CA2079268A1

CA2079268A1 - Substituted imidazolyl-propenoic acid derivatives

Info

Publication number: CA2079268A1
Application number: CA002079268A
Authority: CA
Inventors: Thomas Kraemer; Juergen Dressel; Rudolf Hanko; Walter Huebsch; Ulrich Mueller; Matthias Mueller-Gliemann; Martin Beuck; Stanislav Kazda; Johannes-Peter Stasch; Andreas Knorr; Stefan Wohlfeil
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1991-10-01
Filing date: 1992-09-28
Publication date: 1993-04-02
Also published as: ZA927500B; TW206223B; FI924355A7; EP0539713A1; MX9205435A; CZ297692A3; JPH05213939A; IL103293A0; HU9203123D0; NO923580D0; DE4132632A1; FI924355A0; AU2602492A; SK297692A3; HUT62576A; AU646596B2; KR930007937A; FI924355L; NO923580L

Abstract

Substituted imidazolyl-propenoic acid derivatives A b s t r a c t The substituted imidazolyl-propenoic acid derivatives can be prepared by reaction of the corresponding aldehydes with CH-acidic compounds and subsequent elimination of water. The substituted imidazolyl-propenoic acid derivatives can be employed as active substances in medicaments, in particular in hypotensive and anti-atherosclerotic medicaments.

Le A 28 592 - US

Description

The invention relates to new substituted imidazolyl-propenoic acid derivatives, to a process for their preparation and to their use in medicaments, in par-ticular as hypotensive and anti-atherosclerotic agents.

It is known that renin, a proteolytic enzyme, eliminates the decapeptide angiotensin I in vivo from angioten-sinogen, which decapeptide is in turn degraded in the lungs, the kidneys or other tissues to give the hyperten-sive octapeptide angiotensin II. The various effects of angiotensin II, such as, for example, vasoconstriction, Nat retention in the kidneys, aldosterone release in the adrenal gland and increase in tone of the sympathetic nervous system, act synergistically in the sense of a blood pressure increase.

Moreover, angiotensin II has the property of promoting the growth and the replication of cells such as, for example, of cardiac muscle cells and smooth muscle cells, these growing and proliferating in an increased manner in various disease states (for example hypertension, athero-sclerosis and cardiac insufficiency).

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

Le A 28 592 - 1 -.

2~7~2~8 In the publications EP 324,377 A2, ~P 403,158 A2 and EP 403,159 A2, phenyl(alkyl)imidazole and imidazolyl-al:kenoic acids are described in which the scope of meaning of position 2 (see compounds according to the invention -CH=CH-Co2R4) encompasses propenoic acids and esters and the terminal phenyl ring is substituted by a tetrazole ring, but without giving a reference to an actual substance representative of this substitution pattern.

The present invention relates to substituted imidazolyl-propenoic acid derivatives of the general formula (I) N ~ R2 ~R3 R J~ N J~ CO2R~

~R6 (I) N
N_N
in which R1 represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, Le A 28 592 - 2 -2079~68 R2 represents hydrogen, halogen, hydroxyl, nitro, ~ cyano, trifluoromethyl, trifluoromethoxy or penta-fluoroethyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, R3 represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, or represents aryl having 6 to 10 carbon atoms or a 5- to 7-membered, saturated or unsaturated hetero-cycle having up to 4 hetero atoms from the series comprising S, N and O, each of which is optionally monosubstituted to trisubstituted by identical or different halogen, hydroxyl, nitro, cyano, tri-fluoromethyl or trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms or by a group of the formula -NR8R~ ~

in which R8 and R~ are identical or different and denote hydrogen, straight-chain or branched alkyl : having up to 6 carbon atoms, or phenyl, R4 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, R5 and R~ are identical or diferent and Le A 28 592 - 3 -, 207926~

represent hydrogen, halogen, cyano, nitro, tri-fluoromethyl, hydroxyl, trifluoromethoxy or straight-chain or branched a~kyl or alkoxy each having up to 6 carbon atoms, R7 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms and their salt6.

The substituted imidazolyl-propenoic acid derivatives according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically accept-able salts of the imidazolyl-propenoic acid derivatives can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.
Particularly preferred salts are, for example, thos~ with hydrochloric acid, hydrobromic acid, sulp~uric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzene~ulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable ~alts can also be metal or ammonium salts of the compounds according to the Le A 28 592 - 4 -2Q7~2~8 invention which have a free carboxyl group. Particularly - preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia or organic amines such as, for example, ethylamine, di- or triethylamine, di- or tri-ethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform constituents ~cf.
E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962].

Heterocycle in general represents a 5- to 7-membered, preferably 5- to 6-membered, saturated or unsaturated ring which as hetero atoms can contain up to 2 oxygen, sulphur and/or nitrogen atoms. 5- and 6-membered rings containing an oxygen, sulphur and/or up to 2 nitrogen atoms are preferred. The following may be mentioned as preferred: thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrazolyl.

Le A 28 592 - 5 -". ' ` ~ ' .

2~792~8 Preferred compounds of the general formula (I) are tho~e in which R1 represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents cyclopropyl, cyclopentyl or cyclohexyl, R2 represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, penta-fluoroethyl, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, R3 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or represents phenyl, furyl, thienyl, imidazolyl, pyrryl or pyridyl, each of which is optionally substituted up to 2 times by identical or dif-ferent fluorine, chlorine! bromine, hydroxyl, nitro, cyano, trifluoromethyl or trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or by a group of the formula -NR8R9, : in which R8 and R9 are identical or different and denote hydrogen or straight-chain or branched alkyl Le A 28 592 - 6 -2~792~8 having up to 4 carbon atoms, R4 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, Rs and R5 are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl having up to 4 carbon atoms, R7 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and their salts.

Particularly preferred compounds of the general formula (I) are those in which 15 R1 represents qtraight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, or cyclopropyl, R2 represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, pentafluoroethyl, phenyl or straight-chain or branched alkyl having up to .
4 carbon atoms, Le A 28 592 - 7 -~. , . . ' '' ` .. : ~ ' .

.. ': . ., 207926~

R3 represent~ hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or represents phenyl, furyl or thienyl, each of which is optionally substituted by fluorine, chlorine, cyano, hydroxyl, trifluoromethyl or trifluoro-methoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by a group of the formula -NR9R9, in which R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R5 and R~ are identical or different and represent hydrogen, fluorine, chlorine or bromine, R7 represents hydrogen, methyl, ethyl, propyl or isopropyl and their salts.

Very particularly preferred compounds of the general formula (I) are those in which Le A 28 592 - 8 -207~68 Rl represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, R2 represents hydrogen, fluorine, chlorine, iodine, trifluoromethyl or pentafluoroethyl, R3 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents phenyl, furyl or thienyl, each of which is optionally substituted by fluorine, chlorine, cyano or methoxy, R4 represents hydrogen, methyl or ethyl and R5, R6 and R7 represent hydrogen and their salts.

In addition, a process for the preparation of the com-pounds of the general formula (I~ according to the invention and their salts has been found, characterised in that aldehydes of the general formula (II) Le A 28 592 - 9 -~: .- ' `

.
.

2~7926~

N--RJ~N
~ R6 (II) 6Hd3C ~,N
N~N

in which R1, R2, R5 and R~ have the abovementioned meaning, are first converted by reaction with compounds of the general formula (III) R3-(CH2)2-Co2Rl (III) in which : ; R~ has the abovementioned meaning and Rl has the abovementioned meaning of R~, but does not represent hydrogen, Le A 28 592 - 10 -;.
, . - , :' , 207926~

in inert solvents, in the presence of a base, to give the compounds of the general formula (IV) R 1¦~(CO2R10 OH Rs ~ R6 (IV) (C6HS)3C ~N ~J
N~) N_N
in which R1, R2, R3, R5, R6 and R10 have the abovementioned meaning, then the free hydroxyl function i6 blocked by introduc-tion of a protective group and in a last step an elimina-tion in inert solvents in the presence of a base is carried out, and in the case of the acids (R4 = H) the esters are hydrolysed and in the case in which R7 does not represent hydroqen, the -NH function is alkylated.

~he proce~ according to the invention can be illu~trated by way of ex~mple by the following reaction scheme~

,:
Le A 28 592 - 11 -.

.
, . . ~ , . . -2~79268 N ~CI

H3C-(CH2)3 ~ N ~

~ ~ (CH2)2-C02-CH3 (C6Hs)3C ~ ~

Cl C6Hs H9C-(CH2)3 1~3~CC~O CH3 H3C-(CHZ)3 J~N~f (CO2CH3 ~q CH2CI2 ~
DMAP ~q (c6Hs)3c ~ (C6Hs)3C~

DBU H,C ICH,~, l~CC,HCH, ~ .
toluene l ;: ~ ~
(C~Hs)3C~ N
N~

.

';~

Le A 28 592 - 12 -.~

2079~68 N ~ Cl ~ C6Hs l.)NaOH ~C-(CH2)3 ~ N ~ CO2H
2.)HCI

N

\NGN

Hydroxyl protective gro~p in the context of the abovemen-tioned definition in general represents a protective group from the series comprising: benzyloxycarbonyl, methanesulphonyl, toluenesulphonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,tert-butoxycarbonyl,allyloxycarbonyl, 4-methoxycarbonyl, acetyl, trichloroacetyl, 2,2,2-tri-chloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 2-(methylthiomethoxy)ethoxycarbonyl, benzoyl, 4-methylben-: 10 : zoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxydbenzoyl. Acetyl, methanesulphonyl and toluene-::sulphonyl are preferred.

Suitable solvents for the procass are the customaryorganic ~olvents which do not change under the reaction conditions. These prsferably include ether~ such a~

:~ :

` ~:

~ Le A 28 592 - 13 -, j 2~79268 diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl - ether, and hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, and halogenohydrocarbons such as dichloromethane, trichloro-methane, tetrachloromethane, dichloroethylene, trichloro-ethylene or chlorobenzene, and ethyl acetate, tri-ethylamine, pyridine, dimethyl sulphoxide, dimethylfor-mamide, hexamethylphosphoric triamide, acetonitrile, acetone and nitromethane. It is al~o possible to use mixtures of the solvents mentioned. Tetrahydrofuran, methylene chloride and toluene are preferred for the various steps.

Bases which can be employed for the process according to the in~ention are in general inorganic or organic bases.
These preferably include 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, and alkali metal or alkaline earth metal alkoxides or amides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide or lithium diisopropylamide (LDA), and organic amines (tri-alkyl(Cl-C6)amine~) such as triethylamine, and hetero-cycles uch as 1,4-diazabicyclo~2.2.2~octane (DA~C0), 1,8-diazabicyclot5.4.0]undec-7-ene (DB~), pyrid~ne, di-aminopyridine, methylpiperidine or morpholine. It ~8 al~o possible to employ as bases alkali metals, such as Le A 28 592 - 14 -2~79268 sodium, or their hydrides such as sodium hydride. Lithium diisopropylamide (LDA) and DBU are preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol, preferably from 1 mol to 2 mol, relative to 1 mol of the compound of the formula (III).

The process according to the invention is in general carried out in a temperature range from -lOO~C to +100C, preferably at -78C.

The process according to the invention is in general carried out at normal pressure. ~owever, it is also possible to carry out the process at elevated pressure or at reduced pres~ure (for example in a range from 0.S to 5 bar).

The introduction of the protective group is in general carried out in one of the abovementioned solvents and a base, preferably in methylene chloride using dimethyl-aminopyridine.

The blocking i~ in general carried out in a temperature range from 0C to +60C, preferably at room temperature and at normal pressure.

The elimination is in general carried out in one of the abovementioned solvents, preferably in toluene and in the pre~ence of one of the bases mentioned, preferably DBU.

Le A 28 592 - lS -.

2~7926~

The elimination is in general carried out in a tempera-ture range from +30C to +130C, preferably at +50C to +100C and at normal pressure.

Suitable bases for the hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxides and alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, and alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium hydrogen carbonate and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Sodium hydroxide or potassium hydroxide is particularly prefer-ably employed.

Suitable solvents for the hydrolysis are wster or the organic solvents customary for hydrolysis. These prefer-ably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, and ethers such as tetrahydrofuran or dioxane, and dimethylformamide, and dimethyl sulphoxide. Particularly preferably, alcohols such as methanol, ethanol, propanol or isopropanol are used. It is also possible to employ mixtures of the sol~ents mentioned.

~ he hydrolysis can optionally also be carried out using acids such as, for example, trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methane-sulphonic acid, sulphuric acid or perchloric acid, Le A 28 592 - 16 -- .~ , . -..:
.
. . . . . . .
: ~ ' ' -.
:' ': ~ .

' . .
.

207926~

preferably using trifluoroacetic acid.

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

In general, the hydrolysis is carried out at normal pressure. However, it is also possible to work at reduced pressure or at elevated pressure (for example from O.S
to 5 bar).

When carrying out the hydrolysis, the base is in general employed in an amount from 1 to 3 mol, preferably from 1 to l.S mol, relative to 1 mol of the ester. Particularly preferably, molar amounts of the reactants are used.

When carrying out the reaction, in the first step the carboxylates of the compounds according to the invention are formed as intermediates which can be isolated. The acids according to the invention are obtained by treating the carboxylates with customary inorganic acids. These preferably include mineral acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. It has proved advantageous in the preparation of the carboxylic acids in this connection to acidify the basic reaction mix~ure from the hydrolysis in a second step without isolation of the carboxylates. The acids can then be isolated in a customary manner. In the case of the basic heterocycles, by treatment of the solutions of the carboxylates with the abovementioned acids the salts of the heterocycle~ with the inorganic Le A 28 592 - 17 -2~79~6~

acids can also be obtained.

The alkylation is in general carried out using alkylating agents such as, for example, (Cl-C~)-alkyl halides, sulphonic acid esters or substituted or unsubstituted (Cl-C6)-dialkyl or (Cl-C~)-diaryl sulphonates, preferably methyl iodide or dimethyl sulphate.

The alkylation i8 in general carried out in one of the abovementioned solvents, preferably in dimethylformamide, in a temperature range from 0C to +70C, preferably from 0C to +30C and at normal pressure.

The compounds of the general formula (II) are known per se or can be prepared by a customary method [cf. PCT WO 91/00277~.

The compounds of the general formula (III) are known or can be prepared by a customary method, [cf., for example, Beilstein 9, 511].

The compounds of the general formula (IV) are, as actual substance r0presentatives, new and can be prepared, for example, by the abovementioned process.

The abovementioned preparation processes are only given for clarification. The preparation of the compounds of the general formula (I) according to tha invention is not restricted to these processe~, and any modification of these processes can be used in the same manner for the Le A 28 592 - 18 -2~7~2~8 preparation.

The substituted imidazolyl-propenoic acid derivatives according to the invention exhibit an unforeseeable, useful pharmacological spectrum of action.

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

They can therefore be employed in medicaments for the treatment of arterial hypertension and atherosclerosis.
Moreover, they can be used for the treatment of coronary heart diseases, cardiac insufficiency, disorders of cerebral function, ischaemic brain disorders, peripheral circulatory disorders, functional disorders of the kidneys and adrenal gland, bronchospastic and vascularly conditioned disorders of the airways, sodium retention and oedemas.

Investi~ation of the inhibition of the contraction induced with a~onists Rabbits of both sexes are anaesthetised by a blow to the necX and bled, or alternativaly anaesthetised with Nembutal (about 60-80 mg/kg i.v.) and sacrificed by Le A 28 592 - 19 -2~7~26~

opening the thorax. The thorax aorta is taken out, freed from adhering connective tissue, divided into 1.5 mm-wide ring segments and these are individually transferred under an initial loading of about 3.5 g to 10-ml organ baths containing 95% 2/5~ CO2-aerated Rrebs-Henseleit nutrient solution, thermostated at 37C, of the following composition: 119 mmol/l NaCl; 2.5 mmol/l CaCl2 x 2H20;
1.2 mmol/l RH2PO4; 10 mmol/l glucose; 4.8 mmol/l KCl;
1.4 mmol/l MgSO4 x 7 H2O and 25 mmol/l NaHCO3.

The contraction~ are detected isometrically by Statham UC2 cells by means of a bridge amplifier (ifd M~lheim or DSM Aalen) and digitised and evaluated by means of an A/D
converter (System 570, Keithley, Munich). The determina-tion of agonist dose-response curves (DRC) is carried out hourly. With each DRC, 3 or 4 individual concentrations are applied to the baths at 4-min intervals. After the end of the DRC and subsequent washing-out cycles (16 times, in each case about 5 sec/min with the above-mentioned nutrient solution), a 28-minute rest or incubation phase follows, in the course of which the contractions as a rule reach the starting value again.

The height of, in the normal case, the 3rd DRC is used as a reference quantity for the assessment of the test sub~tance to be investigated in further passages, which test substance in the following DRCs is applied at the stsrt of the incubation time to the bath~, in each case in an increasing dose. Each aorta rlng is in this case stimulsted for the whole day, always with the same Le A 28 592 - 20 -2~79~6~

agonist.

Aqonists and their standard concentrations (administr-ation volume ~er individual dose = 100 ~

XCl 22.7;32.7;42.7;52.7mmol/l l-Noradrenaline 3x10-9;3x108;3x10-7;3x10-6 gtml Serotonin lOa;10';106;10 g/ml B-HT 920 10-7 lo~6 10-5 g/ml Methoxamine 10-' 10-6 10-5 g/ml Angiotensin II 3x109;108;3xlOa;107g/ml For the calculation of the IC50 (concentration at which the substance to be investigated causes a 50% inhibi-tion), the effect in each case at the 3rd = submaximal agonist concentration i9 used as a basis.

The compounds according to the invention inhibit the contraction of the isolated rabbit aorta induced by angiotensin II in a dose-dependent manner. The con-traction induced by potassium depolarisation or other agonists was not inhibited, or only weakly inhibited at high con~entrations.

Blood ~ressure measurements on the an~iotensin II-infused rat Male ~istar rats ~Moellegaard, Copenhagen, Denmark) having a body weight of 300-350 g are anaesthetised with thiopental (100 mg/kg i.p.). After tracheotomy, one Le A 28 592 - 21 -2~79268 catheter is inserted in the femoral artery for blood pressure measurement and one catheter is inserted for angiotensin II infusion and one catheter is inserted for substance administration, both in the femoral veins.
After administration of the ganglionic blocker pento-linium (5 mg/kg i.v.), the angiotensin II infusion ~0.3 ~g/kg/min) 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 blood pressure changes under the influence of substance are indicated in the table as average values + SEM.

Determination of the antihypertensive activity in conscious hypertensive rats Th~ oral antihypertensive activity of the compounds according to the invention was tested on conscious rats having surgically induced unilateral renal artery sten-osis. For this, the right renal artery was constricted with a silver clip of 0.18-mm internal width. In this form of hypertension, the plasma renin activity is increased in the first six weeks after intervention.
The arterial blood pressure of these animals was measured by bloodless means at defined time intervals af~er substance administration using the ~tail cuff". The substances to be tested were administered intragastrally (llorallyl') by ~tomach tube in different doses, suspended in a ~ylose su~pension. ~he compound~ according to the invention lower the arterial blood pressure of the Le A 28 592 - 22 -~' ''.`'~

, 2~79268 hypertensive rats at a clinically relevant dosage.

In addition, the compounds according to the invention inhibit the specific binding of radioactive angiotensin I I in a concentration-dependent manner.

Interaction of the compounds accordina to the invention -with the angiotensin II receptor on membrane fractions of the adrenal aland cortex of cattle Adrenal gland cortice~ of cattle (AGC), which have been freshly removed and carefully freed from gland medulla, are comminuted in sucro~e solution (0.32 M) with the aid of an ~ltra-Turrax (Janke & Kunkel, Staufen i.B.) to give a coarse membrane homogenate and are partially purified in two centrifugation steps to give membrane fractions.
The receptor binding investigations are carried out on partially purified membrane fractions of bovine AGC using radioactive angiotensin II in an assay volume of 0.25 ml, which in detail contains the partially purified membranes (50-80 ~g)~ 3H-angiotensin II (3-5 nM), test buffer solution (50 mM tris, pH 7.2, 5 mM MgCl2, 0.25% BSA) and the substances to be investigated. After an incubation time of 60 min at room temperature, the unbound radio-activity of the samples is separated by means of moistened glass fibre filters (Whatman GF/C) and the bound radioactivity is measured spectrophotometrically in a scintillation cocktail after washing the protein with ice-cold buffer solution (50 mN tris/HCl, pH 7.4, 5% PEG 6000). ~he analysis of the raw data was carried Le A 28 592 - 23 -207~2~8 out using computer programs to give K~ or IC50 values (Kl: IC50 values corrected for the radioactivity used; IC50 values: concentration at which the substance to be investigated causes a sO% inhibition of the total binding of the radioligand).

Investiaation of inhibition of the proliferation of smooth muscle cells by the comPounds accordina to the invention To determine the antiproliferative action of the com-pounds, smooth muscle cells are used which have been obtained from the aortas of rats by the media explant technique ~R. Ross, J. Cell. Biol. 50, 172, 1971]. The cells are inoculated in suitable culture dishes, as a rule 24-hole plates, and cultured at 37C in 5% C02 for 2-3 days in medium 199 containing 7.5% FCS and 7.5~ NCS, 2 mM L-glutamine and 15 mM HEPES, pH 7.4. After this, the cells are synchronised by withdrawal of serum for 2-3 days and then stimulated into growth with AII, serum or other factors. At the same time, test compounds are added. After 16-20 hours, 1 ~Ci of 3H-thymidine is added and the incorporation of this substance into the TCA-pre-cipitable DNA of the cells is determined after a further 4 hours.

The new active substance can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emul-sions, suspensions and solu~ions, using inert, non-toxic, Le A 28 592 - 24 -' ' ' ' ' ' ~ , : , .
. -: , . ~

2~7~2~

pharmaceutically suitable excipients or solvents. The therapeuti-cally active compound should in each case be present ir. a concen-tration of about 0.5 to 90% by weight of the total mixture, i.e.
in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extend-ing the active substances with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate.
Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral administration, solutions of the active substance using suitable liquid excipients can be employed.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention together with instructions for its use for treating arterial hypertension and atherosclerosis.
In general, it has proved advantageous on 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 on oral administration the dosage is about 0.01 to 20 mgtkg, preferably 0.1 to 10 mg/kg of body weight.
In spite of this, it may be necessary to depart from the amounts mentioned, in particular depending on the body , . ` '~
' , ' weight or the type of administration route, on individual behaviour towards the medicament, the manner of its fo~mulation and the time or interval at which admini-stration takes place. Thus, in some cases, it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the admini-stration of larger amounts, it may be advisable to divide these into several individual doses over the course of the day.

Startin~ Com~ounds ExamPle I

Methyl 2-benzyl-3-t2-n-butyl-4-chloro-1-{(2'-(N-tri-phenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl}-lH-imidazol-5-yl]-3-hydroxy-propionate c~

~ ~\CO2CH~
l~

(C6H5)3C y~ ~

Le A 28 592 - 26 -. . :.:'' :

2~7~268 180.4 mg (l.1 mmol) of methyl 3-phenylpropionate are dissolved in 2 ml of THF, then 0.8 ml of a l.S M s~lution of lithium diisopropylamide in cyclohexane (1.2 mmol) is added at -78C. The mixture is stirred at -78C for 30 min, 662.5 mg tl.0 mmol) of 2-n-butyl-4-chloro-1-t(2~-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-lH-imidazol-5-carboxaldehyde in 5 ml of THF are added, the mixture is stirred at -78C for 30 min, 5 ml of saturated ammonium chloride solution are added at 0C and the mixture is extracted three times with 20 ml of ether.
The organic phase is dried over sodium sulphate and the residue is chromatographed on silica gel 60 using ethyl acetate/petroleum ether (l:1).
Yield: 300 mg (36~ of theory) ~L = 0.53 and 0.48 diastereomer mixture (ethyl acetate:
petroleum ether l:1) Example II

Methyl (E)-2-benzyl-3-[2-n-butyl-4-chloro-1-{t2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl}-lH-imidazol-5-yl]-2-propenoate Le A 28 592 - 27 -207926~

~ N CO2CH3 (C6Hd3C N ~) N~3 1 N_N

300 mg (O.36 mmol) of the compound from ExEmple I are dissolved in 3 ml of dichloromethane, then 16 mg tO.13 mmol) of N,N-dimethylaminopyridine ~DMAP) and 41 mg (O.4 mmol) of acetic anhydride are added successively, the mixture is stirred at 2SC for 1 h, and 2 ml of water and 10 ml of ether are added. The organic phase is extracted successively with 3 ml each of saturated sodium hydro~en carbonate solution and saturated sodium chloride solution, and the extracts are dried over sodium sulphate and concentrated. The crude product thus obtained is dissolved in 3 ml of toluene, then 183 mg (1.2 mmol) of ~;~ 1,8-diazabicyclo[5.4.03undec-7-ene (DBU) are added and the mixture is stirred at 90C for 20 h. After cooling, 3 ml of ether are added, the mixture i9 extracted with 5 ml of ~aturnted ~odium chloride ~olution, the organic pha~e i~ concentrated and the residue is chromatographed :

` .
Le A 28 592 - 28 -, 2~79268 on sil~ca gel 60 using ethyl acetate/petroleum ether (1:2).
Yield: 120 mg (41~ of theory) Rf = 0.63 (ethyl acetate: petroleum ether 1:1) ExamPle III

Ethyl (E)-3-[2-n-butyl-4-chloro-1-{(2'-(N-triphenyl-methyltetrazol-5-yl)-biphenyl-4-yl)-methyl)-lH-imidazol-S-yl]-2-(2-methylpropyl)-2-propenoate J\CO2C2HS

~C6Hd3C
In analogy to the procedure of Example II, the title compound was prepared from 1.72 g (2.13 mmol) of ethyl 3-[2-n-butyl-4-chloro-1-{(2'-(N-triphenylmethyltetrazol-5-yl)bi-phenyl-4-yl)methyl}-lH-imidazol-5-yl]-3-hydroxy-2-(2-methylpropyl)-2-propenoate.

Yield: 440 mg ~27~ of theory) Rs ~ 0.71 (ethyl acetate~petroleum ether ~ ls2) Le A 28 592. - 29 -,, :
.

2~7~268 xample IV

2-n-Butyl-1-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-b:iphenyl-4-yl)methyl]-lH-imidazole-5-carboxaldehyde N

H

~JN

Ph ~C

A solution of 12.0 g (18.1 mmol) of 2-n-butyl-4-chloro-1-[(2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-lH-imidazole-5-carboxaldehyde in 150 ml of methanol is hydrogenated at about 3 bar for 1.5 h at 25C
in the presence of 1.2 q of palladium on carbon (5~
strength) and 2.46 g ~18.1 mmol) of sodium acetate trihydrate. The solution is then filtered off from the catalyst and concentrated and the residue i6 chromato-graphed on silica gel using ethyl acetate/petroleum ether ( 1 : 1 ) .
Yield~ 3.85 g (34~ of theory) R~ ~ O.41 (ethyl a¢etate/petroleum ether - 1s1) Le A 28 S92 - 30 -:

.

:

207926~

Example V

Ethyl 3-[2-n-butyl-1-{(2~-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl}-lH-imidazol-5-yl]-2-(2-methyl-propyl)-3-hydroxy-propionate N
N ~ CO2CH2CH3 OH

j~)N
Ph3~
5.15 ml (8.25 mmol) of a 1.6 N solution of n-butyllithium in n-hexane are injected under protective gas at -78C
into a solution of 0.89 g (8.75 mmol) of N,N-diisopropyl-amine in 10 ml of THF. The reaction solution is then briefly warmed to 0C, cooled again to -789C and 1.24 ml (7.5 mmol) of ethyl isocaproate in 5 ml of THF are added.
~he mixture is stirred at -78C for 30 min, 3.14 g (5 mmol) of the compound from Example IV in 20 ml of THF
are added and the mixture is additionally stirred at -78C for 1 h. It i9 then 810wly warmed to 25C, 20 ml of satd. ammon~um chloride solution are added and it i9 extrscted three time~ with 50 ml of ethyl acetste in each Le A 28 592 - 31 -case. The organic phase is dried over sodium sulphate and concentrated and the residue is purified on silica gel using ethyl acetate/petroleum ether (3:1).

Yield: 1.82 g (47~ of theory) R~ = 0.27 (ethyl acetate/petroleum ether = 2:1, diastereomer mixture) Example VI

Ethyl 3-acetoxy-3-[2-n-butyl-1-{(2'-(N-triphenylmethyl-tetrazol-S-yl)biphenyl-4-yl)-methyl}-lH-imidazol-S-yl]-2-(2-propylmethyl)-propionate `N CO2CH2CH3 OAc N
j~N
Ph~C

11.1 g (14.4 mmol) of the compound from Example V are dissolved in 100 ml of dichloromethane, treated with Le A 28 592 - 32 -2~79,~68 626 mg (5.13 mmol) of N,N~-dimethylaminopyridine (DMAP) and 2.04 ml (21.6 mmol) of acetic anhyride and the mixture is stirred at 25C for 16 h. It is diluted with ether, washed with water (l x 50 ml), satd. sodium hydrogen carbonate solution (l x 50 ml) and satd. sodium chloride solution (1 x 50 ml), and the organic phase is dried over sodium sulphate and concentrated. The crude product thus obtained is chromatographed on silica gel using ethyl acetate/petroleum ether (2:1).

Yield: 11.7 g (lO0~ of theory) Rf = 0.52 (ethyl acetate/petroleum ether = 2:1, diastereomer mixture) Example VII

Ethyl 3-[2-n-butyl-1-{(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl}-lH imidazol-5-yl]-2-(2-methyl-propyl)-2-propenoate ~CO2CH2CH3 \~1 j~) N
PhJC

Le A 28 592 - 33 -207926~

11.7 g (14.3 mmol) of the compound from Example VI are dissolved in 150 ml of toluene, 5.3 ml (35.8 mmol) of ll8-diazabicyclo[5.4.o]undec-7-ene (DBU) are added and the mixture is boiled under reflux for S h. A further 2 ml (13.5 mmol) of DBU are then added and the mixture is boiled under reflux for an additional 2.5 h. After cooling, it is washed with satd. sodium chloride solution (1 x 70 ml), and the organic phase is dried over sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel using ethyl acetate/petroleum ether (1:1).

Yield: 3 g (28~ of theory) R~ = 0.68 (ethyl acetate/petroleum ether 1:1) Le A 28 592 - 34 -2~79268 reparation Examples ExamPle 1 (E)-2-Benzyl-3-~2-n-butyl-4-chloro-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-lH-imidazol-S-yl~-2-propenoic S acid ~3 /~ N CO2H
~1 N
\\N_NH
81 mg (0.1 mmol) of the compound from Example II are dissolved in 3 ml of 2 N methanolic sodium hydroxide solution, and the mixture is heated to boiling for 30 min, and acified, after cooling to pH 1 with conc.
hydrochloric acid and extracted with 20 ml of dichloro-methane. After concentration, the residue is chromato-graphed on silica gel 6Q using dichloromethane/methanol/
glacial acetic acid (lO:lsO.05).
Yield: 37 mg (67% of theory) Rr - 0.40 (dichloromethane/methanol/glacial acetic acid -10:1:0.05) Le A 28 592 - 35 -' ' ' , .

207926~

Exam~le 2 (E)-3-~2-n-Butyl-4-chloro-1-{(2'-(tetrazol-S-yl)-bi-phenyl-4-yl)-methyl}-lH-imidazol-5-yl]-2-(4-methoxy-benzyl)-2-propenoic acid ~OCH3 N--~ N J~CO2H
~ ., N ' _ /~
N
\\N_.NH
2 ml of water and 2 ml of trifluoroacetic acid are added to a solution of 356 mg (0.42 mmol) of methyl 3-[2-n-butyl-4-chloro-1-~(2'-(N-tripheny}methyltetrazol-5-yl)bi-phenyl-4-yl)methyl}-lH-imidazol-5-yl]-2-(4-methoxy-benzyl)-2-propenoate in 6 ml of THF. The mixture is stirred at 25DC for 6 h, concentrated, taken up with dioxane/water (1:1) and rendered alkaline with conc.
lithium hydroxide solution. The reaction mixture is stirred at 25C for 3 h, extracted by shaking with ethyl acetate, and the aqueous phase i9 acidified with dil.
hydroahloric acid and extracted once again with ethyl Le A 28 592 - 36 -207~26~

acetate. The organic phase is dried over sodium sulphate and concentrated and the residue is chromatographed on silica gel 60 using dichloromethane/methanol (8:1).

Yield: 230 mg (94% of theory) S Rf = 0.63 (dichloromethane/methanol = 8:1) Le A 28 592 - 37 -~, . : . . ., ~ . .
.

2~7~8 Example 3 Ethyl (E)-3-[2-n-butyl-4-chloro-1-{(2'-(tetrazol-5-yl)-biphenyl-4-yl)methyl} lH-imidazol-5-yl]-2-(2-methyl-propyl)-2-propenoate c~

~\CO2Et \\N--NH
~: 5 1.5 ml of H2O and 1.5 ml of trifluoroacetic acid are added successiv21y to a solution of 440 mg (0.56 mmol) of the compound ~rom Example III in 10 ml of ~HF. The mixture is stirred at 25C for 24 h, rendered basic with conc.
sodium hyd.roxide solution and washed with 20 ml of ether, ~:~ 10 and tha~aqueous phase iB :acidified with half-concentrated hydrochloric acid and extracted three:times with 30 ml of ; ethyl acetate each time. The organic phases are dried over sodium sulphate and concentrated and tha residue is , chromatographed on sllica gel 60 using ~ dichloromethane/methanol (10:1).

Yield:~130 m~ (43% of theory~
: R~ - 0.31 (dichloromethane/methanol = 10:1) : Le A 28 592 - 38 -: ~

,~: ~ . , ;. : '. ,.,: - ~ :

' : .
. . - .

2~7~26~

ExamPle 4 ( E ) - 3-t2-n-sutyl-4-chloro-l-~t2~-(tetrazol-5-yl)biphenyl-4 yl)methyl}-lH-imidazol-S-yl]-2-(2-thienylmethyl)-2-pxopenoic acid Cl ~3 --~\COOH

N
\\N_NH
In analogy to the procedure of Example 1, the title compound was prepared from 410 mg (0.72 mmol) of methyl (E)-3-[2-n-butyl-4-chloro-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-lH-imidazol-5-yl]-2-(2-thienylmethyl)-2-propenoate.

Yield: 110 mg (28% of theory) Rf = 0.27 (dichloromethane/methanol = 10:1) Le A 28 592 - 39 -2~79~6~

xample 5 Et.hyl 3-[2-n-butyl-1-{(2'-ttetrazol-5-yl)biphenyl~4-yl)-me!thyl}-lH-imidazol-5-yl]-2-(2-methylpropyl)-2-propènoate N , H3C ~ 1~, N
\~N_NH

A solution of 3.0 g (3.9 mmol) of the compound from S Example VII in 30 ml of methanol is 810wly treated with 2 ml of conc. hydrochloric acid. After 15 min, the reaction solution is poured into 300 ml of water and extracted with dichloromethane (4 x 70 ml), and the organic phase is dried over sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel using toluene/methanol~glacial acetic acid : (3555:0.5).
Yield: 1.88 g (94% of theory) R~ - 0.21 (toluene/methanol/glacial acetic acid -35s5~0.2) Le A 28 592 - 40 -207926~

Example 6 3-~2-n-Butyl-1-{(2'-(tetrazol-S-yl)biphenyl-4-yl)methyl~-lH-imidazol-5-yl]-2-(2-methylpropyl)-2-propenoic acid /~
H3C N ~3~J~co2 N
~\N_NH
A solution of 1 g of sodium hydroxide in 10 ml of methanol is added to a solution of 1.44 g (2.8 mmol) of the compound from Example 5 in 50 ml of methanol and the mixture is stirred at 50C for 16 h. After cooling, it is rendered acidic with dil. hydrochloric acid, extracted with dichloromethane (3 x 75 ml) and ethyl acetate (3 x 75 ml), and the combined organic phases are dried over sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel using toluene/methanol/glacial acetic acid (35:5:0.2).
Yield: 0.41 g (30% of theory) R~ = 0.12 (toluene/methanol~glacial acetic acid 35:5:0.2) The compounds shown in Table 1 are prepared in analoqy to the abovementioned procedures.

General rocedure for the re aration of the salts:
P P P
A solution of the corresponding imidazolyl-propenic acid in dioxane/water is neutralized with equimolar amounts of 1 N NaOH, freezed and lyophilized ~~
overnight.

Le A 28 592 - 41 -:, 2~7~26~
Table1:

N----~' ,~
H3C'`~ N ~ Co2R4 ~, ~fq ,N
N
\`N_NH

Ex.No. R2 R3 R4 Isomer Rf 7 CI ~ H (Z) 0,32b) 8 H ~ -CH3 0~l8c) 9 H ~ H 0,17d) s H ~ H 0,19a) 11 H ~ OCH3 H O,lSd) 12 H ~ H 0,16d) 13 H ~F H 0~l6d) ~: 14 H ~ -CH3 0,24d) :
a) dichloromethane/methanol ~ 10:1 ~; b) dichloromethane/methanol ~ 5:1 c) toluenetmethanol/glacial acetic acid = 35:5:0.2 d) toluene/methanol/glacial acetic acid = 35:5:1 ~: e) dichloromethane/methanol/glacial acetic acid 10:1:0.05 LeA2859_ -42-207926~

The compounds of Table 2 are prepared according t the above prepartion procedure.
Table 2:

N
H3C-(CH2)3--~';~ Co2R4 ,~

N ~J
N~ ,~M~3 N

Ex.No. R3 R4 M
CH(CH3)2 C2H5 Na 16 CH(CH3)2 Na Na 17 ~ CH3 Na 18 J~3 Na Na 19 J3' CH3 Na ~¢~ F Na Na :
:

Le A 28 592 - 43 -, :

~; ' . . ~ .. . .
. : '`

'' , , ~, . ~

Claims

1. Substituted imidazolyl-propenoic acid derivatives of the general formula (I) in which R1 represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted by cyclo-alkyl having 3 to 6 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, R2 represents hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or pentafluoroethyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, Le A 28 592 - 44 -R3 represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, or represents aryl having 6 to 10 carbon atoms or a 5- to 7-membered, saturated or unsaturated heterocycle having up to 4 hetero atoms from the series comprising S, N and O, each of which is optionally monosubstituted to trisubstituted by identical or different halogen, hydroxyl, nitro, cyano, trifluoromethyl or trifluoro-methoxy, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, or phenyl, R4 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, R5 and R6 are identical or different and represent hydrogen, halogen, cyano, nitro, tri-fluoromethyl, hydroxyl, trifluoromethoxy or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R7 represents hydrogen or straight-chain or Le A 28 592 - 45 -branched alkyl having up to 6 carbon atoms and their salts.

2. Substituted imidazolyl-propenoic acid derivatives according to Claim 1, in which R1 represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted by cyclo-propyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents cyclopropyl, cyclopentyl or cyclo-hexyl, R2 represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoro-methoxy, pentafluoroethyl, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, R3 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or represents phenyl, furyl, thienyl, imidazolyl, pyrryl or pyridyl, each of which is optionally substituted up to 2 times by identical or dif-ferent fluorine, chlorine, bromine, hydroxyl, Le A 28 592 - 46 -nitro, cyano, trifluoromethyl or trifluoro-methoxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R4 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R5 and R6 are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl having up to 4 carbon atoms, R7 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and their salts.

3. Substituted imidazolyl-propenoic acid derivatives according to Claim 1, in which Le A 28 592 - 47 -R1 represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, or cyclopropyl, R2 represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, pentafluoro-ethyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R3 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or represents phenyl, furyl or thienyl, each of which is optionally substituted by fluorine, chlorine, cyano, hydroxyl, trifluoromethyl or trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R5 and R6 are identical or different and represent hydrogen, fluorine, chlorine or bromine, Le A 28 592 - 48 -R7 represents hydrogen, methyl, ethyl, propyl or isopropyl and their salts.

4. Substituted imidazolyl-propenoic acid derivatives according to Claim 1, in which R1 represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, R2 represents hydrogen, fluorine, chlorine, iodine, trifluoromethyl or pentafluoroethyl, R3 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents phenyl, furyl or thienyl, each of which is optionally substituted by fluorine, chlorine, cyano or methoxy, R4 represents hydrogen, methyl or ethyl and R5, R6 and R7 represent hydrogen and their salts.

Le A 28 592 - 49 -

5. The compound ethyl 3-[2-n-butyl-1-{(2'-tetrazol-5-yl)biphenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(2-methylpropyl)-2-propenoate of the formula or a salt thereof.

6. The compound 3-[2-n-butyl-1-{(2'-tetrazol-5-yl)bi-phenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(2-methylpropyl)-2-propenoic acid of the formula or a salt thereof.

7. The compound methyl-3-[2-n-butyl-1-{(2'-tetrazol-5-yl)biphenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(thienyl-2-ylmethyl)-2-propenoate of the formula or a salt thereof.

8. The compound 3-[2-n-butyl-1-{(2'-tetrazol-5-yl)bi-phenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(2-thien-2-ylmethyl)-2-propenoic acid of the formula or a salt thereof.

9. The compound 3-[2-n-butyl-4-chloro-1-{(2'-tetrazol-5-yl)biphenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid of the formula or a salt thereof.

10. The compound 3-[2-n-butyl-1-{(2'-tetrazol-5-yl)bi-phenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(4-chloro-benzyl)-2-propenoic acid of the formula or a salt thereof.

11. The compound 3-[2-n-butyl-1-{(2'-tetrazol-5-yl)bi-phenyl-4-yl)-methyl}-1H-imidazol-5-yl]-2-(4-fluorobenzyl)-2-propenoic acid of the formula or a salt thereof.

12. A process for preparing a substituted imidazolyl-propenoic acid derivative of the formula (I), as defined in claim 1, or a salt. thereof, which process comprises subjecting a com-pound of the general formula (IV) in which the hydroxyl group is protected and R1, R2, R3, R5 and R6 are as defined in claim 1, R7' represents straight-chain or branched alkyl having up to 6 carbon atoms or a protecting group and R10 represents straight-chain or branched alkyl having up to 6 carbon atoms, to an elimination reaction in the presence of a base to eliminate the protected hydroxy group, followed, if required, by removal of the protecting group in the case where R7' is a protecting group and, if required, by alkylation to obtain a compound in which R7 represents straight-chain or branched alkyl having up to 6 carbon atoms and, if required, by hydrolysis to convert an ester in which R4 represents other than hydrogen to an acid in which R4 represents hydrogen and, if required, by converting an obtained compound of formula (I) into a salt thereof.

13. A process according to claim 12 in which R7' represents a trityl protecting group.

14. A process according to claim 13 or 14 in which the compound of the general formula (IV) is obtained by reacting an aldehyde of general formula (II) in which R1, R2, R5 and R6 and R7' are as defined in claim 12, with a compound of the general formula (III) R3-(CH2)2-CO2R10 in which R3 and R10 are as defined in claim 12.

15. A composition for the treatment of arterial hyper-tension and atherosclerosis comprising an amount effective therefor of a compound according to any one of claims 1 to 11, or a physiologically acceptable salt thereof, and a pharmacologi-cally acceptable diluent.

16. A process for preparing a composition for the treat-ment of arterial hypertension and atherosclerosis, which process comprises admixing a compound according to any one of claims 1 to 11, or a physiologically acceptable salt thereof, with a pharmacologically acceptable diluent.

17. The use of a compound according to any one of claims 1 to 11, or a physiologically acceptable salt thereof, for treating arterial hypertension and atherosclerosis.

18. A commercial package containing as active pharmaceu-tical ingredient, a compound according to any one of claims 1 to 11, or a physiologically acceptable salt thereof, together with instructions for its use for treating arterial hypertension and atherosclerosis.

19. A compound of the general formula (IV) as defined in claim 12 or a derivative thereof that is protected at the hydroxyl group.

20. A method of treating arterial hypertension and atherosclerosis in a patient in need thereof which comprises administering to such patient an amount effective therefor of a compound according to any one of claims 1 to 11, or a physiologically acceptable salt thereof.