Cyclic-substituted imidazolyl-propenoic acid derivatives can be prepared by reaction of aldehydes and subsequent elimination of water. The cyclic-substituted imidazolylpropenoic acid derivates are suitable as active substances in medicaments, in particular for the treatment of high blood pressure and atherosclerosis.

The invention relates to cyclic-substituted imidazolylpropenoic acid 
derivatives, to a process for their preparation and to their use in 
medicaments, in particular as hypotensive and anti-atherosclerotic agents. 
It is known that renin, a proteolytic enzyme, eliminates the decapeptide 
angiotensin I in vivo from angiotensinogen, which decapeptide is in turn 
degraded in the lungs, the kidneys or other tissues to give the 
hypertensive octapeptide angiotensin II. The various effects of 
angiotensin II, such as, for example, vasocnstriction, Na.sup.+ 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, 
atherosclerosis and cardiac insufficiency). 
In addition to the inhibition of renin activity, a possible starting point 
for intervention in the reninangiotensin system (RAS) is the inhibition of 
the activity of angiotensin-converting enzyme (ACE) and the blockade of 
angiotensin II receptors. 
The publications EP 324,377 A2, EP 403,158 A2 and EP 403,159 A2 disclose 
phenyl(alkyl)imidazole and imidazolylalkenoic acids which have an 
angiotensin II receptor-blocking action. 
The present invention relates to cyclic-substituted imidazolyl-propenoic 
acid derivatives of the general formula (I) 
##STR1## 
in which R.sup.1 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, 
R.sup.2 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, 
n represents a number 0, 1, 2, 3, 4 or 5, 
R.sup.3 represents cycloalkyl having 3 to 8 carbon atoms, 
R.sup.4 represents hydrogen, straight-chain or branched alkyl having up to 
8 carbon atoms, or phenyl, 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
halogen, cyano, nitro, trifluoromethyl, hydroxyl, trifluoromethoxy or 
straight-chain or branched alkyl or alkoxy each having up to 6 carbon 
atoms, 
R.sup.7 represents hydrogen or straight-chain or branched alkyl having up 
to 6 carbon atoms and their salts. 
The cyclic-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 acceptable 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, those with 
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, 
methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, 
benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic 
acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid 
or benzoic acid. 
Physiologically acceptable salts can also be metal or ammonium salts of the 
compounds according to the 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 or 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]. 
Preferred compounds of the general formula (I) are those in which 
R.sup.1 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, 
R.sup.2 represents hydrogen, fluorine, chlorine, bromine, iodine, 
trifluoromethyl, trifluoromethoxy, pentafluoroethyl, phenyl or 
straight-chain or branched alkyl having up to 6 carbon atoms, 
n represents a number 0, 1, 2, 3 or 4, 
R.sup.3 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 
cycloheptyl 
R.sup.4 represents hydrogen or straight-chain or branched alkyl having up 
to 6 carbon atoms, 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or 
straight-chain or branched alkyl having up to 4 carbon atoms, 
R.sup.7 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 
R.sup.1 represents straight-chain or branched alkyl or alkenyl each having 
up to 4 carbon atoms, or cyclopropyl, 
R.sup.2 represents hydrogen, fluorine, chlorine, bromine, iodine, 
trifluoromethyl, pentafluoroethyl, phenyl or straight-chain or branched 
alkyl having up to 4 carbon atoms, 
n represents a number 1, 2 or 3, 
R.sup.3 represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, 
R.sup.4 represents hydrogen or straight-chain or branched alkyl having up 
to 4 carbon atoms, 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
fluorine, chlorine or bromine, 
R.sup.7 represents hydrogen, methyl, ethyl, propyl or isopropyl and their 
salts. 
Very particularly preferred compounds of the general formula (I) are those 
in which 
R.sup.1 represents straight-chain or branched alkyl or alkenyl each having 
up to 4 carbon atoms, 
R.sup.2 represents hydrogen, fluorine, chlorine, iodine, trifluoromethyl or 
pentafluoroethyl, 
n represents a number 1 or 2, 
R.sup.3 represents cyclopropyl, cyclopentyl or cyclohexyl, 
R.sup.4 represents hydrogen, methyl or ethyl and 
R.sup.5, R.sup.6 and R.sup.7 represent hydrogen and their salts. 
In addition, a process for the preparation of the compounds of the general 
formula (I) according to the invention has been found, characterised in 
that aldehydes of the general formula (II) 
##STR2## 
in which 
R.sup.1, R.sup.2, R.sup.5 and R.sup.6 have the abovementioned meaning, are 
first converted by reaction with compounds of the general formula (III) 
EQU R.sup.3 --(CH.sub.2).sub.n --CO.sub.2 R.sup.8 (III) 
in which 
R.sup.3 and n have the abovementioned meaning and 
R.sup.8 has the abovementioned meaning of R.sup.4, but does not represent 
hydrogen, in inert solvents, in the presence of a base, to give the 
compounds of the general formula (IV) 
##STR3## 
in which 
R.sup.1, R.sup.2, R.sub.3, R.sub.5, R.sup.6, R.sup.8 and n have the 
abovementioned meaning, then the free hydroxyl function is blocked by 
introduction of a protective group and in a last step an elimination in 
inert solvents in the presence of a base is carried out, and in the case 
of the acids (R.sup.4 =H) the esters are hydrolysed and in the case in 
which R; does not represent hydrogen, the --NH function is alkylated. 
The process according to the invention can be illustrated by way of example 
by the following reaction scheme: 
##STR4## 
Hydroxyl protective group in the context of the abovementioned 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-methylbenzoyl, 
4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxydbenzoyl. 
Acetyl, methanesulphonyl and toluenesulphonyl are preferred. 
Suitable solvents for the process are the customary organic solvents which 
do not change under the reaction conditions. These preferably include 
ethers such as 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, trichloromethane, tetrachloromethane, dichloroethylene, 
trichloroethylene or chlorobenzene, and ethyl acetate, triethylamine, 
pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric 
triamide, acetonitrile, acetone and nitromethane. It is also 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 invention 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(C.sub.1 -C.sub.6)amines) such as triethylamine, and 
heterocycles such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, 
methylpiperidine or morpholine. It is also possible to employ as bases 
alkali metals, such as 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 -100.degree. C. to +100.degree. C., preferably at 
-78.degree. C. 
The process according to the invention is in general carried out at normal 
pressure. However, it is also possible to carry out the process at 
elevated pressure or at reduced pressure (for example in a range from 0.5 
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 dimethylaminopyridine. 
The blocking is in general carried out in a temperature range from 
0.degree. C. to +60.degree. C., 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 presence of one of the bases 
mentioned, preferably DBU. 
The elimination is in general carried out in a temperature range from 
+30.degree. C. to +130.degree. C., preferably at +50.degree. C. to 
+100.degree. C. 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 preferably employed. 
Suitable solvents for the hydrolysis are water or the organic solvents 
customary for hydrolysis. These preferably 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 solvents mentioned. 
The 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, 
preferably using trifluoroacetic acid. 
The hydrolysis is in general carried out in a temperature range from 
0.degree. C. to +100.degree. C., preferably from +20.degree. C. to 
+80.degree. 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 0.5 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 1.5 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 mixture 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 heterocycles with the inorganic acids can also be obtained. 
The alkylation is in general carried out using alkylating agents such as, 
for example, (C.sub.1 -C.sub.6)-alkyl halides, sulphonic acid esters or 
substituted or unsubstituted (C.sub.1 -C.sub.6)-dialkyl or (C.sub.1 
-C.sub.6)-diaryl sulphonates, preferably methyl iodide or dimethyl 
sulphate. 
The alkylation is in general carried out in one of the abovementioned 
solvents, preferably in dimethylformamide, in a temperature range from 
0.degree. C. to +70.degree. C., preferably from 0.degree. C. to 
+30.degree. C. 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 by esterification of the commercially available acids 
[cf., for example, MSD Book 2, 1593 D]. 
The compounds of the general formula (IV) are, as actual substance 
representatives, 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 
the invention is not restricted to these processes, and any modification 
of these processes can be used in the same manner for the preparation. 
The cyclic-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 
secretion-stimulating effects of angiotensin II. Moreover, 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. 
Investigation of the inhibition of the contraction induced with agonists 
Rabbits of both sexes are anaesthetised by a blow to the neck and bled, or 
alternatively anaesthetised with Nembutal (about 60-80 mg/kg i.v.) and 
sacrificed by 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% O.sub.2 /5% CO.sub.2 -aerated 
Krebs-Henseleit nutrient solution, thermostated at 37.degree. C., of the 
following composition: 119 mmol/l NaCl; 2.5 mmol/l CaCl.sub.2 
.times.2H.sub.2 O; 1.2 mmol/l KH.sub.2 PO.sub.4 ; 10 mmol/l glucose; 4.8 
mmol/l KCl; 1.4 mmol/l MgSO.sub.4 .times.7 H.sub.2 O and 25 mmol/l 
NaHCO.sub.3. 
The contractions are detected isometrically by Statham UC2 cells by means 
of a bridge amplifier (ifd Mulheim or DSM Aalen) and digitised and 
evaluated by means of an A/D converter (System 570, Keithley, Munich). The 
implementation 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 
abovementioned 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 substance to be investigated in 
further passages, which test substance in the following DRCs is applied at 
the start of the incubation time to the baths, in each case in an 
increasing dose. Each aorta ring is in this case stimulated for the whole 
day, always with the same agonist. 
Agonists and their standard concentrations (administration volume per 
individual dose =100 .mu.l): 
______________________________________ 
KCl 22.7; 32.7; 42.7; 52.7 mmol/l 
1-Noradrenaline 
3 .times. 10.sup.-9 ; 3 .times. 10.sup.-8 ; 3 .times. 10.sup.-7 
; 3 .times. 10.sup.-6 g/ml 
Serotonin 10.sup.-8 ; 10.sup.-7 ; 10.sup.-6 ; 10.sup.-5 g/ml 
B-HT 920 10.sup.-7 ; 10.sup.-6 ; 10.sup.-5 g/ml 
Methoxamine 
10.sup.-7 ; 10.sup.-6 ; 10.sup.-5 g/ml 
Angiotensin II 
3 .times. 10.sup.-9 ; 10.sup.-8 ; 3 .times. 10.sup.-8 ; 
10.sup.-7 g/ml 
______________________________________ 
For the calculation of the IC.sub.50 (concentration at which the substance 
to be investigated causes a 50% inhibition), the effect in each case at 
the 3rd =submaximal agonist concentration is 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 contraction induced by potassium depolarisation or other 
agonists was not inhibited, or only weakly inhibited at high 
concentrations. 
Blood pressure measurements on the angiotensin II-infused rat 
Male Wistar rats (Moellegaard, Copenhagen, Denmark) having a body weight of 
300-350 g are anaesthetised with thiopental (100 mg/kg i.p.). After 
tracheotomy, one 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 
pentolinium (5 mg/kg i.v.), the angiotensin II infusion (0.3 .mu.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 
The oral antihypertensive activity of the compounds according to the 
invention was tested on conscious rats having surgically induced 
unilateral renal artery stenosis. 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 after substance 
administration using the "tail cuff". The substances to be tested were 
administered intragastrally ("orally") by stomach tube in different doses, 
suspended in a Tylose suspension. The compounds according to the invention 
lower the arterial blood pressure of the hypertensive rats at a clinically 
relevant dosage. 
In addition, the compounds according to the invention inhibit the specific 
binding of radioactive angiotensin II in a concentration-dependent manner. 
Interaction of the compounds according to the invention with the 
angiotensin II receptor on membrane fractions of the adrenal gland cortex 
of cattle) 
Adrenal gland cortices of cattle (AGC), which have been freshly removed and 
carefully freed from gland medulla, are comminuted in sucrose solution 
(0.32 M) with the aid of an Ultra-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 .mu.g), 
.sup.3 H-angiotensin II (3-5 nM), test buffer solution (50 mM tris, pH 
7.2, 5 mM MgCl.sub.2, 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 mM tris/HCl, pH 7.4, 5% PEG 
6000). The analysis of the raw data was carried out using computer 
programs to give K.sub.i or IC.sub.50 values (K.sub.i : IC.sub.50 values 
corrected for the radioactivity used; IC.sub.50 values: concentration at 
which the substance to be investigated causes a 50% inhibition of the 
total binding of the radioligand). 
Investigation of inhibition of the proliferation of smooth muscle cells by 
the compounds according to the invention 
To determine the antiproliferative action of the compounds, 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 37.degree. C. in 5% CO.sub.2 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 .mu.Ci of 
.sup.3 H-thymidine is added and the incorporation of this substance into 
the TCA-precipitable 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, emulsions, suspensions and solutions, using inert, 
non-toxic, pharmaceutically suitable excipients or solvents. The 
therapeutically active compound should in each case be present in a 
concentration 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 extending 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. 
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 mg/kg, 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 
formulation and the time or interval at which administration 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 administration of larger 
amounts, it may be advisable to divide these into several individual doses 
over the course of the day. 
Starting Compounds

EXAMPLE I 
Methyl 
3-[2-n-butyl-4-chloro-1-{(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl 
)methyl}-1H-imidazol-5-yl]-2-cyclohexylmethyl-3-hydroxy-propionate 
##STR5## 
10.3 ml 16.5 mmol) of a 1.6 mM solution of n-butyl lithium in n-hexane are 
injected under protective gas at -78.degree. C. into a solution of 1.77 g 
(17.5 mmol) of N,N-diisopropylamine in 20 ml of THF. The reaction solution 
is then briefly warmed to 0.degree. C. and cooled again to -78.degree. C., 
and 2.55 g (15 mmol) of methyl 3-cyclohexylpropionate in 10 ml of THF are 
added. The mixture is stirred at -70.degree. C. for 30 min, 6.63 g (10 
mmol) of 
2-n-butyl-4-chloro-1-[(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)me 
thyl]-1H-imidazole-5-carboxaldehyde in 15 ml of THF are added and the 
mixture is additionally stirred at -70.degree. C. for 1 h. It is then 
slowly warmed to 25.degree. C., 20 ml of satd. ammonium chloride solution 
are added and it is extracted three times with 50 ml of ethyl acetate. The 
organic phase is dried over sodium sulphate and concentrated, and the 
residue is further reacted without purification. 
R.sub.f =0.43 and 0.32 (diastereomer mixture, ethyl acetate/petroleum 
ether=1:2) 
EXAMPLE II 
Methyl 
3-acetoxy-3-[2-n-butyl-4-chloro-1-((2'-(N-triphenylmethyltetrazol-5-yl)bip 
henyl-4-yl)methyl}-1H-imidazol-5-yl]-2-cyclohexylmethyl-propionate 
##STR6## 
8.7 g (10.4 mmol) of the compound from Example I are dissolved in 150 ml of 
dichloromethane, then 443 mg (3.63 mmol) of N,N-dimethylaminopyridine 
(DMAP) and 1.12 g (10.9 mmol) of acetic anhydride are added successively 
and the mixture is stirred at 25.degree. C. for 3 h. 30 ml of ether are 
then added, washed successively with 50 ml each of satd. sodium hydrogen 
carbonate solution and satd. sodium chloride solution, dried over sodium 
sulphate and concentrated. The product thus obtained is further reacted in 
Example III. 
Yield: 8.75 g (96% of theory) 
R.sub.f =0.63 (ethyl acetate/petroleum ether=1:2) 
EXAMPLE III 
Methyl 
3-[2-n-butyl-4-chloro-1-{(2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-y 
l)methyl}-1H-imidazol-5-yl]-2-cyclohexylmethyl-2-propionate 
##STR7## 
8.75 g (10.4 mmol) of the compound from Example II are dissolved in 100 ml 
of toluene, then 3.8 g (25 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-en 
(DBU) are added and the mixture is stirred at 90.degree. C. for 20 h. 
After cooling, it is taken up in toluene/H.sub.2 O, the organic phase is 
dried over sodium sulphate and concentrated, and the residue is 
chromatographed on silica gel 60 using ethyl acetate/petroleum ether 
(1:3). 
Yield 2.8 g (34% of theory) 
R.sub.f -0.52 (ethyl acetate/petroleum ether =1:3) 
EXAMPLE IV 
2-n-butyl-1-[(2'-(N-triphenylmethyl-tetrazol-5-y-1)biphenyl-4-yl)methyl]-1H 
-imidazole-5-carboxaldehyde 
##STR8## 
A solution of 12.0 g (18.1 mmol) of 
2-n-butyl-4-chloro-1-[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)met 
hyl]-1-H-imidazole-5-carboxaldehyde in 150 ml of methanol is hydrogenated 
at 25.degree. C. in the presence of 1.2 g of palladium on carbon (5% 
strength) and 2.46g (18.1 mmol) of sodium acetate trihydrate for 1.5 h at 
a hydrogen pressure of about 3 bar. The solution is then filtered off from 
the catalyst and concentrated, and the residue is chromatographed on 
silica gel using ethyl acetate/petroleum ether (1:1). 
Yield: 3.85 g (34% of theory) 
R.sub.f =0.41 (ethyl acetate/petroleum ether=1:1) 
EXAMPLE V 
Methyl 
3-[2-n-butyl-1-{(2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl} 
-1H-imidazol-5-yl]-2-cyclopentylmethyl-3-hydroxy-propionate 
##STR9## 
4.1 ml (6.6 mmol) of a 1.6 N solution of n-butyllithium in n-hexane are 
injected under protective gas at -78.degree. C. into a solution of 0.7 g 
(7 mmol) of N,N-diisopropylamine in 10 ml of THF. The reaction solution is 
then briefly warmed to 0.degree. C. and cooled again to -78.degree. C., 
and 0.94 g (6 mmol) of methyl 3-cyclopentylpropionate in 5 ml of THF is 
added. The mixture is stirred at -78.degree. C. for 30 min, 2.51 g (4 
mmol) of the compound from Example IV in 10 ml of THF are added and the 
mixture is additionally stirred at -78.degree. C. for 1 h. It is then 
slowly warmed to 25.degree. C., 20 ml of satd. ammonium chloride solution 
are added and the mixture is extracted three times with 50 ml of ethyl 
acetate in each 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: 2.18 g (70% of theory) 
R.sub.f =0.18 (ethyl acetate/petroleum ether -1:2, diastereomer mixture) 
EXAMPLE VI 
Methyl 
3-acetoxy-3-[2-n-butyl-1-{(2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4- 
yl)methyl}-1H-imidazol-5-yl]-2-cyclopentylmethyl-propionate 
##STR10## 
11.3 g (14.4 mmol) of the compound from Example V are dissolved in 100 ml 
of dichloromethane, the solution is treated with 694 mg (5.69 mmol) of 
N,N-dimethylaminopyridine (DMAP) and 2.04 ml (21.6 mmol) of acetic 
anhydride and the mixture is stirred at 25.degree. C. for 16 h. It is 
diluted with ether, washed with water (1.times.40 ml) and satd. with 
sodium hydrogen carbonate solution, 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: 9.38 g (79% of theory) 
R.sub.f =0.61 (ethyl acetate/petroleum ether=2:1) 
EXAMPLE VII 
Methyl 
3-[2-n-butyl-1-{(2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl} 
-1H-imidazol-5-yl]-2-cyclopentylmethyl-2-propionate 
##STR11## 
9.38 g (11.4 mmol) of the compound from Example VI are dissolved in 100 ml 
of toluene, 4.26 ml (28.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-en(DBU) 
are added and the mixture is boiled under reflux for 6 h. A further 4.25 
ml (28.5 mmol) of DBU are then added and the contents of the flask are 
stirred at 80.degree. C. for 16 h. After cooling, the mixture is washed 
with satd. sodium chloride solution (1.times.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 (1:2). 
Yield: 5.1 g (58% of theory) 
R.sub.f =0.72 (ethyl acetate/petroleum ether=1:1) 
Preparation Examples 
EXAMPLE 1 
3-[2-n-Butyl-4-chloro-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-1H-imidaz 
ol-5-yl]-2-cyclohexylmethyl-2-propenoic acid 
##STR12## 
2.8 g (3.43 mmol) of the compound from Example III are dissolved in 40 ml 
of THF, 9.1 ml of water and 9.1 ml of trifluoroacetic acid are added and 
the mixture is stirred at 25.degree. C. for 16 h. The reaction mixture is 
acidified again with dil. hydrochloric acid and extracted three times with 
20 ml of ethyl acetate in each case. The organic phases are dried over 
sodium sulphate and concentrated and the residue is chromatographed on 
silica gel 60 using dichloromethane/methanol (10:1). 
Yield: 1.07 g (54% of theory) 
R.sub.f =0.43 (dichloromethane/methanol=10:1) 
EXAMPLE 2 
Methyl 
3-[2-n-butyl-4-chloro-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-1H-imida 
zol-5-yl]-2-cyclopentylmethyl-2-propenoate 
##STR13## 
In analogy to the procedure of Example 1, the title compound was prepared 
from 2.8 g (3.5 mmol) of methyl 
3-[2-n-butyl-4-chloro-1-{(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl 
)methyl)-1H-imidazol-5-yl]-2-cyclopentyl-methyl-2-propenoate 
Yield: 1.2 g (62% of theory) 
R.sub.f =0.45 (ethyl acetate/petroleum ether 2:1) 
EXAMPLE 3 
Methyl 
3-[2-n-butyl-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-1H-imidazol-5-yl] 
-2-cyclopentylmethyl-2-propenoate 
##STR14## 
A solution of 5.0 g (6.66 mmol) of the compound from Example VII in 50 ml 
of methanol is slowly 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 (3.times.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 (35:5:0.2). 
Yield: 2.06 g (75% of theory) 
R.sub.F =0.25 (toluene/methanol/glacial acetic acid 5:5:0.2) 
EXAMPLE 4 
3-[2-n-Butyl-1-{(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl}-1H-imidazol-5-yl]- 
2-cyclopentylmethyl-2-propenoic acid 
##STR15## 
A solution of 1 g of sodium hydroxide in 10 ml of methanol is added to a 
solution of 1.8 g (3.4 mmol) of the compound from Example 3 in 50 ml of 
methanol and the mixture is stirred at 50.degree. C. for 16 h. After 
cooling, it is rendered acidic with dil. hydrochloric acid, extracted with 
ethyl acetate (2.times.50 ml) and dichloromethane (3.times.50 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: 1.41 g (80% of theory) 
R.sub.f =0.14 (toluene/methanol/glacial acetic acid=35:5:0.2) 
The compounds shown in Table 1 were prepared in analogy to the procedures 
of Examples 1-4. 
General method to prepare salts 
A solution of the corresponding imidazolyl-propenic acid in dioxan/water is 
neutralized with equimolar amounts of 1 N NaOH, freezed and lyophilized 
overnight. 
TABLE 1 
______________________________________ 
##STR16## 
Ex. No. R.sup.2 R.sup.3 R.sup.4 R.sub.f 
______________________________________ 
5 Cl 
##STR17## H 0.2.sup.b) 
6 H 
##STR18## H 0.23.sup.d) 
______________________________________ 
According to this general procedure the following compounds are prepared. 
TABLE 2 
______________________________________ 
##STR19## 
Ex. No. R.sup.3 R.sup.4 
M.sup..sym. 
______________________________________ 
##STR20## CH.sub.3 
Na 
8 
##STR21## Na Na 
______________________________________ 
a) Ethyl acetate/petroleum ether=2:1 
b) Toluene/methanol/glacial acetic acid=35:5:1 
c) Dichloromethane/methanol= 
d) Toluene/ethyl acetate/glacial acetic acid=10:30:1