CA2108815A1 - Alkoxymethyl-substituted pyridonebiphenyls - Google Patents

Abstract

Alkoxymethyl-substituted pyridonebiphenyls A b s t r a c t Alkoxymethyl-substituted pyridonebiphenyls are prepared by reacting corresponding pyridones with biphenylmethyl halogen compounds. The alkoxymethyl-substituted pyridone-biphenyls can be employed as active compounds in medicaments in particular for the treatment of hyper-tension and atherosclerosis.

Description

-- 21~83~ ~

The invention relates to alkoxymethyl-substituted pyridonebiphenyls, processes for their preparation and their use in medicaments, in particular as antihypertensive and antiatherosclerotic agents.

S It is known that renin, a proteolytic enzyme, splits off the decapeptide angiotensin I from angiotensinogen in vivo, the angiotensin I in turn being broken down in the lung, kidney~ or other tissues to give the hypertensive octapeptide angiotensin II. The various effects of angiotensin II, such as, for example, vasoconstriction, Na~ retention in the kidneys, release of aldosterone in the adrenals and an increase in the tonicity of the sympathetic nervous system, have a synergistic action in the context of increasing blood pressure.

Angiotensin II moreover has the property of promoting the growth and multiplication of cell9, such as, for example, of cardiac muscle cells and smooth muscle cells, these growing and proliferating to an increased degree under various disease states (for example hypertension, athero-sclerosis and cardiac insufficiency).

In addition to inhibition of renin activity, a possiblestarting point for intervention in the renin-angioten~in system ~RAS) is inhibition of the activity of angiotensin-converting enzyme (A OE) and blockade of angiotensin II receptors.

he A 29 379 - 1 -8 ~ ~

?yridone-substituted biphenyis having antihypertensive properties are described in European Patent Applications EP 487 745 and soo 297.

The invention thus relates to a selection of alkoxy-s methyl-substituted pyridonebiphenyls of the general formula (I) Rl R ~ X ~ O

2 ~ (I), in which Rl represents a carboxyl group or represents a Cl-C~-alkoxycarbonyl group, 0 R2 represents CL-C1O-alkyl (straigh~-chain or branched), which is optionally substituted by phenyl, R3 represents halogen, hydrogen, CL-C6-alkyl, hydroxyl, CL-C,-alkoxy, trifluoromethyl or trifluoromethoxy, R' repre~ents carboxyl or represents tetrazolyl and Le A 29 379 - 2 -2 ~

X represents oxygen or sulphur, and salts thereof.

The alkoxymethyl-substituted pyridonebiphenyls according to the invention can also be in the form of their salts.
Salts with organic or inorganic bases may be mentioned in general here.

Physiologically acceptable salts are preferred in the context of the present invention.

Physiologically acceptable salts of the alkoxymethyl-substituted pyridonebiphenyls are in general metal or ammonium salts of the compounds according to the invention. Particularly preferred salts are, for example, lithium, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di-or triethylamine, di- or triethanolamine, dicyclohexyl-amine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms either as enantiomers or as diastereomers. The invention relates both to the enantiomers or diastereomers and to their particular mixtures. The racemate forms can be separated into the 8tereoisomerically uniform constituents in a known manner, a~ can the diastereomers [cf. E.L. Eliel, Le A 29 379 - 3 -2 ~ 1 3 Stereochemistry of Carbon Compounds, McGraw Hill, 1962].
The formation of atropic isomers is furthermore possible.
Preferred compounds of the general formula ~I) are those in which R1 represents a carboxyl group or represents a Cl-C6-alkoxycarbonyl group, R2 represents Cl-C8-alkyl (straight-chain or branched), which can optionally be substituted by phenyl, R3 represents fluorine, chlorine, bromine, hydrogen, 10 Cl-C6-alkyl, hydroxyl, C1-C4-alkoxy, trifluoromethyl or trifluoromethoxy, Ri represents carboxyl or tetrazolyl and X represents oxygen, and salts thereof.

Particularly preferred compounds of the general formula (1) are those in which Le A 29 379 - 4 -21~ S

R- represents a carboxyl group or represents a Cl-C4-alkoxycarbonyl group, R2 represents Cl-C6-alkyl (straight-chain or branched), R3 represents fluorine, chlorine, hydrogen, hydroxyl, Cl-C4-alkyl, methoxy, trifluoromethyl or trifluoro-methoxy, R4 represents tetrazolyl and X represents oxygen, and salts thereof.

Especially preferred compounds of the general formula (I) are those in which Rl represents carboxyl, methoxycarbonyl or ethoxy-carbonyl, R2 represents ethyl or methyl, R3 represents fluorine, chlorine, methyl, hydroxyl, trifluoromethyl or trifluoromethoxy, Le A 29 379 - S -~ represents tetrazolyl and x represents oxygen, and salts thereof.

The alkoxymethyl-substituted pyridonebiphenyls of the general formula (I) are prepared by a process in which ~A] pyridones of the general formula (II) Rl R / ~

in which Rl and R2 have the abovementioned meaning, are react~d with compounds of the general formula (III) E-H2C ~ (III), in wh~ch Le A 29 379 - 6 -2~ 23189-7558 R3 has the above-mentioned meaning, E represents a leaving group, for example a chlorine or bromine atom or a methanesulphonyloxy or a toluenesulphonyloxy group, of which chlorine and bromine are preferred, and R represents Cl-C4-alkoxycarbonyl or represents a group of the formula I ~ T

N - N
in which T' represents a protecting group, for example an amine protecting group known from peptide chemistry such as the carbomethoxy, the sulphonyl-, cyano- or benzyloxycarbonyl, the benzyl group or the triphenylmethyl group, of which the triphenylmethyl group is preferred, in inert solvents, in the presence of a base and if appropriate with addition of a catalyst, or [B] in the case where R4 represents tetrasolyl, compounds of the general formula ~IV) ~X~
~R3 ( IV), ~L

ln whlch Rl, R2 and R3 have the above-mentioned meaning and L represents a typical leaving group, such as, for 2~3~ ~

example, chlorine, bromine, iodine or methane-, toluene-, fluorine- or trifluoromethanesulphonyloxy, preferably bromine, are reacted with compounds of the general formula ~V) N

I ~ T
N N
~ B(OH)2 (V), in which T represents hydrogen, or represents a protecting group T' as defined above, preferably the triphenylmethyl group, in inert solvents, in the presence of a base and under metal catalysis, and subsequently, in the case of the free tetrazole 10 (R /T) the triphenylmethyl group is split off with acids in organic solvents and/or water, and in the case of the carboxylic acids (R4 ), the corresponding ester is hydrolysed, and if appropriate the compounds are converted into their salts using bases.

2 1 ~

The process according to the invention can be illustrated by way of example by the following equation:
[A]

COOCH N--N
~ J I (3~ C(C6Hs)3 H~C~ J~N~O E~r-CH2 ~
F

CDs2co3 H3C~ ~ ~ N--N C(C,Hs~, COOCH~

~ ~ ~c~ - a-l la~

L~ A 29 379 _ 9 _ 2~81~

[B~

CO2C;~, ,.
N N H
,~ 1 C~
H,CO-H2C N O ~ E~(0~)2 ~ W
F 9r Na2co3~ OME- EtOH H20 H~CO~H2C~ N C--~H

F~

Suitable solvents for the process are the customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as ~e A 29 379 2~8~1~
diethyl ether, dioxane, tetrahydrofuran or dimethoxy-ethane, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons, such as methylene chloride, chloro-form, carbon tetrachloride, dichloroethyiene, trichloro-ethylene or chlorobenzene, or ethyl acetate, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is likewise possible to use mixtures of the solvents mentioned. Tetrahydrofuran, acetone, dimethylformamide and dimethoxyethane are preferred.

Inorganic or organic bases can in general be employed as bases for process [A] according to the invention. These bases include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkali metal or alkaline earth metal carbonates, such as calcium carbonate or caesium carbonate, or alkali metal or alkaline earth metal alcoholates or amides, such as sodium methanolate or potassium methanolate, sodium ethanolate or potassium ethanolate or potassium tert-butylate, or lithium diisopropylamide (LDA), or organic amines (trialkyl(C,-Cc)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclot2.2.2]-octane (DABC0), 1,8-diazabicyclo[5.4.0]undec-7-ene ~DBU), pyridine, diaminopyridine, methylpiperidine or morpho-line. It i~ also pos~ible to employ alkali metals, such Le A 29 379 - 11 -2 ~

as sodium, or hydrides thereof, such as sodium hydride, as bases. Potassium carbonate, sodium hydride, potassium tert-butylate or caesium carbonate are preferred.

The base in case [A] is in general employed in an amount of 0.05 mol to lo mol, preferably 1 to 2 mol, per mol of the compound of the formula (III).

Process [A] according to the invention is in general carried out in a temperature range from -100C to +100C, preferably from 0C to 80C.

The processes according to the invention are in general carried out under normal pressure. However, it i8 also possible to carry out the processes under increased pressure or under reduced pressure (for example in a range from 0.5 to 5 bar).

Suitable solvents for process [B] according to the invention are customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulph-oxide, dimethylformamide, hexamethylphosphoric acidtriamide, acetonitrile, acetone or nitromethane. It is ~e ~ 29 379 - 12 -21-3~3 also possible to use mixtures of the solvents mentioned.

Tetrahydrofuran, acetone, dimethylformamide and dimeth-oxyethane are preferred. It is likewise possible to use mixtures of the solvents mentioned with water.

Process [s] according to the invention is in general carried out in a temperature range from -200C to +150C, preferably from +40C to +100C.

Suitable catalysts are in general metal complexes of nickel,.palladium or platinum, preferably palladium(0) complexes, such as, for example, tetrakistriphenylphos-phinepalladium. It is also possible to employ phase transfer catalysts, such as, for example, tetra-n-butyl-ammonium bromide or crown ethers.

The catalyst is employed in an amount of 0.005 mol to 0.2 mol, preferably 0.01 mol to 0.05 mol, per mol of the compound of the general formula (IV).

Suitable bases are in general organic tertiary, non-nucleophilic bases, such as, for example, triethylamine or diisopropylethylamine,- or inorganic bases, such as alkali metal carbonates or hydroxides, for example potassium carbonate or hydroxide, sodium carbonate or hydroxide or thallium carbonate or hydroxide, or alkox-ides of these alkali metals. Sodium carbonate or potas-sium carbonate are preferred.

21~3~13 The base is in general employed in an amount of 1 mol to lo mol, preferably of 1 mol to 5 mol, in each case per mol of the compounds of the formula (IV).

If appropriate, the inorganic bases are employed in aqueous solution.

The triphenylmethyl group is split off with acetic acid or trifluoroacetic acid and water or one of the above-mentioned alcohols, or with aqueous hydrochloric acid in the presence of acetone, or likewise with alcohols, or in a solution of hydrogen chloride in dioxane.

The splitting-off is in general carried out in a temperature range from 0C to 150C, preferably from 200C
to 100C, under normal pressure.

Suitable catalysts are potassium iodide or sodium iodide, preferably sodium iodide.

Suitable bases for the hydrolysis of the esters are the customary inorganic bases. These include, preferably, alkali metal hydroxides or alkaline earth metal hydrox-ides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbon-ates, such as sodium carbonate or potassium carbonate, or sodium bicarbonate, or alkali metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium methano-late, potassium ethanolate or pota~sium tert-butanolate.
Sodium hydroxide or potassium hydroxide are particularly Le A 29 379 - 14 -2108~

preferably employed.

Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis. These include, preferably, alcohols, such as methanol, ethanol, propan-ol, isopropanol or butanol, or ethers, such as tetra-hydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. Alcohols, such as methanol, ethanol, propanol or isopropanol, are particularly preferably used. It is also possible to employ mixtures of the solvents mentioned.

If appropriate, the hydrolysis can also be carried out with acids, such as, for example, trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric acid, preferably with trifluoroacetic acid.

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

The hydrolysis is in general carried out under normal pressure. However, it is also possible to carry out the hydrolysis under reduced pressure or under increased pressure (for example from 0.5 to 5 bar).

In carrying out the hydrolysis, the base is in general employed in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mol of the ester. Molar amounts of the reactants are particularly preferably used.

Le A 29 379 - 15 -2la~

The hydrolysis of tert-bu~yl esters is in general carried out with acids, such as, for example, hydrochloric acid or trifluoroacetic acid, in the presence of one of the abovementioned solvents and/or water or mixtures thereof, preferably with dioxane or tetrahydrofuran.

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

The compounds of the general formula (III) are known per se or can be prepared by known methods.

The compound of the formula (V) in the case where (T = H) is new and can be prepared by a process in which phenyltetrazole is first reacted in an inert solvent and in the presence of a base under an inert gas atmosphere, trimethyl borate i8 then added and the product is hydrolysed with acids in a last step.

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

Suitable bases are prim-, sec- and tert-butyllithium and phenyllithium. n-Butyllithium is preferred.

The ba~e is employed in an amount of 2 mol to 5 mol, preferably 2 mol to 3 mol, per mol of phenyltetrazole.

Le A 29 379 - 16 -210~81~
Suitable acids are in general mineral acids, such as, for example, hydrochloric acid, Cl-C4-carboxylic acids, such as, for example, acetic acid, or phosphoric acids.
Hydrochloric acid is preferred.

The acid is in general employed in an amount of 1 mol to lo mol, preferably 1 mol to 3 mol.

The process is in general carried out in a temperature range from -70C to +25C, preferably from -10C to 0C.

The procesæ according to the invention i8 in general carried out under normal pressure. However, it iæ also possible to carry out the process under increased pressure or under reduced pressure (for example in a range from 0.5 to 5 bar).

The compounds of the general formula (IV) are new in most : 15 cases and can be prepared, for example, by a process in which compounds of the general formula (VI) ~x~ (VI) in which Rl, R' and X have the abovementioned meaning, .

~ç ~ 29 379 - 17 -21 ~8~

are reacted with compounds of the general formula (VII) V-H2C ~ (VII) in which R3 and L have the abovementioned meaning and V represents halogen, preferably bromine, in inert solvents, in the presence of a base and/or catalyst.

Suitable solvents for the process are customary organic solvents which do not change under the reaction condi-tions. These include, preferably, ethers, such as diethylether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogeno-hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethyl sulphoxide, dimethylformamide or dimethoxyethane, hexamethylphos-phoric acid triamide, acetonitrile, acetone or nitro-methane. It i8 also po~sible to use mixtures of the solvent~ mentioned. Tetrahydrofuran, acetone, dimethyl-Le A 29 379 - 1~ -.

2 ~

formamide, dimethoxyethane, alcohols, such as methanol, ethanol or propanol, and/or water, toluene and methanol/
water are preferred for the process.

sases which can be employed for the processes according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydrox-ides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate or caesium carbonate, or alkali metal or alkaline earth metal alcoholates or amides, such as sodium methanolate or potassium methanolate, sodium ethanolate or potassium lS ethanolate or potassium tert-butylate, thallium carbonate or hydroxide, or lithium diisopropylamide (LDA), or organic amines (trialkyl(C1-C6)amines), such as triethyl-amine, or heterocyclic compounds, such as 1,4-diaza-bicyclo ~2 . 2 . 2] octane (DABC0)., 1, 8-diaza-bicyclo[5.4.0]undec-7-ene (DBU), pyridine, diamino-pyridine, methylpiperidine or morpholine. It is also possible to employ alkali metals, such as sodium, or hydrides thereof, such as sodium hydride, as bases.
Potassium carbonate, sodium hydride, potassium tert-butylate or sodium carbonate are preferred for the process .

The base is in general employed in an amount of 0.05 mol to lO mol, preferably from 1 mol to 2 mol, in each case Le A 29 379 - 19 -2~8~ ~
per mol of the compounds of the formula (VII) .

The process according to the invention is in general carried out in a temperature range from -100C to +100C, preferably from ooc to 80C, under an inert gas atmos-phere The process according to the invention is in general carried out under normal pressure. However, it i~ also possible to carry out the process under increased pres-sure or under reduced pressure (for example in a range from 0.5 to 5 bar).

Suitable catalysts for the process are potassium iodide or sodium iodide, preferably sodium iodide. It i8 also possible to employ phase transfer catalysts, such as, for example, tetra-n-butylammonium bromide or crown ethers.

The catalyst is employed in an amount of 0.1 mol to 10 mol, preferably 1 mol to 2 mol, per mol of the com-pound of the general formula (VII).
. .
The above preparation processes are given merely for illustration. The preparation of the compounds of the general formula (I) according to the invention i8 not limited to these processes, and any modification of these processes can be used for the preparation in the same manner.

The alkoxymethyl-~ub8tituted pyridonebiphenyls according Le A 29 379 - 20 -2~81~

to the invention exhibit an unforeseeable and valuable spectrum of pharmacological action.

The compounds according to the invention have a specific A II-antagonistic action, since they competitively inhibit bonding of angiotensin II to the receptors. They suppress the vasoconstrictory and aldosterone secretion-stimulating effects of angiotensin II. They moreover inhibit proliferation of smooth muscle cells.

They can therefore be employed in medicaments for the treatment of arterial hypertension and atherosclerosis.
They can moreover be employed for the treatment of coronary heart diseases, cardiac insufficiency, disturb-ances in cerebral performance, ischaemic cerebral diseases, peripheral circulatory disturbances, dysfunctions of the kidneys and adrenals, bronchospastic and vascular-related diseases of the respiratory passages, sodium retention and oedemas.

Investiaation of the inhibition of contractions induced bv aaonists Rabbits of both sexes are stunned by a blow to the neck and exsanguinated, or in some cases anaesthetised with Nembutal (about 60 - 80 mg/kg intravenously) and ~acri-ficed by opening the thorax. The thoracic aorta is removed, freed from adhering connective tissue, divided ~nto ring 8egments 1.5 mm wide and introduced individu-ally, under an initial load of about 3.5 g, in 10 ml Le A 29 379 - 21 -2~ ~8~3 organ baths containing carbogen-gassed Krebs-Henseleit nutrient solution, temperature-controlled at 37C, of the following composition: 119 mmol/l of NaCl; 2.5 mmol/l of CaCl2 x 2 H20; 1.2 mmol/l of KH2Po9; 10 mmol/l of glucose;
4.8 mmol/l of KCl; 1.4 mmol/l of MgS04 x 7 H20 and 25 mmol/l of NaHC03.

The contractions are recorded isometrically by Statham UC2 cells via bridge amplifiers (from M~lheim or DSM Aalen) and digitalised by means of an A/D converter (system 570, Keithley Munich) and evaluated. The agonist/
dose effect curves (DEC) are plotted hourly. With each DEC, 3 or 4 individual concentrations are applied to the baths at intervals of 4 minutes. After the end of the DECs and subsequent wash-out cycles (16 times for in each case about 5 seconds/minutes with the abovementioned nutrient solution), a 28 minute rest or incubation phase follows, within which the contractions as a rule reach the starting value again.

The level of the 3rd DEC in the normal case is used as the reference parameter for evaluation of the test substance to be investigated in subsequent passes, the test substance being applied to the baths during the subsequent DECs in each case in an increasing dosage at the start of the incubation period. In this procedure, each aortic ring is always stimulated with the same agoni~t over the whole day.

,L,e, A 29 379 - 22 -Aaonists and thelr standard concentrations (a~lication volume per individual dose = 100 ~

KCl 22.7;32.7;42.7;52.7 mmol/1 l-noradrenaline 3x10-9;3xIo-~;3x10-';3x10-6 g/ml serotonin lo~8;1o~7;lo~6;10~5 g/ml B-~T 920 10-7;1o-6;10 5 g/ml methoxamine I0-';10-6;10-s g/ml angiotensin II 3x10-9;10-~;3x10-a;10-' g/ml To calculate the ICso (concentration at which the sub-stance to be investigated causes 50% inhibition), theeffect in each case at the 3rd = submaximum agonist concentration is taken as the basis.

The compounds according to the invention inhibit the angiotensin II-induced contraction of the isolated rabbit lS aorta as a function of the dose. The contraction induced by pota~sium depolari~ation or other agonists was not inhibited or only weakly inhibited at high concentra-tion~.

Blood oressure mea~urements on the anaiotensin II-infused E~

Male Wi~tar rat~ (Moellegaard, Copenhagen, Denmark) ha~ing a body weight of 300 - 350 g are anaestheti~ed with thiopental ~100 mg/kg intraperitoneally). After tracheotomy, a catheter for blood prossure mea~urement is ~ntroduced into th femoral artery and a catheter for Le A 29 379 - 23 -2~ ~g~ 5 angiotensin II infusion and a catheter for administration of the substance are introduced into the femoral veins.
After administration of the ganglionic blocker pento-linium (5 mg/kg intravenously), the angiotensin II
infusion (0.3 ~g/kg/minute) is started. As soon as the blood pressure values have reached a stable plateau, the test substances are administered either intravenously, or orally as a suspension or solution in 0.5~ Tylose. The changes in blood pressure under the influence of the sub~tance are stated as mean values + SEM in the table.

Determination of the antihyDertensive activity on conscious hYpertensive rats The oral antihypertensive activity of the compounds according to the invention was tested on conscious rats with surgically induced unilateral renal artery stenosis.
For this, the right-hand renal artery was constricted with a silver clip of 0.18 mm internal diameter. With this form of hypertension, the plasma renin activity is increased in the first six weeks after the intervention.
The arterial blood pressure of these animals was measured bloodlessly using a "tail cuff n at defined intervals of time after administration of the substance. The substan-ces to be tested were administered intragastrally (norally~) by gavage in various doses as a suspension in a Tylose su8pension. The compounds according to the invention lowor the arterial blood pres8ure of the hyperten8ive rats in a clinically relevant dosage.

Le A 29 379 - 24 -2~881~3 The compounds according to the invention moreover inhibit the specific bonding of radloactive angiotensin II as a function of their concentration.

Interaction of the compounds accordinq to the invention 5 with anqiotensin II receptor on membrane fractions of the adrenal cortex (bovine) Freshly removed bovine adrenal cortices (AC) thoroughly freed from the medulla of the capsule are comminuted in sucrose solution (0.32 M) with the aid of an Ultra-Turrax (Janke & Kunkel, Staufen i.B.) to a coarse membrane homogenate and partly purified to membrane fractions in two centrifugation steps.

The studies on receptor bonding are carried out on partly purified membrane fractions of bovine AC with radioactive angiotensin II in an assay volume of 0.25 ml, which comprises, specifically, the partly purified membranes (50 - 80 ~g), 3H-angiotensin II (3-5 nM), test buffer solution (50 mM Tris, pH 7.2), 5 mM MgCl2 and the sub-stances to be investigated. After an incubation time of 60 minutes at room temperature, the non-bonded radio-activity of the samples is separated off by means of moi~tened glass fibre filter~ (Whatman GF/C) and the radioactivity bonded is measured spectrophotometrically in a scintillation cocktail after the protein ha~ been wa~hed with ice-cold buffer solution (50 mM Tris/HCl, pH
7.4, 5% of PEG 6000). The raw data were analysed with computer program~ to give K~ and ICso values (Kl: ICso Le A 29 379 - 25 -21~8~

values corrected for the radioactivity used; ICso values:
concentration at which the substance to be investigated causes 50~ inhibition of specific bonding of the radio-ligands).

s Investiqation of the inhibition of ~roliferation of smooth muscle cells bY the com~ounds accordinq to the invention Smooth muscle cells which have been isolated from the aortas of rats by the media explantate technique tR. Ross, J. Cell. Biol. S0, 172, 1971] are used to determine the antiproliferative action of the compounds.
The cells are sown in suitable culture dishes, as a rule 96-well plates, and cultured at 37C for 2 - 3 days in medium 199 with 7.5% of FCS and 7.S% of NCS, 2 mM L-glutamine and 15 mM HEPES, pH 7.4, in S% CO2. Thereafter, the cells are synchronised by withdrawal of serum for 2 -3 days and are then stimulated to growth with AII, serum or other factors. Test compounds are added at the same time. 1 ~Ci 3H-thymidine is added after 16 - 20 hours, and the incorporation of this substance into the DNA of the cells which can be precipitated with T Q is deter-mined after a further 4 hours.

The active compound concentration which causes half the maximum inhibition of thymidine incorporation caused by 10~ of FCS on sequential dilution of the active compound is calculatod for the determination of the IC,o values.

~e A 29 379 - 26 -2~881~
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
The therapeutically active compound should in each case be present here in a concentration of about 0.5 to 90~ by weight of the total mixture, that is to say in amounts which are sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifying agents and/or dispersing agents, and, for example, in the case where water i8 U8ed as the diluent, organic solvents can be used as auxiliary solvents if appropriate.

Administration is effected in the customary manner, preferably orally or parenterally, in particular perlin-gually or intravenously.

In the case of parenteral use, solutions of the active compound can be employed, using suitable liguid excipient materials.

In general, it has proved advantageous in the case of intravenous administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to achievo effective re8ults, and in the case of oral administration, the dosage is about 0.01 to ~e A 29 379 - 27 -- 2 ~ ~ ~ 8 ~ ~ 23189-7558 20 mg~kg, preferably o.l to lO mg/kg of body weight.

Nevertheless, it may at times be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the body weight or the nature of the s administration route, or of the behaviour of the individual towards the medicament, of the nature of its formulation and of the time or interval at which administration takes place. Thus, in some cases it may be sufficient to employ less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. If relatively large amounts are administered, it may be advisable to divide these into several individual doses over the course of the day.
The invention also extends to a commercial package contain-ing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for treatment of hypertension and atherosclerosis.

Le A 29 379 - 28 -219~8~

Startinq compounds ExamDle N~ Hydroxy-2-methyl-prop-2-yl)-2-methoxy-benzoic acid amide Oq~NH~<~
H3CO ~

15.2 g (100 mmol) of 2-methoxy-benzoic acid are dissolved in 300 ml of methylene chloride and the solution is stirred with 14.2 g (lOS mmol) of 1-hydroxy-benzoic acid triazole x 1 H~0 and 21.66 g (lOS mmol) of N,N-dicyclo-hexylcarbodiimide at 0C. The suspension thus obtained i~
stirred at room temperature for O.S hour, cooled to 0C
again, and a solution of 9.89 g (111 mmol) of 1-hydroxy-2-methyl-2-propylamine and 12.65 g ~125 mmol) of tri-ethylamine in 300 ml of methylene chloride is added. The reaction i8 complete after 1 hour. The reaction mixture is washed with 1 M of hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo. The crude product is stirred with petroleum ether, filtered off with suction, sub~equently rinsed with the solvent and dried under a high vacuum.

e A 29 379 - 29 -2~ ~3~ ~

Exam~le II

4,5-Dihydro-s,s-dimethyl-2-(2-methoxyphenyl)-oxazole N ~O
H3CO ~
~J

17.1 ml (283.4 mmol) of thionyl chloride are added to 16.0 g (71.7 mmol) of the compound from Example 1 at room temperature and stirred for 3 hours. Thereafter, excess reagent i8 evaporated off and the residue is extracted by stirring with 500 ml of ether and filtered off with-suction. The solid is dissolved in water, the solution is covered with a layer of ether and the corresponding base is liberated with 2 M sodium hydroxide solution. After the aqueou~ phase has been extracted three times with ethyl acetate, the combined organic phases are dried with sodium sulphate and evaporated and the residue is freed from the residual solvent under a high vacuum.

Le A 29 379 - 30 -2~ ~81S
Example III

4,5-Dihydro-5,5-dimethyl-2-(3'-fluoro-4'-methyl-biphenyl-2-yl)oxazole H3C ~3 14.7 g (605.7 mol) of magnesium filings are initially introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g t623 mmol) of 4-bromo-2-fluoro-toluene in 500 ml of analytical grade tetrahydrofuran are-added, while stirring. A clear solution forms at 35 -40C within 2 hours. A solution of 74.0 g (360.5 mmol) of the compound from Example II in S00 ml of analytical grade tetrahydrofuran is added dropwise at room tempera-ture and the mixture is subsequently ~tirred at about 25C for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is lS subseguently rinsed in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride ~olution at 10C, dried with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any ~olid residue is filtered off with suction and the crude product is oxtractod into the aquoous phaso by ~everal extractions with 2 M hydrochloric acid. This Le A 29 379 - 31 -2 1 ~

aqueous phase is covered with a layer of ether and brought to pH 13 with sodium hydroxide solution. After three extractions with ether, the product phase is dried with sodium sulphate and evaporated and the residual S solvent is removed under a high vacuum.

Example IV

2-(3-Fluoro-4-methylphenyl)-benzonitrile H3C ~ CN
F ~

97.0 g (343 mmol) of the compound from Example III are - initially introduced into S00 ml of pyridine, and 31.3 ml (343 mmol) of phosphorus oxychloride are added at 0C, while stirring. The mixture is heated slowly, and is finally boiled under reflux for 1 hour. After cooling to room temperature, ether and an amount of 1 M hydrochloric acid such that the pH of the aqueous phase is 1.5 are lS added. The organic phase is washed three more time~ with 1 M sulphuric acid, dried with sodium sulphate and evaporated on a rotary evaporator and the residue is freed from the residual solvent under a high vacuum.

Le A 29 379 - 32 -~1 ~g81~
Exam~le v 5-(3'-Fluoro-4'-methyl-biphenyl-2-yl)-lH-tetrazole N--NH
H3C ~ N ~h F ~

2.26 g (10.7 mmol) of the compound from Example IV are boiled .under reflux with 3.48 g (53.6 mmol) of sodium S azide and 7.37 g (53.6 mmol) of triethylammonium chloride in 30 ml of analytical grade dimethylformamide for 24 . hours. After cooling, the mixture i8 partitioned between 3, ether and 1 M sulphuric acid, the organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated off. The crude product is extracted by stirr$ng in toluene and, after filtration with suction, the product is dried in vacuo (1.89 g, 7.2 mmol). The mother liquor is evaporated on a rotary evaporator and the residue is purified again as above (0.43 g, 1.7 mmol).

Le A 29 379 - 33 -2 ~
Exam~le VI

5-(~-Fluoro-4-methyl-biphenyl-2-yl)-2-triphenylmethyl-lH-tetrazole ,Ctc6Hs)3 N--N
Il \
H3C ~3N

50.55 g (199.2 mmol) of the compound from Example .V are stirred with 58.58 g (210.0 mmol) of triphenylchloro-methane and 33.2 ml (239.0 mmol) of triethylamine in 700 ml of methylene chloride at room temperature for 17 hours. The reaction mixture is washed once with water and once with 1 M aqueous citric acid, dried with sodium sulphate and evaporated on a rotary evaporator and the residue i9 freed from the residual solvent under a high vacuum.

~ A 29 379 ~ 34 ~

21~881S
Exam~le VII

5-(4'-Bromomethyl-3'-fluoro-biphenyl-2-yl)-2-triphenyl-methyl-lH-tetrazole C(C6Hs)3 8r N--N

F~3 82.90 g (173.2 mmol) of the compound from Example VI are boiled under reflux with 30.84 g (173.2 mmol) of N-bromosuccinimide and 0.87 g (5.3 mmol) of azobisiso-butyronitrile, as a free radical initiator, in 1 1 of carbon tetrachloride for 6 hours. After cooling, the -succinimide which has precipitated is filtered off with suction and washed with carbon tetrachloride. The fil-trate i8 evaporated and the residue is dried under a high vacuum.

ExamDle VIII

Methyl 2,4-dioxo-5-methoxy-pentanoate O O
H3CO ~ OCH3 L~ A 29 379 _ 35 _ q :~ $ ~

A solution of 88 1 g (1 mol) of methoxyacetone and 8.1 g (1 mol) of dimethyloxylate in 150 ml of methanol is added dropwise to a solution of 59.4 g (1.1 mol) of sodium methylate in 200 ml of methanol under reflux in the course of 30 minutes and the mixture is heated under reflux for a further 2 hours. The cooled reaction mixture is poured onto 800 ml of ice-water, brought to pH 1.5 with concentrated sulphuric acid and washed three times with 500 ml of ethyl acetate each time. The combined organic phases are washed with 500 ml of 1~ sodium bicarbonate solution, dried with sodium sulphate and distilled.
(Boiling point 125C/20 mbar) ExamDle IX

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

H3C ~ N ~ O
H
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 com-pound from Example VIII are heated under reflux in 200 ml of acetone for 2 hours. The reaction mixture is dissolved in 500 ml of water and washed twice with 250 ml of diothyl other each time, the aqueous product phase is Le A 29 379 - 36 -2 ~

brought to pH = 1.5 with concentrated hydrochloric acid and the precipitate ls filtered off with suction.
Melting point: 200-2030c (decomposition) Example x 4-Carboxy-6-methoxymethyl-2-oxo-1,2-dihydropyridine COOH

H C'O ~ O

10.41 g (46.8 mmol) of the compound from Example IX are heated under reflux in 20 ml of water and 16.7 ml of concentrated sulphuric acid for 4 hours. The reaction mixture is poured onto 700 ml of ice-water and brought to ; 10 pH = 2 with 5 N sodium hydroxide solution, the solution i8 saturated with sodium chloride, and a mucilaginous precipitate is filtered off with suction and freeze dried.

Le A 29 379 - 37 -8 ~ ~
Example x I

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1,2-dihydro-pyridine H3C ~ O

4 ml (55.4 mmol) of thionyl chloride are added dropwise to a su~pen~ion of 8.95 g (48.9 mmol) of the compound from Example X in 100 ml of methanol and the reaction mixture i~ stirred at 50C for 18 hours. It is concen-trated to dryness and the residue is chromatographed over 100 g of silica gel 60 using methylene chloride/methanol mixtures (20:1 to 7:1).
Xelting point: 16SC.

, .
Le A 29 379 - 38 -Exam~le XII

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-{[3-fluoro-2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]-methyl}-1,2-dihydropyridine H C'~J~o N~C(C6H5)3 A suspension of 1.99 g (lo.l mmol) of the compound from Example XI and 3.29 g (10.1 mmol) of caesium carbonate in 20 ml of dimethoxyethane i8 stirred at room temperature for 10 minutes, a solu~ion of 5.84 g (10.1 mmol) of the compound from Example VII in 20 ml of.dimethoxyethane is added, and the mixture is stirred at room temperature for 20 hours and then heated under reflux for 2 hours. After addition of 100 ml of water, the reaction solution is extracted with 3 x 100 ml of ethyl acetate. Drying, concentration and silica gel chromatography (petroleum ether: ethyl acetate . 5:1 ~ 1) of the organic phases give a colourless foam.

~e A 29 379 - 39 -2~o~1 3 Example XIII

2-(Tetrazol-5'-yl)phenylboronic acid N=N
N ~,N H
(HO) ~B ~

17.6 ml (44 mmol) of a 2.5 M solution of n-butyllithium in n-hexane are added to a ~olution of 2.9 g (20 mmol) of S 5-phenyltetrazole in S0 ml of tetrahydrofuran at -SC
under argon. The mixture is stirred at -SC to 0C for 30 minutes, and 10 ml (88 mmol) of boric acid trimethyl ester are added at this temperature. The cooling bath is then removed and 10 ml of half-concentrated hydrochloric acid are added to the solution at room temperature. After 1 hour, the mixture is extracted with 100 ml of ethyl acetate, the organic phase is separated off and the aqueous pha~e is extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are dried lS over sodium sulphate and concentrated and the residue is i purified on silica gel using toluene/ glacial acetic acid/ methanol (38 : 0.1 : 2).

Yield: 2.6S g (70% of theory) Rt - 0.26 (toluene/methanol/glacial acetic acid ~ 32:8:1) l3C-NMR: ~ - 156.7; 137.9; 133.5; 129.8; 128.9; 127.7;
126.9 ppm.

Le A 29 379 - 40 -2 ~ 5 Exam~le XIV

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-(2-fluoro-4-iod-phenylmethyl)-1,2-dihydropyridine ~,~ OCH3 H3C ~ J~N ~O

F~
A solution of 2 g (10.14 mmol) of the compound from Example XI, 4.12 g (13.1 mmol) of 2-fluoro-4-iodobenzyl bromide and 4.89 g (15 mmol) of caesium carbonate in , 20 ml of tetrahydrofuran i9 stirred under argon at 20C
for 16 hours. The solvent is then removed in vacuo, the ~ residue is taken up in methylene chloride/water, the -r 10 aqueous phase is extracted once with methylene chloride, and the combined organic phases are dried over sodium sulphate and concentrated. The residue is purified over silica gel using petroleum ether/ethyl acetate (5:1 and 3:1).

Yield: 1.3 g (30 % of theory) F~: 0.16 (petroleum ether/ethyl acetate ~ 3:1).

~e A ~_379 - 41 -2~88~ S
Exam~le XV

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-(2-chloro-4-iod-phenylmethyl)-1,2-dihydropyridine Cl ~ ' "
The title compound is prepared analogously to the instructions of Example ~IV.

Rf: 0.25 (solvent: petroleum ether:ethyl acetate 1:2) Example XVI

Methyl 3-chloro-4-trifluoromethylsulphonyloxy-benzoate H~COzC~

~090~-CF, a 5.5 ml of trifluoromethanesulphonic anhydride (33 mmol) are slowly added dropwise to a solution of 5.49 g of methyl 3-chloro-4-hydroxy-benzoate (29.4 mmol) in 15 ml of pyrid~ne at 0C. After the reaction mixture has been t~

stirred at oC for 5 mlnutes and at room temperature for 4 hours, it is partitioned between water and ether. The organic phase is washed in succession with water, 10 %
strength hydrochloric acid, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated and the residue is chromatographed over ; silica gel using methylene chloride to give 8.93 g of a pale yellow thinly mobile oil [95.2% of theory, Rf 0.63 (hexane:ethyl acetate = 3:1)].

ExamDle XVII

5-(2'-Chloro-4'-methoxycarbonyl-biphenyl-2-yl)-2-triphenylmethyl-lH-tetrazole C~ (C5H5)3 N--N
~\
H3CO2C ~¢~

Argon is pas~ed through a solution of 1.00 g (3.14 mmol) of the compound from Example XVI in 50 ml of toluene.
After addition of 168 mg of Pd(P(C~Hs) 3)~ (0.146 mmol), 6 ml of methanol, 1.63 g (3.77 mmol) of 2-(N-tri-phenylmethyl-tetrazol-5-yl)-phenylboronic acid and a solution of 333 mg (3.14 mmol) of sodium carbonate in 4 ml of degas~ed water, the emul~ion i~ ~tirred at 100C
overnight. Addition of the same amount of catalyst, L~ 29 379 _ 43 _ 2 ~ ~ ~Q ~

followed by stirring at 100C for 2.5 hours, brings the reaction to completion. The reaction mlxture is partitioned between water and ethyl acetate, the organic phase is washed with dilute sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated and the residue is chromatographed over silica gel (hexane:ethyl acetate =
10:1 to 8:1), to give 10.1 g of a pale yellow solid [57.9% of theory, Rf 0.46 (hexane:ethyl acetate = 3:1)].

Example XVIII

5-(2'-Chloro-4'-hydroxymethyl-biphenyl-2-yl)-2-triphenyl-methyl-lH-tetrazole C(C6H5)3 HO N--N
N N
~3' 1.27 g of methanol (39.6 mmol) and 1.29 g of lithium borohydride (59.4 mmol) are added to a solution of 22.0 g (39.6 mmol) of the compound from Example XVII in 180 ml of tetrahydrofuran, and the mixture is then stirred at room temperature for 30 minutes and under reflux for 1 hour. Addition of a further 0.63 g of methanol ~0.20 mmol) and stirring under reflux for 1 hour brings the reaction to completion. The reaction mixture is Le A 29 379 - 44 -2~

concentrated; the residue is taken up in 200 ml of methylene chloride and lOo ml of 1 N potassium hydrogen sulphate solution are slowly added under a vigorous stream of argon, using an ice-bath. After the phases have been separated, 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, to give 20.5 g of white crystals [98.19~ of theory; melting point 186-7C
(decomposition); R~ 0.15 (hexane:ethyl acetate = 3:1)].

Example XIX
r 5-(4'-~romomethyl-2'-chloro-biphenyl-2-yl)-2-triphenyl-methyl-lH-tetrazole C(C6Hs)3 Br N-N
~N

Cl First 6.79 g of bromine (42.5 mmol) and then 20.4 g of the compound from Example XVII in 300 ml of methylene chloride are added dropwise to a solution of 11.2 g of . triphenylphosphine ~42.5 mmol) in 100 ml of methylene 7 chloride under argon in an ice-bath. After the reaction mixture has been ~tirred at room temperature for l hour, it i~ filtered through silica gel and eluted with Le A 29 379 - 45 -2 ~

methylene chloride. Concentration of the filtrate and digestion of the residue with hexane give 15.8 g of white crystals [6J3.9~ of theory; melting point 15-60C; R~ 0.40 : (hexane/ ethyl acetate = 3:1)].

s Exam~le XX

4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-{[2-chlor-2'--; (N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl}-1,2-dihydropyridine CH ' ~ C(C~Hs)3 ~ N

0.17 g of the title compound is obtained from 0.46 g (2.33 mmol) of the compound from Example XI and 1.38 g (2.33 mmol) of the compound from Example XIX analogously to the instructions of Example XII [10 % of theory; R~
0.31 (hexane:ethyl acetate - 1:1)].

Le A 29 379 - 46 -r.

3 ~ ~
Preparation Examples : Example 1 4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-[(3-fluor-2'-tetrazol-5-yl-biphenyl-4-yl)methyl]-1,2-dihydropyridine ,0 ~ O N=N

I~NH

3.19 g (4.61 mmol) of the compound from Example XII are dissolved in 30 ml of methanol and 1.53 ml (18.4 mmol) of 12 N hydrochloric acid. After 1 hour, the suspension is cooled and the precipitate is filtered off with suction.

Le A 29 379 - 47 -- 2 ~ 3 ~ Example 2 .
4-Carboxy-6-methoxymethyl-2-oxo-1-[(3-fluor-2~-tetrazol-5-yl-biphenyl-4-yl)-methyl]-1,2-dihydropyridine disodium salt COONa H3C N ~0 N = N
~N;i 1.04 g (2.4 mmol) of the compound from Example 1 are stirred in 5 ml of methanol, 5 ml of tetrahydrofuran and 4.8 ml of 1 N sodium hydroxide solution at room tempe-rature for 2 hours. The solvent is distilled off and the aqueous residue is freeze dried.
Rf: 0.1l (toluene/ethyl acetate/glacial acetic ac1d . 10:30:1 Le A 29 379 - 48 -2 ~
ExamDle 3 4-Carboxy-6-methoxymethyl-2-oxo-~-[3-fluor-2'-tetrazol-5-yl-biphenyl-4-yl)-methyl]-1,2-dihydropyridine COOH

H3CO~ ~ N = N
/
~NH

321 mg of tetrakistriphenylphosphinepalladium(0), 8.34 ml (16.7 mmol) of 2 M sodium carbonate solution, 634 mg (3.34 mmol) of the compound of Example XIII and 1.5 ml of ethanol are added in succession to a solution of 1.2 g (2.78 mmol) of the compound from Example XIV in 20 ml of DMF and the mixture is heated under reflux for 16 hours.
After the reaction mixture has cooled~ it is filtered off with ~uction over kieselghur, the residue is rinsed with methanol, the solvent is removed and the residue is purified on silica gel using toluene/ethyl acetate/glacial acetic acid (30:10:1 and 20:20:1).
Yield: 285 mg (24 % of theory) Rr: 0.11 (toluene/ethyl acetate/glacial acetic acid =
10:30:1) .

The compound~ listed in the following tablo were prepared analogously to Examples 1, 2 and 3:

e A 29 379 - 49 -2 ~
Table:

R2 ' ~ ~o N--N
~_H

Example No. Rl R2 R3 5alt/acid 4 CO2H CH3 2-Cl Acid CO2H CH3 3-Cl Acid 6 CO2H CH3 2-Me Di-Na salt . 7 CO2CH3 CH3 3-Me Acid : 8 CO2H C2Hs 2-OH Acid 9 CO2H C2Hs 3-OH Acid CO2CH3 C2Hs 2-CF3 Mono-K salt 11 CO2H C2Hs 3-CF3 Di-Li salt 12 CO2c2Hs CzHs 2-OCF3 Acid - 13 CO2H C2Hs 3-OCF3 Acid 14 CO2H CH3 2-F Acid CO2CH3 CH3 2-F Acid 16 CO2CH3 CH3 2-F Mono-K salt ' 17 CO2CH3 CH3 2-Cl Acid ¦ 18 CO2CH3 CH3 2-Cl Mono-K salt -~
19 CO2H CH3 3-Cl Di-K salt COOH CH3 3-F Mono-K salt 21 CO,CH3 CH3 3-Cl Acid 22 COsCH~ CH3 3-Cl Mono-K salt Le A 29 379 - 50 -

Claims (16)

1. Alkoxymethyl-substituted pyridonebiphenyls of the general formula (I), in which R1 represents a carboxyl group or represents a C1-C8-alkoxycarbonyl group, R2 represents C1-C10-alkyl (straight-chain or branched), which is optionally substituted by phenyl, R3 represents halogen, hydrogen, C1-C6-alkyl, hydroxyl, C1-C8-alkoxy, trifluoromethyl or tri-fluoromethoxy, R4 represents carboxyl or represents tetrazolyl and X represents oxygen or sulphur, and salts thereof.

2. Alkoxymethyl-substituted pyridonebiphenyls according to Claim 1 in which R1 represents a carboxyl group or represents a C1-C6-alkoxycarbonyl group, R2 represents C1-C6-alkyl (straight-chain or branched), which can optionally be substituted by phenyl, R3 representg fluorine, chlorine, bromine, hydrogen, C1-C6-alkyl, hydroxyl, C1-C4-alkoxy, trifluoromethyl or trifluoromethoxy, R4 represents carboxyl or tetrazolyl and X represents oxygen, and salts thereof.

3. Alkoxymethyl-substituted pyridonebiphenyls according to Claim 1, in which R1 represents a carboxyl group or represents a C1-C4-alkoxycarbonyl group, R2 represents C1-C6-alkyl (straight-chain or branched), R3 represents fluorine, chlorine, hydrogen, hydroxyl, C1-C4-alkyl, methoxy, trifluoromethyl or trifluoromethoxy, R4 represents tetrazolyl and X represents oxygen, and salts thereof.

4. Alkoxymethyl-substituted pyridonebiphenyls according to Claim 1, in which R1 represents carboxyl, methoxycarbonyl or ethoxy-carbonyl, R2 represents ethyl or methyl, R3 represents fluorine, chlorine, methyl, hydroxyl, trifluoromethyl or trifluoromethoxy, R4 represents tetrazolyl and X represents oxygen, and salts thereof.

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

6. The compound 4-carboxy-6-methoxymethyl-2-oxo-1-[(3-fluoro-2'-tetrazol-5-yl-biphenyl-4-yl)methyl]-1,2-dihydropyridine disodium salt.

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

8. Alkoxymethyl-substituted pyridonebiphenyls according to any one of claims 1 to 7 and physiologically acceptable salts thereof for therapeutic use.

9. Process for the preparation of an alkoxymethyl-substituted pyridonebiphenyls according to claim 1, characterised in that [A] a pyridone of the general formula (II) (II), in which R1 and R2 have the meanings given in claim 1, is reacted with a compound of the general formula (III) (III), in which R3 has the meaning given in claim 1, E represents a leaving agent and R4' represents C1-C4-alkoxycarbonyl or represents a group of the formula in which T' represents a protecting group, in inert solvents, in the presence of a base, or [B] in the case where R4 represents tetrazolyl, a compound of the general formula (IV) (IV), in which R1, R2 and R3 have the meanings given in claim 1 and L represents a leaving group, is reacted with a compound of the general formula (V) (V), in which T represents hydrogen, or represents a protecting group, in inert solvents, in the presence of a base and under metal catalysis, and, if required, the protecting group T' is split off from the tetrazolyl group and, if required, an alkoxycarbonyl group R1 or R4' is hydrolysed to the free acid and, if required, an obtained compound is converted into its salt.

10. A process according to claim 9 wherein the protecting group T or T' is the triphenylmethyl group, which is subsequently split off by the action of acid in organic solvent or water.

11. A medicament containing an alkoxymethyl-substituted pyridonebiphenyl according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, together with a suitable diluent or carrier.

12. Medicaments according to claim 11 for the treatment of hypertension and atherosclerosis.

13. A process for preparing a medicament which comprises admixing an alkoxymethyl-substituted pyridonebiphenyl according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, with a suitable diluent or carrier.

14. A commercial package containing, as active pharma-ceutical ingredient, an alkoxymethyl-substituted pyridonebi-phenyl according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, together with instructions for its use for the treatment of hypertension and atherosclerosis.

15. A compound of the formula (V) as defined in claim 9, wherein T is hydrogen.

16. A compound of the formula (IV) as defined in claim 15.