AU666222B2 - Alkoxymethyl-substituted pyridonebiphenyls - Google Patents

Description

I _I Our Ref: 484559 668222 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT a Applicant(s): Bayer Aktiengesellschaft D-51368 LEVERKUSEN

GERMANY

Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Alkoxymethyl-substituted pyridonebiphenyls The following statement is a full description of this invention, including the best method of performing it known to me:- 5020

I

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

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, kidneys or other tissues to give the hypertensive octapeptide angiotensin II. The various effects of 10 angiotensin II, such as, for example, vasoconstriction, .o 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 cells, such as, for example, S* of cardiac muscle cells and smooth muscle cells, these growing and proliferating to an increased degree under various disease states (for example hypertension, atherosclerosis and cardiac insufficiency).

In addition to inhibition of renin activity, a possible *i starting point for intervention in the renin-angiotensin system (RAS) is inhibition of the activity of angiotensin-converting enzyme (ACE) and blockade of angiotensin II receptors.

Le A 29 379 1 Pyridone-substituted biphenyls having antihypertensive properties are described in European Patent Applications EP 487 745 and 500 297.

The invention thus relates to a selection of alkoxymethyl-substituted pyirdonebiphenyls of the general formula (I)

XR

2 R, N O bee

S.

0. 0 5555

S.

S i in which

R

1 represents a carboxyl group or represents a C,-C-alkoxycarbonyl group,

R

2 represents C 1

-C

0 ,-alkyl (straight-chain or branched), which is optionally substituted by phenyl,

R

3 represents halogen, hydrogen, C 1

-C

6 -alkyl, hydroxyl, C-C.-alkoxy, trifluoromethyl or trifluoromethoxy,

R

4 represents carboxyl or represents tetrazolyl 0 o and Le A 29 379 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- 10 substituted pyridonebiphenyls are in general metal or ammonium salts of the compounds according to the o goe invention. Particularly preferred salts are, for example, lithium, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are derived from ammonia 15 or organic amines, such as, for example, ethylamine, dior triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in 20 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 stereoisomerically uniform constituents in a known manner, as can the diastereomers [cf. E.L. Eliel, Le A 29 379 3 Stereochemistry of Carbon Compounds, McGraw Hill, 1962].

The formation of atropic isomers is furthermore possible.

Preferred compounds of the general formula are those in which

R

1 represents a carboxyl group or represents a Cl-C6-alkoxycarbonyl group,

R

2 represents C 1

-C

8 -alkyl (straight-chain or branched), which can optionally be substituted by phenyl,

SR

3 represents fluorine, chlorine, bromine, hydrogen, 10 C 1

-C

6 -alkyl, hydroxyl, C 1

-C

4 -alkoxy, trifluoromethyl or trifluoromethoxy, goo

R

4 represents carboxyl or tetrazolyl and X represents oxygen, '15 and salts thereof.

Particularly preferred compounds of the general formula are those i w in which Le A 29 379 4 R represents a carboxyl group or represents a C,-C 4 -alkoxycarbonyl group,

R

2 represents C 1

-C

6 -alkyl (straight-chain or branched),

R

3 represents fluorine, chlorine, hydrogen, hydroxyl, Cl-C 4 -alkyl, methoxy, trifluoromethyl or trifluoromethoxy,

R

4 represents tetrazolyl and X represents oxygen, and salts thereof.

Especially preferred compounds of the general formula (I) are those in which *oo•

R

1 represents carboxyl, methoxycarbonyl or ethoxycarbonyl, 2 represents ethyl or methyl, 0.

R

3 represents fluorine, chlorine, methyl, hydroxyl, trifluoromethyl or trifluoromethoxy, Le A 29 379 5

R

4 represents tetrazolyl and X represents oxygen, and salts thereof.

The alkoxyrnethyl -subs t ituted pyridonebiphenyls of the general formula are prepared by a process in which see: pyridones of the general formula (II) R2 N 0 in which Le A 29 379-6 6 R 3 has the abovementioned meaning, E represents chlorine or bromine and R 4 represents Cl-C,-alkoxycarbonyl or represents a group of the formula ~jlC(C 6

H

53 *oN in inr sovns0ntepeeneo aeadi

R

2 o 0 0: 0. 10i hc apRoRate wi hv addiomtion e ofeactalstno [Bantecsnweed erset erzll Le A 29 379-7 7 I L I L represents a typical leaving group, such as, for example, bromine, iodine or methane-, toluene-, fluorine- or trifluoromethanesulphonyloxy, preferably bromine, are reacted with compounds of the general formula (V)

N-N

NT

B(OH) V),

O*

0 in which 0 0 T represents hydrogen, or represents the triphenylmethyl group, in inert solvents, in the presence of a base and under S 10 metal catalysis, and subsequently, in the case of the free tetrazole

(R

4 the triphenylmethyl group is split off with acids in organic solvents and/or water, and in the case of the carboxylic acids (R 4 the correse '*15 ponding ester is hydrolysed, and if appropriate the compounds are converted into their salts using bases.

Le A 29 379 8 The process according to the invention can be illustrated by way of example by the following equation:

[A]

COOCH

3 0' HC~ N 0 r-CH 2

F

S.

'4 4 *~S0 iGee

S

5* 4 0 4SS* a to S 0 0I Sets

S

0009

DME

CS

2

CO

3

H

3 C 11 .4

S

0*.4

SO

OS '4

S

*54 40 4 4 4.

t b0 Aceton

HCI

Le A 29 379 9 N-N H N N

B(OH)

2 H 3

CO-H

2

C'

0* 0

OS

6 .6

S

Na 2

CO

3 DMS. EtOH, H 2 0 ~1 H 3

CO-H

2 0' Suitable solvents for the process are the customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as Le A 29 379 -1 10 diethyl ether, dioxane, tetrahydrofuran dimethoxyethane, or hydrocarbons, such as be. ae, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene 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 ,,10 mentioned. Tetrahydrofuran, acetone, dimethylformamide and dimethoxyethane are preferred.

S

Inorganic or organic bases can in general be employed as bases for process 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 tertbutylate, or lithium diisopropylamide (LDA), or organic 5*9 s 25 amines (trialkyl(C 1 amines), such as triethylamine, or S' heterocyclic compounds, 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. It is also possible to employ alkali metals, such Le A 29 379 11 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 is in general employed in an amount of 0.05 mol to 10 mol, preferably 1 to 2 mol, per mol of the compound of the formula (III).

Process according to the invention is in general carried ouc in a temperature range from -100 0 C to +100 0

C,

preferably from 0 C to 80 0

C.

10 The processes according to the invention are in general carried out under normal pressure. However, it is 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).

15 Suitable solvents for process 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 20 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 sulphoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is Le A 29 37-9 12 also possible to use mixtures of the solvents mentioned.

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

Process according to the invention is in general carried out in a temperature range from -20 0 C to +150 0

C,

preferably from +40 0 C to +100 0

C.

*O

Soo: Suitable catalysts are in general metal complexes of nickel, palladium or platinum, preferably palladium(0) 1o0 complexes, such as, for example, tetrakistriphenylphosphinepalladium. It is also possible to employ phase transfer catalysts, such as, for example, tetra-n-butylamimonium bromide or crown ethers.

The catalyst is employed in an amount of 0.005 mol to 15 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, nonnucleophilic bases, such as, for example, triethylamine or diisopropylethylamine, or inorganic bases, such as "20 alkali metal carbonates or hydroxides, for example e" potassium carbonate or hydroxide, sodium carbonate or hydroxide or thallium carbonate or hydroxide, or alkoxides of these alkali metals. Sodium carbonate or potassium carbonate are preferred.

Le A 29 379 13 The base is in general employed in an amount of 1 mol to 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- *O.e *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.

00 The splitting-off is in general carried out in a temperature range from 0°C to 1500C, preferably from 200C to 100 0 C, under normal pressure.

Suitable catalysts are potassium iodide or sodium iodide, 15 preferably sodium iodide.

Suitable bases for the hydrolysis of the esters are the

O

customary inorganic bases. These include, preferably, alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium 20 hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium bicarbonate, or alkali metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate or potassium tert-butanolate.

Sodium hydroxide or potassium hydroxide are particularly Le A 29 379 14 preferably employed.

Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis. These include, preferably, alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as tetrahydrofuran 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 10 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 0 C to +100 0 C, preferably from +200C to +80 0

C.

The hydrolysis is in general carried out under normal pressure. However, it is also possible to carry out the 20 hydrolysis under reduced pressure or under increased S" 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 mol, per mol of the ester. Molar amounts of the reactants are particularly preferably used.

Le A 29 379 15 The hydrolysis of tert-butyl 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 .o0: se or can be prepared by known methods.

10 The compound of the formula in the case where (T H) o is new and can be prepared by a process in which phenyltetrazole is first reacted in =n inert solvent and in the presence of a base under an inert gas atmosphere, trimethyl borate is then added and the product is 15 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.

*0 0 20 Suitable bases are prim-, sec- and tert-butyllithium and "phenyllithium. n-Butyllithium is preferred.

The base 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 Suitable acids are in general mineral acids, such as, for example, hydrochloric acid, Ci-C 4 -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 mol, preferably 1 mol to 3 mol.

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

6000 *0*S The process according to the invention is in general *0SS S, 10 carried out under normal pressure. However, it is 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)

R

X (VI) 0 R2 0

H

in which

R

1

R

2 and X have the abovementioned meaning, Le A 29 379 17 are reacted with compounds of the general formula (VII)

R

3 V-H2C

(VII)

in which

R

3 and L have the abovementioned meaning and 5 V represents halogen, preferably bromine,

OS

0O.0 in inert solvents, in the presence of a base and/or catalyst.

Suitable solvents for the process are customary organic Ssolvents which do not change under the reaction condi- *10 tions. These include, preferably, ethers, such as diethyl f. ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons, such as methylene chloride, chloroform, 15 carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethyl sulphoxide, dimethylformamide or dimethoxyethane, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, acetone, dimethyl- Le A 29 379 18 formamide, dimethoxyethane, alcohols, such as methanol, ethanol or propanol, and/or water, toluene and methanol/ water are preferred for the process.

Bases which can be employed for the processes according to the invention are in general inorganic or organic bases. These 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, alkaline earth metal carbonates, such as calcium carbonate or oa .caesium carbonate, or alkali metal or alkaline earth metal alcoholates or amides, such as sodium methanolate S- or potassium methanolate, sodium ethanolate or potassium ethanolate or potassium tert-butylate, thallium carbonate or hydroxide, or lithium diisopropylamide (LDA), or organic amines (trialkyl(Ci-CG) amines) such as triethylamine, or heterocyclic compounds, such as 1,4-diaza- Sbicyclo[2.2.2]octane (DABCO)., 1,8-diaza- 20 bicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, 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- *.25 butylate or sodium carbonate are preferred for the process.

The base is in general employed in an amount of 0.05 mol to 10 mol, preferably from 1 mol to 2 mol, in each case Le A 29 379 19 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 -100 0 C to +100 0

C,

preferably from 0 C to 80 0 C, under an inert gas atmosphere.

The process according to the invention is in general carried out under normal pressure. However, it is 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).

Q*

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

S15 The catalyst is employed in an amount of 0.1 mol to 5* 10 mol, preferably 1 mol to 2 mol, per mol of the compound of the general formula (VII).

The above preparation processes are given merely for illustration. The preparation of the compounds of the 20 general formula according to the invention is not limited to these processes, and any modification of these processes can be used for the preparation in the same manner.

The alkoxymethyl-substituted pyridonebiphenyls according Le A 29 379 20 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.

*O

They can therefore be employed in medicaments for the o**O 10 treatment of arterial hypertension and atherosclerosis.

They can moreover be employed for the treatment of coronary heart diseases, cardiac insufficiency, disturbances 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.

Investigation of the inhibition of contractions induced by agonists Rabbits of both sexes are stunned by a blow to the neck o* and exsanguinated, or in some cases anaesthetised with Nembutal (about 60 80 mg/kg intravenously) and sacrificed by opening the thorax. The thoracic aorta is removed, freed from adhering connective tissue, divided into ring segments 1.5 mm wide and introduced individually, under an initial load of about 3.5 g, in 10 ml Le A 29 379 21 organ baths containing carbogen-gassed Krebs-Henseleit nutrient solution, temperature-controlled at 37 0 C, of the following composition: 119 mmol/l of NaC1; 2.5 mmol/1 of CaC12 x 2 H 2 0; 1.2 mmol/l of KH 2

PO

4 10 mmol/l of glucose; 4.8 mmol/l of KC1; 1.4 mmol/l of MgSO 4 x 7 H 2 0 and mmol/l of NaHCO 3 The contractions are recorded isometrically by Statham UC2 cells via bridge amplifiers (from Malheim or DSM Aalen) and digitalised by means of an A/D converter *L (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 020 the reference parameter for evaluation of the test substance to be investigated in subsequent passes, the .o 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 agonist over the whole day.

Le A 29 379 22 Aqonists and their standard concentrations (application volume per individual dose 100 ul): KC1 22.7;32.7;42.7;52.7 mmol/l 1-noradrenaline 3x10- 9 ;3x10-8;3x10 7 ;3x10 6 g/ml serotonin 10-8; 107; 10-; 10- g/ml B-HT 920 10-7; 10-6; 10- g/ml methoxamine 10-7; 106; 10-s g/ml angiotensin II 3x10-9;10"9;3x10-8;10 7 g/ml 9 0e

G..

S" To calculate the ICs 5 (concentration at which the substance .to be investigated causes 50% inhibition), the o. effect in each case at the 3rd submaximum agonist concentration is taken as the basis.

66 The compounds according to the invention inhibit the angiotensin II-induced contraction of the isolated rabbit 15 aorta as a function of the dose. The contraction induced by potassium depolarisation or other agonists was not inhibited or only weakly inhibited at high concentra- C.OO tions Blood pressure measurements on the anqiotensin II-infused rat Male Wistar rats (Moellegaard, Copenhagen, Denmark) having a body weight of 300 350 g are anaesthetised with thiopental (100 mg/kg intraperitoneally). After tracheotomy, a catheter for blood pressure measurement is introduced into the femoral artery and a catheter for Le A 29 379 23 angiotensin II infusion and a catheter for administration of the substance are introduced into the femoral veins.

After administration of the ganglionic blocker pentolinium (5 mg/kg intravenously), the angiotensin II infusion (0.3 Ag/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 *10 substance are stated as mean values SEM in the table.

Determination of the antihypertensive activity on o conscious hypertensive rats The ,ral 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 0* 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.

s* "20 The arterial blood pressure of these animals was measured bloodlessly using a "tail cuff" at defined intervals of time after administration of the substance. The substan- 0 ces to be tested were administered intragastrally ("orally") by gavage in various doses as a suspension in a Tylose suspension. The compounds according to the invention lower the arterial blood pressure of the hypertensive rats in a clinically relevant dosage.

Le A 29 379 24 The compounds according to the invention moreover inhibit the specific bonding of radioactive angiotensin II as a function of their concentration.

Interaction of the compounds according to the invention 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 O^ *sucrose solution (0.32 M) with the aid of an Ultra-Turrax *.10 (Janke Kunkel, Staufen to a coarse membrane ee.e *g 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 15 angiotensin II in an assay volume of 0.25 ml, which comprises, specifically, the partly purified membranes (50 80 Hg), 3 H-angiotensin II (3-5 nM), test buffer solution (50 mM Tris, pH 5 mM MgC 2 1 and the substances to be investigated. After an incubation time of 60 minutes at room temperature, the non-bonded radioactivity of the samples is separated off by means of moistened glass fibre filters (Whatman GF/C) and the radioactivity bonded is measured spectrophotometrically in a scintillation cocktail after the protein has been washed with ice-cold buffer solution (50 mM Tris/HCl, pH 7.4, 5% of PEG 6000). The raw data were analysed with computer programs to give K i and ICS, values (Ki: IC, 0 Le A 29 379 25 values corrected for the radioactivity used; ICso values: concentration at which the substance to be investigated causes 50% inhibition of specific bonding of the radioligands).

Investigation of the inhibition of proliferation of smooth muscle cells by the compounds according to the invention Smooth muscle cells which have been isolated from the aortas of rats by the media explantate technique Ross, J. Cell. Biol. 50, 172, 1971] are used to determine the antiproliferative action of the compounds.

e, The cells are sown in suitable culture dishes, as a rule se" 96-well plates, and cultured at 37 0 C for 2 3 days in medium 199 with 7.5% of FCS and 7.5% of NCS, 2 mM Lglutamine and 15 mM HEPES, pH 7.4, in 5% CO 2 Thereafter, the cells are synchronised by withdrawal of serum for 2 S3 days and are then stimulated to growth with AII, serum or other factors. Test compounds are added at the same time. 1 ACi H-thymidine is added after 16 20 hours, "20 and the incorporation of this substance into the DNA of the cells which can be precipitated with TCA is determined after a further 4 hours.

*i 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 calculated for the determination of the ICs 0 values.

Le A 29 379 26

I

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, nontoxic, 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.

O S

S*O*

*10 The formulations are prepared, for example, by extending *the active compounds with solvents and/or excipients, if S0.4 appropriate using emulsifying agents and/or dispersing *o agents, and, for example, in the case where water is used as the diluent, organic solvents can be used as auxiliary solvents if appropriate.

*0 Administration is effected in the customary manner, preferably orally or parenterally, in particular perlingually or intravenously.

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

S

DA 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 achieve effective results, and in the case of oral administration, the dosage is about 0.01 to Le A 29 379 27 mg/kg, preferably 0.1 to 10 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 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 10 amount, while in other cases the upper limit mentioned I 6 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.

ago 6 4 a C** 6 tt J Le A 29 379 28 Startinc compounds Example I N-(l-Hydroxy-2-methyl-prop-2-yl)-2-methoxy-benzoic acid amide 0 NH

OH

a 5 15.2 g (100 mmol) of 2-methoxy-benzoic acid are dissolved

HCO

in 300 ml of methylene chloride and the solution is stirred with 14.2 g (105 mmol) of 1-hydroxy-benzoic acid triazole x 1 H20 and 21.66 g (105 mmol) of N,N-dicyclohexylcarbodiimide at 0°C. The suspension thus obtained is stirred at room temperature for 0.5 hour, cooled to 0°C again, and a solution of 9.89 g (111 mmol) of 1-hydroxy- 0 0 2-methyl-2-propylamine and 12.65 g (125 mmol) of triethylamine in 300 ml of methylene chloride is added. The reaction is complete after 1 hour. The reaction mixture is washed with 1 M of hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulphate a and concentrated in vacuo. The crude product is stirred with petroleum ether, filtered off with suction, subsequently rinsed with the solvent and dried under a high vacuum.

Le A 29 379 29 I .1 Example II 4,5-Dihydro-5,5-dimethyl-2-(2-methoxyphenyl)-oxazole N O

H

3

CO

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 5 temperature and stirred for 3 hours. Thereafter, excess reagent is 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 10 is liberated with 2 M sodium hydroxide solution. After the aqueous 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.

O*

4* 0 **o Le A 29 379 30 Example III 4,5-Dihydro-5, 5-dimethyl-2- -fluoro-4' -methyl-biphenyl- 2-yl)oxazole

H

3 C N 0 14.7 g (605.7 mol) of magnesium filings are initially o* *ve 5 introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g (623 mmol) of 4-bromo-2-fluorotoluene in 500 ml of analytical grade tetrahydrofuran are added, while stirring. A clear solution forms at 35 40 0 C within 2 hours. A solution of 74.0 g (360.5 mmol) of 10 the compound from Example II in 500 ml of analytical S grade tetrahydrofuran is added dropwise at room temperature and the mixture is subsequently stirred at about 0 C for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is 15 subsequently rinsed in 600 ml of ethyl acetate and 800 ml )0e ,o of saturated ammonium chloride solution at 10°C, dried 6 @0 with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any solid residue is filtered off with suction and the crude product is extracted into the aqueous phase by several extractions with 2 M hydrochloric acid. This Le A 29 379 31

L

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 solvent is removed under a high vacuum.

Example IV 2-(3-Fluoro-4-methylphenyl)-benzonitrile HC CN

F

97.0 g (343 mmol) of the compound from Example III are initially introduced into 500 ml of pyridine, and 31.3 ml (343 mmol) of phosphorus oxychloride are added at 0°C, 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 :;15 added. The organic phase is washed three more times 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.

eoS Le A 29 379 32 ExamDle V 5-(3'-Fluoro-4'-methyl-biphenyl-2-yl)-H-tetrazole

N-NH

II

H

3 C N N

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 se: 5 azide and 7.37 g (53.6 mmol) of triethylammonium chloride in 30 ml of analytical grade dimethylformamide for 24 g hours. After cooling, the mixture is partitioned between 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 stirring 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, 15 1.7 mmol).

OS

Le A 29 379 33 L I IL I Example VI 5-(3-Fluoro-4-methyl-biphenyl-2-yl)-2-triphenylmethyl-1Htetrazole C(0 6 Hs) 3

N-N

II

H

3 C N N

F

e 50.55 g (199.2 mmol) of the compound from Example V are S 5 stirred with 58.58 g (210.0 mmol) of triphenylchloromethane 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 i M aqueous citric acid, dried with sodium sulphate and eraporated on a rotary evaporator and the residue is freed from the residual solvent under a high vacuum.

0 0 *9 4* Le A 29 379 -1 Examole VII (4 -Bromomethyl-3' -fluoro-biphenyl-2-yl) -2-triphenylmethyl H- tetrazole /C(C 6 HS)3 Br N-N N N

F

82.90 g (173.2 mmol) of the compound from Example VI are 5 boiled under reflux with 30.84 g 1*173.2 mmol) of N- C0 bromosuccinimide and 0.87 g (5.3 mmol) of azobisisobutyronitrile, as a free radical initiator, in 1 1 of Cse carbon tetrachloride for 6 hours. After cooling, the succinimide which 'has precipitated is filtered off with suction and washed with carbon tetrachloride. The filtrate is evaporated and the residue is dried under a high .09:..vacuum.

*00:0*Example VIII Methyl 2, 0 0 C. H 3 CO OH 0 Le A 29 379 -335 I -I- A solution of 88.1 g (1 mol) of methoxyacetone and 118.1 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 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 1250C/20 mbar) 0'6* Example IX 0:64 moo* 3-Cyano-4-methoxycarbonyl-6-methoxymethyl-2-oxo-l,2dihydropyridine

COOCH

3

CN

O 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 compound 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 diethyl ether each time, the aqueous product phase is Le A 29 379 36 I brought to pH 1.5 with concentrated hydrochloric acid and the precipitate is filtered off with suction.

Melting point: 200-2030C (decomposition) Example X 4-Carboxy-6-methoxymethyl-2-oxo-1,2-dihydropyridine

COOH

H

3 C N 0

H

10.41 g (46.8 mmol) of the compound from Example IX are oo 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 pH 2 with 5 N sodium hydroxide solution, the solution is saturated with sodium chloride, and a mucilaginous precipitate is filtered off with suction and freeze dried.

.o o* c Le A 29 379 37 aa, Example XI 4-Methoxycarbonyl-G-methoxymethyl-2-oxo-l,2-dihydropyridine

COOCH

3

H

3 C 0 I

A-

4 ml (55.4 mmol) of thionyl chloride are added dropwise to a suspension of 8.95 g (48.9 mmol) of the compound from Example X in 100 ml of methanol and the reaction mixture is stirred at 500C for 18 hours. It is concen- 9****trated to drns and the residue is chromatographed over 100 g of silica gel 60 using methylene chloride/methanol mixtures (20:1 to 7:1).

Melting point: 1G5 0

C.

Le A 29 379 38 Example XII 4-Methoxycarbonyl-6-methoxymethyl-2-oxo-l-{[3-fluoro-2'- (N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]-methyl}- 1,2-dihydropyridine

COOCH

3 H3C N 0 N -N C(C6)3 N 'V'

F

F 5 A suspension of 1.99 g (10.1 mmol) of the compound from Example XI and 3.29 g (10.1 mmol) of caesium carbonate in ml of dimethoxyethane is stirred at room temperature for 10 minutes, a solution of 5.84 g (10.1 mmol) of the compound from Example VII in 20 ml of.dimethoxyethane is :10 added, and the mixture is stirred at room temperature for *e 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 15 ether: ethyl acetate 5:1 1:1) of the organic phases give a colourless foam.

o: Le A 29 379 39 r _1 Example XIII acid

N=N

N NH

(HO)

2

B

17.6 ml (44 mmol) of a 2.5 M solution of n-butyllithium in n-hexane are added to a solution of 2.9 g (20 mmol) of 5 5-phenyltetrazole in 50 ml of tetrahydrofuran at -5 0

C

under argon. The mixture is stirred at -5 0 C to 0 C for 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 phase is extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and concentrated and the residue is purified on silica gel using toluene/ glacial acetic acid/ methanol (38 0.1 2).

S. Yield: 2.65 g (70% of theory) Rf 0.26 (toluene/methanol/glacial acetic acid 32:8:1) 1 3 C-NMR: 6 156.7; 137.9; 133.5; 129.8; 128.9; 127.7; 126.9 ppm.

Le A 29 379 40 II Example XIV 4-Methoxycarbonyl-6-methoxymethyl-2-oxo-1-(2-fluoro-4iod-phenylmethyl)-1,2-dihydropyridine 0 OCH 3 HCO N O Example XI, 4.12 g (13.1 mmol) of 2-fluoro-4-iodobenzyl bromide and 4.89 g (15 mmol) of caesium carbonate in ml of tetrahydrofuran is stirred under argon at 200C for 16 hours. The solvent is then removed in vacuo, the residue is taken up in methylene chloride/water, the 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) RE: 0.16 (petroleum ether/ethyl acetate 3:1).

Le A 29 379 41 0*

S

*0eS

S

eGo.

S CS

*SOO

55 9 5

SO.

C

*555 Examole XV 4-Methoxycarbonyl-6-methoxymethyl-2-oxo-l. (2-chloro-4lod-phenylmethyl) -1,2 -dihydropyridine 00 2

CH

3

H

3 C-O.HZC N 0 C11 The title compound is prepared analogously to the instructions of Example XIV.

Rf: 0.25 (solvent: petroleum ether:ethyl acetate 1:2) Example XVI Methyl 3-chloro-4-trifluoromethylsulphonyloxy-benzoate C. SC S C

S

*t S S SC S

H

3

CO

2

C

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 pyridine at O 0 C. After the reaction mixture has been Le A 29 379-4 42 I stirred at 0 C for 5 minutes 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 10 Example XVII 5-(2'-Chloro-4'-methoxycarbonyl-biphenyl-2-yl)-2triphenylmethyl-lH-tetrazole

C(C

6

H

5 3

N-N

I COC

N

H

3 0 2

CN

CI Argon is passed 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(CHs) 3 4 (0.146 mmol), 6 ml of methanol, 1.63 g (3.77 mmol) of 2-(N-triphenylmethyl-tetrazol-5-yl)-phenylboronic acid and a solution of 333 mg (3.14 mmol) of sodium carbonate in 4 ml of degassed water, the emulsion is stirred at 1000C overnight. Addition of the same amount of catalyst, Le A 29 379 43

D-

followed by stirring at 100 0 C for 2.5 hours, brings the reaction to completion. The reaction mixture 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 to give 10.1 g of a pale yellow solid [57.9% of theory, Rf 0.46 (hexane:ethyl acetate Example XVIII 0000 5- -Chloro-4' -hydroxymethyl-biphenyl-2-yl) -2-triphenylmethyl-1H-tetrazole OS

C(C

6

H

5 3 0000 N-N HO Cl

N**

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 S*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

I

V concentrated; the residue is taken up in 200 ml of methylene chloride and 100 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 186-7°C (decomposition); Rf 0.15 (hexane:ethyl acetate 3:1)] Example XIX 5-(4'-Bromomethyl-2'-chloro-biphenyl-2-yl)-2-triphenylmethyl-lH-tetrazole

S.

C(C

6

H

5 3 Br

N-N

N N 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 See triphenylphosphine (42.5 mmol) in 100 ml of methylene chloride under argon in an ice-bath. After the reaction mixture has been stirred at room temperature for 1 hour, it is filtered through silica gel and eluted with Le A 29 379 45 96 fee% methylene chloride. Concentration of the filtrate and digestion of the residue with hexane give 15.8 g of white crystals 1i8.90i of theory; melting point 15-G0 0 C; Rf 0.40 (hexane/ ethyl acetate Example XX 4-Methoxycarbonyl-G-methoxymethyl-2-oxo-l-{( [2-chlor-2' biphenyl-4-yl] -methyl)}- 1,2 -dihydropyridine C0 2

CH

3 C(0 6

H

5 3 C II 0.17 g of the title compound is obtained from 0.46 g 0 (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 0e 00 0 U 6 *004 0 00 s~ 0) Le A 29 379 46 Prenarat ion Examnies vote a 1 *at* 0aw.

Example 1 4-Methoxycarbonyl-6-methoxymethyl-2-oxo-l- [(3-fluor-2' tetrazol-5-yl-biphenyl-4-yl)methyl] 2-dihydropyridine

COOCH

3 HC' 0 N 0 N=N N NH

F

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.

4.

a B aBS Va 4 04 U Ba Le A 29 379 -447 Examole 2 4-Carboxy-6-methoxymethyl-2-oxo-l- Ii(3-fluor-2' -tetrazol- 5-yl-biphenyl-4-yl) -met hyl] 2-dihydropyridine d~isodium salt COONa 0 '1 N 0 N=N HC SN~ NNa *060 F 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 temperature for 2 hours. The solvent is distilled off and the aqueous residue is freeze dried.

R :0.11 (toluene/ethyl acetate/glacial acetic acid 10:30:1 Le A 29 379 48 ExamDle 3 4-Carboxy-6-methoxymethyl-2-oxo-1- [3-fluor- 2 yl-biphenyl-4-yl)-methyl]-1,2-dihydropyridine

COOH

H3CO IN SN 0 N=N N

NH

F

9 ea g 321 mg of tetrakistriphenylphosphinepalladium(0), 8.34 ml 5 (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 suction over kieselghur, the residue is rinsed with r 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) Rf: 0.11 (toluene/ethyl acetate/glacial acetic acid 10:30:1).

The compounds listed in the following table were prepared analogously to Examples 1, 2 and 3: Le A 29 379 49 Table:

RI

0I

R

2 N N 0 N-N H R3 Example No. R' R 3 Salt/acid 4 C0HS.2-l Ai 4 CO 2 H CH 3 2-Cl Acid 56C0 2 H CH-1 3 2-Me Di-Na salt 7 CO 2

CH

3

CH

3 3-Me Acid *8 CO 2 H C 2

H

5 2-OH Acid 9 C0 2 H C 2

H

5 3-OH Acid

CO

2

CH

3

C

2

H

5 2-CF 3 Mono-K salt 11 CO 2 H C 2

H

5 3-CF 3 Di-Li salt 12 C0 2

C

2

H

5

C

2

H

5 2-OCF 3 Acid 513 C0 2 H C 2

H

5 3 -OCF 3 Acid 14 C0 2 H CH 3 2-F Acid

CO

2

CH

3

CH

3 2-F Acid 16 CO 2

CH

3

CH

3 2-F Mono-K salt 17 CO 2

CH

3

CH

3 2-Cl Acid 18 CO 2

CH

3

CH

3 2-Cl Mono-K salt *19 C0 2 H CH 3 3-Cl Di-K salt 2 COH H 3 3-F Mono-K salt 21 CO 2

CH

3

CH

3 3-Cl Acid 22 CO 2

CH

3

CH

3 3-Cl Mono-K salt Le A 29 379 -550

Claims (8)

1. Alkoxymethyl -substituted pyridonebiphenyls of the general formula RNO 5 Se. S. S S S .10 *5 5 in which R 1 represents a carboxyl group or represents a C, 1 -C 8 -alkoxycarbonyl group, R 2 represents C 1 -C 1 0 O-alkyl (straight-chain or branched), which is optionally substituted by phenyl, R 3 represents halogen, hydrogen, Cl-C.-alkyl, hydroxyl, Cl-C.-alkoxy, trifluoromethyl. or tri- fluoromethoxy, R 4 represents carboxyl. or represents tetrazolyl and X represents oxygen or sulphur, S. S 0.* S. S 0 5 5* Le A 29 379 51 I_ and salts thereof.

2. Alkoxymethyl-substitutedpyridonebiphenyls according to Claim 1 in which R represents a carboxyl group or represents a Ci-C 6 -alkoxycarbonyl group, R 2 represents Cl-Cg-alkyl (straight-chain or branched), which can optionally be substituted by phenyl, R 3 represents fluorine, chlorine, bromine, hydrogen, C,-C 6 -alkyl, hydroxyl, C,-C 4 -alkoxy, trifluoromethyl or trifluoromethoxy, R 4 represents carboxyl or tetrazolyl and 15 X represents oxygen, and salts thereof.

3. Alkoxymethyl-substitutedpyridonebiphenyls according to Claim 1, in which Le A 29 379 52 R represents a carboxyl group or represents a C,-C 4 -alkoxycarbonyl group, R 2 represents branched), C 1 -C.-alkyl (straight-chain R3 represents fluorine, chlorine, hydrogen, hydroxyl, C 1 -C 4 -alkyl, methoxy, trifluoromethyl or trifluoromethoxy, S Sees S S. 5 5605 10 5 5 0@ S. S *SSS R4 represents tetrazolyl and X represents oxygen, and salts thereof. @5 S S S S. Sa S S a. 15

4. Alkoxymethyl -substituted pyridonebiphenyls according to Claim 1, in which R represents carboxyl, methoxycarbonyl or ethoxy- carbonyl, R 2 represents ethyl or methyl, R 3 represents fluorine, chlorine, methyl, hydroxyl, trifluoromethyl or trifluoromethoxy, .5 S SS* S. C eS 5 Le A 29 379 53 54 R 4 represents tetrazolyl and X represents oxygen, and salts thereof. '10 oo Process for the preparation of alkoxymethyl-substi- tuted pyridonebiphenyls according to Claim 1, characterised in that pyridones of the general formula (II) R, R 2 N O H in which R 1 and R 2 have the abovementioned meaning, are reacted with compounds of the general formula (III) I t E-H2C(III), R 3 R4' in which R 3 has the abovementioned meaning, E represents chlorine or bromine and 00 S.

5 R 4 represents C 1 -C 4 -alkoxycarbonyl or 4* e g0 represents a group of the formula N N I C(C 6 H,) 3 in inert solvents, in the presence of a base and if appropriate with addition of a catalyst, or in the case where R 4 represents tetrazolyl, compounds of the general formula (IV) so *0 0 4.* Le A 29 379 55 R 2 N 0 (IV), R 3 in which R 1 R 2 and R 3 have the abovementioned meaning and L represents a typical leaving group, such as, S 5 for example, bromine, iodine or methane-, Stoluene-, fluorine- or trifluoromethane- sulphonyloxy, preferably bromine, are reacted with compounds of the general formula a. N-N SB(OH) 2 0, 10 in which T represents hydrogen, or represents the Le A 29 379 56 D 0 O triphenylmethyl group, in inert solvents, in the presence of a base and under metal catalysis, and subsequently, in the case of the free tetrazole (R 4 the triphenylmethyl group is split off with acids in organic solvents and/or water, and in the case of the carboxylic acids (R 4 /R 1 the corresponding ester is hydrolysed, and if appropriate the compounds are converted into their salts using bases.

6. Medicament containing at least one compound according to claim 1 in association with one or more pharmaceutically suitable excipients or solvents. 20

7. A method for the treatment of hypertension and atherosclerosis wherein there is administered, to a subject in need of such treatment, a compound according to claim 1, or a medicament according to claim 6.

8. A compound according to claim 1 substantially as herein described with reference to any one of the foregoing examples thereof. DATED this 20th day of November, 1995. BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys <1 DAVIES COLLISON CAVE p:\wpdocs\grs\484559\kd Alkoxymethvl-substituted Pyridonebiphenyls A bs t r a cLt 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. Le A 29 379 Foreign countries