SK35094A3 - Phenylglycinamides heterocyclic substituted derivatives of phenylacetic acid, method of their production, medicines contains these matters, method of their production and using of these matters - Google Patents

Abstract

Phenylglycinamides of the general formula <IMAGE> and medicaments containing these compounds for the treatment of arterial hypertension and Atherosclerosis.

Description

Technical field

The invention relates to phenylglycine amides of heterocyclically substituted phenylacetic acid derivatives, to a process for their preparation and to their use in medicaments, in particular as blood pressure lowering agents and as 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 a blood pressure-increasing octapeptide angiotensin II. Various effects of angiotensin II, such as vasoconstriction, sodium retention in the kidneys, release of aldosterone 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 increase and proliferate in various disease states (e.g., hypertonia, atherosclerosis and cardiac insufficiency).

Possible intervention in the renin-angiotensin system (RAS) is in addition to inhibiting renin activity, inhibiting angiotensin-converting enzyme (ACE) activity, as well as blocking angiotensin II receptors.

SUMMARY OF THE INVENTION

The present invention relates to the phenylglycine amides of the heterocyclically substituted phenylacetic acid derivatives of the general formula I

in which

A is a straight or branched alkyl or alkenyl group of up to 8 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms,

B represents a hydrogen atom, a halogen atom or a perfluoroalkyl group having up to 5 carbon atoms,

D is -CH ₂ -OR ⁶ or -CO-R ⁷ , wherein

R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, and

R represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group having up to 8 carbon atoms,

E represents a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 6 carbon atoms each, a cyano group or a carboxy group,

L represents a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms,

R ¹ represents a cycloalkyl group of 3 to 8 carbon atoms, a straight or branched alkyl group of up to 8 carbon atoms or a straight or branched alkyl group of up to 8 carbon atoms, substituted with a cycloalkyl group of 3 to 8 carbon atoms.

R ² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R ³ represents a hydrogen atom, a hydroxy group, a halogen atom or a straight or branched alkoxy group having up to 6 carbon atoms, and

R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group, a pyridyl group, a cycloalkyl group of 3 to 8 carbon atoms, a straight or branched alkyl group of up to 8 carbon atoms or a straight or branched alkyl group of up to 8 carbon atoms which is substituted by hydroxy, pyridyl, carboxy, straight or branched alkoxycarbonyl of up to 6 carbon atoms or -NR ⁸ R ⁹ , wherein:

R ⁸ and R ⁹ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms or

R ⁴ and R ⁵ together with the nitrogen atom form a six membered heterocycle with up to three heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen, 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, salts with organic or inorganic bases or acids can be mentioned.

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

The physiologically acceptable salts of the novel phenylglycine amides of the heterocyclically substituted phenylacetic acid derivatives may be salts of the compounds of the present invention with mineral acids, sulfonic acids or carboxylic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, citric acid. , maleic acid or benzoic acid.

Physiologically acceptable salts may be metal or ammonium salts of the compounds of the present invention having free carboxyl groups. Particularly preferred are, for example, sodium salts, potassium salts, magnesium salts or calcium salts, as well as ammonium salts derived from ammonia or organic amines, such as, for example, ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine. ethylene diamine.

The compounds of the present invention may exist in stereoisomeric forms, which occur either as an image rather than as an image, and the mirror invention also relates to their respective mixtures, such as known diastereomers and the mirror image (enantiomers) or image (diastereomers). The present enantiomers or diastereomers, such as the racemate forms, can also be resolved into stereoisomerically uniform constituents by methods (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Preferred are compounds of formula I wherein:

A represents a straight or branched alkyl or alkenyl group of up to 6 carbon atoms or a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group,

B represents a hydrogen atom, a fluorine, chlorine or bromine atom or a perfluoroalkyl group having up to 4 carbon atoms,

D is -CH ₂ -OR ⁶ or -CO-R ⁷ , wherein

R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 7 carbon atoms, and

R represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group of up to 6 carbon atoms,

E represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group, a straight or branched alkyl group,

alkoxy or alkoxycarbonyl of up to 4 carbon atoms or carboxy, L represents a hydrogen atom or a methyl group, R ¹ represents a cyclopropyl group, a cyclohexyl group, a cyclopentyl group or a cycloheptyl group, a straight or branched alkyl group of up to 4 carbon atoms or a straight or branched alkyl group of up to 4 substituted with cyclopropyl, * cyclopentyl, cyclohexyl or cycloheptyl, means a hydrogen atom or straight or branched alkyl of up to 4 carbon atoms, R ³ represents a hydrogen atom, a hydroxy group, a fluorine, chlorine or bromine atom or a straight or branched alkoxy group with up to 4 carbon atoms and R ⁴ a R ⁵ are the same or different and represent a hydrogen atom, a pyridyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a straight or branched alkyl group a group having up to 6 carbon atoms or a straight or branched alkyl group having up to 6 carbon atoms which is substituted by a hydroxy group, a pyridyl group, a carboxy group, a straight or branched alkoxycarbonyl group having up to 4 carbon atoms or an OQ group of the formula * R and R ³⁷ are the same or different and represent a hydrogen atom or a methyl group; R ⁴ a r5 together with the nitrogen atom form a morpholine, a piperazine or piperidine ring

and salts thereof.

Particularly preferred are compounds of formula I in which

A represents a straight or branched alkyl or alkenyl group of up to 4 carbon atoms in each case or a cyclopropyl group, a cyclopentyl group or a cyclohexyl group,

B represents a hydrogen atom, a fluorine or chlorine atom or a perfluoroalkyl group having up to 2 carbon atoms,

D is -CH ₂ -OR or -CO-R, wherein

R ⁶ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, and

R ⁷ represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group having up to 4 carbon atoms,

E represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group or a methyl group,

L represents a hydrogen atom or a methyl group,

R ¹ = cyclohexyl, cyclopentyl or cycloheptyl, straight-chain or branched alkyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms, substituted cyclopentyl, cyclohexyl or cycloheptyl,

R ² represents hydrogen, methyl or ethyl,

R ³ represents a hydrogen atom, a hydroxy group, a fluorine, chlorine or bromine atom or a methoxy group, and

R ⁴ and r ⁵ are the same or different and represent a hydrogen atom, a pyridyl group, a cyclohexyl group, a phenyl group, a straight or branched alkyl group having up to 4 carbon atoms or a straight or branched alkyl group having up to 4 carbon atoms which is substituted by hydroxy; a carboxy group, a straight or branched alkoxycarbonyl group having up to 3 carbon atoms, an amino group or a dimethylamino group, or

R ⁴ and R ⁵ together with the nitrogen atom form a morpholine, piperazine or piperidine ring and salts thereof.

The present invention further provides a process for the preparation of the compounds of formula (I) which comprises the steps of:

A) either react the compounds of formula II,

A

(II),

CO ₂ H ^y in which A, B, D, E, and R ¹ as defined above, with compounds of formula III

wherein L, R ² , R ³ , R ⁴ and R ^{5 have} the same meaning as previously defined or are

B) reacting compounds of formula IV

(IV), wherein L, A, B, R ¹ , R ² and R ^{3 are} as defined above,

D 'is -CH ₂ -OH and

X represents an alkyl group having 1 to 4 carbon atoms, amines or ammonia of the general formula V

HNR ⁴ R ⁵ (V) in which R ⁴ and R ^{5 are} as previously defined, in inert solvents in the presence of a base and an adjuvant, and when R ² , R ⁴ and / or R 6 do not represent a hydrogen atom, alkylation is carried out, and the substituents A, B, D and E are converted by conventional methods, such as reduction, and, where appropriate, the isomers are separated and, in the case of salts, reacted with the corresponding bases or acids.

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

[A]

K-methanesulfonium chloride DMF, N (C ₂ H ₅ ) ₃ egg ₆ h ₅

2.) h ₂ n ' ^x ^' co-nk ₂

4- (N, N-Dimethylamino) -pyridine [B]

H 3 C- (CH ₂ ) ₃

+ nh ₃

Suitable solvents for the process according to the invention 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, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloromethane chlorobenzene and further ethyl acetate, trimethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran and dimethylformamide are preferred.

Suitable bases for the process according to the invention are generally 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 sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate , alkali or alkaline earth metal alcoholates or amides, such as sodium or potassium ethanolate, sodium or potassium methoxide, sodium or potassium tert-butylate, 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. Alkali metals such as sodium or hydrides thereof such as sodium hydride can also be used as a base. Preferred include potassium carbonate, sodium hydride, potassium tert-butylate, triethylamine, pyridine 4- (N, N-dimethylamino) pyridine.

In general, the bases are used in an amount of 0.05 mol to 10 ml, 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 -30 ° C to 100 ° C, preferably -30 ° C to 60 ° 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.

The amidation is generally carried out in one of the solvents mentioned above, preferably in N, N-dimethylformamide.

The amidation is optionally carried out via an activated step of acid halides or mixed anhydrides which can be prepared from the corresponding acids by reaction with thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus tribromide, oxalyl chloride or methanesulfonic acid chloride.

The amidation or acylsulfonamidation is generally carried out at a temperature in the range of -50 ° C to 80 ° C, preferably -30 ° C to 20 ° C and under normal pressure.

Suitable bases here are, in particular, the abovementioned bases, in particular triethylamine and / or dimethylaminopyridine, DBU or DABCO.

The bases are used in an amount of 0.5 mol to 10 mol, preferably 1 mol to 5 mol, based on 1 mol of the corresponding carboxylic acid compound.

As acid binding agents for amidation or sulfoamidation, alkali metal or alkaline earth metal carbonates such as sodium carbonate and potassium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide or potassium hydroxide, organic bases such as pyridine, triethylamine and N-methylpiperidine or bicyclic amidines, such as

1,5-diazabicyclo [3.4. O] nonene-5 (DBN) or 1,5-diazabicyclo [3.4.0] undecene-5 (DBU). Triethylamine is preferred.

Suitable dehydrating agents are carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, carbonyl compounds such as carbonyldiimidazole, 1,2-oxazolium compounds such as 2-ethyl-5 - phenyl-1,2-oxazolium-3-sulfonate, propanephosphoric anhydride, isobutyl chloroformate, benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in the presence of, for example, N, N, N, methylpiperidine, dicyclohexylcarbodiimide or N-hydroxysuccinimide.

The acid binding agents and dehydrating agents are generally used in an amount of 0.5 mol to 3 mol, preferably 1 mol to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.

The reduction of the alkoxycarbonyl compounds or aldehydes to the corresponding alcohols is generally carried out with hydrides, such as lithium aluminum hydride or sodium borohydride, preferably with lithium aluminum hydride in inert solvents such as ethers, hydrocarbons or alcohols or mixtures thereof. Ethers such as diethyl ether, tetrahydrofuran or dioxane or alcohols such as ethyl alcohol are preferably used. In the case of aldehydes, sodium borohydride in ethyl alcohol is preferably used. The process is carried out at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of 20 ° C to 100 ° C and at normal pressure.

The alkylation is carried out in one of the abovementioned solvents by means of alkylating agents such as, for example, C1 -C8 alkyl halides, sulfonic acid esters or substituted C1 -C6 dialkyl sulfates or C1 -C10 diaryl sulfates, preferably methyl iodide, an acid ester p-toluenesulfone or dimethyl sulfate.

The compounds of formula (II) are novel and can be prepared by reacting compounds of formula (VI)

CO ₂ -W (VI) in which

E and R ¹ are as defined above,

T is typically a leaving group such as a chlorine, bromine or iodine atom, a tosylate or a mesylate, preferably a bromine atom, and

W is a straight or branched alkyl group having 1 to 4 carbon atoms, first reacted with imidazoles of formula VII

I

H in which A, B and D are as defined above, in one of the abovementioned solvents, optionally in the presence of a base and under a protective gas atmosphere, and in the last step, the ester is saponified by conventional means.

Dimethylformamide is preferably used as a solvent for the reaction of compounds of formula IV.

As bases, sodium hydride, potassium carbonate, triethylamine, pyridine and potassium tert-butylate are preferably used.

Generally, the base is used in an amount of 0.05 to 10, preferably 1 mol to 2 mol, based on 1 mol of the compound of the general formula IV.

The process of the present invention is generally carried out at a temperature in the range of -30 ° C to 100 ° C, preferably in the range of -10 ° C to 60 ° 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 bases for hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, 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 sodium or potassium ethanolate, sodium or potassium methanolate, or potassium tert-butylate. Lithium hydroxide, sodium hydroxide or potassium hydroxide are particularly preferred.

Suitable solvents for the saponification are water or the organic solvents customary for hydrolysis. These preferably include alcohols such as methanol, ethyl alcohol, propanol, isopropanol 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 can also advantageously be carried out with aqueous acids such as trifluoroacetic acid, acetic acid, hydrochloric acid / dioxane, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, preferably trifluoroacetic acid or hydrochloric acid / dioxane.

The saponification is generally carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 20 ° C 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 generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mole of ester. Molar amounts of the reactants are particularly preferably used.

In carrying out the reaction, carboxylates of the compounds of the present invention are formed in the first step as intermediates which can be isolated. The acids of the present invention are obtained by treating carboxylates with conventional inorganic acids. These preferably include acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or trifluoroacetic acid. It has proven advantageous in the production of carboxylic acids to acidify the basic saponification reaction mixture in the second step without isolating the carboxylates. The acids can then be isolated by conventional methods.

Compounds of formulas III, V and VII are known.

The compounds of formula (VI) are for the most part novel and can be prepared by reacting the corresponding 4-methyl compounds by substitution, for example by halogenation in the presence of one of the abovementioned bases and / or auxiliaries and in the presence of one of the abovementioned solvents.

The compounds of formula IV are novel and can be prepared, for example, by reacting compounds of formula II with compounds of formula VIII

(VIII), wherein L, R 1, R ³ and X are as defined above in (A).

The compounds of formula VIII are known in part or can be prepared by customary methods.

The compounds of the formula I according to the invention exhibit 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 may be used in medicaments for the treatment of 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 blood flow disorders, renal and adrenal disorders, bronchospatic and vascular disorders of the respiratory tract, sodium retention and swelling.

Assay for blockade of agonist contractions

Rabbits of both sexes were sacrificed by wounds to the ligaments and exsanguinated or possibly killed following anesthesia with Nembutal (ca. 60-80 mg / kg i.v.) by opening torax. The torax aorta was removed and de-adhered, cut into 1.5 mm annular segments and processed individually at an initial loading of about 3.5 g in a 10 ml organ bath.

Krebs-Henseleit nutrient solution, saturated oxide dioxide and tempered to 37 ° C, p with the following composition: 119 mmol / l NaCl 2.5 mmol / l _CaCl2 x 2 H ₂ 0 1.2 mmol / l kh ₂ Mon ₄ 10 mmol / l glucose 4.8 mmol / l KCI 1.4 mmol / l MgSO ₄ x 7 H ₂ O a 25 mmol / l NaHCO. contractions were recorded isometrically on Satham UC2 over the bridge amplifier (ifd Mulheim, possibly DSM Aalen)

and digitized and evaluated using an A / D-Wandler (System 570, Keithley, Munchen). The evaluation of the agostin effect curves (DWK) is performed 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, as a rule, during which the contractions generally return to 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 subsequent DWKs. Each aortic ring was always stimulated with the same agonist throughout the day.

Agonists and their standard single dose = 100 μΐ) concentration (application volume for

KC1 22.7? 32.7; 42.7; 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 methoxamine 10 ^-7 ; 10 ^-6 ; 10 “ ⁵ g / ml angiotensin II 3x10 ~ ⁹ ; 10 ~ ⁸ ; 3x10 ^-8 ; 10 ⁷ g / ml

For the calculation of IC ₅₀ (the concentration at which the test substance causes 50% inhibition), the effect is always based on 3. = submaximal agonist concentrations.

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 300-350 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 delivery catheter were inserted into the femoral vein. Following the dose of pentolinium ganglioblocator (5 mg / kg i.v.), angiotensin II infusion was started (0.3 µ9 / kg / min). 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 effect in non-clogged hypertensive rats

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. To this end, the right kidney artery was narrowed with a silver print with an inside diameter of 0.18 mm. In this form of hypertonia, plasma renin activity is increased in the first six weeks after intervention.

The arterial blood pressure of these animals was measured at defined time intervals after administration of the substance in a bloodless manner via the tail vein cuff. The test substances were applied in various doses by means of an esophagus probe intragastrally (orally) dispersed in a tylose suspension. The compounds of the present invention lower 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 angiotensin II receptor on adrenal cortex membrane fractions (cattle)

The bovine adrenal cortex, freshly removed and carefully debulled, was further crushed in glucose solution (0.32 M) using 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 bovine cortex cortex fractions with radioactive angiotensin II in 0.25 ml test chambers, each containing partially purified membranes (50 to 80 pg), ³ H-angiotensin II (3 to 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 period 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% PEG 6000) spectrophotometrically. in a scintillation cocktail. The raw data analysis was performed using a computer program for K i values or IC ₅₀ values (K i: IC ₅₀ values corrected for the radioactivity used; IC ₅₀ : concentration at which the test substance showed 50% inhibition of specific radioligand binding).

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

Smooth muscle cells obtained from porcine aorta by the Media-Explantat technique (R. Ross, J. Cell. Biol. 50, 172, 1971) were used to determine the antiproliferative effect of the compounds. 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. Then the cells were synchronized for 2-3 days with serum yield and then stimulated to grow with 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 IC 50 values ^{, the} concentration of the active compound that causes a semi-maximal inhibition of thymidine in the corporation induced by 10% FCS at sequential dilution of the active compound ^is calculated.

Table B

Por.č. ^IC 50

1.0

0.2

The novel active compounds can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using known methods, using inert, non-toxic and pharmaceutically acceptable carriers or solvents. The therapeutically active compounds are to be present in a concentration of about 0.5 to 90% by weight of the total composition, i.e. in an amount 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 and / or dispersing agents, where, for example, if water is used as a 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 be necessary to dispense with the abovementioned amounts, depending on the body weight or the type of application, but also on the individual tolerance of the medicament, the type and type of preparation and the time or interval at which the application takes place. . Thus, in individual cases, it may be sufficient if starting from less than the above-mentioned minimum doses, while exceeding the above-mentioned upper limits, it is possible to recommend the individual doses during the day.

DETAILED DESCRIPTION OF THE INVENTION

Moving phases:

in other cases I will have to

In the case of a larger dose, divide into a larger number

A petroleum ether: ethyl acetate = 3 : 7 B dichloromethane : methyl alcohol = 8: 1 C petroleum ether: ethyl acetate = 1 : 4 D petroleum ether: ethyl acetate = 1 : 1 E dichloromethane : methyl alcohol = 5: 1 F dichloromethane : ethyl acetate = 10: 1 G dichloromethane : ethyl acetate = 1 - 1 H petroleum ether: ethyl acetate = 2 : 1 I dichloromethane : methyl alcohol 20: 1.

Starting compounds

Example I

4-Methanephenylacetic acid tert-butyl ester

CO ₂ C (CH ₃ ) ₃

450 g (3 mol) of 4-methylphenylacetic acid, 1.13 l (12 mol) of tert-butyl alcohol and 90 g (0.74 mol) of dimethylaminopyridine are dissolved in 2 l of dichloromethane. After the addition of 680 g (3.3 mol) of dicyclohexylcarbodiimide dissolved in 400 ml of dichloromethane, the reaction mixture is stirred for 20 hours at 25 DEG C., the precipitated urea is filtered off with suction, washed with 200 ml of dichloromethane and the organic phase is washed twice with 500 ml. ml of 2 N hydrochloric acid and water. The organic phase is then concentrated and distilled.

Yield: 408 g (66% of theory)

Boiling point: 73-78 ° C / 0.2 mm.

Example II

2-Cyclopentyl-2- (4-methylphenyl) -acetic acid tert-butyl ester

CO ₂ C (CH ₃ ) ₃

33.5 g (0.3 mol) of potassium tert-butylate are placed in 100 ml of dimethylformamide, avoiding moisture at 0 ° C, and 51.6 g (0.25 mol) of 4-methylphenylacetic acid tert-butyl ester are added dropwise. 250 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes at 0 ° C and then 32.2 ml (0.3 mol) of cyclopentyl bromide in 150 ml of dimethylformamide is added dropwise at 5 to 15 ° C and stirred for 20 hours at room temperature. 25 'C. After concentration, the residue is partitioned between water and diethyl ether, the ether phase is dried over sodium sulphate and concentrated. The product crystallizes.

Yield: 67 g (97.5% of theory)

Pour point: 51-53 ° C.

Example III

2- (4-Bromomethylphenyl) -2-cyclopentylacetic acid tert-butyl ester

br

CO ₂ C (CH ₃ ) ₃

27.4 g (0.1 mol) of 2-cyclopentyl-2- (4-methylphenyl) acetic acid tert-butyl ester are dissolved in 200 ml of carbon tetrachloride and the solution is heated to boiling. After the addition of 0.82 g of azoisobutyronitrile, 18.7 g (0.015 mol) of N-bromosuccinimide are added in portions and the reaction mixture is refluxed for one hour, cooled to 0 DEG C. and succinimide is filtered off. After concentrating the filtrate, the product precipitates, which is washed with petroleum ether (40/60) and dried.

Yield: 20 g (57% of theory)

Freezing point: 73-76 ° C

Example IV

2- [4- (2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl) phenyl] -2-cyclopentylacetic acid tert-butyl ester

Under a protective gas atmosphere, 1.6 g (0.053 mol) of sodium hydride (80%) is suspended in 50 ml of dimethylformamide and 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole are added dropwise at 0 ° C. according to EP 324 377) in 100 ml of dimethylformamide. The reaction mixture was stirred at 0 ° C for 15 minutes and then 18.9 g (0.053 mol) of tert-butyl 2- (4-bromomethylphenyl) -2-cyclopentylacetic acid tert-butyl ester in 100 ml of dimethylformamide was added dropwise. The mixture is stirred for 2 hours at 0 DEG C., then the solvent is evaporated, the residue is taken up in diethyl ether, filtered and the residue is then chromatographed on silica gel 60 using dichloromethane.

Yield: 16.2 g (66.7% of theory)

Freezing point: 101 to 102 C.

Example V

2- [4- (2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl) phenyl] -2-cyclopentylacetic acid

C1

co ₂ h

2.3 g (5 mmol) of the compound of Example IV are stirred in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid for 5 hours at 25 ° C. After concentration, the crude product is chromatographed on silica gel 60 with dichloromethane / methanol (100: 5).

Yield: 1.8 g (87.6% of theory)

Pour point: 95 to 98 C.

Example VI

2- {2- [4- (2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl) phenyl] -2-cyclopentyl) acetamido-2- (2-hydroxyphenyl) acetic acid methyl ester

C1

CHO

OH

CO-NH CO ₂ CH ₃

6.0 g (15 mmol) of the compound of Example V are dissolved in 180 ml of anhydrous tetrahydrofuran and treated at 0 ° C with 4.2 ml (30 mmol) of triethylamine and 1.26 ml (16.5 mmol) of methanesulfonyl chloride. . After one hour, a solution of 3.92 g (18 mmol) of 2-hydroxyphenylglycine methyl ester hydrochloride, 1.82 g (15 mmol) of 4- (N, N-dimethylamino) pyridine and 2.52 ml (18 mmol) of triethylamine in 60 ml was added. ml of tetrahydrofuran, and the reaction mixture was stirred for 18 hours, raising the reaction temperature to room temperature. The crude mixture was taken up in water, acidified with 2M hydrochloric acid to pH = 2-3 and extracted with diethyl ether. The organic phase is dried over anhydrous magnesium sulphate and evaporated. After chromatography on silica gel 60 (Merck, petroleum ether / ethyl acetate = 2: 1), 4.03 g (7.1 mmol) of the title compound are obtained.

_Rf = 0.18 (dichloromethane: methanol = 50: 1)

Production examples

Example 1

2- {2- [4- (2-Butyl-4-chloro-5-formyl-imidazol-1-yl-methyl) phenyl] -2cyklopentyl) acetamido-2-phenyl-acetamide

CO-NI

CONH

1.54 g (3.8 mmol) of the compound of Example V is treated with 1.06 ml (7.6 mmol) of triethylamine and 0.48 g (4, 4, 10, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 40) at -30 ° C. 2 mmol) of methanesulfonic acid chloride. After one hour, 0.69 g (4.6 mmol) of phenylglycine amide and 0.47 g (3.8 mmol) of 4- (N, N-dimethylamino) pyridine are added and stirred slowly for 24 hours at room temperature. . The reaction mixture was poured into diethyl ether, treated with water and acidified to pH = 2 with 1 M hydrochloric acid. The aqueous phase is extracted with diethyl ether and the combined organic phases are washed several times with 0.01 M hydrochloric acid. It is then extracted several times with aqueous sodium hydroxide at pH = 10, washed with water, the organic phase is dried over sodium sulphate and the solvent is evaporated off. The crude product is purified by chromatography (silica gel 60, Merck, 40-63 µm, petroleum ether: ethyl acetate = 1: 1).

Yield: 1.56 g (2.9 mmol)

_Rf = 0.16 and 0.12 (petroleum ether: ethyl acetate = 1: 1).

Analogously to Example 1, the compounds listed in the following Table 1 were prepared:

Table 1 ci

CHO

R.

CON.

'2

Example diastereomer

_Rf (Solvent.) Dia

0.47 (A) dia

0.57 (B)

Example 4

2- [4- (2-Butyl-4-chloro-5-formyl-imidazol-1-ylmethyl) -phenyl] -2-cyclohexyl-acetic acid phenylglycinamidoamide

0.42 g (1 mmol) of 2- [4- (2-butyl-4-chloro-5-formylimidazol-1-ylmethyl) phenyl] -2-cyclohexyl-acetic acid in 25 ml of dichloromethane was mixed at room temperature with 0.2 g (2 mmol) of triethylamine and 0.23 g (1.5 mmol) of 1-hydroxy-1H-benzotriazole in 5 ml of tetrahydrofuran and the reaction mixture is cooled to 0 [deg.] C. 0.5 mmol) of dicyclohexylcarbodiimide in 10 ml of dichloromethane and stirring for thirty minutes is added a solution of 0.32 g (1.2 mmol) of phenylglycine and 0.1 g (1.2 mmol) of triethylamine in 10 ml of dichloromethane and the reaction mixture is stirred overnight at For working-up, it is extracted after addition of dichloromethane and the combined organic phases are dried over anhydrous sodium sulphate, filtered, concentrated and chromatographed on silica gel 60 (ethyl acetate / petroleum ether = 1: 1).

Yield: 0.31 g (0.56 mmol, 56% of theory)

Rf = 0.52 (dichloromethane / methanol = 9: 1).

Example 5

2- [4- (2-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-ylmethyl) -phenyl] -2-cyclohexyl-acetic acid phenylglycine-amide

0.15 g (0.3 mmol) of 2- [4- (2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl) -phenyl] -2-cyclohexylacetic acid phenylglycinamide amide in 5 ml of ethyl alcohol at room temperature 10 mg of sodium borohydride are added and the reaction mixture is stirred for 2 hours at room temperature. For working-up, water was added and acidified with 1N hydrochloric acid to pH = 4-5 and extracted three times with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated.

Yield: 0.16 g (0.29 mmol, 98% of theory)

_Rf = 0.48 (dichloromethane / methyl alcohol = 9: 1).

Example 6

2- {2- [4- (2-Butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl-methyl) -phenyl] -2-cyclopentyl) acetamido-2-phenyl-acetamide

1.37 g (2.6 mmol) of the compound of Example 1 was treated with 0.10 g (2.6 mmol) of sodium borate in 20 ml of ethanol at 20 ° C. In the incomplete reaction (DC-control), additional sodium borate was added after two hours. After a total of 3 hours, water and diethyl ether are added, the excess borate is removed with hydrochloric acid at pH = 2, then the pH is adjusted to 7.5 with 1 M aqueous sodium hydroxide and extracted several times with diethyl ether. The organic phases are dried over sodium sulphate and evaporated.

Yield: 1.06 g (2.0 mmol)

Rf = 0.78 and 0.75 (dichloromethane / methanol = 5: 1).

Analogously to Example 6, the compounds listed in Table 2 are prepared:

table

'. _x R 1 R ² R ³ R ⁴ R ⁵ R _f (Solvens)

Pr. c. Diastereomer rac dia A

H H H H 0.37 (A) rac dia B

H H H H 0.26 (A) dia

H 2 -OH H H 0.42 (C)

Example 10

2- {2- [4- (2-Butyl-4-chloro-5-formyl-imidazol-1-ylmethyl) phenyl] -2-cyclopentyl} acetamido-2- (2-hydroxyphenyl) acetamide

mg (0.11 mmol) of the compound of Example VI are dissolved in 2 ml of anhydrous tetrahydrofuran and treated with 1 ml of a 25% aqueous ammonia solution for 6 hours at 50 ° C. The reaction mixture was then acidified with 0.1 M sulfuric acid to pH = 7 and extracted several times with diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate and concentrated. Removal of the residual solvent under high vacuum gave 40 mg (0.07 mmol) of product.

Rf = 0.21 (petroleum ether / ethyl acetate = 1: 1).

The compounds shown in Tables 3 and 4 below are separated diastereomers of Examples 1 and 2 and can be prepared by resolution of these by conventional methods.

Table 3

Pr. no. diastereomer Rf (Solvens) 11 dia A 0.16 (D) 12 dia B 0.12 (D) 13 dia C 0.16 (D) 14 dia D 0.12 (D)

Pr. no. diastereomer Rf (Solvens) 15 dia A 0.78 (E) 16 diaB 0.75 (E) 17 dia C 0.78 (E) 18 dia D 0.75 (E)

Analogously to Example 10, the compounds listed in Table 5 are prepared:

Pr. no. R ⁵ Rf (Solvens) 19 CH ₂ CO ₂ CH ₂ CH ₃ 0.35 (F) 20 CH ₂ CH ₂ N (CH ₃ ) ₂ 0.47 (E) 21 (Ln 0.53 (G) 22 0.75 (E) 23 Ό 0.61 (G) 24 CH ₂ CH ₂ OH 0.33 (G) 25 • Ό 0.37 (H)

ch ₃

0.14 (I)

Analogously to Example 6, the compounds listed in the following Table 6 were prepared:

Pr. no. L FROM 27 ch ₃ nh ₂ 28 H Ό 29 H / - \ N 0

R _f (LM)

0.32 (I)

H

Analogously to Table 7 described in the Example, compounds are prepared,

Table 7

Pr. c.

L

CH ₃

H

H

From nh ₂

Ό

Rf (LM)

0.06 (D)

Example 35

N NH

<2- {2- [4- (2-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-ylmethyl) -phenyl] -2-cyclopentyl} -acetamido-2-phenyl-acetamido> acetic acid

CO-NH CONH COOH mg (0.1 mmol) of the compound of Example 19 was dissolved in 2 mL of ethyl alcohol and treated at 4 ° C with 4 mL of aqueous 1 M sodium hydroxide for one hour. The reaction mixture is then diluted with water, the ethyl alcohol is evaporated and the product is precipitated by acidification with 2 M hydrochloric acid. The precipitate formed is washed with water and dried over liceapent under high vacuum.

Yield: 43 mg

Rf = 0.60 (dichloromethane / methanol = 10: 1).

Claims (10)

Phenylglycine amides of heterocyclically substituted phenylacetic acid derivatives of the general formula I in which A is a straight or branched alkyl or alkenyl group of up to 8 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms, B represents a hydrogen atom, a halogen atom or a perfluoroalkyl group having up to 5 carbon atoms, 7ς 7 D is -CH ₂ -OR or -CO-R ', wherein R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, and R represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group having up to 8 carbon atoms, E represents a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a straight or branched alkyl, alkoxy or alkoxycarbonyl group each having up to 6 carbon atoms, cyano or carboxy group, L represents a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, R ¹ represents a cycloalkyl group of 3 to 8 carbon atoms, a straight or branched alkyl group of up to 8 carbon atoms or a straight or branched alkyl group of up to 8 carbon atoms, substituted with a cycloalkyl group of 3 to 8 carbon atoms. R ² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R ³ represents hydrogen, hydroxy, halogen or straight-chain or branched alkoxy radical having up to 6 carbon atoms, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group, a pyridyl group, a cycloalkyl group of 3 to 8 carbon atoms, a straight or branched alkyl group of up to 8 carbon atoms or a straight or branched alkyl group of up to 8 carbon atoms which is substituted by hydroxy, pyridyl, carboxy, straight or branched alkoxycarbonyl of up to 6 carbon atoms or -NR ⁸ R ⁹ , wherein: 8 Q R ³ and R ³ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms or R ⁴ and R ⁵ together with the nitrogen atom form a six membered heterocycle with up to three heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen, and salts thereof. 2. A compound according to claim 1, wherein the compound of claim 1, wherein: A represents a straight or branched alkyl or alkenyl group of up to 6 carbon atoms or a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, B represents a hydrogen atom, a fluorine, chlorine or bromine atom or a perfluoroalkyl group having up to 4 carbon atoms, D is -CH ₂ -OR ⁶ or -CO-R ⁷ , wherein R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 7 carbon atoms, and R ⁷ represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group having up to 6 carbon atoms, E represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group, a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 4 carbon atoms in each case or a carboxy group, L represents a hydrogen atom or a methyl group, R ¹ is cyclopropyl, cyclohexyl, cyclopentyl or cycloheptyl, straight or branched (C 4 -C 4) alkyl or straight or branched (C 4 -C 4) alkyl substituted by cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl R ² represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R ³ represents a hydrogen atom, a hydroxy group, a fluorine, chlorine or bromine atom or a straight or branched alkoxy group of up to 4 carbon atoms, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a pyridyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a straight or branched alkyl group of up to 6 carbon atoms or a straight or alkyl group of up to 6 carbon atoms substituted with hydroxy, a pyridyl carboxy group, a straight or branched alkoxycarbonyl group having up to 4 carbon atoms or a group of the formula -NR ⁸ R ⁹ , which is a branched group wherein: Q Q R c and R c are the same or different and represent a hydrogen atom or a methyl group; R ⁴ and R ⁵ together with the nitrogen atom form a morpholine, piperazine or piperidine ring and salts thereof. 3. A compound according to claim 1, wherein the phenylglycine amides of the heterocyclically substituted phenylacetic acid derivative are: A represents a straight or branched alkyl or alkenyl group of up to 4 carbon atoms in each case or a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, B represents a hydrogen atom, a fluorine or chlorine atom or a perfluoroalkyl group having up to 2 carbon atoms, D is -CH ₂ -OR ⁶ or -CO-R ⁷ , wherein R ⁶ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, and R ⁷ represents a hydrogen atom, a hydroxy group or a straight or branched alkoxy group having up to 4 carbon atoms, E represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group or a methyl group, L represents a hydrogen atom or a methyl group, R ¹ = cyclohexyl, cyclopentyl or cycloheptyl, straight-chain or branched alkyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms, substituted cyclopentyl, cyclohexyl or cycloheptyl, R ² represents hydrogen, methyl or ethyl, R ³ represents a hydrogen atom, a hydroxy group, a fluorine, chlorine or bromine atom or a methoxy group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a pyridyl group, a cyclohexyl group, a phenyl group, a straight or branched alkyl group of up to 4 carbon atoms or a straight or branched alkyl group of up to 4 carbon atoms substituted with hydroxy, pyridyl, carboxy, straight or branched alkoxycarbonyl of up to 3 carbon atoms, amino or dimethylamino, or R ⁴ and R ⁵ together with the nitrogen atom form a morpholine, piperazine or piperidine ring and salts thereof. 4. Phenylglycinamides of heterocyclically substituted phenylacetic acid derivatives as medicaments. A process for the production of phenylglycine amides of heterocyclically substituted phenylacetic acid derivatives according to claims 1 to 3, characterized in that A) reacts with compounds of formula II (Π), CO ₂ H ^y in which A, B, D, E, and R ¹ as defined above, with compounds of formula III (III), A ⁴ in which L, R ² , R ³ , R ⁴ and R ^{5 are} as defined above or are as defined above B) reacting compounds of the general formula IV (IV) in which L, A, B, R ¹ , R ² and R ^{3 are} as defined above, D 'is -CH ₂ -OH and X represents an alkyl group having 1 to 4 carbon atoms, amines or ammonia of the general formula V HNR ⁴ R ⁵ (V) in which R ⁴ and R ^{5 are} as previously defined, in inert solvents in the presence of a base and an adjuvant, and when R ² , R ⁴ and / or R ³ do not represent a hydrogen atom, alkylation follows, and the substituents A, B, D and E are converted by conventional methods, such as reduction, and, where appropriate, the isomers are separated and, in the case of salts, reacted with the corresponding bases or acids. A medicament comprising at least one phenylglycinamide of heterocyclically substituted phenylacetic acid derivatives. The medicament of claim 6 for the treatment of high arterial blood pressure and atherosclerosis. Method for the production of medicaments according to claims 6 and 7, characterized in that the active substance is optionally converted into a suitable dosage form by means of customary carriers and auxiliaries. Use of phenylglycine amides of heterocyclically substituted phenylacetic acid amides for the manufacture of medicaments. Use of phenylglycine amides of heterocyclically substituted phenylacetic acid amides for the manufacture of anti-atherosclerotic drugs.