotensin-converting enzyme (ACE) activity as well as blocking angiotensin

II-receptor.

EP 487 745 and 500 297 disclose pyridone-substituted biphenyls which exhibit blood pressure lowering properties.

SUMMARY OF THE INVENTION

The present invention relates to alkoxymethyl-substituted pyridone biphenyls of formula I

in which

R ¹ represents a carboxyl group or an alkoxycarbonyl group. of 1 to 8 carbon atoms,

R is a straight or branched (C 1 -C 10) alkyl group optionally substituted by a phenyl group,

R ³ represents a halogen atom, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms, a trifluoromethyl group or a trifluoromethoxy group,

R ⁴ represents a carboxyl group or a tetrazolyl group and

X represents an oxygen or sulfur atom and salts thereof.

The compounds of the formula I according to the invention can also be present in the form of their salts. In general, their salts with organic or inorganic bases can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention.

Physiologically acceptable salts of alkoxymethyl-substituted pyridone biphenyls are metal or ammonium salts of the compounds of the present invention. Particularly preferred are, for example, Utne salts, sodium salts, potassium salts, magnesium salts or calcium salts, as well as ammonium salts derived from ammonia or organic amines such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds of the present invention may exist, or as stereoisomeric forms, either as enantiomeric diastereomers. The present invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemate forms can be resolved into stereoisomerically uniform constituents by known methods (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962). In addition, the formation of atropic isomers is also possible.

Preferred are compounds of formula I wherein:

R ¹ is a carboxyl or alkoxycarbonyl group having 1 to 6 carbon atoms,

R ² is straight or branched alkyl group having 1 to 8 carbon atoms, which is optionally substituted by phenyl,

R ³ represents a fluorine, chlorine or bromine atom, a hydrogen atom, a hydroxy group, a C 1 -C 4 alkoxy group, a C 1 -C 6 alkyl group, a trifluoromethyl group or a trifluoromethoxy group.

R represents a carboxyl or tetrazolyl group and

X represents an oxygen atom and salts thereof.

Particularly preferred are compounds of formula I in which

R ¹ is a carboxyl or alkoxycarbonyl having 1 to 4 carbon atoms,

R ² is straight or branched alkyl group having 1 to 6 carbon atoms,

R ³ represents a fluoro-FCOM ·, chlorine, hydrogen, hydroxyl, alkyl of 1 to 4 carbon atoms, methoxy, trifluoromethyl or trifluoromethoxy,

R ⁴ represents a tetrazolyl group and

X represents an oxygen atom and salts thereof.

Most preferred are compounds of Formula I wherein:

R ¹ represents a carboxyl group, a methoxycarbonyl group or an ethoxycarbonyl group,

R ² is ethyl or methyl;

R ³ represents a fluorine or chlorine atom, a methyl group, a hydroxy group, a trifluoromethyl group. or trifluoromethoxy,

R ⁴ represents a tetrazolyl group and

X represents an oxygen atom and salts thereof.

Alkoxymethyl-substituted pyridone biphenyls of formula

I is prepared by reacting the [A] pyridone of formula II

(Π), wherein R ¹ and R ^{2 are} as defined above, with a compound of formula III

o in which R is as defined above,

á. '

R @ 1 represents an alkoxycarbonyl group having 1 to 4 carbon atoms or a radical of formula

E represents a chlorine or bromine atom, in inert solvents, in the presence of a base and optionally with the addition of a catalyst, or [B] when R ⁴ represents a tetrazolyl group, a compound of formula IV

(IV), · in which R ^1, R ² and R ³ as defined above, and

L represents a typical leaving group such as bromine or iodine, methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy or trifluoromethanesulfonyloxy, preferably bromo, with a compound of formula V

in which it represents a hydrogen atom or a triphenylmethyl group, in an inert solvent, in the presence of a base and a metal catalyst, then, in the case of free tetrazole (R ⁴ / T), the triphenylmethyl group is cleaved using an acid in an organic solvent and / or water; R @ ¹ R), the corresponding esters are hydrolysed and the compound is optionally converted into a salt thereof.

The process of the present invention can be illustrated, for example, by the following reaction scheme:

[A]

DME

Cs ₂ CO ₃

acetone

-------- ►

HCl

[B]

NaoCO3, D M E, EtOH, HgO

Tetrakis (triphenyiphosphin) paJladium

As organic do not change. K diethyl ether, hydrocarbons, cyclohexane such as dichloroethylene, ethyl acetate,

solvents suitable for the above process [A] are conventional solvents which are preferably included under the reaction conditions. ethers, ... as. .J. e, for example, dioxane, tetrahydrofuran or dimethoxyethane, such as benzene, toluene, xylene, hexane, or petroleum fractions, halohydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichlorethylene or chlorobenzene, and dimethylsulfoxide, dimethylformamide, dimethylsulfoxide, dimethylformamide, dimethylformamide acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, acetone, dimethylformamide and dimethoxyethane are preferred.

Bases which are generally suitable for process [A] according to the invention are inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as cesium carbonate, carbonates such as calcium carbonate, sodium or alkaline metal or potassium, sodium, potassium carbonate or alkaline earth metals such as alcoholates or alkaline earth amides such as sodium or potassium ethanolate, potassium tert-butylate or lithium diisopropylamide (LDA), organic amines (trialkyl / C 1 -C 8) - amines), such as triethylamine or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. The bases can also be alkali metals such as sodium or hydrides thereof such as sodium hydride. Potassium carbonate, sodium hydride, potassium tert-butylate or cesium carbonate are preferred.

In general, in the case of [A], the bases are used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, based on 1 mol of the compound of the general formula (III).

The process of the present invention is generally carried out at a temperature of -100 ° C to 100 ° C, preferably 0 ° C - to-SO ·· G.

The process according to the invention is generally carried out under normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

Solvents for solvents which are preferably dioxane, tetrahydrofuran, for example benzene, toluene, xylene, fractions, halogenated hydrocarbons, trichloromethane, carbon tetrachloride or chlorobenzene, and furthermore triethylamine, nitromethane. solvents.

the organic process [B] under given ethers, or dimethoxyethane, hydrocarbons, toluene, are suitable conventional reaction conditions do not change.

such as diethyl ether such as hexane, cyclohexane or petroleum such as dichloromethane, dichloroethylene, trichlorethylene ethyl acetate, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or acetone;

Mixtures of the foregoing may also be used

Tetrahydrofuran, acetone, dimethylformamide and dimethoxyethane are preferred. It is also possible to work in mixtures of the solvents mentioned with water.

The process [B] of the present invention is generally carried out at a temperature in the range of -20 ° C to 150 ° C, preferably in the range of 40 ° C to 100 ° C.

Suitable catalysts are generally metal complexes of nickel, palladium or platinum, preferably palladium (O) complexes such as tetrakistriphenylphosphine palladium. Phase transfer catalysts such as tetra-n-butylammonium bromide or a cronene ether can also be used.

The catalyst is used in an amount of 0.005 mol to 0.2 mol, preferably 0.01 mol to 0.05 mol, based on 1 mol of the compound of the general formula IV.

Suitable bases are, in general, organic tertiary non-nucleophilic bases, such as diisopropylethylamine or organic bases, alkali metal carbonates or triethylamine hydroxides or, for example, alkali metals, preferably sodium, potassium or thalliate or potassium, sodium or thallium hydroxide. Also suitable are alkoxides of said alkali metals. Sodium or potassium carbonate is particularly preferred.

In general, the base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 5 mol, based on 1 mol of the compound of the general formula IV.

The inorganic bases are optionally used in aqueous solution.

The triphenylmethyl group is cleaved with acetic acid or trifluoroacetic acid and water or with one of the abovementioned alcohols or with aqueous hydrochloric acid in the presence of acetone or also with alcohols or with a solution of hydrogen chloride in dioxane.

The cleavage is generally carried out at a temperature in the range

0 ° C to 150 ° C, preferably in the range of 20 ° C to 100 ° C and under normal pressure.

Suitable catalysts are potassium iodide and sodium iodide, especially potassium iodide.

Suitable bases for saponification of esters are customary inorganic bases. These preferably include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate, sodium bicarbonate or potassium carbonate or alkali metal alcoholates such as for example sodium or potassium ethanolate, sodium or potassium methanolate or potassium tert-butylate. Sodium hydroxide or potassium hydroxide is particularly preferred. ........ ...................

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol, or ethers such as tetrahydrofuran or dioxane or also dimethylformamide and dimethylsulfoxide. Alcohols such as methanol, ethyl alcohol, propanol or isopropyl alcohol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

The saponification may preferably be carried out with acids such as trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid. Trifluoroacetic acid is particularly preferred.

The hydrolysis is in general carried out in a temperature range from 0 DEG C. to 100 DEG C., preferably 20 DEG to 80 ^C.

In general, the saponification is carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.05 to 0.5 MPa.

In carrying out the saponification, the base is used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of ester. Molar amounts of the reactants are particularly preferably used.

The saponification of tert-butyl esters is generally carried out with acids such as hydrochloric acid or trifluoroacetic acid in the presence of one of the abovementioned solvents and / or water or a mixture thereof, preferably with dioxane or tetrahydrofuran.

The compounds of formula (II) are known in part and can be prepared by known methods.

The compounds of formula III are known in part and can be prepared by known methods.

Compounds of formula (V) are new when T = hydrogen atom and can be prepared by reacting phenyltetrazole first under protective atmosphere in an inert solvent and in the presence of a base and then introducing boric acid trimethyl ester and hydrolyzing with the final step acids.

Suitable solvents for this process are aprotic solvents such as ethers, for example tetrahydrofuran and diethyl ether, toluene, hexane or benzene. Tetrahydrofuran is preferred.

Suitable bases are n-butyllithium, sec-butyllithium and tert-butyllithium and phenyllithium. Preferred is n-butyllithium.

The base is used in an amount of 2 to 5 mol, preferably 2 to 3 mol, based on 1 mol of phenyltetrazole.

Suitable acids are, in general, mineral acids such as, for example, hydrochloric acid or phosphoric acids or carboxylic acids having 1 to 4 carbon atoms, such as, for example, acetic acid. Hydrochloric acid is preferred.

The acids are generally used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol.

Said process is generally carried out at a temperature in the range of -70 ° C to 25 ° C, preferably in the range of -10 ° C to 0 ° C.

The process according to the invention is generally carried out under normal pressure, but it is also possible to work under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

Compounds of formula IV are largely novel and can be prepared, for example, by reacting compounds of formula VI

R ¹

(VI) wherein R ¹ and R ² and X are as defined above,

wherein R ^J and L are as defined above and av

represents a halogen atom, preferably bromine, in inert solvents and in the presence of a base and / or a catalyst.

Suitable solvents for this process are customary organic solvents which do not change under the reaction conditions.

These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene fraction, halocarbons such as trichloromethane, carbon tetrachloride or chlorobenzene, and furthermore dimethyl cyclohexane, hexane, dimethylformamide, dimethylformamide, dimethylformamide is, for example, dichloromethane, dichloroethylene, trichlorethylene ethyl acetate, dimethoxyethane, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preferred is tetrahydrofuran, acetone, dimethylformamide and dimethoxyethane, alcohols such as methanol, ethyl or propyl alcohol and / or water, toluene and methanol / water.

Suitable bases for the process are generally inorganic or preferably alkaline sodium or potassium hydroxide, such as a hydroxide such as cesium carbonate, carbonates such as calcium carbonate, metals or alkaline metals according to the present invention, suitable organic bases. These include metals such as hydroxides of alkaline earth metal hydroxides, barium, alkali metal carbonates, sodium, potassium carbonate or alkaline earth metals such as alcoholates or alkaline earth amides such as sodium or potassium ethoxide, sodium or potassium methoxide, tertiary .-butylate or lithium diisopropylamide (LDA), thallium hydroxide or carbonate, organic amines (trialkyl / Cf-C _g / - amines), such as trietvlamín or heterocycles such as 1,4-diazabicyclo [2.2.2joktán ( DABCO), 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or hydrides thereof such as sodium hydride can also be used as a base. Preferred are potassium carbonate, sodium hydride, potassium tert-butylate or sodium carbonate.

In general, the bases are used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, based on 1 mol of the compound of the general formula (VII).

The process of the present invention, in general proceeds in a temperature range from -100 ° C to about 100 ^C, preferably 0 ° C to 80 ° C

The process according to the invention is generally carried out under normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

Suitable catalysts for this process are potassium iodide and sodium iodide. It is also possible to use phase transfer catalysts such as tetra-n-butylammonium bromide or a cronene ether.

The catalyst is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 2 mol, based on 1 mol of the compound of the general formula (VII).

The methods described above are given for clarity only. The preparation of the compounds of the present invention of formula I is not limited to the processes described, any modification of these processes is equally applicable to the production.

The alkoxymethyl-substituted pyridone biphenyls according to the invention of the general formula I are characterized by an unpredictable valuable pharmacological spectrum of action.

The compounds of the present invention have a specific A II-antagonistic effect since they competitively inhibit the binding of angiotensin II to A II receptors. They suppress the vasoconstrictor and aldosterone secretion-stimulating effects of angiotensin II. In addition, they inhibit the proliferation of smooth muscle cells.

Thus, the compounds can be used to treat arterial hypertonia and atherosclerosis. In addition, they can be used for the treatment of coronary heart disease, cardiac insufficiency, brain tension disorders, ischemic brain disorders, peripheral vascular disorders, renal and adrenal disorders, bronchospatic and vascular diseases of the respiratory tract, sodium retention and swelling.

Assay for blockade of contractions caused by agonists

Rabbits of both sexes were sacrificed by a wound to the ligaments and exsanguinated or possibly killed following anesthesia with Nembutal (ca. 60-80 mg / kg i.v.) by opening the torax. The aorta of the torax was removed and free of adhering binding tissues, cut into 1.5 mm wide annular segments and individually treated under an initial loading of about 3.5 g in a 10 ml saturated Krebs-Henseleit nutrient solution saturated with oxide. dioxide

and tempered to 37 ’C, p with the following composition: 119 mmol / 1 NaCl 2.5 mmo1 / 1 _CaCl2 x 2 H ₂ 0 1.2 mmol / 1 kh ₂ Mon ₄ 10 mmol / 1 glucose 4.8 mmol / 1 KC1 1.4 mmol / 1 MgSO 4 x 7 H ₂ O a 25 mmol / 1 NaHCO ₃ .

Contractions were recorded isometrically on Satham UC2-Zellen via a bridge amplifier (ifd Múlheim or DSM Aalen, respectively) and digitized and evaluated using an A / D-Wandler instrument (System 570, Keithley, Munchen). Agostin effect curves (DWK) are evaluated hourly. For each DWK, 3 or 4 individual concentrations were applied to the bath at four minute intervals. After the end of the DWK and subsequent wash cycles (sixteen times each 5 s / min with the above nutrient solution), the 28-minute resting or incubation phase ends, during which, as a rule, the contractions regain their baseline values.

Those values, which normally belonged to the 3rd DWK, were used as comparative values for the evaluation of the substances tested in the subsequent course, which were applied to the bath at increasing doses from the beginning of the incubation for the following DWKs. Each aortic ring was always stimulated with the same agonist throughout the day.

Agonists and their standard concentrations (application rate for single dose = 100 μ.1)

KC1 22.7; 3 2.7; 4 2.7; 52.7 mmol / 1 1-noradrenaline 3x10 ^-9 ; 3x10 ~ ⁸ ; 3x10 ^-7 ; 3x10 “ ⁶ g / ml serotonin 10 ^-8 ; 10 ^-7 ; 10 ^-6 ; 10 ^-5 ...... g / ml · - B-HT 920 10 ^-7 ; 10 ^-6 ; 10 ^-5 g / ml metoxamine 10 ~ ⁷ ; 10 ⁶ ; 10 “ ⁵ g / ml angiotensin II 3x10 ~ ⁹ ; 10 “ ⁸ ; 3x10 ^-8 ; ⁷ ' ⁷ g / ml.

To calculate the _IC50 (concentration at which a test compound causes 50% inhibition), the effect is always the 3rd = submaximal agonist concentration.

The compounds of the present invention inhibit angiotensin II induced contraction of isolated rabbit aorta. These contractions, indicated by potassium depolarization or other agonists, were not inhibited at all or only weakly at high concentrations.

Blood pressure measurement in angiotensin II infused rats

Male Wistar rats (Moellegaard, Kopenhagen, Denmark) weighing 200-350 g were anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a blood pressure catheter was inserted into the femoral artery and one angiotensin II infusion catheter and one substance administration catheter were inserted into the femoral vein. Angiotensin II infusion (0.3 gg / kg / rain) was started following a pentolinium ganglioblocator dose (5 mg / kg i.v.). Once the blood pressure values reached a stable level, the test substance was administered either intravenously or orally as a suspension or solution in 0.5% tylose.

Determination of antihypertensive hypertensive rats effect on unused

The oral antihypertensive action of the compounds of the present invention was tested in non-clogged rats in which unilateral renal artery stenosis was surgically induced. In addition, it was a silver print and the brightness of the kidney artery hypertonia is plasma renin six weeks after the intervention.

Arterial blood pressure of these animals at intervals of time after tail vein administration. Tested doses using a smuggler dispersed into a tylose suspension. Compounds of the present invention

In this form, increased in the first agent substance probes were measured in a defined bloodless manner were applied intragastrally by the cuff of the invention reducing the arterial blood pressure of hypertensive rats at a clinically relevant dosage.

In addition, the compounds of the present invention inhibit dose-specific binding of radioactive angiotensin II in a dose-dependent manner.

Interaction of the compounds of the invention with the angiotensin II receptor on the adrenal cortex membrane fractions (cattle)

The bovine adrenal cortex, freshly removed and carefully debulled, was further crushed in glucose solution (0.32 M) with Ultra-Turrax (Janke & Kunkel, Staufen iB) to coarse membrane homogenate and partially purified to membrane membranes in two centrifugation stages. fractions.

Receptor binding experiments were performed on partially purified bead adrenal cortex fractions with radioactive angiotensin II in 0.25 ml test chambers, each containing partially purified membranes (50-80 μς), ³ H-angiotensin II (3 - 5 nM) and assay buffer (50 mM Tris, pH 7.2, 5 mM MgCl ₂ 0.25% BSA) of the test substance. After an incubation time of 60 minutes at room temperature, unbound radioactivity of the samples was separated by a moistened glass filter (Whatman GF / C) and the bound radioactivity was measured after washing the protein with ice buffer (50 mM Tris / HCl pH 7.4, 5% PG 6000) spectrophotometrically. in a scintillation cocktail. The raw data were analyzed with computer programs to, optionally IC ₅ Q (Ki: an IC _5Q, Jcppig.oyané for the radioactivity used; IC _5Q: concentration at which a test substance has a 50% inhibition of specific binding of the radioligand).

Investigation of inhibition of smooth muscle cell profiling by the compounds of the invention

Smooth muscle cells used for the antiproliferative assay, obtained by the Media-Explantat technique (R. Ross, compound treatment) were from rat aorta and porcine J. Cel.1. Biol. 50, 172,

1971). Cells were seeded in suitable culture dishes, typically 96-well dishes and cultured for 2-3 days in 199 medium with 7.5% FCS and 7.5% NCS, 2 mM L-glutamine and 15 mM HEPES and pH 7 4 in 5% CO ₂ at 37 ° C. Thereafter, the cells were synchronized for 2-3 days with serum yield and then stimulated to grow with angiotensin II, serum or other factors. Test compounds are also added. After 16-20 hours, 1 µl of ³ H-thymidine is added and after a further 4 hours the incorporation of these substances into TCA-precipitatable DNA cells is determined.

To determine the IC ₅₀ value, the concentration of active compound that causes a semi-maximal inhibition of thymidine incorporation caused by 10% FCS at sequential dilution of the drug is calculated.

The novel active ingredients can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using known, non-toxic and / or solvents, by known methods. Therapeutically present at a concentration of about 0.5 of the composition, that is, in an amount of pharmaceutically acceptable carriers of the active compound herein to be up to 90% by weight of the total is sufficient to achieve the stated dosage range.

For example, the formulations are prepared by mixing the active ingredient with solvents and / or carriers, optionally using emulsifying agents. and / or dispersing agents, where, for example, if water is used as the diluent, organic solvents may optionally be used as co-solvents.

Administration is effected by conventional means, preferably orally or parenterally, in particular perlingually or intravenously.

For parenteral administration, solutions of the active ingredient using suitable liquid carrier materials can be used.

In general, it has proven advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight, for intravenous administration to achieve effective results. For oral administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may still be necessary to withdraw the abovementioned amounts, depending on the body weight or the type of application, but also on the individual tolerance to the medicament, the type and type of the preparation and the time or interval at which the application takes place. . Thus, it may be sufficient in individual cases that starting from less than the abovementioned minimum doses, while in other cases the above limits will have to be exceeded. In the case of administration of larger amounts, it is advisable to divide this dose into a larger number of individual doses during the day.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

N- (1-hydroxy-2-methyl-prop-2-yl) -2-methoxybenzoic acid amide

15.2 g (100 mmol) of 2-methoxybenzoic acid are dissolved in 300 ml of dichloromethane and treated at 0 ° C with 14.2 g (105 mmol) of 1-hydroxy-benzotriazole x 1 H ₂ O and 21.66 g. (105 mmol) of N, N-dicyclohexylcarbodiimide. The suspension thus obtained was stirred for 30 minutes at room temperature, re-cooled to 0 ° C and treated with a solution of 9.89 g (111 mmol) of 1-hydroxy-2-methyl-2-propylamine and 12.65 ( 125 mmol) of triethylamine in 300 ml of dichloromethane. After one hour, the reaction is complete. The reaction mixture was washed with 1M hydrochloric acid and saturated sodium bicarbonate solution and concentrated in vacuo. The crude product is triturated with petroleum ether, filtered off with suction, washed again with solvent and dried under high vacuum.

Example II

4, D-dihydro-5, a-dimethyl-2- (2-methoxyphenyl) oxazole

16.0 g (71.7 rooms, mixed mmol) of the compound of Example I were treated with 17.1 ml (283.4 mmol) of thionyl chloride and the reaction mixture was stirred for 3 hours. Excess reagents are then evaporated, the residue is stirred with 500 ml of diethyl ether and filtered off with suction. The solid is dissolved in water, overlaid with diethyl ether, and the corresponding base is released by

M sodium hydroxide. After extracting the aqueous phase three times with ethyl acetate, the combined organic phases are dried over anhydrous sodium sulfate and freed from the residual solvent under high vacuum.

Example III

4,5-dihydro-5,5-dimethyl-2- (3'-fluoro-4'-methyl-biphenyl-2-yl) -oxazole

14.7 g (605.7 mmol) of magnesium sawdust are placed under argon in 50 ml of tetrahydrofuran AR and mixed with 117.7 g (623 mmol) of 4-bromo-2-fluoro-toluene in 500 ml of tetrahydrofuran AR under stirring. . At a temperature of 35-40 C. ^The formed for two hours a clear solution. To this solution was added dropwise at room temperature a solution of 74.0 g (360.5 mmol) of the compound of Example II in 500 ml of tetrahydrofuran AR and stirred first with gentle cooling at about 25 ° C for 16 hours. The solvent is then evaporated and the crude product is washed at 600C in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution, dried over sodium sulphate and evaporated in vacuo. For purification, it is taken up in 600 ml of diethyl ether, the optional solid is filtered off with suction and the crude product is extracted into the aqueous phase several times with 2 M hydrochloric acid. This was overlaid with diethyl ether and basified to pH 13 with sodium hydroxide. After extraction three times with diethyl ether, it was dried over anhydrous sodium sulphate, evaporated and the residual solvent removed under high vacuum.

Example IV

2- (3-fluoro-4-methylphenyl) benzonitrile

97.0 g (343 mmol) of the compound of Example III are introduced in 500 ml of pyridine and mixed with 31.3 ml (343 mmol) of phosphoryl chloride at 0 ° C with stirring. The reaction mixture is slowly heated and finally refluxed for one hour. After cooling to room temperature, diethyl ether and 1 M hydrochloric acid were added until the pH of the aqueous phase was 1.5. The organic phase is washed three times with 1 M sulfuric acid, dried over sodium sulphate, concentrated on a rotary evaporator and freed from the residual solvent under high vacuum.

Example V

5- (3'-fluoro-4'-methyl-biphenyl-2-yl) -lH-tetrazole

2.26 g (10.7 mmol) of the compound of Example IV is boiled with 3.48 g (53.6 mmol). . sodium azide and 7.37 g (53.6 mmol) of triethylammonium chloride in 30 ml of dimethylformamide p.a. for 24 hours at reflux. After cooling, the mixture was partitioned between diethyl ether and 1M sulfuric acid, the organic phase was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was stirred with toluene and dried under vacuum (1.89 g). The mother liquor was evaporated on a rotary evaporator and purified again as above (0.43 g, 1.7 mmol).

Example VI

5- (3-fluoro-4-methyl-biphenyl-2-yl) -N-trityl-lH-tetrazol _{ζ θ} (Η Ο _{6 5) 3}

N-N

U \

N

- 26 50.55 g (199.2 mmol) of the compound of Example V is stirred with 58.58 g (210.0 mmol) of triphenylchloromethane and 33.2 ml (239.0 mmol) of triethylamine in 700 ml of dichloromethane for 17 hours at room temperature. The reaction mixture was washed once with water and once with 1M aqueous citric acid solution, dried over anhydrous sodium sulfate, evaporated on a rotary evaporator and freed from solvent residues under high vacuum.

Example VII

5- (4'-bromomethyl-3'-fluoro-biphenyl-2-yl) -N-trityl-lH-tetrazol

82.90 g (173.2 mmol) of the compound of Example VI was refluxed for 6 hours in one liter of carbon tetrachloride with 30.84 g (173.2 mmol) of N-bromosuccinimide and 0.87 g (5.3 mmol) of azoisobutyronitrile as a free-radical starter. After cooling the reaction mixture, the precipitated succinimide is filtered off with suction and washed with carbon tetrachloride. The filtrate obtained is concentrated and then dried under high vacuum.

Example VIII 2,4-Dioxo-5-methoxy-pentanoic acid methyl ester

To a solution of 59.4 g (1.1 mol) of sodium ethylate in 200 ml of methanol is added dropwise a solution of 88.1 g (1 mol) of methoxyacetone and 118.1 g (1 mol) of dimethyl oxalic acid dimethyl ester in 150 ml of methanol in The reaction mixture was heated at reflux for a further two hours. The cooled reaction mixture is poured into 800 ml of ice water, acidified with concentrated hydrochloric acid to pH = 1.5 and extracted three times with 500 ml of ethyl acetate each time. The combined organic phases are washed with 500 ml of 1% sodium hydrogen carbonate solution, dried over anhydrous sodium sulphate and distilled.

Boiling point: 125 ° C / 2 kPa.

Example IX

3-Cyano-4-methoxycarbonyl-6-methoxymethyl-2-oxo-1,2-dihydropyridine cooch ₃

X. ýCN

18.9 g (0.224 mol) of cyanoacetamide, 31 g (0.224 mol) of potassium carbonate and 34.6 g (0.224 mol) of the compound of Example VIII are heated under reflux in 200 ml of acetone for 2 hours. The reaction mixture is then dissolved in 500 ml of water, washed twice with 250 ml of diethyl ether each time, the aqueous phase with the product is acidified with concentrated hydrochloric acid to pH = 1.5 and the precipitate formed is filtered off with suction.

Melting point: 200

203 C.

Example X

4-carboxy-6-methoxy-2-oxo-1,2-dihydro-pyridine

10.41 g (46.8 mmol) of compound z and 16.7 ml of concentrated acid for 4 hours to 700 ml of glacial sodium to pH = 2, the precipitate is filtered off with suction of Example IX in 20 ml of hydrochloric water

The reaction mixture is heated and then poured under reflux of N hydroxide.

The solution was saturated with sodium chloride, slurry and then lyophilized.

Example XI

4-methoxycarbonyl-6-methoxymethyl-2-oxo-l, 2-dihydropyridin

To a suspension of 8.95 g (48.9 mmol) of the compound of Example x in 100 mL of methanol was added dropwise 4 mL (55.4 mmol) of thionyl chloride and the reaction mixture was stirred for 18 hours at 50 ° C. It is then concentrated to dryness and the residue is chromatographed on 100 g of silica gel 60 using dichloromethane / methanol (20: 1 to 7: 1).

Melting point: 165 ° C.

Example XII

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1 - {[3-fluoro-2 '- (N-triphenylmethyltetrazol-5-yl) -biphenyl-4-yl] methyl} -1,2-dihydropyridine

A suspension of 1.99 g (10.1 mmol) of the compound of Example XI and 3.29 g (10.1 mmol) of cesium carbonate in 20 ml of dimethoxyethane is stirred for 10 minutes at room temperature, then mixed with a solution of 5.84. g (10.1 mmol) of the compound of Example VII in 20 ml of dimethoxyethane was stirred for 20 hours at room temperature and then heated under reflux for 2 hours. After addition of 100 ml of water, the reaction solution is extracted three times with 100 ml of ethyl acetate each time. After drying, concentration and chromatography of the organic phase on silica gel using a mixture of petroleum ether and ethyl ether (5: 1 -> 1: 1), the product is obtained in the form of a colorless foam.

Example XIII

2- (Tetrazol-5-yl) -phenylboronic acid

A solution of 2.9 g (20 mmol) of 5-phenyltetrazole in 50 ml of tetrahydrofuran was treated with 17.6 ml (44 mmol) of a 2.5 M solution of n-butyllithium in n-hexane at -5 ° C under an argon atmosphere. The reaction mixture is allowed to stir for 30 minutes at a temperature in the range of -5 ° C to 0 ° C and at this temperature 10 ml (88 mmol) of trimethyl borate are added. The cooling bath was then removed and the solution was treated at room temperature with 10 ml of semi-concentrated hydrochloric acid. After one hour, it is extracted with 100 ml of ethyl acetate, the organic phase is separated and the aqueous phase is extracted twice with 20 ml of ethyl acetate each. The combined organic phases are dried over anhydrous sodium sulphate, concentrated and the residue is purified on silica gel using toluene / glacial acetic acid / methanol (38: 0.1: 2).

Yield: 2.65 g (70% of theory)

_Rf = 0.26 (toluene / methanol / glacial acetic acid = 32: 8: 1) ¹³ C-NMR: δ = 156.7; 137.9; 133.5; 129.8; 128.9; 127.7; 126.9 ppm.

Example XIV

4-methoxycarbonyl-6-methoxymethyl-2-oxo-l- (2-fluoro-4-jódfenylmetyl) 1,2-dihydropyridin

A solution of 2 g (10.14 mmol). of the compound of Example XI, 4.12 g (13.1 mmol) of 2-fluoro-4-iodo-benzyl bromide and 4.89 g (15 mmol) of cesium carbonate in 20 ml of tetrahydrofuran were stirred for 16 hours at argon under argon. 20 'C. The solvent is evaporated in vacuo, the residue is taken up in a mixture of dichloromethane and water, the aqueous phase is extracted once with dichloromethane and the combined organic phases are dried over sodium sulphate and concentrated. The residue obtained is purified on silica gel using a mixture of petroleum ether and ethyl acetate (5: 1 and 3: 1).

Yield: 1.3 g (30% of theory)

Rf = 0.16 (petroleum ether / ethyl acetate = 3: 1).

Example XV

4-methoxycarbonyl-6-methoxymethyl-2-oxo-l- (2-chloro-4-jódfenylmetyl) 1,2-dihydropyridine

The title compound was prepared analogously to Example XIV.

Rf = 0.25 (petroleum ether / ethyl acetate = 1: 2).

Example XVI

3-Chloro-4-trifluoromethylsulfonyloxy-benzoic acid methyl ester

To a solution of 5.49 g (29.4 mmol) of 3-chloro-4-hydroxy-benzoic acid methyl ester in 15 mL of pyridine at 0 ° C was slowly added dropwise 5.5 mL of trifluoromethanesulfonic anhydride (33 mmol). After stirring at 0 ° C for five minutes and at room temperature for four hours, the reaction mixture was partitioned between water and diethyl ether. The organic phase is washed successively with water, 10% hydrochloric acid, water and saturated sodium chloride solution, dried over anhydrous sodium sulphate, concentrated and the residue is chromatographed on silica gel using methylene chloride, whereby the product is obtained in the form of a pale yellow viscous oil.

Yield: 8.93 g (95% of theory) Rf = 0.63 (hexane / ethyl acetate = 3: 1).

Example XVII

5- ^{(2-chloro-1-methoxycarbonyl-4} ' -biphenyl-2-yl) -2-trifenylmety1-1Htetrazol

Argon was bubbled into a solution of Example XXXIII (1.00 g, 3.14 mmol) in toluene (50 mL). After addition of 168 mg of Pd ((C ₆ H ₅ ) ₃ ) ₄ (0.146 mmol), 6 mL of methanol, 1.63 g (3.77 mmol) of 2- (N-triphenylmethyl-tetrazol-5-yl) -phenylboronic acid. and a solution of 333 mg (3.14 mmol) of sodium carbonate in 4 ml of degassed water was stirred overnight at 100 ° C. Addition of the same amount of catalyst is followed by stirring for 2.5 hours at 100 ° C, and the reaction is complete.

The reaction mixture was partitioned between water and ethyl acetate, the organic phase was washed with dilute sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and chromatographed on silica gel using hexane: ethyl acetate = 10: 1. 10.1 g of product are obtained in the form of a pale yellow solid (57.9% of theory).

Rf = 0.46 (hexane: ethyl acetate = 3: 1).

Example XVIII

5- ^(2-chloro-1 4'-methoxycarbonyl-biphenyl-yl) 1H-tetrazol--trifenyImetyl

A solution of 22.0 g (39.6 mmol) of the compound of Example XXXIV in 180 mL of tetrahydrofuran was treated with 1.27 g of methanol (39.6 mmol) and 1.29 g of lithium borohydride (59.4 mmol), followed by reaction mixture. Stir for 30 minutes at room temperature and for one hour at reflux. The reaction is complete by adding an additional 0.63 g of methanol (0.20 mmol) and stirring at reflux for 1 hour. The reaction mixture is then concentrated, the residue is taken up in 200 ml of methylene chloride and slowly mixed with 100 ml of 1N potassium hydrogen carbonate solution under a strong argon stream. After phase separation, the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. 20.5 g of product are obtained in the form of white crystals (98.19% of theory).

Melting point: 186-187 DEG C. (decomposition) Rf = 0.15 (hexane / ethyl acetate = 3: 1).

Example XIX

5- (4'-bromomethyl-2'-chloro-biphenyl-2-yl) -2-tetrazol-trifenylraetyl

To a solution of 11.2 g of triphenylphosphine (42.5 mmol) in 100 mL of methylene chloride was first added dropwise 6.79 g of bromine (42.5 mmol) and then 20.4 g of the compound of Example XXXV in 300 mL in an ice bath under an argon atmosphere. irietylénchloridu. After stirring at room temperature for 1 hour, the reaction mixture was filtered through silica gel and eluted with methylene chloride. After concentrating the filtrate and digesting the residue with hexane, 15.8 g of product are obtained in the form of white crystals (68.9% of theory).

Melting point: 15-60 ° C

_Rf = 0.40 (hexane / ethyl acetate = 3: 1).

Example XX

4-methoxycarbonyl-6-methoxymethyl-2-oxo-l - {[2-chloro-2 ¹ - (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl} -1,2-dihydropyridin

Analogously to Example XII, the title compound is obtained from 0.46 g (2.33 mmol) of the compound of Example XI and 1.38 g (2.33 mmol) of the compound of Example XIX.

Yield: 0.17 g (10% of theory)

Rf = 0.31 (hexane / ethyl acetate = 1: 1).

Production examples

Example 1

4-methoxycarbonyl-6-methoxymethyl-2-oxo-l - [(3-fluoro-2'-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2-dihydropyridine

3.19 g (4.61 mmol) of the compound of Example XII are dissolved in 30 ml of methanol and 1.53 ml (18.4 mmol) of 12 N hydrochloric acid. After one hour, the suspension is cooled and the precipitate formed is filtered off with suction.

Example 2

4-Carboxy-6-methoxymethyl-2-oxo-1 - [(3-fluoro-2'-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2-dihydropyridine dibasic sodium salt

1.04 g (2.4 mmol) of the compound of Example 1 is stirred in 5 ml of methanol, 5 ml of tetrahydrofuran and 4.8 ml of 1 N sodium hydroxide for 2 hours at room temperature. The solvent was then distilled off and the aqueous residue was lyophilized.

Example 3

4-carboxy-6-methoxymethyl-2-oxo-l - [(3-fluoro-2'-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2-dihydropyridine

COOH

A solution of 1.2 g (2.78 mmol) of the compound of Example XIV in 20 mL of dimethyl ether was sequentially mixed with 321 mg of tetrakisphenylphosphine palladium (0), 8.34 mL (16.7 mmol) of a 2 M sodium carbonate solution, 634 mg (3, 34 mmol) of the compound of Example XII and 1.5 ml of ethyl alcohol, and the reaction mixture is heated under reflux for 16 hours, after cooling, the reaction mixture is filtered through diatomaceous earth, washed with methanol, the solvent is removed and the residue is purified on silica gel. using a mixture of toluene, ethyl acetate and glacial acetic acid (30: 10: 1 and 20: 20: 1).

Yield: 285 mg (24% of theory)

Rf = 0.11 (toluene / ethyl acetate / glacial acetic acid = 10:30):

D ·

The compounds listed in the following table were prepared analogously to Examples 1, 2 and 3.

Example R ¹ R ² R ³ salt / acid 4 co ₂ h ^CH 3 2-C1 acid 5 co ₂ h . ch ₃ ..... 3-C1 ,. acid 6 co ₂ h ch ₃ 2-Me di-Na 7 ^CO 2 ^CH 3 ch ₃ 3-Me acid 8 co ₂ h ^C 2 ^H 5 2-OH acid 9 co ₂ h ^C 2 ^H 5 3-OH acid 10 co ₂ ch ₃ ^C 2 ^H 5 2-CF ₃ mono-C 11 co ₂ h ^C 2 ^H 5 3-CF ₃ di-Li 12 ^CO 2 ^C 2 ^H 5 ^C 2 ^H 5 2-OCF ₃ acid 13 co ₂ h ^C 2 ^H 5 3-OCF ₃ acid

taboo Example 1 and R ¹ (continued) ^R2 R ³ salt / acid 14 co ₂ h ch ₃ 2-F acid 15 ^CO 2 ^CH 3 ^CH 3 2-F acid 16 ^CO 2 ^CH 3 ch ₃ 2-F mono-di 17 co ₂ ch ₃ ch ₃ 2-C1 acid 18 ^CO 2 ^CH 3 CH. □ 2-C1 mono-C 19 co ₂ h ch ₃ 3-C1 di-C 20 COOH ch ₃ 3-F mono-C 21 ^CO 2 ^CH 3 ch ₃ 3-C1 acid 22 ^CO 2 ^CH 3 ch ₃ 3-C1 mono-C

Claims (10)

PATENT CLAIMS The alkoxymethylsubstituted pyridone biphenyls of the general formula I in which: R ¹ is a carboxyl or alkoxycarbonyl group having 1 to 8 carbon atoms, R ² is straight or branched alkyl group having 1 to 10 carbon atoms, which is optionally substituted by phenyl, R ³ represents a halogen atom, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms, a trifluoromethyl group or a trifluoromethoxy group, R ⁴ represents a carboxyl group or a tetrazolyl group and X represents an oxygen or sulfur atom and salts thereof. The alkoxymethyl-substituted pyridone biphenyls according to claim 1 of the general formula I, in which R ¹ is a carboxyl or alkoxycarbonyl group having 1 to 6 carbon atoms, R represents a straight or branched alkyl group having 1 to 8 carbon atoms which may be optionally substituted by a phenyl group, o R represents a fluorine, chlorine or bromine atom, a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group, a C1-C6 alkyl group, a trifluoromethyl group or a trifluoromethoxy group, R ⁴ represents a carboxy or tetrazolyl group and X represents an oxygen atom and salts thereof. The alkoxymethyl-substituted pyridone biphenyls according to claim 1 of the general formula I, in which R ¹ is a carboxyl or alkoxycarbonyl having 1 to 4 carbon atoms, R ⁶ represents a straight or branched alkyl group having 1 to 6 carbon atoms, ABOUT R represents a fluorine or chlorine atom, a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, a methoxy group, a trifluoromethyl group or a trifluoromethoxy group, R ⁴ represents tetrazolyl, and is an oxygen atom, and salts thereof. The alkoxymethyl-substituted pyridone biphenyls according to claim 1, wherein: R ¹ represents a carboxyl group, a methoxycarbonyl group or an ethoxycarbonyl group R ² is ethyl or methyl; R ³ represents a hydroxy atom, a trifluoromethoxy group, a fluorine or chlorine atom, a trifluoromethyl methyl group, or R ⁴ represents tetrazolyl, and is an oxygen atom <·, and salts thereof. 5. Alkoxymethyl-substituted pyridone biphenyls according to therapeutic use. of claim 1 A process for the preparation of alkoxymethyl-substituted pyridone biphenyls according to claim 1, characterized in that the [A] pyridone of formula II (II) is reacted. wherein R ¹ and R ^{2 are} as defined above, with a compound of formula III wherein R ^{3 is} as defined above, R ⁴ 'is C 1 -C 4 alkoxycarbonyl or the moiety nMT ^{O (C 8 H 5) 3} represents a chlorine or bromine atom, in inert solvents, in the presence of a base and optionally with the addition of a catalyst, or [B] when R ⁴ is a tetrazolyl group, a compound of formula IV wherein R ¹ , R ² and R ^{3 are} as defined above and L is a typical leaving group such as bromine or iodine, methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy ... or "trifluoromethanesulfonyloxy", preferably bromine, with a compound of formula V wherein: T represents a hydrogen atom or a triphenylmethyl group, in an inert solvent, in the presence of a base and a metal catalyst, then, in the case of free tetrazole (R ⁴ / T), the triphenylmethyl group is cleaved with an acid in an organic solvent and / or water, in the case of a carboxylic acid ⁴ (R ¹ ), the corresponding ester is saponified and the compound is optionally converted to its salt. A medicament comprising at least one alkoxymethyl-substituted pyridone biphenyl of formula I according to claim 1. The medicament of claim 7 for the treatment of high blood pressure and atherosclerosis. Use of the alkoxymethyl-substituted pyridone biphenyls according to claim 1 for the manufacture of medicaments. Use of the alkoxymethyl-substituted pyridone biphenyls according to claim 1 for the production of antihypertensive and antiatherosclerotic agents.