SK27593A3 - Cycloalkyl and heterocyclyl substituted derivatives of imidazolylpropenoic acid - Google Patents

Abstract

Cycloalkyl- and heterocyclyl-substituted imidazolylpropenoic acid derivatives can be prepared by reaction of imidazolylaldehydes with appropriate carboxylic acid derivatives and subsequent dehydrogenation. The compounds can be employed as active ingredients in medicaments, in particular for the treatment of hypertension and atherosclerosis.

Description

Technical field

The invention relates to cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives. processes for their manufacture and their use in medicaments, in particular as blood pressure lowering and antiatherosclerotic agents.

BACKGROUND OF THE INVENTION

Renin is a known proteolytic enzyme. cleaves in vivo from angiotensinogen the decapeptide angiotensin I, which in the lungs, kidneys or other tissues again breaks down to a blood pressure-increasing octapeptide angiotensin II. Various effects of angiotensin

II. such as vasoconstriction, sodium ion retention in the kidneys, aldosterone release in the adrenal gland, and an increase in the sympathetic nervous system tone, act synergistically to increase blood pressure.

In addition, angiotensin II has the property of promoting the growth and multiplication of cells, such as cardiac muscle cells and smooth muscle cells, which in many disease states (e.g., hypertonia, atherosclerosis and cardiac insufficiency) increase and proliferate.

A possible intervention in the renin-angiotensin system (RAS) is, besides inhibiting renin activity, inhibiting angiotensin-converting enzyme (ACE) activity as well as blocking angiotensin II receptors.

EP 425 211 A1 and EP 403 159 A2 disclose imidazolyl derivatives. which have an angiotensin / II-receptor blocking effect.

SUMMARY OF THE INVENTION

The present invention provides cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives of the general formula I

in which

R ¹ is straight or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms,

R ² represents hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl luórnne the hunting, trifluoromethoxy or pentafluoroethyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms,

R ³ represents a cycloalkyl group having 3 to 8 carbon atoms, or a heterocyclyl group having 3 to 8 carbon atoms and up to 3 heteroatoms from the group consisting of sulfur, oxygen or -NA, wherein:

A is a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, n is 0, 1, 2, 3 or 4,

R ⁴ represents a hydrogen atom.

a straight or branched alkyl group having up to 8 carbon atoms or a phenyl group, and

R ⁵ represents a radical of formula

while

R ⁶ represents hydrogen, halogen, cyano, nitro, trifluoromethyl, hydroxy.

trifluoromethoxy, or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms in each case, and

R ⁷ represents a carboxyl group, a straight or branched alkoxycarbonyl group of up to 6 carbon atoms, or a tetrazolyl group, optionally alkylated with 1 to 1 carbon atoms, and their

The imidazolylpropenoic acid derivatives of the present invention may also exist in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of cycloalkylsubstituted and heterocycloalkylsubstituted imidazolylpropenoic acid derivatives may be salts of the compounds of the present invention with mineral acids, sulfonic acids or carboxylic acids. Particularly preferred are, for example, salts with hydrochloric acid. hydrobromic acid. sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, beiisenesulfonic acid, naphthalenedisulfonic acid, acetic acid. propionic acid, lactic acid.

tartaric acid or benzoic acid.

Physiologically acceptable salts also include metal or ammonium salts of the compounds of the present invention having a free carboxyl group. Sodium salts are particularly preferred. potassium salts. magnesium or calcium salts as well as ammonium salts derived from ammonia or organic amines. such as ethylamine, diethylamine. triethylamine, diethanolamine. triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds of the present invention may exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or not as image and mirror image (dlastereomers). The present invention relates to both antipodes and racemic forms. as well as diastereomeric mixtures. Racemic forms, like diastereomers, can be resolved into stereoisomerically uniform moieties by known methods (see E. L. Eliel. Stereochemistry of Carbon Compounds. McGraw Hill, 1962).

Heterocycloalkyl is generally a 5- to 6-membered ring with up to 2 heteroatoms from the group consisting of nitrogen. sulfur, oxygen or -NH. or an N-alkyl group having 1 to 6 carbon atoms. such as ditiolanyl, pyranyl or piperidyl. A dithiolanyl or pyranyl group is preferred.

Preferred are compounds of formula I wherein:

R ¹ represents a straight or branched alkyl or alkenyl group of up to 6 carbon atoms each optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or cyclopropyl. cyclopentyl or cyclohexyl,

R ² represents H, F, Cl, Br, I, trifluoromethyl, trifluoromethoxy or 1uórmetoxyskupinu pentaf1uórety1ovú chain or branched alkyl having up to 6 carbon atoms and.

R ³ is a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a dithiolanyl group, a pyranyl group, or, n is 0, 1, 2 or 3,

R ⁴ represents a hydrogen atom. straight or branched chain alkyl of up to 6 carbon atoms; and

R ⁵ represents a radical of formula

while

R ⁶ represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group, a trifluoromethoxy group, or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and

R ⁷ represents a carboxyl group. a straight or branched alkoxycarbonyl group having up to 3 carbon atoms or a tetrazolyl group.

and salts thereof.

Particularly preferred are compounds of formula I in which

R ¹ represents a straight or branched alkyl or alkenyl group of up to 4 carbon atoms in each case, or a cyclopropyl group.

R ² represents H, F, Cl, Br, I, trifluoromethyl, trifluoromethoxy or pentaf1uóretylovú chain or branched alkyl having up to 4 carbon atoms,

R ³ represents cyclopropyl, cyclopentyl or cyclohexyl, n is 0, 1 or 2,

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

R ⁵ represents a radical of formula

atom group, wherein

R ⁶ represents a hydrogen atom,

R ⁷ represents a carboxyl alkoxycarbonyl group, a tetrazolyl group, and salts thereof.

fluorine, chlorine or bromine and straight or branched carbon atoms or with up to 3

The present invention further provides a process for the preparation of the compounds of the formula I according to the invention, which process comprises first converting an aldehyde of the formula II,

(II) wherein R ¹ , R ² and R ^{5 are} as defined above.

first with compounds of formula III.

R ³ - (CH 2) n -CO 2 -T (III).

wherein R ³ and n are as defined above and

T represents a straight or branched alkyl group having up to 8 carbon atoms or a phenyl group, in an inert solvent and in the presence of a base, to a compound of formula IV

(IV) in which they have R ¹ . R ^2, R ^3, T as defined above, followed by blocking the free hydroxyl function by protecting and last step is performed to eliminate in an inert solvent in the presence of a base, and in the case of when R ⁴ / R ⁷ = H, the esters are hydrolysed , and optionally the substituents R ¹ and R ² are converted by conventional methods, for example by hydrogenation or alkylation.

and when R ⁷ is an alkylated tetrazolyl group, the -NH function is alkylated.

For example, the process of the present invention can be illustrated by the following reaction scheme:

- 8 Cl

H ₃ C- (H ₂ C) ₃

+

LDA

--- ►

THF co ₂ ch ₃

H ₃ C- (H ₂ C) ₃

N - η ^ ^Cl r OH ^ CO ₂ CH ₃ A M ^x co ₂ ch ₃

AC10 CH-CI, DMP

CO ₂ CH ₃

The hydroxy protecting group within the above definition is generally a protecting group selected from the group consisting of benzyloxycarbonyl, methanesulfonyl. toluenesulfonyl group. 2-nitrobenzyl,

4-nitrobenzyl, 2-nitrobenzyloxycarbonyl,

4-nitrobenzyloxycarbonyl. a tert-butoxycarbonyl group. allyloxycarbonyl. 4-methoxycarbonyl, acetyl, trichloroacetyl. 2.2.2-trichloroethoxycarbonyl. 2,4-dimethoxybenzyloxycarbonyl group. 2-methylmethoxyethoxy) ethoxycarbonyl, benzoyl, n-methylbenzoyl.

4-nitrobenzoyl. 4-fluorobenzoyl.

4-chlorobenzoyl and 4-methoxybenzoyl. Acetyl, methanesulfonyl and toluenesulfonyl are preferred.

Suitable solvents for this process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers. such as diethyl ether, dioxane. tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene. and ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, methylene chloride and toluene are preferred for the various steps.

Suitable bases for the process according to the invention are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium, alkali alcoholates the metals are, for example, carbonate or alkaline earth metals. such as sodium or potassium ethanolate, sodium or potassium tert-butoxide, or organic amines (trialkyl / C 6 -C 6 / amines). such as triethylamine or heterocycles. such as

1,4-diazab: cyclo [2.2.2] octane (DABCO). 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine. It is also possible to use alkali metals such as sodium or their hydrides as bases. such as sodium hydride. Lithium diisopropylamide (LDA) and DBU are preferred.

Generally, the bases are used in an amount of 0.05 mol to 10 mol. preferably 1 mol to 2 mol. based on one mole of the compound of formula III.

The process of the present invention is generally carried out at a temperature in the range of -100 ° C to 100 ° C, preferably at -78 ° C.

The process according to the invention is generally carried out under normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

The deprotection is generally carried out in one of the abovementioned solvents and in the presence of a base, preferably methylene chloride with dimethyaminopyridine.

The blocking is generally carried out at a temperature in the range of 0 ° C to 60 ° C. preferably at room temperature and under normal pressure.

The elimination is generally carried out in one of the abovementioned solvents, preferably toluene and in the presence of one of the abovementioned bases. preferably DBU.

The elimination generally takes place at a temperature in the range of 30 ° C to 130 ° C, preferably 50 ° C to 100 ° C and at normal pressure.

Suitable bases for saponification are conventional inorganic bases. These preferably include alkali metal or alkaline earth metal hydroxides, such as sodium or potassium hydroxide, barium hydroxide, alkali metal carbonates, such as sodium carbonate. potassium carbonate or sodium bicarbonate or alkali metal alcoholates such as sodium or potassium ethanolate, sodium or potassium methanolate, or potassium tert-butanolate. Sodium hydroxide or potassium hydroxide is particularly preferably used.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol. ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol or ethers such as tetrahydrofuran or dioxane, or also dimethylformamide and dimethylsulfoxide. Alcohols such as methanol are particularly preferred. ethyl alcohol or isopropyl alcohol. It is also possible to use mixtures of the solvents mentioned.

The saponification can also be carried out with acids such as trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, preferably with trifluoroacetic acid.

The saponification is generally carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C.

In general, the saponification is carried out at normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

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

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

The alkylation is generally carried out with alkylating agents, such as, for example, C1 -C6 alkyl halides, sulfonic acid esters or substituted or unsubstituted (C1-C6) -dialkylsulfonates or (C1-C6) diarylsulfonates, preferably methyl iodide or dimethylsulfate.

The alkylation is generally carried out in one of the abovementioned solvents, preferably dimethylformamide, at a temperature in the range of 0 ° C to 70 ° C. preferably 0 ° C to 30 ° C and under normal pressure.

The hydrogenation is generally carried out by conventional methods in one of the abovementioned solvents, preferably in methanol.

with hydrogen and a Pd / C system in the presence of sodium acetate.

Generally, the hydrogenation is carried out at elevated pressure (about 0.2 to 0.3 MPa). However, it is also possible to operate under reduced or normal pressure.

The hydrogenation is generally carried out at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature.

The compounds of formula (II) are partially known (R ⁵ = phenyl.

see, for example, EP 425 211) or can be produced in this way. A compound according to claim 1, wherein the compounds of the general formula V

wherein R ¹ and R ^{2 are} as defined above, are reacted with compounds of formula VI

(VI).

wherein R ^{5 is} as defined above and

M represents a halogen atom, preferably bromine, in one of the abovementioned solvents, preferably dimethylformamide, in the presence of one of the abovementioned bases. preferably potassium carbonate or potassium t-butylate.

Compounds of formulas V and VI are known.

The compounds of formula III are known or can be prepared by saponification of commercially available acids by conventional methods (see, for example, MSD Book 2. 1593 D).

The compounds of formula (IV) are, as specific representatives of the substance, novel and can be prepared, for example, by the above processes.

The above production methods are given for clarity only.

The preparation of the compounds of the present invention of formula (I) is not limited to these methods, any modification of these processes being applicable in the same manner to the production.

The compounds of the formula I according to the invention are distinguished by an unpredictable, valuable pharmacological spectrum of action.

The compounds of the present invention have a specific A II-antagonistic effect by inhibiting the binding of angiotensin II to A II receptors. They suppress the vasoconstrictor and aldosterone secretion-stimulating effects of angiotensin II. In addition, they inhibit the proliferation of smooth muscle cells.

Thus, the compounds can be used for the treatment of arterial hypertonia and atherosclerosis. In addition, they can be used to treat coronary heart disease. cardiac insufficiency.

brain tension disorders.

ischemic brain diseases.

peripheral vascular disorders.

renal and adrenal disorders.

bronchospheres and vascular-induced respiratory diseases, sodium and swelling retention.

Assay for blockade of agonist contractions

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

and tempered to 37 ° C with ice 119 mmol / 1 NaCl 2.5 mmol / 1 CaC12 x 2 H2O 1.2 mmol / 1 KH ₂ P04 10 mmol / 1 glucose 4.8 mmol / 1 KC1 1.4 mmol / 1 MgSOo x 7 H2 0 a 25 mmol / 1 NaHC0 ₃ -

Contractions were recorded isometrically on Satham UC2-Zellen via a bridge amplifier (ifd Mulheim or DSM Aalen, respectively) and digitized and evaluated using an A / D-Vandler instrument (System 570, Keithley, Munchen). Agostin effect curves (DWK) are evaluated hourly. For each DWK, 3 or 4 individual concentrations were applied to the bath at 4 minute intervals. After the end of the DVK and subsequent wash cycles (sixteen times at 5 s / min with the above nutrient solution), the 28-minute resting or incubation phase ends, during which the contractions generally reach contractions again by default.

Those values, which normally belonged to the 3rd DVK, were used as comparative values for the evaluation of the substances tested in the subsequent course, which were applied to the bath at increasing doses from the beginning of the incubation for the following DWKs. Each aortic ring was always stimulated with the same agonist throughout the day.

Agonists and their standard concentrations (application volume for single dose = 100ul)

KC1 22.7; 32.7; 42.7; 52.7 mmol / 1 1-noradrenaline 3x10 ^-9 ; 3x10-®; 3x10 ~ ⁷ ; 3x10 ^-6 g / ml serotonin 10 ~ ⁸ ; ⁷ “ ⁷ ; ΙΟ “ ⁶ ; ÍO ⁵ g / ml B-HT 920 ΙΟ ⁷ ; 10 ~ ⁶ ; ÍO ⁵ g / ml methoxamine IO- ⁷ ; 10 ^-6 ; ÍO ' ⁵ g / 1 angiotensin II 3xi0- ⁹ ; 10 “ ⁸ ; 3x10 ^-8 ; 10 ⁷ g / l

For calculation

IC50 (concentration.

in which the test substance causes 50% inhibition), the effect of the third (= submaximal) agonist concentrations is always taken as the basis.

The compounds of the present invention inhibit angiotensin II induced contraction of isolated rabbit aorta. These contractions, indicated by depolarization

potassium or i and i with i i. were not inhibited or at all only weakly higher concentrations. The results are listed in the following Table. Example IC50 [NMJ

18

1100

Blood pressure measurement in rats infused with angiotensin II

Vistar rats (Moellegaard, Kopenhagen, Denmark) weighing 200-350 g were anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a blood pressure catheter was inserted into the femoral artery and one angiotensin II infusion catheter and one substance delivery catheter were inserted into the femoral vein. Angiotensin II infusion (0.3 µg / kg / min) was started following a dose of pentolinium ganglioblocator (5 mg / kg i.v.). Once the blood pressure values reached a stable level, the test substance was administered either intravenously or orally as a suspension or solution in 0.5¾ tylosis. Changes in blood pressure due to test substances are shown in the following table as mean KJSEM values.

Example of dosages

0.01 mg / kg i.v.-27

0.01 mg / kg p.o.-19

Determination of antihypertensive effect in non-clogged hypertensive rats

The orally antihypertensive activity of the compounds of the present invention was tested in non-clogged rats.

in which one-sided renal artery stenosis was surgically induced. To this end, the right kidney artery was narrowed with a silver print and a clearance of 0.18 mm. In this form of hypertonia, plasma renin activity; increased in the first six weeks after the intervention.

The arterial blood pressure of these animals was measured at defined time intervals by bloodless cuff in the tail vein. The test substances were applied in various doses by means of an esophagus probe intragastrally (orally) dispersed in a tylose suspension. The compounds of the present invention lower the arterial blood pressure of hypertensive rats at a clinically relevant dosage. The results are shown in the following table.

Example dose mmHg

10 mg / kg P.O. -2

10 mg / kg p.o. -3

In addition, the compounds of the present invention inhibit dose-specific binding of radioactive angiotensin II in a dose-dependent manner.

Interaction of the compounds of the invention with angiotensin II receptor on adrenal cortex membrane fractions (cattle)

The bovine adrenal cortex, which was freshly removed and gently debulled, was further crushed in glucose solution (0.32 M) with U1tra-Turrax (Janke & Kunkel, Staufen iB) to coarse membrane homogenate and partially purified to two centrifugation stages membrane fractions.

Receptor binding experiments were performed on partially purified bead adrenal cortex fractions with radioactive angiotensin II in 0.25 ml test cells so. that individually contained partially purified membranes (50-80 µg). ³ H-angiotensin II <3-5 nM) and assay buffer solution <50 mM Tris, pH 7.2, 5 mM MgCl 2 0.25% BSA) of the test substance. After an incubation time of 60 minutes at room temperature, unbound radioactivity of the samples was separated by a moistened glass filter (Vhatman GF / C) and the bound radioactivity was measured after washing the protein with ice buffer (50 mM Tris / HCl pH 7.4, 5% PEG 6000) spectrophotometrically in a scintillation cocktail. The raw data analysis was performed using a computer program for K i values, respectively IC 50 <K i = IC 50 values corrected for the radioactivity used; IC50 ^: concentration at which the test substance shows 50% inhibition of specific radioligand binding). The results are shown in the following table.

Example

Ki <nM)

11

51

1100

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

Smooth muscle cells obtained from aortic rats and pigs using the Media-Explantat® technique were used to determine the antiproliferative effect of the compounds. Ross, J. Cell. Biol. 50, 172 (1971). Cells were seeded in suitable culture dishes, typically 24-well dishes and cultured for 2-3 days in 199 medium with 7.5% FCS and 7.5% NCS, 2 mM L-glutamine and 15 mM HEPES and pH 7 , 4 in 5¾ CO2 at 37 ° C. Thereafter, the cells were synchronized for 2-3 days with serum yield and then stimulated to grow with angiotensin II, serum or other factors. Test compounds are also added. After 16-20 hours, 1 µCi of ³ H-thymidine is added and after a further 4 hours the incorporation of these substances into TCA-precipitatable DNA cells is determined.

To determine the IC50 value, the concentration of active compound that causes a semi-maximal suppression of tyraidine incorporation induced by 10% FCS at sequential dilution of the drug is calculated.

The novel active compounds can be converted into conventional preparations such as tablets, coated tablets, pills by known methods.

granulates. aerosols, syrups, use of inert, non-toxic or solvents. Therapeutically present at a concentration of about 0.5 of the composition, that is, in the amount that the emulsions, suspensions and solutions, and the pharmaceutically acceptable carriers of the active compound herein are to be up to 90% by weight overall are sufficient to achieve the stated dosage range.

For example, the formulations are prepared by mixing the active ingredient with solvents and / or carriers, optionally with emulsifying agents and / or dispersing agents, whereby, for example, if water is used as a diluent, organic solvents may optionally be used as co-solvents.

Administration is effected by conventional means, preferably orally or parenterally, in particular perlingually or intravenously.

For parenteral administration, solutions of the active ingredient using suitable liquid carrier materials can be used.

In general, it has proven advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight, for intravenous administration to achieve effective results. For oral administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to withdraw the abovementioned amounts, depending on the body weight or the type of administration, but also on the individual tolerance to the medicament, the type and type of the preparation and the time or interval at which the administration takes place. . Thus, it may be sufficient in individual cases that starting from less than the above-mentioned minimum doses, while in other cases the above-mentioned upper limits will have to be exceeded. In the case of administration of larger amounts, it is advisable to divide this dose into a larger number of individual doses during the day.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

4-Bromomethyl-benzoic acid methyl ester

g (0.3 mol) of methyl p-tolyl ester and 53.4 g (0.3 mol) of N-bromosuccinimide are heated together with 1.97 g of azoisobutyronitrile to boiling in 375 ml of carbon tetrachloride for one hour, then cooled to a temperature of ° C and succinimide is filtered off. The residue is chromatographed on silica gel with ethyl acetate / petroleum ether (1:10).

Yield ^: 55.7 g (81% of theory)

Rf = 0.58 (ethyl acetate / petroleum ether = 110)

Example II

4-Bromomethyl-3-chloro-benzoic acid methyl ester

Analogously to Example I, the title compound is prepared from 9.0 g (48.8 mol) of methyl ester

3-chloro-p-tolyl.

Yield: 7.3 g <57% of theory)

Rf = 0.62 (ethyl acetate / petroleum ether = 1 = 5)

Example III

5-Bromomethylthiophene-2-carboxylic acid methyl ester

Analogously to Example I, the title compound is prepared from 20 g (0.13 mol) of 5-methyl-11-phenyl-2-carboxylic acid methyl ester.

Yield 22 g <73% of theory)

Rf = 0.43 (dichloromethane / methanol = 10 1)

Example IV

Acid methyl ester

- [<2-n-butyl-4-chloro-5-formyl-imidazol-1-yl) methyl] -benzoic acid

CO ₂ CH ₃

20 g of CO, 107 moles) of 2-n-butyl-4-chloro-5-formylimidazole (produced according to EP 324 377) in dimethylformamide are stirred with 13 g (0.107 moles) of potassium tert-butylate for 30 minutes under a protective gas atmosphere. at 25 ° C, then 36 g (0.157 mol) of the compound of Example I in dimethylformamide are added dropwise and the reaction mixture is stirred for 25 hours at 25 ° C. After concentration, the crude product is chromatographed on silica gel 60 using a mixture of ethyl acetate and petroleum ether (1). Yield ^: 25.5 g (69% of theory)

Rf = 0.7 (ethyl acetate / petroleum ether = 1: 2).

Example V

Methyl ester acid

4 - [(2-n-butyl-4-chloro-5-formyl-imidazol-1-yl) methyl] -3-chlorobenzoic acid

CO ₂ CH ₃

Analogously to Example IV, the title compound is obtained from 3.16 g (12 mmol) of the compound of Example II. Yield 2.3 g (78% of theory)

Rf = 0.38 (ethyl acetate / petroleum ether = 1: 5)

Example VI

Acid methyl ester

5- (2-n-butyl-4-chloro-5-form-1-imidazol-1-yl) methyl] thiophene-2-carboxylic acid

CO ₂ CH ₃

14.4 g (77 mmol) of 2-n-butyl-4-chloro-5-formylimidazole, 20 g (85 mmol) of the compound of Example III and 21.3 g (154 mmol) of potassium carbonate are stirred in 300 ml of dimethylformamide. for 20 hours at 25 ° C. After concentration, the residue is taken up in water

300 ml of dichloromethane and 250 ml of water, the organic phase is separated, dried over sodium sulphate and concentrated. The product thus obtained is chromatographed on silica gel 60 using a 1: 3 mixture of ethyl acetate and petroleum ether.

Yield 14.9 g (57% of theory)

Rf = 0.54 (ethyl acetate / petroleum ether = 1 · 3).

Example VII

Acid methyl ester

4 - [(2-n-butyl-5-formyl-imidazol-1-yl) methyl] -benzoic acid

CO ₂ CH ₃ g (63 mmol) of the compound of Example IV in 300 ml of methyl 1 and 1 cock are hydrogenated at 25 ° C in the presence of 2 g of palladium on charcoal (5 µm) and 8.6 g (63 mmol) of trihydrate sodium acetate for 3 hours at a hydrogen pressure of about 0.3 MPa. The solution is then filtered from the catalyst and concentrated. The residue was then chromatographed on silica gel with ethyl acetate / petroleum ether (3: 1).

Yield = 13.4 g (75% of theory)

Rf = 0.48 (ethyl acetate / petroleum ether = 3 = 1)

Example VIII

Acid methyl ester

4 - [(2-n-butyl-5-formyl-imidazol-1-yl) methyl] -3-chloro-benzoic acid

CO ₂ CH ₃

Analogously to Example VII, the title compound was prepared from 3.1 g (8.4 mmol) of the compound of Example II. Yield 2 g (71% of theory)

Rf = 0.54 (ethyl acetate / petroleum ether = 5 = 1)

EXAMPLE IX

Acid methyl ester

5- [(2-n-buty1-4-chloro-5-formy1- imidazol-1-y1) mety1] f o uránkarboxy1ove _3c

co ₂ c ₂ h ₅

Analogously to Example VI, the title compound is obtained

18.7 g (0.1 mole)

2-n-butyl-4-chloro-5-formylimidazole and 24.1 g (0.103 mol) of 5-bromomethylfuran-2-carboxylic acid ethyl ester.

Yield: 22.8 g (65% of theory)

Rf = 0.38 (ethyl acetate / petroleum ether = 1: 2).

Example X

Ethyl ester of the acid

5 - [(2-n-butyl-4-chloro-5-formyl-imidazol-1-yl) methyl] -furanocarboxylic acid

CO ₂ C ₂ H ₅

Analogously to Example VI, the title compound was prepared from 14.51 g (42 mmol) of the compound of Example IX. Yield: 7.31 g (57% of theory)

Rf = 0.39 (ethyl acetate / petroleum ether = 1 ^: 1).

Example XI

Ethyl ester of the acid

5-f (2-n-butyl-5-formyl-imidazol-1-yl) methyl] thiophene-2-carboxylic acid

Analogously to Example VII, the title is mentioned

compound from 6.5 g (19.1 mmol) of the compound of Example VI. Yield ^: 4 g (68% of theory) R f = 0.21 (ethyl acetate / petroleum ether = 1: 1). Example 1 a d XII

Methyl ester acid

3 - [(2-n-butyl-1-C (2-ethoxycarbonylfuran-5-yl) methyl) -1-imidazol-5-yl] -2-cyclopentylmethyl-3-hydroxypropionic acid

CO ₂ CH ₂ CH ₃

To a solution of 0.89 g (8.75 mmol) of N, N-diisopropylamine in 10 ml of tetrahydrofuran was injected under a protective gas atmosphere at -75 ° C with 5.16 ml (8.25 mmol) of a 1.6 N solution of n-butyllithium in n-hexane. The reaction was then briefly warmed to 0 ° C, re-cooled to -78 ° C, and 1.17 g (7.5 mmol) of methyl 3-cyclopentylpropionate in 5 mL of tetrahydrofuran was added. The reaction mixture is stirred for 30 minutes at -78 ° C, and 1.52 g (5 mmol) of the compound of the example is added.

X in 15 ml tetrahydrofuran and the reaction mixture was stirred for 45 minutes at -78 ° C. It is then slowly warmed to 25 ° C, 20 ml of saturated ammonium chloride solution are added and extracted three times with 50 ml of ethyl acetate each time. The organic phases are dried over anhydrous sodium sulphate, concentrated and the residue is purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (2 L). Yield: 1.1 g (48% of theory)

Rf = 0.09 (ethyl acetate / petroleum ether = 2 ^: 1, mixture of diastereomers).

Example XIII

Acid methyl ester

3 - [(2-n-butyl-1 - ((4-methoxycarbonylphenyl) methyl) -1H-imidazol-5-yl] -2-cyclopentyl-methyl-3-hydroxypropionic acid

CO ₂ CH ₃

Analogously to Example XII, the title compound was prepared and 8.75 mmol) of the compound of Example VII were reacted further without purification.

R f = 0.17 (ethyl acetate / petroleum ether = 4 1 mixture of diastereomers).

Example XIV

Acid methyl ester

3 - [(2-n-butyl-1-C (2-methoxycarbonyl-thiophene) methyl) -1H-imidazol-5-yl] -2-cyclopentyl-methyl-3-hydroxy-propionic acid

Analogous to that described in Example XI, the title is mentioned

compound prepared from 1.53 g (5 mmol) of the compound of Example XII. Yield: 1.25 g (54% of theory) Rf = 0.12 (ethyl acetate / petroleum ether = 2: 1 mixture of diastereomers). Example 1 a d XV

Acid methyl ester

3-Acetoxy-3- [C2-n-butyl-1- (C2-ethoxycarbonylfuran-5-yl) methyl] -1H-imidazol-5-yl] -2-cyclopentyl-1-propionic acid

2.45 g (5.36 mmol) of the compound of Example XII are dissolved in 50 ml of dichloromethane, mixed

264 mg (2.16 mmol)

Of N, N * -dimethylaminopyridine acetic anhydride and a reaction temperature of 25 ° C. Then (DMftP) mixture was added

0.76 mL (8.04 mmol) was stirred for

It was diluted with diethyl ether for 166 hours, washed with water (1 x 40 mL) and saturated sodium bicarbonate solution.

the organic phase is dried over sodium sulphate and concentrated. The crude product thus obtained is chromatographed on silica gel with ethyl acetate / petroleum ether (3 ^: 2).

Yield: 1.93 g (72% of theory)

Rf = 0.65 (ethyl acetate / petroleum ether = 3 ^: 2).

Example XVI

Acid methyl ester

3-acetoxy-3 - [(2-n-buty1-l - <(4-carboxyphenyl) methyl) H-imidazol-5-y11-2-cyklopentylmety1-propionic acid

CO ₂ CH ₃

Analogously to Example XV, the title compound is prepared from the crude product of Example XIII.

Yield 1.7 g (G6% of theory)

Rf = 0.63 (ethyl acetate / petroleum ether = 4: 1 mixture of diastereomers).

Example XVII

Acid methyl ester

3-Acetoxy-3 - [(2-n-butyl-1 - ((2-methoxycarbonylthiophen-5-yl) methyl) -1Himidazol-5-yl] -2-cyclopentylmethyl-propionic acid

Analogously to Example XV, the title compound was prepared from 1.2 g (2.6 mmol) of the compound of Example XIV. Yield; 1.23 g (94% of theory)

Rf = 0.67 (ethyl acetate / petroleum ether = 2 - 1 mixture of diastereomers).

Production examples

Example 1

3-Acetoxy-3 - [(2-n-butyl-1 - {(2-methoxycarbonylfuran-5-yl) methyl) -1Himidazol-5-yl] -2-cyclopentylmethyl-2-propenoic acid methyl ester

1.9 g (3.78 mmol) of the compound of Example XV are dissolved in ml of toluene, added

1.13 ml (7.566 mmol)

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) at 80 ° C.

the reaction mixture is stirred for 6 hours

DBU (1.13 mL, 7.56 mmol) was added again and the contents were stirred at 80 ° C for hours. After cooling, washed with saturated sodium chloride solution (1 x 30 mL), the organic phase was dried over anhydrous sodium sulfate. , filtered and concentrated. The residue is chromatographed on silica gel using ethyl acetate / petroleum ether (1: 1).

2).

yield

1.16 g (69% of theory)

Rf = 0.68 (ethyl acetate / petroleum ether = 1 L).

Example 2

Acid methyl ester

3 - [(2-n-butyl-1 - <(4-methoxycarbonylphenyl) methyl) -1H-imidazol-5-yl] 2-cyclopentylmethyl-2-propene

Analogously to Example 1, the title compound was prepared from 1.6 g (3.2 mmol) of the compound of Example XVI. Yield: 0.61 g (43% of theory)

Rf = 0.63 (ethyl acetate / petroleum ether = 2 ^: 1).

Example 3

Acid methyl ester

- [(2-n-butyl-1 - ((4-methoxycarbonylthiophen-5-yl) methyl) -1H-imidazole -

5-y1] -2-propenoate-cyklopentylmety1-2

- WITH

What is ₂ ch ₃

Analogously to Example 1, the title compound was prepared from 1.2 g (2.38 mmol) of the compound of Example XVII. Yield: 0.5 g (47% of theory)

Rf = 0.55 (ethyl acetate / petroleum ether = 1 = 1)

Example 4

Acid for 3 - [(2-n-butyl-1- (4-carboxyphenyl) methyl) -1H-imidazole-

5-γ 11-2-cyclopentylmethyl-2-propene

To a solution of 1.266 g (2.88 mmol) of the compound of Example 2 in 30 ml of methanol was added 1 g of sodium hydroxide in 20 ml of a mixture of methyl alcohol and water (1 = 1). The mixture is stirred for 16 hours at 50 ° C, then acidified with dilute hydrochloric acid, poured into 300 ml of water and extracted three times with 75 ml of dichloromethane and three times with 40 ml of ethyl acetate each time. The organic phase is dried over anhydrous sodium sulphate, filtered and freed from the solvent. The crude product is purified on silica gel (toluene / ethyl acetate / glacial acetic acid 10 - 30 - 0.1 -> toluene / methanol / glacial acetic acid 35 ^: 5

0.2).

Yield ^: 342 mg (29% of theory)

Rf = 0.25 (toluene / methanol / glacial acetic acid = 35: 5 ^: 1).

Example 5

Acid for 3 - [(2-n-butyl-1 - ((2-carboxytiophen-5-yl) methyl) -1Himidazol-5-yl] -2-cyclopentylmethyl-2-propenoic acid

Analogously to Example 4, the title compound was prepared from 500 mg <1.13 mmol) of the compound of Example 3. Yield: 101 mg (21% of theory)

Rf = 1.13 (toluene / ethyl acetate / glacial acetic acid = 10 · 30 · 0.2).

Example 6

3 - [(2-n-butyl-1 - ((2-carboxyfuran-5-yl) methyl) -1Himidazol-5-yl] -2-cyclopentylmethyl-2-propenoic acid

COOH

Analogously to Example 4, the title compound was prepared from 1.g (1.13 mmol) of the compound of Example 1. Yield 380 mg (39% of theory).

Rf = 0.07 (toluene / ethyl acetate / glacial acetic acid = 10 · 30 = 1)

Example 7

3 - [(2-n-butyl-1-C (2-carboxyphenyl) methyl) -1H-imidazol-5-yl] -2-cyclopentylmethyl-2-propenoic acid, disodium salt

340 mg (0.83 mmol) of the compound of Example 4 are dissolved in a mixture of methanol and water, treated with 1.66 ml of 1 N sodium hydroxide and then freed from the solvent. 376 mg of the title compound are obtained (100% of theory).

Example 8

3-E (2-n-butyl-1-C (2-carboxythiophen-5-yl) methyl) -1H-imidazol-5-yl-2-cyclopentylmethyl-2-propenoic acid, disodium salt

CO ₂ 'Na ⁺

Analogously to Example 7, the title compound was prepared from 330 mg (79 mmol) of the compound of Example 5.

Example 9

Acid for 3 - [(2-n-butyl-1 - <(2-carboxyfuran-5-yl) methyl] -1H-imidazol-5-yl] -2-cyclopentylmethyl-2-propene, disodium salt

CO2'Na ⁺

Analogously to Example 7, the title compound was prepared from 376 mg (0.94 mmol) of the compound of Example 6-

Claims (10)

PATENT REQUIREMENTS Cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives of the general formula I in which: R ¹ is straight or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted cykloalkylcivou having 3 to 6 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms. R ² represents hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, pentafluoroethyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms, R ³ represents a cycloalkyl group having 3 to 8 carbon atoms, or a heterocyclyl group having 3 to 8 carbon atoms and up to 3 heteroatoms from the group consisting of sulfur, oxygen or -NA, wherein: A is a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, n is 0, 1, 2, 3 or 4, R ⁴ represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R ⁵ represents a radical of formula wherein R ⁶ represents a hydrogen atom. a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and R ⁷ represents a carboxyl group, a straight or branched alkoxycarbonyl group of up to 6 carbon atoms or a tetrazolyl group, optionally alkylated with 1 to 4 carbon atoms. salts thereof. Second Cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives according to claim 1 of the general formula: R ¹ is straight or branched alkyl or alkenyl each having up to, 6 carbon atoms, which are optionally substituted by cyclopropyl, cyk1obutýlovou, cyclopentyl or cyclohexyl or a cyclopropyl group, a cyclohexyl group, ^R2 is hydrogen, trifluoromethyl, pentafluoroethyl EIL straight or branched al cyclopentyl or F, Cl, Br, I, trifluoromethoxy, alkyl group having up to 6 carbon atoms, R ³ is a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a dithiolanyl group, a pyranyl group, or, n is 0, 1, 2 or 3, R ⁴ represents a hydrogen atom. straight or branched chain alkyl of up to 6 carbon atoms; and R ⁵ represents a radical of formula wherein R ⁶ represents a hydrogen atom, a fluorine, chlorine or bromine atom, a trifluoromethyl group. trifluoromethoxy, or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms in each case, and R ⁷ represents a carboxyl group, a straight or branched alkoxycarbonyl group of up to 3 carbon atoms or a tetrazolyl group, and salts thereof. The cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives according to claim 1 of the general formula I in which: R ¹ is straight or branched alkyl or alkenyl each having up to 4 carbon atoms, or cyclopropyl, R ² represents H, F, Cl, Br, I, trifluoromethyl, trifluoromethoxy or pentafluoroethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms and, R ³ represents a cyclopropyl group. cyclopentyl or cyclohexyl, n is 0, 1 or 2, R ⁴ represents a hydrogen atom. straight or branched and 1 keel group with up to 4 carbon atoms; and R ⁵ represents a radical of formula wherein R ⁶ represents a hydrogen atom, a fluorine, chlorine or bromine atom and R ⁷ represents a carboxyl group, a straight or branched alkoxycarbonyl group of up to 3 carbon atoms or a tetrazolyl group, and salts thereof. The cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives according to claim 1 for therapeutic use. A process for the preparation of cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives according to claim 1, characterized in that the aldehyde of formula II (Π) is first converted in which R ¹ , R ² and R ^{5 are} as defined above, first by reaction with a compound of formula III R ³ - (CH ₂ ) n -CO ₂ -T (III). wherein R ³ and n are as defined above and represents a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group. an inert solvent, and in the presence of a base, to a compound of formula IV r ₃ (IV) x wherein R ¹ . R ² . R ³ to T as defined above, then blocking the free hydroxyl function by introducing a protecting group, and in the final step, elimination is carried out in an inert solvent in the presence of a base, and in the case of an acid where R 6 / R ⁷ = H, the ester is saponified; R ^{@ 1} and R ^{@ 2} are converted by conventional methods, for example by hydrogenation or alkylation, and when R @ ⁷ is an alkylated tetrazolyl group, the -NH function is alkylated. The process according to claim 5, characterized in that it is operated at a temperature in the range of -100 ° C to 100 ° C. A medicament comprising at least one cycloalkyl substituted or heterocyclyl substituted imidazolylpropenoic acid derivative according to claim 1. Medicament according to claim 7 for the treatment of hypertonia and atherosclerosis. A process for the manufacture of medicaments according to claim 6, characterized in that the cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives are converted, if necessary using conventional excipients and carriers, into a suitable dosage form. Use of the cycloalkyl-substituted and heterocyclyl-substituted imidazolylpropenoic acid derivatives according to claim 1 for the manufacture of medicaments.