SK279261B6 - Benzimidazole deivatives, pharmaceutical agents containing them and process for their preparation - Google Patents

Abstract

The invention relates to benzimidazoles of the general formula wherein particular symbols are defined in the description; mixtures of the 1 and 3 isomers thereof, and their salts with inorganic and organic salts or bases, especially those, which are physiologically acceptable. The description further describes preparation method of the derivatives and pharmaceutical agents containing thereof. The compounds are useful as angiotensin II antagonists.

Description

Technical field

The invention relates to benzimidazole derivatives, a process for their preparation and a pharmaceutical composition containing them.

BACKGROUND OF THE INVENTION

EP-A-0 468470, EP-A-0 459 136, EP-A-0 420 237 and EP-A-0 392 317 as well as US-A-4 880 804 disclose benzimidazole derivatives which are good antagonists angiotensin II.

SUMMARY OF THE INVENTION

The present invention provides the benzimidazole derivatives of the formula (I), which are known from the derivatives described in particular in EP-A-0400835 difference being the substituent ^R2, which is pyridyl or imidazolyl,

R ¹

R ⁴ where

R1 represents a fluorine, chlorine or bromine atom, alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl and

R ² represents a 5, 6 or 7 membered alkyléniminoskupinu alkenyliminoskupinu or optionally substituted by one or two alkyl radicals one or a tetramethylene or pentamethylene group, wherein the methylene group is optionally replaced by a carbonyl group or a sulfonyl group, maleínimidoskupinu, optionally substituted by one or two alkyl or one or two phenyl radicals, the substituents of which may be the same or different, further benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted in the 1-position by an alkyl radical of 1 to 6 carbon atoms or a cycloalkyl radical, wherein the phenyl radical of the benzimidazole group is optionally further substituted by a fluorine atom, a methyl or trifluoromethyl radical, furthermore imidazo [2,1b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5, 6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [4,5-b] -pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [1,2-c] pyrimidin-2-yl, imidazo [1,2- a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imidazo [4,5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, or imidazo A [4,5-d] pyridazin-2-yl, pyridyl or imidazolyl group, optionally bonded at the 1-position via an alkyl group or a carbon atom of a benzyl group, and the imidazolyl group is additionally optionally substituted in the carbon chain by an alkyl residue,

R 3 represents an alkyl radical of 1 to 5 carbon atoms or a cycloalkyl radical of 3 to 5 carbon atoms, and

R ⁴ is carboxy or lH-tetrazolyl group, and their salts, especially salts with inorganic or organic acids or bases, wherein, unless otherwise indicated, include alkanoyl, alkyl and alkoxy radicals in each case 1 to 3 carbon atoms and the cycloalkyl moiety comprises 3 to 7 carbon atoms.

Preferred benzimidazole derivatives of the general formula (I) are those in which, within the scope of the above definitions for the radicals R1 to R3, said radicals may have, for example, the following specific meanings.

R1 is fluorine, chlorine or bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl,

R ² is 2-oxo-pyrrolidino, 2-oxopiperidino-, 2-oxo-hexametylénimino-, propanesultam-l-yl, butánsultam-l-yl, pentánsultam-l-yl, maleimido-, 2-metylmaleínimido- 2-methyl-3-phenylmaleimido-, 2-pyridyl-, 4-methylimidazol-2-yl-, 1-methylimidazol-4-yl-, 1-methylimidazol-5-yl-, 1-benzyl-imidazole-4- yl-, 1-benzylimidazol-5-yl-, 1,2-dimethylimidazol-4-yl-, 1,2-dimethylimidazol-5-yl-, 1-benzyl-2-methylimidazol-4-yl-, 1-benzyl -2-methyl-imidazol-5-yl-, benzimidazol-2-yl-, 1-methylbenzimidazol-2-yl-, 1-ethylbenzimidazol-2-yl-, 1-n-propylbenzimidazol-2-yl-, 1- isopropylbenzimidazol-2-yl-, 1-n-butyl-benzimidazol-2-yl-, 1-isobutylbenzimidazol-2-yl-, 1-n-pentylbenzimidazol-2-yl-, 1-n-hexylbenzimidazol-2-yl-, 1 -cyclopropylbenzimidazol-2-yl-, 1-cyclobutylbenzimidazol-2-yl-, 1-cyclopentylbenzimidazol-2-yl-, 1-cyclohexylbenzimidazol-2-yl-, 5-methylbenzimidazol-2-yl-, 1,5-dimethylbenzimidazole- 2-yl-, 1,6-dimethylbenzimidazol-2-yl-, 1,4-dimethylbenzimidazol-2-yl-, 5-fluorobenzimidazol-2-yl-, 6-fluoro-1-methyl 5-trifluoromethyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydrobenzimidazol-2-yl-, 4-trifluoromethyl-benzimidazol-2-yl-, 5,6,7-tetrahydro-l-methyl-benzimidazol-2-yl,

4,5,6,7-tetrahydro-1-ethylbenzimidazol-2-yl-, 4,5,6,7-tetrahydro-1H-butylbenzimidazol-2-yl-, 4,5,6,7-tetrahydro-1H-hexylbenzimidazole- 2-yl-, 4,5,6,7-tetrahydro-1-cyclopropylbenzimidazol-2-yl-, 4,5,6,7-tetrahydro-1-cyclohexylbenzimidazol-2-yl-, imidazo [1,2-a] ] pyrimidin-2-yl,

5.6.7.8-tetrahydroimidazo [1,2-a] pyrimidin-2-yl-, imidazo [4,5-c] pyridin-2-yl-, imidazo [2,1-b] thiazol-6-yl-, imidazo [ 2,1c] pyrimidin-2-yl-, imidazo [1,2-a] pyrazin-2-yl-, imidazo [1,2-a] pyridazin-2-yl-, purin-8-yl-, imidazo- [4,5-b] pyrazin-2-yl-, imidazo [4,5-c] pyridazin-2-yl-, imidazo [4,5-d] pyridazin-2-yl-, R 3 is methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl-, cyclopropyl, cyclobutyl, cyclopentyl.

Preferred compounds of formula (I) are those in which:

R1 is chlorine, C1-C3 alkyl or trifluoromethyl;

R ² represents a 5, 6 or 7 membered alkyléniminoskupinu which methylene group is replaced by a carbonyl or sulfonyl, maleínimidoskupinu, optionally substituted with one to two C1-3 alkyl radicals or by one or two phenyl radicals, the substituents may be identical or different, benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted at the 1-position with C 1 -C 6 alkyl or cycloalkyl, the phenyl of the benzimidazole group being optionally substituted with fluoro, methyl or trifluoromethyl radical, further imidazo [2,1b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2- yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [1,2-c] pyrimidin-2-yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imidazo [4,5-b] pyrazine -2-yl, imidaz o [4,5-c] pyridazin-2-yl or imidazo [4,5-d] pyridazin-2-yl, pyridyl or imidazol-4-yl, optionally bonded in the 1-position via an alkyl group of 1 to 3 carbon atoms or via a carbon atom of a benzyl group and the imidazolyl group is additionally optionally substituted in the carbon chain by an alkyl radical having 1 to 3 carbon atoms,

R ³ is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl and R 4 is carboxyl or 1H-tetrazolyl, and salts thereof with inorganic or organic acids or bases.

Particularly preferred compounds of formula (I) are those in which:

R1 represents a methyl group or a chlorine atom,

R ² represents a 5, 6 or 7 membered alkyléniminoskupinu, wherein the methylene group is replaced by a carbonyl or sulfonyl, maleínimidoskupinu, optionally substituted by one or two alkyl or phenyl radicals, the substituents may be identical or different, benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted at the 1-position with a C 1-6 alkyl radical, wherein the phenyl residue of the benzimidazole group is optionally further substituted by a fluorine atom, imidazo [1,2-a] pyridin-2-yl, 5 , 6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [4,5-b] pyridin-2-yl, or imidazo [2,1b] thiazol-6-yl or a 4-imidazolyl group substituted in the 1-position with an alkyl radical of 1 to 3 carbon atoms,

R ³ represents an alkyl radical of 1 to 5 carbon atoms or a cycloalkyl radical of 3 to 5 carbon atoms and

R ⁴ represents a carboxyl group or a 1H-tetrazolyl group, and salts thereof with inorganic or organic acids or bases.

According to the process of the invention, the compounds of formula (I) as defined above can be obtained by:

a) cyclizes a compound of formula (II)

R ¹

Y ¹ where

R 1 and R ² are as defined above and one of the radicals X ³ or Y ³ represents a group of the general formula

R ⁴ and one of the radicals X] or Y] is the residue of the formula all ·

where

R ³ and R ^2, are as defined above,

R 8 represents a hydrogen atom or a group R ³ -CO, where R ³ is as defined above,

Z ³ and Z ² , the same or different, are amino, optionally substituted or hydroxy or mercapto, optionally substituted by a lower alkyl radical, or both together represent an oxygen atom, a sulfur atom, an imino radical, optionally substituted by an alkyl radical of 1 to 3 carbon atoms, alkylenedioxy or alkylenedithio, in each case having 2 or 3 carbon atoms, one of the symbols

X ³ or Y ³ each represents a group of the general formula

R ⁴ or

wherein the individual symbols are as defined above and optionally the corresponding N-oxides obtained are reduced.

The cyclization is preferably carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin or an excess of acylating compound. of the formula (II), for example in the corresponding nitrile, anhydride, halide, ester or acid amide, for example at 0 to 250 ° C, preferably at the boiling point of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or, optionally, in the presence of a base such as potassium ethoxide or tert-butoxide. However, the cyclization can also be carried out without a solvent and / or a condensing agent.

Preferably, however, the reaction is carried out by preparing a compound of formula (II) directly in the reaction mixture by reducing the corresponding o-nitroamino compound, optionally in the presence of a carboxylic acid of formula R ³ COOH, wherein R ³ is as defined herein or by acylating the corresponding o-diamino compound. When the reduction of the nitro group at the hydroxylamine step is interrupted, the N-oxide of the compound of formula (1) is obtained by subsequent cyclization. This compound can then be converted to the corresponding compound of formula (I) by reduction.

The subsequent reduction of the obtained N-oxide of the compound of formula (I) is preferably carried out in a solvent such as water, a mixture of water and ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide under hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium on activated carbon by treatment of a metal such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulfuric acid, with salts such as ferrous sulphate, stannous chloride or sodium dithionite or hydrazine in the presence of Raney nickel at 0 to 50 ° C preferably at room temperature.

The benzimidazoles of formula (I) may also be obtained by:

(b) to a benzimidazole derivative of the general formula (III)

R ¹

H (III), wherein

R ¹ to R 6 are as defined above, acting as a biphenyl derivative of the general formula (IV)

s ⁴ where

R ⁴ is defined as above and Z 3 represents a nucleophilic leaving group, e.g. a halogen such as chlorine, bromine or iodine atom or a substituted sulfonyloxy, for example methanesulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy.

The reaction is preferably carried out in a solvent or solvent mixture, for example methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent, for example sodium or potassium carbonate, potassium hydroxide, potassium tert-butoxide, triethylamine or pyridine, wherein triethylamine or pyridine can also be used as a solvent, the reaction is preferably carried out at a temperature of 0 to 100 ° C, for example at room temperature to 50 ° C.

The reaction usually yields a mixture of 1- and 3-isomers that can be separated, preferably by chromatography using a carrier, for example silica gel or alumina, to give the corresponding isomers at the 1 or 3 positions.

When a compound of formula (I) in which R ⁴ is a carboxy group is to be obtained, the procedure is as follows:

c) converts a compound of formula (V)

where

R1 to R3 are as defined above and

R ⁴ 'is a group which can be converted by hydrolysis, heat treatment or hydrogenolysis to a carboxyl group to a compound in which R ⁴ is a carboxyl group.

For example, functional derivatives of a carboxyl group such as unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, a nitrile group or a tetrazolyl group can be converted into a carboxyl group by hydrolysis, esters such as the tert-butyl ester is can be converted to a carboxyl group by thermolysis and esters with arylalkanols, for example the benzyl ester can be converted to a carboxyl group by hydrogenolysis.

The hydrolysis is carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trichloroacetic or trifluoroacetic acid in the presence of a base such as potassium or sodium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or a mixture of water and dioxane at -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture. In the case of hydrolysis in the presence of an organic acid, for example trichloroacetic acid or trifluoroacetic acid, the hydroxy groups of the alcohol can optionally be converted simultaneously to the corresponding acyloxy group, for example trifluoroacetoxy.

When R ⁴ 'in the compound of formula (V) is cyano or amino, these groups can also be converted by treatment with a nitrite such as sodium nitrite in the presence of an acid such as sulfuric acid, which preferably serves simultaneously as a solvent. the carboxyl group is carried out at a temperature of 0 to 50 ° C.

When R ⁴ 'in the compound of formula (V) is, for example, a tert-butoxycarbonyl group, the tert-butyl group can also be cleaved by heat treatment, for example in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane , preferably in the presence of a catalytic amount of an acid, for example p-toluenesulfonic acid, sulfuric, phosphoric or polyphosphoric acid, preferably at the boiling point of the solvent used, for example at a temperature in the range of 40 to 100 ° C.

When R ⁴ 'in the compound of formula (V) is, for example, benzyloxycarbonyl, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at 0 to 50 ° C, for example at room temperature and at a hydrogen pressure of 1 to 5 bar. At the same time, other hydrogen residues may be reduced during hydrogenolysis, for example nitro to amino, benzyloxy to hydroxy, vinylidene to the corresponding alkylidene or cinnamic acid to the corresponding phenylpropionic acid, or they can be replaced by a hydrogen atom, for example halogen hydrogen atom.

For the preparation of compounds of formula (I) in which R ⁴ represents a ΙΗ-tetrazolyl group, the process is carried out by:

d) cleaves the protecting group from a compound of formula (VI) _R 1 X 1? ^- * '

where

R1 to R3 are as defined above and

R ⁴ represents a ΙΗ-tetrazolyl group in the 1 or 3 position protected by a protecting group.

Suitable protecting groups are, for example, triphenylmethyl, the tributylline or triphenyleine residue.

The protecting group used may be cleaved preferably in the presence of a hydrogen halide, preferably hydrogen chloride, in the presence of a base such as sodium hydroxide or an alcoholic solution of ammonia in a suitable solvent such as methylene chloride, methanol, methanol / ammonia, ethanol or isopropanol at temperatures of 0 to 100 ° C; preferably at room temperature or when the cleavage is carried out in the presence of an alcoholic ammonia solution also at a higher temperature, for example at 100 to 150 ° C, preferably 120 to 140 ° C.

The preparation of a compound of formula (1) in which r 4 is a ΙΗ-tetrazolyl group can also be carried out by:

e) to a compound of formula (VII)

R ¹

CW where

R1 to R1 are as defined above, treated with hydrochloric acid or salts thereof.

The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at a temperature in the range of 80 to 150, preferably at 125 ° C. To this end, preferably, the hydrochloric acid is liberated during the reaction from an alkali metal azide, for example sodium azide, in the presence of a weak acid such as ammonium chloride or the tetrazolide salt obtained in the reaction mixture by reaction with hydrochloric acid salts, preferably aluminum azide or tributyltin. They are preferably obtained directly in the reaction mixture by reacting aluminum chloride or tributyltin chloride with an alkali metal azide, for example sodium azide, liberated by acidification with a dilute acid, for example 2N hydrochloric acid or 2N sulfuric acid.

In the preparation of compounds of formula (I) wherein R 2 is imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [1,2-c] pyrimidine -2-yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, or imidazo [2,1-b] thiazol-6-yl, proceed as follows:

f) to a compound of formula (VIII)

NHj (VIII), where one of the symbols

A, B, C or D represents a methine group, optionally substituted by a methyl group or a nitrogen atom, and the others are methine groups or

A and B are methine groups and the chain -C = D- is sulfur, is treated with a compound of formula (IX)

where

R ^1, R 3 and R ^ are as defined and represents a nucleophilic leaving group, e.g. a halogen such as chlorine or bromine.

The reaction is preferably carried out in a solvent or solvent mixture, for example ethanol, isopropanol, benzene, glycol, glycol monomethyl ether, dimethylformamide or dioxane, for example at 0 to 150 ° C, preferably 20 to 100 ° C. However, the reaction can be carried out without the use of a solvent.

In the preparation of compounds of formula (I) wherein R 2 is benzimidazol-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [4] 5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, imidazo [4,5-d] pyridazin-2-yl or purin-8-yl

g) cyclizes a compound of formula (X)

where none, one or two of the symbols

A ¹ , B ¹ , C ¹ or D 1 is a nitrogen atom and the rest are methine groups,

RH is hydrogen, fluoro, methyl or trifluoromethyl, χ2 or γ2 is R13-NH- and the other is of formula

wherein R 1, R 3 and r 4 are as defined above, one of R 13 or R 14 is hydrogen and the other hydrogen, C 1-6. .galkyl or C 3-7 cycloalkyl,

Z 5 and Z ⁶ identical or different represent an amino group optionally substituted or a hydroxy group or a mercapto group, an optionally substituted lower alkyl, or together are O or S, NH, optionally substituted C] _3alkylovým residue, alkylenedioxy or alkylénditioskupinu each having 2 or 3 carbon atoms then, optionally, subsequent reduction of the corresponding N-oxides thus obtained and possible hydrolysis.

The cyclization is preferably carried out in a solvent or a mixture of solvents, for example ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetraline, tetraline, X, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at 0 to 250 ° C, preferably at the boiling point of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid , p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base, for example potassium ethoxide or potassium tert-butoxide. However, the cyclization can also be carried out without the use of a solvent and / or a condensing agent.

In a particularly preferred manner, the reaction is carried out by obtaining a compound of formula (X) in the reaction mixture by reduction of the corresponding o-nitroamino compound, optionally in the presence of a carboxylic acid of formula (XI)

where

R, R 3 and R ⁴ are as defined above, and acylating the corresponding a-diamino compound with a carboxylic acid of formula (XI).

When the reduction of the nitro group is interrupted to give the hydroxylamine, the N-oxide of the compound of formula (I) is obtained by subsequent cyclization, which can then be converted by reduction to the corresponding compound of formula (I).

This subsequent reduction of the obtained N-oxide is preferably carried out in a solvent such as water, a mixture of water and ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformaide by treatment with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium on activated carbon, by treatment with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulfuric, treatment with salts such as ferrous sulfate, stannous chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at 0 to 50 ° C, preferably at room temperature.

The subsequent hydrolysis is preferably carried out by treatment with an acid such as hydrochloric, sulfuric, phosphoric, trichloroacetic acid in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol / ethanol / water / ethanol / water / isopropanol or water and dioxane at a temperature in the range of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture. During hydrolysis in the presence of organic acids, for example trichloroacetic acid or trifluoroacetic acid, the present alcoholic hydroxy groups can be simultaneously converted to the corresponding acyloxy groups, for example trifluoroacetoxy.

In carrying out the reactions described, reactive groups present, for example hydroxy, amino or alkylamino, may be optionally protected during the reaction using conventional protecting groups, which are then cleaved again after the reaction is complete.

Suitable protecting groups for the hydroxyl group include, for example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and the protecting group for amino, alkylamino or imino is acetyl, benzoyl, ethoxycarbonyl or benzoyl.

The optional subsequent cleavage of the protecting group used is preferably carried out by hydrolysis in an aqueous solvent, for example water, in a mixture of isopropanol and water, tetrahydrofuran and water or dioxane and water in the presence of an acid such as hydrochloric or sulfuric acid or alkali metal hydroxide such as sodium hydroxide. or potassium at a temperature of 0 to 100 ° C, preferably at the boiling point of the reaction mixture. The cleavage of the benzyl residue can be advantageously carried out by hydrogenolysis, for example by treatment with hydrogen in the presence of a catalyst such as palladium on activated carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally in the presence of an acid such as hydrochloric acid. 50 ° C, preferably at room temperature and at a hydrogen pressure of 0.1 to 0.7, preferably 0.3 to 0.5 MPa.

The mixture of isomers of the compound of formula (I) thus obtained is optionally separated, preferably by chromatography using a carrier, for example silica gel or alumina.

In addition, the compounds of the formula I obtained can be converted into acid addition salts, in particular their physiologically acceptable salts with inorganic or organic acids, suitable for pharmaceutical use. Suitable acids are, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acids.

In addition, the novel compounds of formula (I) thus obtained, if they contain a carboxyl group or a 1H-tetrazolyl group, can optionally be converted into salts with inorganic or organic bases, preferably into physiologically acceptable salts which are pharmaceutically usable. Useful bases include, for example, sodium hydroxide, potassium hydroxide, cyclohexylatine, ethanolamine, diethanol amine, and triethanolamine.

The compounds of formulas (II) to (XI) which are used as starting materials are partly known from the literature or can be obtained by known methods.

For example, the compound of formula (II) may be obtained by alkylation of the corresponding o-aminonitro compound followed by reduction of the nitro group.

The starting compound of formula (III), (V), (VI), (VII), (IX), (X) or (XII) may be obtained by acylation of the corresponding o-phenylenediamine or acylation of the corresponding o-aminonitro compound followed by reduction of the nitro group; followed by cyclization of the o-diaminophenyl compound thus obtained and, if appropriate, subsequent cleavage of the protecting group used, or alternatively cyclization of the corresponding substituted benzimidazole with the corresponding amine or NH-alkylation of the corresponding 1H-benzimidazole, whereupon the mixture of isomers obtained can then be separated by conventional techniques, for example Said starting materials have already been described in part in European patent specification no. 392 317.

For example, it is possible to obtain 2-n-propyl-5- (imidazo [1,2-a] pyridin-2-yl) -3H-benzimidazole by reaction of p-aminoacetophenone with butyric acid followed by nitration, bromination, ring closure with 2 with aminopyridine to give 6-n-butanoylamido-3- (imidazo [1,2-a] pyridin-2-yl) nitrobenzol, which is then converted to the desired title compound by reduction of the nitro group and cyclization.

2-n-propyl-4-methyl-6- (1-methylbenzimidazo-2-yl) -1H-benzimidazole can be obtained by nitration of 3-methyl-4-n-prpanoylamidobenzoic acid methyl ester followed by reduction of the nitro group and cyclization to 2-n -propyl-4-methyl-6-methoxycarbonyl-1H-benzimidazole, which is then converted by treatment with 2-methylaminoaniline with cyclization to give the desired product.

The novel compounds of formula (I) and their physiologically acceptable salts have valuable pharmacological properties. They are angiotensin antagonists, in particular angiotensin II.

In particular, the following compounds have been tested for their biological activity:

A: 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid,

B: 4 '- [[2-n-Propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl , C: 4 '- [[2-n-propyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl,

D: 4 '- [[2-n-butyl-6- (2,3-dimethylmaleimino) -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid hemihydrate,

E: 4 '- [(2-cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

F: 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-5-fluorobenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

G: 4 '- [(2-n-propyl-4-methyl-6- [3- (imidazo [1,2- a] pyrimidin-2-yl) benzimidazol-1-yl) methyl] -2- (1 H-tetrazol-5-yl] biphenyl,

H: 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-yl) methyl ] -biphenyl-2-carboxylic acid,

I: 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl,

J: 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl hydrochloride and

K: 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid.

L: 4 '- [(2-n-propyl-4-methyl-6- [2-oxopiperidin-1-yl] -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl, M: 4 '- [(2-n-propyl-4-methyl-6- [2-pyridyl] benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl,

N: 4 '- [[2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid.

O: 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5- yl) biphenyl,

P: 4 '- [[2-n-propyl-4-methyl-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid.

Q: 4 '- [(2-n-Propyl-4-methyl-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) R) 4 '- [[2-n-propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid.

S: 4 '- [[2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid .

T: 4 '- [(2-n-Propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -benzimidazol-1-yl) methyl] - 2- (1H-tetrazol-5-yl) biphenyl.

In monitoring the efficacy of these agents as angiotensin II antagonists, binding of these agents to the respective receptors has been observed as follows:

Binding to angiotensin II receptors

Rat lung tissue was homogenized in tris buffer containing 50 mmol tris, 150 mmol NaCl, 5 mmol EDTA at pH 7.40, then the material was centrifuged twice at 20,000 g for 20 minutes each. The pellet was then suspended in an incubation buffer containing 50 mmol of tris, 5 mmol of magnesium chloride, 0.2% BSA at pH 7.40, at a ratio of 1:75, based on the water content of the tissue. Each 0.1 ml of homogenate was incubated for 60 minutes at 37 ° C with 50 pM of 125 I- gi _{of an enz} t; _nu [[(NEII, Dreieich, Germany) at increasing concentrations of test substance in a total volume of 0.25 ml. Incubation was terminated by rapid filtration through a glass fiber filter. The filter was washed with 4 ml of ice buffer containing 25 mmol of tris, 2.5 mmol of magnesium chloride, 0.1% BSA at pH 7.40. Bound radioactivity was measured by a gamma counter. The corresponding IC 50 value was then determined from dose-response potency.

Said compounds A to S have IC 50 values in the experiment described in the table below.

IC50 (nM)

A3,7

B14,0

C1,2

D20,0

E12,0

F26,0

G3,4

H1,2

I1,7

J20,0

K7,8

L4,1

M5,1

N1,2

O0,45

P1.5

Q1,5

R14,0

S3,8

T2,6

In addition, compounds A, B, C, D, E, and G have also been tested in awake rats with renal hypertension for effect following oral administration, following the usual procedures described in the literature. At a dose of 10 mg / kg of weight, the compounds had the effect of decreasing elevated blood pressure.

No toxic side effects such as no negative inotropic effect and no cardiac rhythm disturbances were observed when the compounds were administered up to 30 mg / kg intravenously. This means that the substances are well tolerated.

Based on their pharmacological properties, the novel compounds of the invention and their physiologically acceptable salts are suitable for the treatment of elevated blood pressure and cardiac insufficiency, further for the treatment of ischemic peripheral blood circulation disorders, cardiac muscle ischemia (angina), myocardium, for the treatment of diabetic nephropathy, glaucoma, diseases of the stomach and intestinal system and bladder.

Further, the novel compounds and their physiologically acceptable salts are useful in the treatment of pulmonary diseases, such as pulmonary edema and chronic bronchitis, to prevent recurrent narrowing of arteries after vascular plastics, to prevent vascular wall thickening after vascular surgery, to prevent arteriosclerosis and diabetic angiopathy. Due to the effect on acetylcholine and dopamine release by angiotensin in brain tissue, the novel angiotensin antagonists are also useful for alleviating central nervous system disorders such as depression, Alzheimer's disease, Parkinson's syndrome, bulimia as well as cognitive impairment.

In order to achieve a corresponding effect in adults, the effective dose for intravenous administration is usually 28 to 100, preferably 30 to 70 mg and for oral administration 50 to 200, preferably 75 to 150 mg, 1 to 3 times daily. The compounds of formula (I) may be administered alone, optionally in combination with other active ingredients, for example blood pressure lowering compounds, diuretic agents and / or calcium antagonists, optionally together with conventional inert carriers and / or diluents, such as corn starch, milk sugar, raw sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric or tartaric acid, water, a mixture of water and ethanol, water and glycerol, water and sorbitol or water and polyethylene glycol, polyethylene glycol, carboxymethylcellulose or fatty substances, for example hardened fats or mixtures thereof, with the compositions used may be tablets, dragees, capsules, powders, suspensions or suppositories.

For the active compound combinations mentioned, for example, Bcndroflumethiazide, Chlorthiazide, Hydrochlorothiazide, Spironolactone, Benzthiazide, Cyclothiazide, Ethacrinic acid, Furosamide, Metopropol, Prazosine, Atenolol, Propranolol, 90i), Hydralazinium hydrochloride, Diclopod, Nifedipine, Nisolcipine and Nitrendipine. The dose of these other active substances is usually at the level of 1/5 of the usually administered lowest dose up to the full usual dose, e.g. 15 to 200 mg for hydrochlorothiazide, 125 to 2000 mg for chlorothiazide, 15 to 200 mg for etacrinic acid, 5 to 80 mg for Furosamide, 20 to 480 mg for Propranol, 5 to 60 mg for Felodipine, 5 to 60 mg for Nifedipine or 5 to 60 mg for Nitrendipine.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example A

4 '- [[2-n-butyl-7- [5- (imidazol-1-yl) pentyloxy] -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid hydrate

0.7 g, 1.15 mmol of 4 '- [[2-n-butyl-7- [5- (imidazol-1-yl) pentyloxy] -4-methyl-benzimidazol-1-yl] methyl tert-butyl ester 1-Biphenyl-2-carboxylic acid was dissolved in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The mixture was then diluted with methylene chloride and shaken with water and saturated aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated in vacuo. The crude product obtained is purified using a silica gel column with a particle size of 0.063-0.02 mm and ethyl acetate, ethanol and ammonia in a ratio of 90: 10: 0.1 as the eluent, and the product is crystallized from acetone. Yield: 0.19 g, 29.9% of theory. M.p .: 185-187 ° C.

H, 7.09; N, 9.85%. Found: C, 72.83; H, 7.19; N, 9.71%. Mass Spectrum: m / e = M ⁺ 550.

Example 1

4 '- [[2-n-Propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was obtained according to the method of Example 1 using 4 '- [[2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2- carboxylic acid and trifluoroacetic acid in dimethylformamide.

Yield: 63.9% of theory. Melting point: 261-263 ° C.

H, 5.87; N, 10.89. Found: C, 76.90; H, 5.85; N, 10.99.

The following compounds can also be obtained in an analogous manner: 4 '- [[2-n-propyl-4-methyl-6- (1-n-propylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2- carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (1-n-hexylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4' - [ [2-n-propyl-4-methyl-6- (1-cyclopropylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4- methyl 6- (1-cyclohexylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid.

Example 2

4 '- [[2-N-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

To a solution of 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2-cyanobiphenyl, 1.60 g, 3.3 mmol. Sodium azide (4.3 g, 66 mmol) and ammonium chloride (3.5 g, 66 mmol) were added in DMF (1 mL) and the mixture was stirred at 140 ° C for 24 h. Water is then added and the resulting precipitate is filtered off with suction. The crude product thus obtained is purified by chromatography on 300 g of silica gel using methylene chloride and 6% ethanol as eluent.

Yield: 900 mg, 51% of theory. Melting point: 228-230 ° C.

H, 5.61; N, 20.80%. Found: C, 73.48; H, 5.55; N, 20.70.

The following compounds were obtained by the method of Example 2: 4 '- [[2-n-propyl-4-methyl-6- (1'-hexylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1) H-Tetrazol-5-yl) biphenyl 1,4 '- [[2-n-propyl-4-methyl-6- (1-cyclobutylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1H- tetrazol-5-yl) biphenyl, 4 '- [[2-n-propyl-4-methyl-6- (1-cyclohexylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1H- tetrazol-5-y 1) b ifeny 1.

Example 3 4 '- [[2-N-propyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product is obtained according to the method of Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 49.0% of theory. Melting point: from 186 DEG C. product sintered. H, 5.77; N, 18.10; S, 5.92%. Found: C, 64.10; H, 5.39; N, 18.01; S, 5.98%. .

Example 4

4 '- [[2-Ethyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl] ethyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained by the method of Example 2 using 4 '- [[2-ethyl-4-methyl-6- (butamsultam-1-yl) -benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide .

Yield: 60.0% of theory.

Melting point: amorphous, sintered from 194 ° C. H, 5.54; N, 18.58; S, 6.08%. Found: C, 63.83; H, 5.66; N, 18.41; S, 5.82%. .

Example 5

4 '- [[2-N-butyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-ylmethyl] -2- (1H-tetrazol-5-yl) benzene

The resulting product was obtained according to the method of Example 2 using 4 '- [[2-n-butyl-4-methyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 48.0% of theory.

Melting point: amorphous; from 183 ° C the product sintered. H, 5.99; N, 17.64; S, 5.77. Found: C, 64.53; H, 5.66; N, 17.63; S, 5.55. .

Example 6 4 '- [[2-N-propyl-4-ethyl-6- (butanesultam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product is obtained according to the method of Example 2 using 4 '- [[2-n-propyl-4-ethyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 27.0% of theory.

Melting point: amorphous, sintered from 189 ° C. H, 5.99; N, 17.64; S, 5.77. Found: C, 64.81; H, 5.68; N, 17.87; S, 5.31. .

Example 7

4 '- [[2-Ethyl-4-ethyl-6- (butanesultam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained by the method of Example 2 using 4 '- [[2-ethyl-4-ethyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield 39.0% of theory.

Melting point: amorphous, sintering from 212 ° C. H, 5.77; N, 18.10; S, 5.92%. Found: C, 64.30; H, 5.51; N, 17.99; S, 5.59. .

Example 8 4 '- [[2-N-propyl-4-isopropyl-6- (butanesulfam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained according to the method of Example 2 using 4 '- [[2-n-propyl-4-isopropyl-6- (butamsultam-1-yl) -benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 22%.

Melting point: amorphous.

H, 6.19; N, 17.21; S, 5.63. Found: C, 65.13; H, 6.10; N, 17.54; S, 5.40. .

Example 9 4 '- [[2-Ethyl-4-isopropyl-6- (butanesulfam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained by the method of Example 2 using 4 '- [[2-ethyl-4-isopropyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 24.0% of theory. Melting point: amorphous, sintered from 289 ° C. H, 5.99; N, 17.64; S, 5.77. Found: C, 64.99; H, 5.71; N, 17.43; S, 5.71. .

Example 10 4 '- [[2-N-propyl-4-trifluoromethyl-6- (butanesulfam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained by the method of Example 2 using 4 '- [[2-n-propyl-4-trifluoromethyl-6- (butamsultam-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 17.0% of theory. Melting point: 199-203 ° C.

H, 4.74; N, 16.46. Found: C, 58.28; H, 4.43; N, 16.22.

Example 11

4 '- [[2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was obtained by the method of Example A using 4 '- [[2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 48.0% of theory. Mp .: 233-235 ° C.

H, 6.10; N, 10.60%. Found: C, 77.10; H, 5.98; N, 10.46.

Example 12 4 '- [[2-N-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) ) biphenyl

The resulting product was obtained according to the method of Example 2 using 4 '- [[2-n-butyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 41.0% of theory. Melting point: 235-237 ° C.

H, 5.84; N, 20.28. Found: C, 73.67; H, 5.81; N, 19.93.

The following compounds can be obtained in an analogous manner to Example 12: 4 '- [[2-n-butyl-4-methyl-6- (1-ethylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-Tetrazol-5-yl) biphenyl, 4 '- [[2-n-butyl-4-methyl-6- (1-cyclopropylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- ( 1H-Tetrazol-5-yl) biphenyl, 4 '- [[2-n-butyl-4-methyl-6- (1-n-pentylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-Tetrazol-5-yl) biphenyl, 4 '- [[2-n-butyl-4-methyl-6- (1-cyclopentylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- ( 1H-Tetrazol-5-yl] biphenyl.

Example 13

4 '- [[2-N-propyl-4-methyl-6- (2-oxo-piperidin-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared according to the method of Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (2-oxopiperidin-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Yield: 51.0% of theory.

Melting point: amorphous, sintered from 140 ° C.

H, 6.18; N, 19.39. Found: C, 71.08; H, 6.22; N, 19.47.

Example 14 4 '- [[2-N-butyl-4-methyl-6- (2-oxo-piperidin-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared by the method of Example 2 using 4 '- [[2-n-butyl-4-methyl-6- (2-oxopiperidin-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Yield 39.0% of theory.

Melting point: amorphous, sintered from 128 ° C. H, 6.40; N, 18.87%. Found: C, 71.44; H, 6.23; N, 18.59.

Example 15

4 '- [[2-N-propyl-4-methyl-6- (2-oxopiperidin-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was obtained using 4 '- [[2-n-propyl-4-methyl-6- (2-oxo-piperidin-1-yl) -benzimidazol-1-yl] ethyl] -2- (2-triphenylmethyl-tetrazole-5). -yl) biphenyl by cleavage of the triphenylmethyl group with a methanolic hydrochloric acid solution.

Yield: 51.0% of theory.

Melting point: amorphous, sintered from 115 ° C. H, 6.18; N, 19.39. Found: C, 71.51; H, 6.39; N, 19.09%.

Example 16

4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the procedure of Example A using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) -benzimidazole] tert-butyl ester. 1-yl] -methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 38.0% of theory.

M.p .: 195-197 ° C after evaporation of the solvent. Melting point: 299 DEG-303 DEG C. after recrystallization from methylene chloride / ethanol (20: 1).

H, 5.64; N, 11.19%. Found: C, 76.55; H, 5.61; N, 10.87%.

Example 17 4 '- [[2-N-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole) 5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 21.0% of theory.

Melting point: from 181 ° C sintered.

H, 5.38; N, 21.36%. Found: C, 73.10; H, 5.24; N, 21.13%.

The following compound can be obtained in an analogous manner to Example 35: 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl.

Example 18

4 '- [[2-n-butyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the procedure of Example A using 4 '- [[2-n-butyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) -benzimidazole] - 1-yl] -methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 51.0% of theory. Melting point: 194-197 ° C.

H, 5.88; N, 10.89. Found: C, 76.81; H, 5.78; N, 10.64.

Example 19 4 '- [[2-N-butyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole) 5-yl) biphenyl

The resulting product was prepared by the method of Example 10 using 4 '- [[2-n-butyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 26.0% of theory.

H, 5.61; N, 20.80%. Found: C, 73.39; H, 5.40; N, 20.92.

Example 20

4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1] tert-butyl ester -yl] methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 47%.

Mp .: 224-226 ° C after evaporation of the solvent. Melting point: 294-297 ° C after recrystallization from methylene chloride / ethanol (20: 1).

H, 5.43; N, 13.96%. Found: C, 74.10; H, 5.31; N, 13.66.

Example 21

4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazole-1] tert-butyl ester methyl-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 43%.

Mp .: 192-195 ° C after evaporation of the solvent. > 300 ° C after recrystallization from methylene chloride / ethanol (20: 1).

SK 279261 Β6

H, 5.17; N, 11.06; S, 6.33 Found: C, 70.97; H, 5.19; N, 10.88; S, 6.09%. .

Example 22 4 '- [[2-N-propyl-4-methyl-6- (imidazo [2,1b] thiazol-6-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole-5- yl) biphenyl

The resulting product was prepared according to the method of Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1b] thiazol-6-yl) benzimidazol-1-yl] methyl] -2 -cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 21.0% of theory.

Melting point: amorphous, sintered from 196 ° C. H, 4.94; N, 21.12; S, 6.04%. Found: C, 67.77; H, 4.94; N, 21.00; S, 5.87%. .

Example 23 4 '- [[2-N-propyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 28.0% of theory.

Melting point: 202-205 ° C.

H, 5.38; N, 21.36. Found: C, 73.01; H, 5.22; N, 21.56%.

The following compounds can be obtained in an analogous manner to Example 23: 4 '- [[2-ethyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1 H-Tetrazol-5-yl] biphenyl, 4 '- [[2-n-butyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5) -yl) biphenyl 1,4 '- [[2-n-propyl-4-methyl-6- (1H-hexyl-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole- 5-yl) biphenyl, 4 '- [[2-n-propyl-4-methyl-6- (1-cyclopropylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] -2- (1H-tetrazol-5-yl) biphenyl, 4 '- [[2-n-propyl-4-methyl-6- (1-cyclohexylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl.

Example 24

4 '- [[2-n-Propyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester and acid trifluoroacetic acid in methylene chloride.

Yield: 43%.

Mp: 239-242 ° C. H, 5.64; N, 11.19. Found: C, 76.55; H, 5.60;

The following compounds can be obtained in an analogous manner to Example 24:

4 '- [[2-ethyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, 4' - [[2-n-butyl-4] methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (1-n-hexylbenzimidazole) 2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (1-cyclopropylbenzimidazol-2-yl) benzimidazol-1 -] - yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (1-cyclohexylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid .

Example 25

4 '- [[2-n-butyl-6- (2,3-dimethylmaleimino) -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid hemihydrate

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-butyl-6- (2,3-dimethyl-maleinimino) -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2- carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 88.9% of theory.

Melting point: 321 to 322 ° C.

H, 6.08; N, 7.92%. Found: C, 72.89; H, 6.16; N, 7.89. C32H31N3O4 * 0.5 H2O (530.62) requires C, 72.43;

Example 26

4 '- [[6- (2,3-Dimethyl-maleimino) -2-n-propyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid hemihydrate

The resulting product was prepared according to the method of Example A using 4 '- [[6- (2,3-dimethyl-maleinimino) -2-n-propyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 75.4% of theory.

Mp .: 329-331 ° C.

H, 5.85; N, 8.13%. Found: C, 72.04; H, 5.84; N, 7.96%.

Example 27

4 '- [[2-n-Propyl-4-ethyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared by the method of Example A using 4 '- [[2-n-propyl-4-ethyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] tert-butyl ester of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 54%.

Melting point: 217-219 ° C.

H, 6.10; N, 10.60. Found: C, 77.12; H, 6.09; N, 10.75%.

Example 28

4 '- [[2-N-propyl-4-ethyl-6- (1-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared by the method of the example using 4 '- [[2-n-propyl-4-ethyl-6- (1-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 15% of theory.

Melting point: 215-217 ° C.

H, 5.84; N, 20.28 Found: C, 73.66; H, 6.02; N, 20.56%.

Example 29

4 '- [[2-Cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-cyclopropyl-4-methyl-6- (1-methyl-1-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] tert-butyl ester biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 52%.

Mp 244-246 ° C.

H, 5.51; N, 10.93. Found: C, 77.75; H, 5.71; N, 10.94.

Example 30

4 '- [[2-Cyclopropyl-4-methyl-6- (1-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-cyclopropyl-4-methyl-6- (1-benzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 59%. Mp 245-247 ° C.

H, 5.26; N, 20.88%. Found: C, 73.95; H, 5.42; N, 20.90%.

Example 31

4 '- [[2-Cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2 tert-butyl ester -carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 63%.

Melting point: 189-191 ° C.

H, 5.74; N, 10.64. Found: C, 77.35; H, 5.92; N, 10.40.

Example 32

4 '- [[2-Cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared according to the method of Example 2 using 4 '- [[2-cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 61%. Melting point: 197-199 ° C.

H, 5.49; N, 20.35 Found: C, 74.12; H, 5.74; N, 20.67%.

Example 33

4 '- [[2-n-Propyl-4-methyl-6- (1-methyl-5-fluorobenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-tert-butyl ester]

methyl-6- (1-methyl-5-fluoro-benzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 34%.

Melting point: 250-252 ° C.

H, 5.49; N, 10.52. Found: C, 74.14; H, 5.64; N, 10.54.

The following compound can be obtained in an analogous manner to Example 33:

4 '- [[2-n-propyl-4-methyl-6- (pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid.

Example 34 4 '- [[2-N-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole- 5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield 16.5% of theory. Melting point: 275 DEG C. dec.

H, 5.38; N, 23.19. Found: C, 68.25; H, 5.50; N, 23.37.

The following compound can be obtained in an analogous manner to Example 34: 4 '- [[2-n-propyl-4-methyl-6- (pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H) tetrazol-5-yl) biphenyl.

Example 35

4 '- [[2-n-Propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl 2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridine)] tert-butyl ester -2-yl) benzimidazol-1-yl] methyl [biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 67%. Melting point: from 240 ° C sintered.

H, 6.39; N, 11.10%. Found: C, 75.94; H, 6.46; N, 11.20%.

The following compounds can be obtained in an analogous manner to Example 35:

4 '- [[2-n-butyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl 2-carboxylic acid 4 '- [[2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-1-yl 2-carboxylic acid.

Example 36 4 '- [[2-N-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-yl] methyl] 2- (lH-tetrazol-5-yljbifenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl)] benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 73.5% of theory.

Melting point: 275 ° C with decomposition.

H, 6.10; N, 21.20. Found: C, 72.40; H, 6.07; N, 21.48.

The following compounds can be obtained in an analogous manner to Example 36:

4 '- [[2-n-butyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2 - (1H-tetrazol-5-yl) biphenyl, 4 '- [[2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl)] ) benzimidazole-l-yl] methyl] -2- (lH-tetrazol-5-yl) biphenyl.

Example 37

4 '- [[2-n-propyl-4-methyl-6- (1-methyl-6-fluorobenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (1-methyl-6-fluoro-benzimidazol-2-yl) -benzimidazole-1] tert-butyl ester -yl] methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 76%.

Melting point: 243-245 ° C.

H, 5.49; N, 10.52. Found: C, 74.74; H, 5.52; N, 10.77. Mass spectrum: m / e = 532.

Example 38

4 '- [[2-n-Propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl tert-butyl ester -2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 52.7% of theory.

Mp .: 292-295 ° C.

H, 5.08; N, 10.45; Cl, 6.63%. Found: C, 71.29; H, 5.21; N, 10.40; Cl, 6.67. C32H27ClN4O2 (535.06) requires C, 71.90; .

Rf = 0.30, using silica gel and methylene chloride / ethanol (19: 1).

Example 39

4 '- [[2-n-Propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) hydrochloride biphenyl

The resulting product was prepared by the method of Example 2 using 4 '- [[2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Yield: 54.8% of theory.

Melting point: from 204 ° C sintered.

H, 4.71; N, 18.85. Cl, 11.85%. Found: C, 62.34; H, 4.97; N, 18.84. 57%.

Rf = 0.20 using silica gel and a 1: 1 mixture of petroleum ether and ethyl acetate with 1% glacial acetic acid.

Example 40

4 '- [[2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

a) 3-Methyl-4-butyrylamino-5-nitroacetophenone

3-Methyl-4-butyrylaminoacetophenone (32.6 g, 148 mmol) was added portionwise to 300 mL of fuming nitric acid with stirring at -15 ° C and then stirred at -15 ° C for 30 minutes. The reaction mixture is poured into 3 liters of ice with stirring, the precipitated crude product is suction filtered, washed with 400 ml of water, dried and purified by recrystallization from a 1: 1 mixture of ethanol and diethyl ether.

Yield: 23.8 g, 61.0% of theory. Rf = 0.32 using silica gel and methylene chloride Rf = 0.48 using silica gel and methylene chloride / methanol 50: 1.

b) 3-Methyl-4-butyrylamino-5-nitro-1-bromoacetophenone

To a solution of 3-methyl-4-butyrylamino-5-nitroacetophenone (23.8 g, 90 mmol) in dichloromethane (900 ml) at room temperature was slowly added dropwise a solution of bromine (16.0 g, 200 mmol) in dioxane (140 ml) at room temperature. complete decolourisation of the reaction mixture occurred. The mixture is stirred for a further 2 hours, evaporated to dryness in vacuo and the residue thus obtained is triturated with 20 ml of a 1: 1 mixture of dichloromethane and diethyl ether and the solid product is filtered off with suction and dried. In a yield of 74% of theory, 23 g of 3-methyl-4-butyrylamino-5-nitro-omega-bromoacetophenone are obtained, which still contains approximately 10% of the starting material. This product was used for the next reaction without purification.

Rf = 0.69 using silica gel and methylene chloride / methanol (50: 1).

Rf = 0.84 using silica gel and methylene chloride / methanol 9: 1.

c) 2-Butyrylamino-3-nitro-5- (imidazol-4-yl) toluene

A solution of 3-methyl-4-butyrylamino-5-nitroomega-bromoacetophenone (6.8 g, 20 mmol) in 20 ml of formamide was heated at 140 ° C for 2 hours. The solution was then cooled, poured into 50 ml of 1N ammonia and stirred for about 15 minutes. The precipitated crude product is filtered off with suction, washed with approximately 50 ml of water and dried. 4.4 g of product are obtained in a yield of 75% of theory which is used for the next reaction without purification.

Rf = 0.29 using silica gel and methylene chloride / methanol 9: 1.

d) 2-Butyrylamino-3-nitro-5- (1-methylimidazol-4-yl) toluene

To a solution of 2-butyrylamino-3-nitro-5- (imidazol-4-yl) toluene (2.5 g, 8.7 mmol) and potassium carbonate dihydrate (5.2 g, 30 mmol) in dimethylsulfoxide (30 ml) was added dropwise at room temperature. Methyl iodide (1.3 g, 9.5 mmol) is added and the mixture is stirred for a further 2 hours. The reaction mixture was poured into 150 ml of water with stirring and the solution was extracted with ethyl acetate (4 x 25 ml). The organic extracts are combined, washed with approximately 30 ml of water, dried and evaporated. The crude product obtained is purified by chromatography on a column of 300 g of silica gel, eluting with a methylene chloride / methanol (30: 1) mixture.

Yield: 640 mg, 24% of theory. Rf = 0.54 using silica gel and methylene chloride / methanol 9: 1.

e) 2-Butyrylamino-3-amino-5- (1-methylimidazol-4-yl) toluene

2-Butyrylamino-3-nitro-5- (1-methylimidazol-4-yl) toluene (640 mg, 2.1 mmol) was hydrogenated in methanol (30 ml) after addition of about 200 mg of 20% palladium on charcoal at room temperature and pressure. of 0.5 MPa. After complete uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The crude product thus obtained was used for the next reaction without further purification.

Yield 600 mg, 100% of theory.

Rf = 0.23 using silica gel and methylene chloride / methanol 9: 1.

f) 2-N-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazole

600 mg, 2.1 mmol of 2-butyrylamino-3-amino-5- (1-methylimidazol-4-yl) toluene were heated to reflux in 10 ml of glacial acetic acid for 1 hour. The reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in 15 ml of water, the solution is basified with ammonia and then extracted with 4 x 10 ml of ethyl acetate. The organic extracts are washed with approximately 15 ml of water, dried and evaporated. The crude product obtained was used for the next reaction without further purification.

Yield 420 mg, 79% of theory.

Rf = 0.37 using silica gel and methylene chloride / methanol 9: 1.

g) 4 '- [[2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester

To a solution of 2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazole (200 mg, 0.79 mmol) and potassium tert-butoxide (90 mg, 0.8 mmol) in dimethyl sulfoxide (5 mL) was added 280 mL. mg, 0.8 mmol of 4'-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for 90 minutes and then poured with stirring into 40 ml of water, extracted with 4 x 10 ml of ethyl acetate. The mixture was washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by chromatography on 100 g of silica gel, eluting with dichloromethane / methanol (30: 1).

Yield: 230 mg, 56% of theory.

Rf = 0.61 using silica gel and methylene chloride / methanol 9: 1.

h) 4 '- [[2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

A solution of 230 mg, 0.44 mmol of 4 '- [[2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2- tert -butyl ester of carboxylic acid and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane are stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in approximately 5 ml of dilute sodium hydroxide, the solution is neutralized with acetic acid, the precipitate formed is suction filtered, washed with water and dried. Yield: 120 mg, 59% of theory. Melting point: 293-295 ° C.

Rf = 0.39 using silica gel and methylene chloride / methanol 9: 1.

The following compounds can be obtained in an analogous manner to Example 40:

4 '- [[2-n-propyl-4-methyl-6- (1-ethylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, 4' - [[2-n] -propyl-4-methyl-6- (1-benzimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (1-Isopropylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylate.

Example 41

4 '- [[2-N-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Yield: 24%.

Mp: 255-257 ° C.

Analysis for C29H28N8 x _H2O (506.62) calculated C 68.75, H 5.97, N 22.12% found C 68.90, H 5.97, N 22.03%.

Rf = 0.24 using 9: 1 silica gel and methylene chloride / methanol.

The following compounds can be obtained in an analogous manner to Example 41:

4 '- [[2-n-propyl-4-methyl-6- (1-ethylimidazol-4-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, acid 4 '- [[2-n-propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, 4' - [[2-n-propyl] -4-methyl-6- (1-isopropyl-limidazol-4-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl.

Example 42

4 '- [[2-N-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-yl] methyl] - 2- (lH-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazole] 1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 21%.

Melting point: amorphous

H, 5.88; N, 21.78. Found: C, 72.01; H, 5.82; N, 21.44.

Rf = 0.27 using silica gel and methylene chloride / ethanol 9: 1.

Example 43

4 '- [[2-n-Propyl-4-methyl-6- (8-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (8-methylimidazo [1,2-a] pyridin-2-yl) -] - benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 87% of theory

Mp .: 295-297 ° C

Analysis for C33H27N7 x _H2O (532.65) calculated C 74.41, H 6.06, N 10.52% found C 74.81, H 6.05, N 10.43%.

Rf = 0.34, using silica gel and methylene chloride / ethanol 9: 1.

Example 44 4 '- [[2-N-propyl-4-methyl-6- (2-pyridyl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared according to the method of Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (2-pyridyl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 56% of theory.

Melting point: from 136 DEG C. with decomposition.

H, 5.71; N, 19.83 Found: C, 72.45; H, 6.01; N, 19.83%.

Example 45 4 '- [[2-N-propyl-4-methyl-6- (8-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H- tetrazol-5-yl) biphenyl

The resulting product was prepared by the method of Example 10 using 4 '- [[2-n-propyl-4-methyl-6- (8-methylimidazo- [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

yield; 19% of the theoretical quantity

Melting point: amorphous

Rf = 0.36, using 9: 1 silica gel and methylene chloride / ethanol.

C33H30N8 (538.61) Mass spectrum: m / e = 538.

Example 46

4 '- [[2-Ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo- [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl- 2-carboxylic acid

The resulting product was prepared by the method of Example 1 using 4 '- [[2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2)] - tert -butyl ester -yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 50% of theory

Rf = 0.16 using 9: 1 silica gel and methylene chloride / ethanol.

Example 47

4 '- [[2-n-Propyl-4-methyl-6- (1-isopropylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (1-isopropylimidazol-4-yl) -benzimidazol-1-yl] methyl] tert-butyl ester of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 84% of theory

Melting point: 285-286 ° C

Rf = 0.55 using silica gel and methylene chloride / methanol 9: 1.

Example 48

4'- [[2-N-propyl-4-methyl-6- (1-isopropylimidazol-4-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 10 using 4 '- [[2-n-propyl-4-methyl-6- (1-isopropylimidazol-4-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Yield: 18% of theory

Melting point: amorphous

Rf = 0.29, using 9: 1 silica gel and methylene chloride / methanol.

C31H32N8 (516.66) Mass spectrum: m / e = 516.

Example 49

4 '- [[2-n-propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The resulting product was prepared according to the method of Example A using 4 '- [[2-n-propyl-4-methyl-6- (1-benzylimidazol-4-yl) -benzimidazol-1-yl] methyl] tert-butyl ester of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Example 50

4 '- [[2-N-propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

The resulting product was prepared as in Example 2 using 4 '- [[2-n-propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and azide of sodium in dimethylformamide.

Any suitable compound of formula (I) may be used in the following examples which illustrate a possible composition of the pharmaceutical compositions, especially those in which R 1 represents a carboxyl or 1H-tetrazolyl group.

Example 51

Ampoules containing 50 mg of active substance in 5 ml of active substance 50 mg potassium dihydrogen phosphate2 mg

Na2HPC> 4 x 2H2O 50mg sodium chloride 12mg water for injections up to 5ml.

Production

Buffer and isotonic agents are dissolved in water. The active substance is added and, after complete dissolution, the solution is made up to the desired volume with water.

Example 52

Ampoules containing 100 mg of active ingredient in 5 ml active ingredient 100 mg methylglucamine 35 mg glucofurol 1000 mg polyethylene glycol-polypropylene glycol copolymer 250 mg water for injections up to 5 ml.

Production

Methylglucamine and the active ingredient are dissolved in the water portion with stirring and heating. After addition of the solvent, the mixture is then made up to volume with water.

Example 53

Tablets containing 50 mg of the active substance active substance 50.0mg calcium phosphate 70.0 mg milk sugar 40.0mg corn starch 35.0mg polyvinylpyrrolidone 3.5mg magnesium stearate 1.5mg

200.0 mg

Production

The active ingredient, dicalcium phosphate, milk sugar and corn starch are uniformly moistened with the polyvinylpyrrolidone solution. The obtained mass is passed through a sieve with a mesh diameter of 2 mm. The material is then dried in a drying oven at 50 ° C, then sieved again.

After the glidant has been added, the granulate is compressed into tablets on a conventional tabletting machine.

Example 54

Dragee, containing 50 mg of active substance active substance 50.0mg lysine 25.0mg milk sugar 60.0mg corn starch 34.0 mg gelatin 10.0mg magnesium stearate 1.0 mg

180.0 mg

Production

The active ingredient is mixed with the excipients and moistened with an aqueous gelatin solution. After sieving and drying, the granulate is mixed with magnesium stearate and pressed into dragee cores.

The cores thus produced are coated by known methods. Coloring agents can be added to the suspension or dragee-forming solution.

Example 55

Dragee, containing 100 mg of active substance active substance 100.0mg lysine 50.0mg milk sugar 86.0mg corn starch 50.0mg polyvinylpyrrolidone 2.8mg microcrystalline cellulose 60.0mg magnesium stearate 1.2mg

350.0 mg

Production

The active ingredient is mixed with the excipients and moistened with an aqueous solution of polyvinylpyrrolidone. The wet mass is passed through a sieve with a 1.5 mm hole diameter and then dried at 45 ° C. After drying, the material is passed through a sieve, and then magnesium stearate is added. The resulting mixture is then pressed into dragee cores.

The cores thus produced are coated by known methods. Coloring agents may be added to the slurry or coating solution.

Example 56

Capsules containing 250 mg of active substance active ingredient 250.0 mg corn starch 68.5 mg magnesium stearate 1.5 mg

320.0 mg

Production

The corn starch and the active ingredient are mixed and moistened with water. The wet mass is passed through a sieve and dried. The dry granulate is sieved again and blended with magnesium stearate. The mixture is filled into hard gelatin size capsules

First

Example 57

Oral suspension containing 50 mg of active substance in 5 ml active ingredient 50.0 mg hydroxyethylcellulose 50.0 mg sorbic acid 5.0mg sorbitol 70% 600.0mg glycerol 200.0mg flavoring 15.0 mg water to 5.0 ml

Production

The distilled water is heated to 70 ° C. Hydroxyethylcellulose is dissolved therein with stirring, the mixture is cooled to room temperature by the addition of a sorbitol-glycerol solution at which sorbic acid, flavorings and the active ingredient are added. The suspension is stirred under vacuum to vent. The 5.0 ml suspension contains a single dose of 50 mg of active ingredient.

Example 58

Suppositories containing 100 mg of active substance active substance 100.0 mg adeps solidus 1600.0 mg

1700.0 mg

Production

The solid fat is melted, and the milled active ingredient is dispersed homogeneously at 40 ° C. The mixture is then cooled to 38 ° C and poured into slightly pre-cooled suppository molds.

Claims (9)

1. Benzimidazole derivatives of the general formula (I) R ¹ Λ ⁴ where R 1 represents a fluorine, chlorine or bromine atom, alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl; and R2 represents a 5-, 6- or 7-membered alkyleneimino or alkenylimino group optionally substituted by one or two alkyl radicals or one tetramethylene or pentamethylene group, the methylene group being optionally replaced by a carbonyl or sulfonyl group, a maleimido group optionally substituted by one or two alkyl groups or one or two phenyl radicals, wherein the substituents may be the same or different, further benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted in the 1-position with an alkyl radical of 1 to 6 carbon atoms, or a cycloalkyl radical, the phenyl radical of the benzimidazole group being optionally further substituted by a fluorine atom, a methyl or trifluoromethyl radical, furthermore an imidazo [2,1-b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5, 6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] 16 -pyrimidin-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [1,2-c] pyrimidin-2-yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imidazo [4,5-b] pyrazin-2-yl , imidazo [4,5-c] pyridazin-2-yl or imidazo [4,5-d] pyridazin-2-yl, pyridyl or imidazolyl, optionally attached at the 1-position via an alkyl group or via a carbon atom of a benzyl group, and the imidazolyl group is additionally optionally substituted in the carbon chain by an alkyl radical, R ³ is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl and R 4 is carboxyl or 1H-tetrazolyl, and salts thereof, in particular salts with inorganic or organic acids or bases, wherein, as is not the case, otherwise, alkanoyl, alkyl or alkoxy radicals each contain 1 to 3 carbon atoms and the cycloalkyl radical contains 3 to 7 carbon atoms. Benzimidazole derivatives of general formula (I) according to claim 1, in which R ¹ represents a chlorine atom, an alkyl of 1 to 3 carbon atoms, or trifluoromethyl a R 2 is a 5-, 6- or 7-membered alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group, a maleimide group optionally substituted by one or two C 1-3 alkyl or phenyl radicals, the substituents being the same or different, benzimidazole-2- or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted in the 1-position by a C 1-8 alkyl or cycloalkyl group, wherein the phenyl residue of the benzimidazole group is optionally further substituted by a fluorine atom, a methyl or trifluoromethyl radical, an imidazo [ 2,1b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [1,2] -c] -pyrimidin-2-yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imidazo [4, 5-b] -pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, or imidazo [4,5-d] pyridazine- 2-yi, pyridyl or A 4-imidazolyl group optionally substituted in the 1-position by a C 1-3 alkyl or benzyl radical, optionally additionally substituted in the carbon chain by an alkyl radical having 1 to 3 carbon atoms, R ³ is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl; and R 4 is carboxyl or 1H-tetrazolyl, and salts thereof with inorganic or organic acids or bases. Benzimidazole derivatives of the general formula (I) according to claim 1, in which R1 is methyl or chlorine; and R ³ represents a 5-, 6- or 7-membered alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group, a maleimido group optionally substituted by one or two alkyl or phenyl radicals, wherein the substituents may be the same or different, benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl, optionally substituted at the 1-position with an alkyl group having 1 to 3 carbon atoms, wherein the phenyl residue of the benzimidazole group is optionally further substituted by a fluorine atom, imidazo [1,2-a] pyridine -2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl or imidazo [2,1-b] thiazol-6-yl, or imidazol-4-yl, substituted in the 1-position with an alkyl radical of 1 to 3 carbon atoms, R ³ represents a C 1 -C 5 alkyl radical or a C 3 -C 5 cycloalkyl radical and R4 represents a carboxyl or 1H-tetrazolyl group, and salts thereof, in particular salts with inorganic or organic acids or bases. The benzimidazole derivatives of the general formula (I) according to claim 1 which are (a) 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid; b) 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, c) 4 '- [[2-n-propyl-4-methyl-6- (butanesulfam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, (d) 4 '- [[2-n-butyl-6- (2,3-dimethylmaleimino) -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid; e) 4 '- [(2-cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, (f) 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-5-fluorobenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid; g) 4 '- [(2-n-propyl-4-methyl-6- [3- (imidazo [1,2- a] pyrimidin-2-yl) benzimidazol-1-yl) methyl] -2- (1) H-tetrazol-5-yl] biphenyl, h) 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid . (i) 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-2-yl) benzimidazol-1-ylmethyl)] - 2- (1H-tetrazol-5-yl) biphenyl, j) 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl, k) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid. l) 4 '- [(2-n-propyl-4-methyl-6- [2-oxopiperidin-1-yl] benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl . m) 4 '- [(2-n-butyl-4-methyl-6- [2-methylbenzimidazol-2-yl] -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl . (n) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid; o) 4 '- [(2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5) -yljbifenyl. P) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazole-) 5-yl) biphenyl, q) 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-6-fluoro-benzimidazol-2-yl) -benzimidazol-1-yl] methyl} -biphenyl-2-carboxylic acid, r) 4 '- [(2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl) methyl] -biphenyl-2 and their salts with inorganic or organic acids or bases. 5. A compound according to claim 1 which is 4 '- [[2-n-propyl-4-methyl-1-6- (1-methyl-benzimidazol-1-yl) -methyl] -biphenyl- 2-carboxylic acid and its salts with inorganic or organic acids or bases. A compound of formula (I) according to claim 1 which is 4 '- [[2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a]] -pyridin-2-yl) -benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid and its salts with inorganic or organic acids or bases. A process for the preparation of the benzimidazole derivatives of the general formula (I) according to claims 1 to 6, characterized in that the process is carried out a) cyclizes a compound of formula (II) R ¹ Y ¹ where R 1 and R ² are as defined above and one of the radicals, χΐ or γΐ, represents a group of the general formula R ⁴ and the other of χΐ or γΐ are a group of formula Z ¹ Z ² - Nh \ / - r3, where R ³ and R ⁴ are as defined in claims 1 to 6 and R 8 represents a hydrogen atom or a group R ³ -CO, where R ³ is as defined above, Z 1 and Z ² are the same or different to represent an amino group, optionally substituted or a hydroxy or mercapto group, optionally substituted by a lower alkyl radical, or Z 1 and Z ² together represent O, S, NH, optionally substituted alkyl radical having 1 to 3 carbon atoms, alkylenedioxy or alkylénditioskupinu each having 2 or 3 carbon atoms, wherein one of R X · or γΐ always represents a group of the general formula R ⁴ or from ¹ of ² - NH - R ³ as defined, then optionally the corresponding N-oxide thus obtained is reduced or (b) to the benzimidazole of general formula (III) I H where R ¹ to R ³ are as defined in Claims I to 6, is treated with a biphenyl compound of formula (IV) R ⁴ where R ⁴ is as defined in claims 1 to 6, Z ³ is a nucleophilic readily cleavable group, or is (c) in the preparation of compounds of formula (I) in which r 4 is a carboxyl group, it converts a compound of formula (V) wherein: R ¹ to R ³ are as defined in claims 1 to 6, and R ⁴ 'means a group which can be converted by hydrogenolysis, thermolysis or hydrogenolysis into a carboxyl group to give the corresponding carboxyl compound, or d) in the preparation of compounds of formula (I) in which R ⁴ is 1H-tetrazolyl, the protecting group is cleaved from the compound of formula (VI) wherein R 1 to R ³ are as defined in claims 1 to 6, and R ⁴ represents a 1 H -tetrazolyl group in the 1 or 3 position, protected by a protecting group, or s e) reacting a compound of formula (VII) in the preparation of compounds of formula (I) in which R ⁴ is 1H-tetrazolyl; R ¹ CS where R ¹ to R ³ are as defined in claims 1 to 6, with hydrazoic acid or one of its salts, or f) in the manufacture of compounds of formula (I) wherein R ² is imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [1,2- c] pyrimidin-2-yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl or imidazo [2,1-b] thiazol-6-yl reacting a compound of formula (VIII),. B B thorn where one of the symbols A, B, C or D represents a methine group or a nitrogen atom and the others are methine groups or A and B represent methine groups and a group -C = D- represents a sulfur atom with a compound of formula (IX) A process for the preparation of a pharmaceutical composition according to claim 7, characterized in that the benzimidazole derivative of the general formula (I) or a salt thereof according to claims 1 to 6 is formulated together with at least one inert carrier and / or diluent. where R 1, R 3 and R ⁴ are as defined in claims 1 to 6 and Z ⁴ is a nucleophilic leaving group, for example a halogen atom, for example chlorine or bromine, or g) in the preparation of compounds of formula (I) wherein R 2 is benzimidazol-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl , imidazo [4,5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, imidazo [4,5-d] pyridazin-2-yl, or purin-8-yl cyclizes the compound of formula (X) End of document where none, one or two of the symbols Al, B1, Cl or D ' is a nitrogen atom and the rest are meth groups, R ¹¹ is hydrogen, fluoro, methyl or trifluoromethyl, one of R 2 or Y 2 is R 13 -NH- and the other of formula R 1, R 3 and R ⁴ are as defined in claims 1 to 6, one of R (13) or R ( ⁴⁾ is hydrogen and the other is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 hydrogen atoms, Z5 and Z6 are identical or different to amino, optionally substituted or hydroxy or mercapto, optionally substituted by amino or lower alkyl, or together form an oxygen or sulfur atom, an imino group optionally substituted by a C1-C3 alkyl group, or Z5 and Z6 together means an oxygen atom or a sulfur atom, an imido group optionally substituted by a C 1-3 alkyl group, an alkylenedioxy- or alkylenedithio group having 2 to 3 carbon atoms, then the optionally obtained N-oxide is reduced and the resulting product is optionally hydrolyzed, then optionally remove the protecting groups introduced during reactions (a) to (g) to protect the reactive groups and / or optionally, the thus obtained mixture of isomers of the compounds of formula (I) is separated into these isomers, and / or the resulting product of formula (I) thus obtained it turns into its salt, in particular to a salt with an inorganic or organic acid or base acceptable from a physiological point of view. A pharmaceutical composition having an angiotensin antagonistic effect, characterized in that it comprises, as its active ingredient, a benzimidazole derivative or a salt of the general formula (1) according to at least one of claims 1 to 6 and optionally at least one inert carrier and / or thinner. Use of the benzimidazole derivatives of the general formula (I) and their salts according to any one of claims 1 to 6 for the production of pharmaceutical compositions having an angiotensin antagonistic effect.