BG62309B2 - Benzimidazoles, medicaments containing them and a process for their preparation - Google Patents

Abstract

The invention relates to benzimidazoles having the generalformulawhere R1 to R4 have the meanings listed in the description, aswell as to a mixture of 1-, 3-isomers and their salts having theproperties. In particular these compounds areangiotensin-II-antagonists.11 claims

Description

EP 0 468 470 A, EP 0 459 136 A and EP 0 420 237 A, which are only a partial publication, as well as EP-A-0 400 835, EP-A-0 399 732 and US-A4 880 804 describes benzimidazoles, which are angiotensin-N-antagonists.

It has now been found that the new benzimidazoles of the general formula

with differing from the benzimidazole residues of 1% as described in those publications, as well as compounds of general formula I in which 1% means a pyridyl or imidazolyl group selected from EP-A-0 400 835 represent even more valuable angiotensin-N- antagonists compared to those known in the literature.

It is therefore an object of the invention to provide novel benzimidazoles of general formula I and their salts, and in particular their physiologically acceptable salts for pharmaceutical use, physiologically acceptable salts of inorganic or organic acids or bases, pharmaceuticals containing these compounds, and a method for their receipt.

In general formula I, the meanings are as follows: R1 represents a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, R1 means one, optionally substituted by one or two alkyl groups, or by a tetramethyl or pentamethyl a 5-, 6- or 7-membered alkyleneimino- or alkynyleneimino group in which one methylene group is substituted with one carbonyl or sulfonyl group, one optionally substituted with one alkyl or phenyl group, a monosubstituted or disubstituted imide group of males a new acid wherein the substituents may be the same or different, one optionally substituted in one place by one alkyl group of 1 to 6 carbon atoms, or by a cycloalkyl group, benzimidazol-2-yl- or 4,5, 6,7-tetrahydro-benzimidazol-2-yl-group, wherein the phenyl nucleus of one of the above-mentioned benzimidazole groups can be further substituted by one fluorine atom, one methyl or trifluoromethyl group, imidazo / 2,1-c (triazol6-yl-, imidazo / 1,2-a) pyridin-2-yl-, 5,6,7,8tetrahydroimidazole / 1,2-a) pyridin-2-yl-, 5,6,

7,8-tetrahydroimidazo (1,2-a) pyridin-2-yl-, imidazo / 1,2-a) pyridin-2-yl, imidazo (4,5-c) pyridin-2-yl-, imidazo- (4,5-c) pyridin-2-yl-, imidazo (1,2-c) pyridin-2-yl, imidazo (1,2-a) pyrazin-2-yl-, imidazo- (1,2- c) pyridazin-2-yl-, purin-8-yl-, imidazo (4,5-c) pyrazin-2-yl-imidazo-4,5-c (pyridazin-2-yl- or imidazo)

4,5-d / pyridazin-2-yl group, one pyridyl group, one optionally attached at one site with one alkyl or benzyl group to one carbon atom, an imidazole group which may be further substituted in the carbon skeleton by one alkyl group, R ₃ means one alkyl group of 1 to 5 carbon atoms or one cycloalkyl group of 3 to 5 carbon atoms and R ₄ means one carboxy or 1H-tetrazolyl group, which, unless otherwise indicated, may contain an alkyl moiety mentioned above typically having 1 to 3 carbon atoms, as is of specified above cycloalkyl moiety typically having from 3 to 7 carbon atoms.

For the values mentioned initially in the definition of R _t to R _3, for example: R ₃ having the meanings of fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl group, R1 is the meaning of 2-oxo-pyrrolidine, 2-oxopiperidine, 2-oxo-piperidine, 2-oxo-hexamethylenimine-, propansultam-1-yl, butanesultam-

1-yl, pentansultam-1-yl, malenecarboximido-,

2-methyl-malenecarboximido, 2-phenyl-malenecarboximido, 2-methyl-3-phenyl-maleicarboximido-, pyridin-2-yl-, 4-methyl-imidazole-

2-yl-, 1-methyl-imidazol-4-yl-, 1-methyl-imidazol-5-yl-, 1-benzyl-imidazol-4-yl-, 1-benzyl-imidazol-5-yl-, 1 , 2-dimethyl-imidazol-4-yl-, 1,2-dimethyl-imidazol-5-yl-, 1-benzyl-

2-methyl-imidazol-4-yl-, 1-benzyl-2-methyl-imidazol-5-yl-, benzimidazol-2-yl-, 1-methylbenzimidazol-2-yl-, 1-ethyl-benzimidazol-2yl-, 1-p-propyl-benzimidazol-2-yl-, 1-isopropyl-benzimidazol-2-yl-, 1-p-butyl-benzimidazol-2-yl-, 1-isobutyl-benzimidazol-2-yl-, 1-p- pentyl-benzimidazol-2-yl-, 1-N-hexyl-benzimidazol-2-yl-, 1-cyclopropyl-benzimidazol-2-yl-, 1-cyclobutyl-benzimidazole-

2-yl-, 1-cyclopentyl-benzimidazol-2-yl-, 1-cyclohexyl-benzimidazol-2-yl-, 5-methylbenzimidazol-2-yl-, 1,5-dimethyl-benzimidazol-2-yl-, 1 , 6-dimethyl-benzimidazol-2-yl-,

1.4- Dimethyl-benzimidazol-2-yl-, 5-fluoro-1methyl-benzimidazol-2-yl-, 6-fluoro-1-methylbenzimidazol-2-yl, 5-trifluoromethyl-benzidazol-2-yl-, 5- trifluoromethyl-1-methyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-1-methyl-benzimidazol-2-yl- , 4,5,6,7-tetrahydro-1-ethylbenzimidazol-2-yl-, 4,5,6,7-tetrahydro-1-butyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro -1-p-hexyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-1-cyclopropyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-1-cyclohexyl-benzimidazol-2-yl , imidazo- (1,2-a) pyrimidin-2-yl-, 5,6,7,8-tetrahydro-imidazo / 1,2-a) pyridin-2-yl-, imidazo / 4,5 -c (pyridin-2-yl-, imidazo) 2,1-c] triazol-6-yl-, imidazo (1,2-c) pyrimidin-2-yl-, imidazo (1,2-a) pyrazine- 2-yl-, imidazo (1,2-c) pyridazin-2-yl-, pyridin-8-yl, imidazo- (4,5-c) pyrazin-2-yl-, imidazo)

A 4.5-c (pyridazin-2-yl- or imidazo) 4,5-d) pyridazin-2-yl group and R ₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, p-pentyl, 1-methyl-butyl, 2-methyl-butyl,

3-methyl-butyl, cyclopropyl, cyclobutyl or cyclopentyl group.

Preferred compounds of the above general formula I are those in which R 1 represents a chlorine atom, an alkyl group of 1 to 3 carbon atoms or a trifluoromethyl group, R 1 represents a 5-, 6- or 7-membered alkyleneimino group in which one methylene group is substituted with one carbonyl or sulfonyl group, one mono- or disubstituted with one alkyl group of 1 to 3 carbon atoms, or with one phenyl group of a maleocarboximidogroup, wherein the substituents may be the same or different, one substituted 1 site with one alkyl group having 1 to 6 carbon atoms or and with one cycloalkyl group of benzimidazol-2-yl- or 4,5,6,7-tetrahydro-benzimidazol-2-yl-group, wherein the phenyl nucleus of the above benzimidazole groups can be further substituted by a fluorine atom , one methyl group or trifluoromethyl group, one imidazo (2,1-c) triazol-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-c (pyridin-2-yl-, imidazo / 4,5-c) -pyridin2-yl-, imidazo (1,2-c) pyrimidin-2-yl-, imidazo (1,2-a) -pyrazin-2-yl-, imidazo / 1,2-in / pyridazin-2-yl-, pyrin-8-yl-, imidazo / 4,5-in / pyrazin-2-yl-, imidazo / 4,5 -c) pyridazin-2-yl- or imidazo (4,5-d) pyridazin-2-yl-group, pyridyl group or substituted in one place with one alkyl group of 1 to 3 carbon atoms or with one gasoline group, imidazol-4-yl-group which may be further substituted in the carbon skeleton by one alkyl group of 1 to 3 carbon atoms, R ₃ means one alkyl group of 1 to 5 carbon atoms, one cycloalkyl g a drop of 3 to 5 carbon atoms and R ₄ means a carboxy or 1 H tetrazolyl group, and salts thereof with inorganic or organic acids and bases. Particularly preferred compounds of general formula I are those in which R 1 represents a methyl group or a chlorine atom, R ₂ represents a 5-, 6- or 7-membered alkylene group in which one methylene group is substituted by a carbonyl or sulfonyl group a group, one optionally substituted with one alkyl group of 1 to 3 carbon atoms, or with one phenyl group, a mono- or disubstituted maleincarboxyimidogroup wherein the substituents may be the same or different, one optionally substituted at 1 site with one alkyl group of 1 to 3 carbon atoms, benz imidazol-2-yl- or 4,5,6,7-tetrahydro-benzimidazol-2-yl group, wherein the phenyl nucleus of one of the above benzimidazole groups can be further substituted by one fluorine atom, one 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- or imidazo (2,1-c) triazol-6-yl-group or one substituted in one place with one alkyl group of 1 to 3 carbon atoms of imidazol-4-yl group, R ₃ means one alkyl group of 1 to 5 carbon atoms or one cycloalkyl group of 3 to 5 carbon atoms and R ₄ means a carboxyl or 1 H-tetrazolyl group, and salts thereof with inorganic or organic acids or bases.

The compounds of the invention are prepared by the method described below: 5 a / cyclization of a compound of the general formula

R 1 and R ₂ have the meanings indicated above; one of the residues X ₂ or Y ₂ denotes a group of general formula 15 ”· * 4 and the other residues X ₁ or Υ ₍ denote 20 groups of general formula

R ₃ and R _g have the meanings given above, R _g denotes one hydrogen atom or one- 25 of an R ₂ CO group in which R ₃ has the above meanings, Z ₍ and Z ₂ , which may be the same or different, optionally substituted by amino groups or optionally by a lower alkyl group substituted by hydroxy or 30 mercapto groups or Z ₍ and Z ₂ together denote one oxygen atom or sulfur atom, one optionally substituted by one alkyl group with 1 up to 3 carbon atoms of an amino group, one alkylenedioxy or alkylenedithio group with typically 2 to 3 carbon atoms, at which they say that one of residues X _] and Y denotes a group of general formula

or

and optionally a reduction of the corresponding N-oxide thus obtained.

The cyclization is suitably carried out in a solvent or in a mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or tetralin. an excess of the acylating agent used in the preparation of a compound of general formula II, such as in the corresponding nitrile, anhydride, acid halide, ester or amide, at a temperature of for example between 0 and 250 ° C, preferably at a temperature of of boiling the reaction mixture, optionally in the presence of a condensing agent such as phosphoroxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, polyphosphoric acid, acetic acid, or a base such as potassium ethylate or potassium tert-butylate. The cyclization can also be carried out without solvent and / or condensing agent.

Particularly advantageously, the reaction can be carried out such that a compound of general formula II can be obtained in the reaction mixture by reduction of the corresponding nitroamino compound optionally in the presence of a carboxylic acid of the general formula RjCOOH or by acylation of the corresponding o - diamino compound. Interruption of the reduction of the nitro group to a hydroxyamine degree is obtained after the final cyclization of an N-oxide compound of general formula I. The resulting N-oxide is finally converted by reduction to a corresponding compound of general formula I.

The final reduction of the resulting N-oxide is preferably carried out in a solvent such as water, water-ethanol, methanol, glacial acetic acid, glacial acetic acid ethyl ester or dimethylformamide with hydrogen in the presence of a hydrogenating catalyst such as Raney-nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc in the presence of an acid such as glacial acetic acid, hydrochloric acid or sulfuric acid, with salts such as iron- / N / sulphate, tin / N / chloride or sodium dithionite, or with hydrazo n in the presence of Raney nickel at temperatures between 0 and 50 ° C, but preferably at room temperature.

c) reacting one benzimidazole with the general formula

in which R to R ₃ have the meanings given above with one biphenyl compound of the general formula

wherein R ₄ has the above meanings and Z ₃ denotes a nucleophilic leaving group such as a halogen atom, chlorine, bromine or iodine, or a substituted sulfonyloxy group, such as a methanesulfonyloxy-, phenylsulfonyloxy- or p-toluenesulfonyloxy group.

The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzyl, optionally in the presence of an acid binder, such as sodium carbonate, potassium carbonate, ylate, carbamylate, hydroxybutyrate or pyridine, wherein the latter two can be simultaneously applied as solvents, preferably at a temperature between 0 and 100 ° C, for example at a temperature between room and 50 ° C.

The reaction preferably results in a mixture of 1- and 3-isomers which, if desired, are finally separated, preferably chromatographically, using a single carrier such as silica gel or aluminum oxide into the corresponding 1- and 3- isomers.

c) for the preparation of a compound of general formula I in which R ₄ means a carboxy group: conversion of a compound of general formula

wherein R ₁ to R ₃ have the meanings indicated above and R ₄ 'represents a group converted by hydrolysis, thermolysis or hydrogenolysis to a carboxy group.

The functional derivatives of the carboxy group, such as their unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoeters, amides or anhydrides, the nitrile group or the tetrazolyl group, can be converted to the carboxy group by hydrolysis, 10 tertiary alcohol esters, for example tertiary alcohol, e.g. thermolysis - into a carboxy group and an aralkanol ester, for example, butyl ester by hydrogenolysis can be converted into a carboxy group.

The hydrolysis is carried out appropriately or in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid in the presence of an ox20 new such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, ethanol , water / ethanol, water / isopropanol or water / dioxane at a temperature between -10 ° C and 120 ° C, for example at temperatures between room temperature and the reflux temperature of the reaction mixture. In hydrolysis in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, it is possible in the present case that the hydroxy groups present can be simultaneously converted to the corresponding acyloxy groups, such as the trifluoroacetoxy group.

When R ₄ 'in the compound of general formula V is a cyano or aminocarbonyl group, these groups may be converted by nitrite, such as sodium nitrite, in the presence of an acid such as sulfuric acid, to which it may be applied. at the same time, at temperatures between 0 and 50 ° C, in one carboxy group.

When R ₄ 'in the compound of general formula V denotes, for example, a tert-butyloxycarbonyl group, the tert-butyl group may also be thermally cleaved in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably in the presence of catalytic amounts of acid, such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the reflux temperature of the solvent used, for example at temperatures between 40 and 100 ° C.

When R ₄ 'in the compound of general formula V means, for example, a benzyloxycarbonyl group, the benzyl group may also be cleaved hydrogensitically in the presence of a hydrogenation catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl glacial acetic acid ester, dioxane or dimethylformamide, preferably at a temperature between 0 and 50 ° C, for example at room temperature and a hydrogen pressure of 1 to 5 bar. In the course of hydrogenolysis, it is possible to convert other residues at the same time, for example a nitro group to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group, or a cinnamoyl group to be converted to the corresponding phenylpropionic group, substituted with hydrogen atoms, for example to replace one halogen atom with one hydrogen atom.

d / For the preparation of a compound of general formula I wherein R ₄ is a 1 H-tetrazolyl group:

cleavage of a protected residue from a compound of the general formula

wherein R _p R ₂ and R j have the meanings indicated above and R ₄ 'means a 1-position or 3-site protected moiety with a 1 H-tetrazolyl group protecting residue.

As a protective residue, for example, a triphenylmethyl group, a dibutylcinnamic group.

The cleavage of a protective residue is preferably carried out in the presence of one halogen, preferably in the presence of hydrogen chloride, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol / ammonia, ethanol or ethanol or ethanol or ethanol temperatures between 0 and 100 ° C, but preferably at room temperature, or also if the conversion takes place in the presence of alcoholic ammonia, at elevated temperatures between 100 and 150 ° C, preferably at temperatures between 120 and 140 ° C.

e) For the preparation of a compound of general formula I, in which R ₄ represents an 1H-tetrazolyl group:

Conversion of a compound of the general formula

in which R 1 to R ₃ have the meanings indicated above, with nitric acid or their salts.

The conversion is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150 ° C, but preferably at 125 ° C. It is appropriate here that the nitric acid is liberated either during the conversion of an alkaline azide, for example sodium azide, in the presence of a weak acid such as ammonium chloride, or to be introduced into the reaction mixture when converted with a nitric acid salt, preferably with aluminum azide or tributylcinnamide azide, which may furthermore be conveniently obtained in the reaction mixture by converting aluminum chloride or tributylcinnamic chloride with an alkali azide such as sodium azide. The resulting tetrazolid salt is finally released by acidification with dilute acid such as 2N hydrochloric acid or 2N sulfuric acid.

f) For the preparation of compounds of general formula I, in which R1 has the above meanings of imidazo (1,2-a) pyridin-2-yl-, imidazo / 1,2-a) -2-yl-, imidazo (1,2-c) pyrimidin-2-yl-, imidazo (1,2-a) pyrazin-2-yl-, imidazo (1,2-c) pyridazin-2-yl- or imidazo) 2,1v of the thiazol-6-yl group.

Interaction (conversion) of a compound of the general formula

(VIII) nh ₂ in which one of the residues A, B, C or D means one methyl group substituted with a methyl group, optionally, or a nitrogen atom and the methylene groups usual for the residues A, B, C or D, or A and C usually denotes one methylene group and -C = D - group and one sulfur atom, with one compound of the general formula

wherein R _p R ₃ and R ₄ have the above meanings and Z ₄ denotes a nucleophilic starting group as one halogen atom, such as a chlorine or bromine atom.

The reaction is suitably carried out in a solvent medium or solvent mixture such as ethanol, isopropanol, benzene, glycol, glycol monomethyl ether or dioxane at a temperature of, for example, between 0 and 150 ° C, but preferably at temperatures between 20 and 100 ° C. However, the reaction may also be carried out in the absence of a solvent.

g) For the preparation of compounds of general formula I in which R ₂ has one of the above meanings benzimidazol-2-yl-, imidazo (4,5-c) pyridin-2-yl-, imidazo / 4,5 -c (pyridin-2-yl-, imidazo) 4,5-c-pyridin-yl-, imidazo (4,5-c) pyridazin-2-yl-imidazo (4,5-d) pyridazin-2-yl - orylpyrin-8-yl-groups

Cyclization of a compound of the general formula 11 k ί (X) in which one or two of the residues A _p B _p C, and D denote a nitrogen atom and the remaining parts of A _p B _p C] and E ₍ denote methylene groups, and R _n denotes one hydrogen atom, one methyl group or trifluoromethyl group, one of the residues X ₂ or

Y ₂ represents R ₁₃ -NH-rpyna and the other of residues X ₂ or Y ₂ represents a group of the general formula

wherein R _p R 1 and R ₄ have the meanings indicated above, one of the residues R ₁₃ or R ₁₄ represents a hydrogen atom and the other means a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms. Ζ ₅ and Ζ ₆ , which may be the same or different, denote optionally substituted amino groups or optionally substituted by lower alkyl groups of hydroxy or mercapto groups or и ₃ and Z ₆ together denote an oxygen atom or a sulfur atom, one, optionally substituted with one alkyl group of 1 to 3 carbon atoms, an imino group, an alkylenedioxy or alkylenedithio group with typically 2 to 3 carbon atoms, and in the latter case the reduction of the corresponding N-oxide thus obtained is carried out and optionally finally hydrolysis is also carried out.

The cyclization is suitably carried out in a solvent medium or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or counteractyl compound of general formula X acylating agent, for example in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250 ° C, preferably at reflux temperature The reaction mixture, optionally in the presence of a condensing agent such as phosphoroxychloride, thionyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, or glacial acetic anhydride, also on a base such as potassium ethylate or potassium tert-butylate.

However, cyclization may also take place in the absence of solvent and / or condensing agent.

Particularly advantageously, the reaction is carried out in such a way that a compound of general formula X in the reaction mixture is obtained by reduction of the corresponding o-nitroamino compound, optionally in the presence of a carboxylic acid of general formula

wherein R _p R ₃ and R ₄ have the above meanings or by acylation of the corresponding o-diamino compound with one carboxylic acid of general formula XI.

By interrupting the reduction of the nitro group to the degree of hydroxylamine, the final cyclization of an N-oxide of a compound of general formula I is obtained. The resulting N-oxide is finally converted by reduction into the corresponding compound of general formula I.

The final reduction of the N-oxide thus obtained is preferably carried out in a solvent medium such as water, water / ethanol, methanol, glacial acetic acid, glacial acetic acid ethyl ester or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney-nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc in the presence of an acid such as glacial acetic acid, hydrochloric acid or sulfuric acid, with salts such as ferric (N) sulfate, tin / I / chloride or sodium dithionite, or with hydrazine in the presence is Raney-nickel at temperatures between 0 and 50 °, preferably at room temperature.

The final hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphonic acid, trichloroacetic acid or trifluoroacetic 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 / dioxane at temperatures between -10 ° C and 120 ° C, for example at temperatures between room temperature and the reflux temperature of the reaction mixture. In the case of hydrolysis in the presence of an organic acid such as trifluoroacetic acid or trichloroacetic acid, it is possible, if necessary, to convert the existing alcohol hydroxy groups simultaneously into one corresponding acyloxy group such as, for example, trifluoroacetoxy group.

In the conversion described above, it is possible to optionally protect the available reactive groups such as hydroxy, amine or alkylamino groups upon conversion with conventional protecting groups which, after completion of the conversion, are cleaved again.

The protective residue for one hydroxy group may be mentioned as trimethylsilyl group, acetyl-, benzene group, methyl, ethyl, tert-butyl group, benzyl or tetrahydropyranyl group and as the protective residue for one amino, alkylamino or imino group the acetyl group may be mentioned , the benzyl, ethoxycarbonyl or benzyl groups.

The final cleavage of an applied protecting group is preferably carried out hydrolytically in an aqueous solvent such as in water, isopropanol / water, in tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide at a temperature between 0 and 100 ° C, but preferably at the reflux temperature of the reaction mixture. However, the cleavage of a benzyl moiety is preferably hydrogenolytic, for example with hydrogen in the presence of palladium / charcoal in a solvent such as methanol, ethanol, glacial acetic acid ethyl ester or glacial acetic acid optionally when an acid such as hydrochloric acid is added at temperatures between 0 and 50 ° C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

Separation of the isomeric mixture thus obtained of a compound of general formula I can be carried out, if desired, and preferably by chromatography, by the use of carriers such as silica gel or aluminum oxide.

Further, the compounds of general formula I obtained can be converted into their acid addition salts, especially for pharmaceutical administration, into their physiologically acceptable salts with inorganic or organic acids. Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the compounds of general formula I thus obtained, if they contain a carboxy- or 1H-tetrazolyl group, are eventually optionally converted into their salts with inorganic bases, in particular for pharmaceutical administration, into their physiologically tolerated salts. Basics include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, diethanolamine and triethanolamine. The starting compounds of the general formulas II-XI used are known in part from the literature or can be prepared by methods described in the literature.

For example, a compound of general formula II is prepared by alkylating the corresponding o-amino-nitro compound and carrying out at the end of the reduction of the nitro group.

One used as a starting compound of the general formulas III, VI, VII, IX or X is obtained by acylating the corresponding o-phenylenediamine or the corresponding o-amino-nitro compound, finally reducing the nitro group and cyclizing the o-diaminophenyl thus obtained compound. Optionally, the cleavage of the protective residue used is carried out either by cyclization of the corresponding substituted benzimidazole with the corresponding amine or by NH-alkylation of the corresponding 1H-benzimidazole, whereby the isomer mixture thus obtained can be separated by conventional methods, for example by chromatography . The starting materials mentioned above are partially described in EP-A-0 392 317.

For example, 2-n-propyl-5- (imidazo (1,2-a) pyridin-2-yl) -3H-benzimidazole is obtained by converting p-amino-acetophenone with butyryl chloride, finally nitrating, brominating, cyclizing with 2 -aminopyridine to 6β-butanoylamido-3- (imidazo) 1,2-a (pyridine)

2-yl / -nitrobenzene, and is finally converted by reduction of the nitro group by cyclization into the desired compound or

2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole is obtained by nitration of 3-methyl-

4-n-Butanoyl-amido-benzoic acid, finally reducing the nitro group and cyclizing to 2-n-butyl-4-methyl-6-methoxycarbonyl-1 H -benzimidazole, which is finally converted to the desired compound by cyclization with 2-methylaminoaniline.

The novel compounds of general formula I and their physiologically tolerated salts exhibit valuable pharmacological properties. They are angiotensin-antagonists, in particular angiotensin-β-antagonists.

The following compounds have been tested for their biological action:

A = 4 '- // 2-n-propyl-4-methyl-6- (1-methyl benzimidazol-2-yl) -benzimidazol-1-yl] 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-dimethylmaleoylcarboximino) -4-methylbenzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid semihydrate,

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-fluoro-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl acid,

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

H = 4 '- // 2-n-propyl-4-methyl-6- (5,6,7,8tetrahydro-imidazo) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl) - methyl-biphenyl-2-carboxylic acid

I = 4 '- // 2-n-propyl-4-methyl-6- (5,6,7,8tetrahydro-imidazo) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl) - methyl (-2- (1H-tetrazol-5yl) -biphenyl,

J = 4 '- // 2-n-propyl-4-chloro-6- (methylbenzimidazol-1-yl) -methyl) -2- (1H-tetrachol-5yl) -biphenyl hydrochloride and

N = 4 '- // 2-n-propyl-4-methyl-6- (imidazo) 2,1-b] triazol-6-yl] -benzimidazol-1-yl (methyl) -biphenyl-2-carboxylic acid .

Description of the method Angiotensin II-receptor binding

The tissue (rat lung) was homogenized in Tris buffer (50 mmol tris., 150 mmol sodium chloride, 5 mmol EDTA, pH 7.40) and centrifuged twice for 20 min at 20,000 xg. The final granules were resuspended in incubation buffer / 50 mmol trice, 5 mmol magnesium dichloride, 0.2% BSA, pH 7.40 / 1:75 relative to the wet weight of the tissue. 0.1 ml of homogenate was incubated for 60 min at 37 ° C with 50 pM (1257 - angiotensin 11 (NEN, Dreieich, FRG) and an increasing concentration of the test substance in a total volume of 0.25 ml. The incubation was completed by rapid filtration through a glass fiber filter, the filter was washed with 4 ml of ice-cold buffer (25 mmol rub, 2.5 mmol magnesium chloride, 0.1% BSA, pH 7.40). Radioactivity is detected by a gamma counter. The corresponding IC ₅₀ value is determined from the dose-activity curve.

Substances A through K show the following 1C ₃₀ values according to the test described above:

Substance IC _J0 - [nM] A 3.7 IN 14,0 P 1,2 D 20,0 Well 12,0 F 26,0 Mr 3.4 N. 1,2 I 1.7 J 20,0 K. 7.8

Additionally, compounds A, B, C, D, E and G were tested on awake, renal hypertensive rats after oral administration by methods known in the literature for their activity (action).

In addition, when given the above compounds at a higher dose of 30 mg / kg i.v. no toxic side effects are observed, for example, no inotropic action and no disturbances of the heart rhythm. In addition, the compounds are well tolerated.

Based on their pharmacological properties, the novel compounds and their physiologically tolerated salts are suitable for the treatment of hypertension and heart failure, also for the treatment of ischemic peripheral circulatory disorders, myocardial ischemia (angina), for the prevention of progressive heart failure following infarction myocardium, for the treatment of diabetic neuropathy, glaucoma, gastrointestinal and respiratory diseases.

In addition, the new compounds and their physiologically tolerated salts are suitable for the treatment of pulmonary diseases, for example, inflammation of the lungs and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, for the thickening of the vascular walls after vessel surgery, for the treatment of arteriosclerosis. of diabetic angiopathy. Based on the effects of acetylcholine and dopamine release by angiotensin in the brain, new angiotensin antagonists are suitable for reducing disorders of the central nervous system, such as depression, Alzheimer's disease, Parkinson's syndrome, bulimia, and bulimia, functions.

The dosage required to achieve appropriate action in adults for intravenous administration is preferably from 20 to 100 mg, preferably from 30 to 70 mg, and from oral administration from 50 to 200 mg, preferably from 75 to 150 mg, typically 1 The compounds of the invention of the general Formula I are combined with other active substances, such as blood pressure lowering agents, diuretics and / or calcium antagonists, together with one or more conventional carriers and / or diluents such as corn starch, cane Zaha , microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fats containing substantially substituted substances in common shaving preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The following active substances are also suitable for the above mentioned combinations such as, for example, bendroflutriazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, ethacrylic acid, furosemide, metoprolol, prazosin, atenol, propranodrolol, nicrodipine, nifedipine, nizoldipine, and nitrendipine. Doses of these active substances are appropriate in amounts of 1/5 of the usual recommended dosage up to 1/1 of the usual recommended dosage. This means, for example, 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorotriazide, 15 to 200 mg of ethacric acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg nitrendipine.

The following examples illustrate the invention in more detail.

Example A. 4 '- // 2-n-Butyl-7- (5-imidazol-1-yl) -phenyloxy] -4-methylbenzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid hydrate

Dissolve 0.7 g (1.5 mmol) of 4 '- (2-n-butyl-7- (5-imidazol-1-yl) -phenyloxy) -4-methyl-benzimide azole tert-butyl ester - 1 yl) -methyl) -biphenyl-2-carboxylic acid in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid were added and stirred at room temperature for 12 h. It is diluted with methylene chloride and extracted with water and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained was purified on a silica gel column / grain size: 0.0630.02 mm, glacial acetic acid ester / ethanol / ammonia = 90:10: 0.1 / and crystallized from acetone.

Yield: 0.19 g (29.9% of theory) /

M.P. 185-187 ₀ C C ₃₄ H ₃₈ N 1 O ₃ N H ₂ O Calc. C, 71.81; H, 7.09; N, 9.85; 72.03 8.19 9.71

Mass Spectrum: We - M + 550 Example 1. 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2- carboxylic acid

Prepared in analogy to Example A, starting from 4 '- [(2-n-propyl-4-methyl-6/1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] - tert-butyl ester - biphenyl-2carboxylic acid and trifluoroacetic acid in diethylformamide.

Yield: 63.9% of theory.

M.P. 261-263 ° C

C ₃₃ H _J0 N ₄ O ₂ / 514.60 /

Est. C, 77.02; H, 5.87; N, 10.89

Paul. 76.90 5.85 10.99

The following compounds were prepared analogously to Example 1:

47 (2-n-propyl-4-methyl-6- (1-p-propylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic acid

4 '- // 2-n-propyl-methyl-6- (1-p-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- (cyclohexylbenzimidazol-2-yl) -benzimidazol-1-yl (methyl) -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 1.60 g (3.3 mmol) 47 / 2n-propyl-4-methyl-6- (1-methylbenzimidazol-2yl) -benzimidazol-2-yl) -benzimidazol-1-yl / methyl / -2 -cyano-biphenyl in 50 ml of dimethylformamide was added 4.3 g / 66 mmol / sodium azide and 3.5 g / 66 mmol / ammonium chloride and the mixture was stirred for 24 hours at 140 ° C. Finally, it is mixed with water and the precipitate is sucked off. The crude product thus obtained was purified on silica gel (300 g silica gel, methylene chloride + 6% ethanol / chromatographic).

Yield: 900 mg / 15% of theory / mp: 228230 ° C

C ₃₃ H _M N, / 538.70 /

Calc. C 73.58 N 5.61 N 20.80 Gender: 73.48 5.55 20.70

The following compounds were prepared analogously to Example 2:

4 '- // 2-n-propyl-4-methyl-6/1-p-hexylbenzimidazolyl-2-yl] -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl

47 (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] 11 methyl] -2- (1H-tetrazol-5-yl) biphenyl

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

Prepared analogously to Example 2, starting from 4 '- // 2-n-propyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl) -methyl) -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 49.0% of theory.

M.P. from 186 ° C sintering

C ₂₉ H _{3 I} N ₇ O ₂ S / 541.70 /

Est. C 64.30 H 5.77 N 18.10 S 5.92

Paul. 64.10 5.39 18.01 5.98

Example 4 4 '// 2-ethyl-4-methyl-6- (butanesultam-1-yl) -ethyl-2- (1H-tetrazol-5-yl) -biphenyl

Prepared in analogy to Example 2 of 4 '- [2-ethyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 60.0% of theory.

M.p .: amorphous, from 194 ° C sintering

Calc'd: C 63.74 H 5.54 N 18.58 S 6.08

Ht .: 63.83 5.66, 18.41, 5.82

Example 5 4 '// 2-n-Butyl-4-methyl-6- (butanesultam-1-yl) -benzimidazol 1-yl] -methyl-2 / 1H-tetrazol-5-yl] -biphenyl

Prepared analogously to Example 2 from 4 '- [2-butyl-4-methyl-6- (butanesultam-1-yl) benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 48.0% of theory.

M.P. amorphous, from 183 ° C sintering

C ₃₀ H ₃₃ N, O ₂ S / 555.10 /

Est. C 64.84 N 5.99 N 17.64 S 5.77 Pa. 64.53 5.66 17.63 5.55

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

Prepared analogously to Example 2 of 4 '- [2-n-propyl-4-ethyl-6- (butanesultam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide .

Yield: 27.0% of theory.

M.p .: amorphous from 189 ° sintering

C _m H ₃₃ N ₇ O ₂ S / 555.70 /

Est. C 64.84 N 5.99 N 17.64 S 5.77 Pa. 64.81 5.68 17.87 5.31.

Example 7 4 '// 2-n-propyl-4-ethyl-6- (butanesultam-1-yl) benzimidazol-1-yl] -methyl] -2 / 1H-tetrazol-5-yl] -biphenyl

Prepared analogously to Example 2 of 4 '- [2-n-propyl-4-ethyl-6- (butanesultam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 39.0% of theory.

M.P. amorphous from 212 ° C sintering

C ₂ , H _{3 |} N _? 0 ₂ S / 541.70 /

Calc'd: C 64.30 H 5.77 N 18.10 S 5.92

Ht .: 64.30 5.51 17.99 5.59

Example 8. 4 '- [(2-ethyl-6- (butanesultam-1-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Obtained analogously to Example 2 from 47 (2-n-propyl-4-isopropyl-6- (butanesultam-1-yl) -benzimidazol-1-yl) -methyl) -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 22.0% of theory.

M.P. amorphous

C ₃₁ H _{3 J} N ₇ 0 ₂ S / 569.70 /

Calc. C 65.35 H 6.19 N 17.21 S 5.63 Pol. 65.13 6.10 17.54 5.40

Example 9. 47 (2-ethyl-4-isopropyl-6- (butanesultam-1-yl) benzimidazol-1-yl) -methyl) -2- (1H-tetrazol-5-yl) -biphenyl

Prepared analogously to Example 2 from 4 '- [2-ethyl-4-isopropyl-6- (butanesultam-1-yl) -benzimidazol-1-yl-methyl] -2-cyanophenyl and sodium azide in dimethylforamide.

Yield: 24.0% of theory.

M.P. amorphous, from 209 ° C sintering C ₃ 0 H ₃₃ N ₃₃ N ₇ 0 ₂ S / 555.10 /

Est. C 64.84 H 5.99 N 17.64 S 5.77 Ex .: 64.99 5.71 17.43 5.71

Example 10. 47 (n-propyl-4-trifluoromethyl-6- (butanesultam-1-yl) -benzimidazol-1-yl) -methyl-2- (1H-tetrazol-5-yl) -biphenyl

Prepared analogously to Example 2 of 4 '- [2-n-propyl-4-trifluoromethyl-6-butanesultam-1-yl] -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 17.0% of theory.

M.P. 199-203 ° C

C ₂ H ₂₈ F ₃ N 0 ₂ S / 595.70 /

Calc: C, 58.48; H, 4.74; N, 16.46

Ht .: 58.28 4.43 16.22

Example 11 4 '- // 2-n-Butyl-4-methyl-6/1-methylbenzimidazol-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] - biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 48.0% of theory.

M.P. 233-235 ° C

With _m H „N ₄ 0 ₂ / 528.70 /

Calcd: C, 77.25; H, 6.10; N, 10.60

Ht .: 77.10 5.98 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

Prepared in analogy to Example 2 of 4 '- [2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide

Yield: 41.0% of theory.

M.P. 235-237 «p

C ₃₄ H ₃₂ N, / 552.70 /

Calc'd: C 73.89 H 5.84 N 20.28

Ht .: 73.67 5.81 19.93

The following compounds can be prepared analogously 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

47/2-n-butyl-4-methyl-6- (1-p-phenylbenzimidazol-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 47 (2-n-propyl-4-methyl-6/2-oxo-piperidin-1-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Prepared in analogy to Example 2 of 4 '- [2-n-propyl-4-methyl-6- (2-oxo-piperidin-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano- biphenyl and sodium azide in dimethylformamide.

Yield: 51.0% of theory.

M.P. amorphous, from 140 ° C sintering of _m n _h] N ₇ o /505.60/

Calculated: C 71.26 H 6.18 N 19.39 Calc .: 71.08 6.22 19.47

Example 14 4 '- // 2-n-Butyl-4-methyl-6-2oxo-piperidin-1-yl] -benzimidazol-1-yl] methyl (-2- (1H-tetrazol-5-yl) - biphenyl

Obtained analogously to Example 2 of

4 '- // 2-n-butyl-4-methyl-6- (2-oxo-piperidin-1-yl) -benzimidazol-1-yl] -methyl-2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 39.0% of theory.

M.P. amorphous from 128 ° C sintering

C ₃₁ H ₃₃ N, 0 / 519.70 /

Calc'd: C 71.65 H 6.40 N 18.87

Lat: 71.44 6.23 18.59

Example 15. 4 '- // 2-n-propyl-4-methyl-6/2-oxo-pyridin-1-yl] -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5 -yl / -biphenyl

Obtained from 4 '- // 2-n-propyl-4-methyl6- (2-oxo-piperidin-1-yl) -benzimidazol-1-yl] -methyl] -2- (2-triphenylmethyl-tetrazol-5yl) -biphenyl by cleavage of the triphenylmethyl group by methanolic hydrochloric acid.

Yield: 51% of theory.

M.P. amorphous, from 115 ° C sintering

C _m H ₃₁ N, 0 / 505.60 /

Calc'd C 71.26 H 6.18 N 19.39

Paul. 71.51 6.39 19.09

Example 16. 47 (-2-n-propyl-4-methyl-6) imidazole (1,2-a) pyridin-2-yl) -benzimidazol-1-yl) -methyl) biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- // 2-n-propyl-4-methyl-6- (imidazol / 1,2-a) pyridin-2-yl / benzimidazol-1-yl tert-butyl ester -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)

M.p .: 299-303 ° (methylene chloride / ethanol = 20: 1)

C ₃₂ N _m N ₄ 0 ₂ / 500.60 /

Est. C, 76.78; H, 5.64; N, 11.19

Ht .: 76.55 5.61 10.87

Example 17. 47 (2-n-propyl-4-methyl-6) imidazole (1,2-a) pyridin-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazole- 5-yl / -biphenyl

Obtained analogously to Example 2 from 4 N - (2-n-propyl-4-methyl-6- (imidazo) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl) -methyl) - 2 cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 21.0% of theory.

M.P. from 181 ° C sintered with _{h 2} n ₂₈ N ₈ / 524,60 /

Calc .: C, 73.26; H, 5.38; N, 21.36

Ht .: 73.10 5.24 21.13

Analogously to Example 17, the following compound was obtained:

4 '- // 2-n-propyl-4-methyl-6- (imidazole) 1,2-a (pyridin-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-carboxyl acid.

Prepared analogously to Example A from 4 '- [2-butyl-4-methyl-6 (imidazo) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl] -methyl] - biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 51.0% of theory.

Mp 194-197 ° C

C _and / 514.60 /

Est. C, 77.02; H, 5.88; N, 10.89

Ht .: 76.81 5.78 10.64

Example 19 4 '- // 2-n-Butyl-4-methyl-6- (imidazole) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl] -methyl] -2-1 H-tetrazole -5-yl / -biphenyl

Prepared analogously to Example 2 from 4 '- // 2-n-butyl-4-methyl-6- (imidazo) 1,2-a (pyridin-2-yl) -benzimidazol-1-yl] -methyl-2 -cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 26.0% of theory.

C _and H _m N _g / 538.60 /

Calc .: C, 73.58; H, 5.61; N, 20.80

Ht .: 73.39 5.40 20.92

Example 20 4 '[2-n-propyl-4-methyl-6- (imidazo) 1,2-a] pyridin-2-yl] -benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid.

Prepared analogously to Example A from 4 '- [2-n-propyl-4-methyl6- [imidazo] 1,2-a] pyridin-2-yl] -benzimidazol-1-yl] - methyl-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 47% of theory.

M.p .: 224-226 ° C / after evaporation of the solvent /

M.p .: 294-297 ° C (methylene chloride / ethanol = 20: 1)

C ₃₁ H ₂₇ N, 0 ₂ / 501.60 /

Est. C, 74.23; H, 5.43; N, 13.96

Ht .: 74.10 5.31 13.66

Example 21 4 '- // 2-n-propyl-4-methyl-6 (imidazo) 2,1-b] triazol-6-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid .

Prepared analogously to Example A from 4 '- [2-n-propyl-4methyl-6- (imidazo) 1,2-c] thiazol-6-yl] benzimidazol-1-yl] - methyl-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 43% of theory.

M.P. 192-195 ° C / after evaporation of the solvent /

M.p .:> 300 ° C (methylene chloride / ethanol = 20: 1)

C _m H _and N ₄ 0 ₂ S / 506.64 /

Calc: C 71.12 H 5.17 N 11.06 S 6.33 Ex .: 70.97 5.19 10.88 6.09

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

Prepared analogously to Example 2 from 4 '- [2-n-propyl-4-methyl-6- (imidazo) 2,1-c] thiazol-6-yl] -benzimidazol-1-yl] -methyl] - 2 cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 21% of theory.

M.p .: amorphous, from 196 ° C sintering C _m H _m N _g S / 530.67 /

Calc .: C, 67.90; H, 4.94; N, 21.12; S, 6.04;

Example 23. 4 '- // 2-n-propyl-4-methyl-6 (benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2-1H-tetrazol-5-yl] -biphenyl

Prepared analogously to Example 2 of 4 '- [2-n-propyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide .

Yield: 28% of theory.

M.P. 202-205 ° C

C ₃₂ N _m N, / 542.64 /

Calc'd: C 73.26 H 5.38 N 21.36

Ht .: 73.01 5.22 21.56

The following compounds were prepared analogously to Example 23:

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

4 '- // 2-n-butyl-4-methyl-6- (benzimidazol-2-yl) -bisimidazol-1-yl] -methyl) -2- (1H-tetrazol-5-yl) -biphenyl

4 '- // 2-n-propyl-4-methyl-6- (1-p-hexylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

4 '- // 2-n-propyl-4-methyl-6/1-cyclopropyl-benzimidazol-2-yl] -benzimidazol-1-yl / methyl (-2-1H-tetrazol-5-yl) - biphenyl

4 '- // 2-n-propyl-4-methyl-6- (1-cyclohexyl-benzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2- (1-tetrazol-5-yl) - biphenyl.

Example 24 4 '- [(2-n-propyl-4-methyl-6) benzimidazol-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid.

Prepared analogously to Example A from 4 '- [2-n-propyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 43% of theory.

M.P. 239-242 ° C

C _3J H _and N ₄ 0 ₂ / 500.61 /

Est. C, 76.78; H, 5.64; N, 11.19

Pol.M 76.55 5.60 11.41

The following compounds were prepared analogously to Example 24:

4'- // 2-ethyl-4-methyl-6- (benzimidazol-2yl) -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-p-hexylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl) -phenyl-2-carboxylic acid

4 '- // 2-n-propyl-4-methyl-6- (1-cyclopropyl-2-yl) -benzimidisalo-1-yl] -methyl] -biphenyl-2-carboxylic acid.

4 '- // 2-n-propyl-4-methyl-6- (1-cyclohexyl-benzimidazol-2-yl) -benzimidazol-1-yl (methyl) -biphenyl-2-carboxylic acid

Example 25. 4 '- // 2-n-Butyl-6- (2,3-dimethylmaleoylcarboximino) -4-methyl-benzimidazol-1-yl] -biphenyl-2-carboxylic acid semihydrate

Prepared analogously to Example A from 4 '- [2-n-butyl-6- (2,3-dimethylmaleoylcarboximino) -4-methylbenzimidazol-1-yl] -methanol] -biphenyl-2-carboxylic ester acid and trifluoroacetic acid in methylene chloride.

Yield: 88.9% of theory.

M.P. 321-322 ° C

C ₃₂ H ₃₁ N ₃ 04 x 0.5 H ₂ 0 / 530.62 /

Calc .: C, 72.43; H, 6.08; N, 7.92

Ht: 72.89 6.16 7.89

Example 26 4 '- // 6- (2,3-Dimethylmaleoylcarboxyimino) -2-n-propyl-4-methyl-benzimidazol-1-yl (1-methyl) -biphenyl-2-carboxylic acid semihydrate.

Prepared analogously to Example A from 4 '- [6- (2,3-dimethylmaleoylcarboximino) -2-n-propyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2 tert-butyl ester -carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 75.4% of theory.

M.P. 329-331 ° C

C ₃₁ H ₂₉ N ₃ 0 ₄ x 0.5 H ₂ 0 / 516.60 /

Calc .: C 72.08 H 5.85 N 8.13 Calc .: 72.04 5.84 7.96

Example 27. 4 '- // 2-n-propyl-4-ethyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-n-propyl-4-ethyl6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 64% of theory.

Melting point: 217 - 219 ° C

C ₃₄ H ₃₂ N ₄ 0 ₂ / 528.70 /

Calc .: C, 77.24; H, 6.10; N, 10.60

Ht .: 77.12 6.09 20.56

Example 28. 4 '- // 2-n-propyl-4-ethyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1 yl) -methyl) -2-1 H-tetrazol-5-yl / - biphenyl

Prepared analogously to Example 2 from 4 '- [2-n-propyl-4-ethyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 15% of theory.

M.P. Mp 215-217 ° C

C ₃₄ ^{N with 2 Ν} »/ 552.70 /

Est. C, 73.89; H, 4.84; N, 20.28

Ht .: 73.66 6.02 20.56

Example 29. 4 '- // 2-Cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-cyclopropyl-4methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl tert-butyl ester acid and trifluoroacetic acid in methyl enchloride.

Yield: 52% of theory.

M.p .: 244-246 ° C

C ₃₃ H ₂₈ N ₄ O ₂ / 512.60 /

Calc'd: C 77.32 H 5.51 N 10.93

Overall: 77.75 5.71 10.94

Example 30. 4 '- // 2-Cyclopropyl-4-methyl6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Prepared analogously to Example 2 of 4 '- [(2-cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl) -2-cyano-biphenyl and sodium azide in dimethylformamide .

Yield: 59% of theory.

M.p .: 245-247 ° ^C hh ^H and ^N g / 536,65 /

Calc .: C, 73.86; H, 5.26; N, 20.88

Ht .: 73.95 5.42 20.90

Example 31 4 '- // 2-Cyclobutyl-4-methyl6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 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% of theory.

M.P. 189-191 ° C

C ₃₄ H ₃₀ N, 0 ₂ / 526.60 /

Calc .: C, 77.55; H, 5.74; N, 10.64

Ht .: 77.35 5.92 10.40

Example 32 4 '- // 2-Cyclobutyl-4-methyl6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Prepared analogously to Example 2 of 4 '- [(2-cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2cyano-biphenyl and sodium azide in dimethylformamide .

Yield: 61% of theory.

Melting point: 197 - 199 ° C ^With 4 ^N z ^N g / 550.70 /

Est. C 74.16 H 5.49 N 20.35

Ht .: 74.12 5.74 20.67

Example 33 4 '- // 2-n-propyl-4-methyl-6/1-methyl-5-fluoro-benzimidazol-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl acid

Prepared analogously to Example A from 4 '- [2-n-propyl-4-methyl6- (1-methyl-5-fluoro-benzimidazol-2-yl) -benzimidazol-1-yl] - methyl-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 34% of theory.

M.p .: 250 - 252 ° C

C ₃₃ H ₂₉ FN ₄ 0 ₂ / 532.60 /

Calc'd: C 74.42 H 5.49 N 10.52

Ht .: 74.14 5.64 10.54

Analogously to Example 33, the following compound was obtained:

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 (pyridin-2-yl) -benzimidazol-1-yl] -methyl-2-1 H-tetrazol-5 -yl / -biphenyl.

Prepared analogously to Example 2 from 4 '- [2-n-propyl-4-methyl-6- (imidazo) 1,2-a] pyridin-2-yl] -benzimidazol-1-yl] -methyl-2cyano -biphenyl and sodium azide in dimethylformamide.

Yield: 16.5% of theory.

M.P. from 275 ° C / decomposition /

C ₃₁ H ₂₇ N, x H ₂ 0 / 543.65 /

Calc'd: C 68.49 H 5.38 N 23.19

Ht .: 68.25 5.50 23.37

The following compounds were prepared analogously to Example 34:

(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-tetrahydro-imidazo (1,2-a) -pyridin2-yl) -benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-n-propyl-4methyl-6- (5,6,7,8-tetrahydro-imidazo) 1,2-a] pyridin-2- tert-butyl ester yl) -benzimidazol-1-yl] -methyl) biphenyl-2-carboxylic acid and trifluoroacetic acid and trifluoroacetic acid in methylene chloride.

Yield: 67% of theory.

Melting point: from 240 ° C (sintering)

C _J2 H ₃₂ N ₄ O ₂ / 504.64 /

Calc'd: C 76.16 H 6.39 N 11.10

Ht .: 75.94 6.46 11.20

The following compounds were prepared analogously to Example 35:

4 '- // 2-n-butyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo / 1,2-a) -pyridin-2-yl) -benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid

4 '- // 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazol / 1,2-a) -pyridin-2-yl] -benzyl-16-azazol-1-yl] - methyl-biphenyl-2-carboxylic acid

Example 36. 4 '- // 2-n-propyl-4-methyl-6 (5,6,7,8-tetrahydro-imidazo (1,2-a) -pyridin2-yl) -benzimidazol-1-yl) -methyl) -2- (1H-tetrazol-5-yl) -biphenyl

Prepared analogously to Example 2 from 4 '- // 2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo / 1,2-a) -pyridin-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 73.5% of theory.

M.P. from 275 ° C (decomposition) ^{C 2 H} 32 ^N s / 528.67 /

Calc'd: C 72.70 H 6.10 N 21.20

Ht .: 72.40 6.07 21.48

The following compounds were prepared analogously to Example 36:

47 (2-n-butyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo) 1,2-a] -pyridin-2-yl) -benzimidazol-1 - [- methyl] - 2- (1H-tetrazol-5-yl) -biphenyl

4 '- // 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo) 1,2-a] -pyridin-2-yl] -benzimidazol-1-yl] -methyl (-2-) 1H-tetrazol-5-yl / biphenyl

Example 37 4 '- // 2-n-propyl-4-methyl-6/1-methyl-6-fluoro-benzimidazol-2-yl] -benzimidazol-1-yl] -methyl) -biphenyl-2-carboxyl acid

Prepared analogously to Example A from 4 '- // 2-n-propyl-4-methyl-6- (1-methyl-6-fluoro-benzimidazol-2-yl) benzimidazol-1-yl tert-butyl ester / -methyl-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 76% of theory.

M.P. Mp 243-245 ° C

C ₃₃ H ₂ FN ₄ 0 ₂ / 532.60 /

Calc'd: C 74.42 H 5.49 N 10.52

Ht .: 74.74 5.52 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

Prepared analogously to Example A from 4 '- [2-n-propyl-4-chloro- [1-methylbenzimidazol-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl tert-butyl ester acid and trifluoroacetic acid in methylene chloride.

Yield: 52.7% of theory.

M.P. 292-295 ° C

C ₃₂ H ₂ , C1N ₄ 0 ₂ / 535.06 /

R _f value: 0.30 [silica gel, methylene chloride / ethanol = 19: 1]

Calc .: C 71.90 H 5.08 N 10.45 C1 6.63 Ex .: 71.29 5.21 10.40 6.76

Example 39 4 '(2-n-propyl-4-methyl-6/1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - biphenyl hydrochloride

Prepared analogously to Example 2 of 47 (2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl) -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 54.8% of theory.

M.P. from 204 ° C sintering with C ₃₂ H ₂₇ ClN _g x HCl (595.55)

R _f value: 0,20 [silica gel, petroleum ether / glacial acetic acid ester = 1: 1 and 1% glacial acetic acid]

Calc .: C 62.55 H 4.71 N 18.85 C1 11.85 Ex .: 62.34 4.97 18.84 11.57

Example 40. 4 '[2-n-Propyl-4-methyl-6/1-methyl-imidazol-4-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid a) 3- methyl-4-butyrylamino-5-nitroacetophenone

32.6 g (148 mmol) of 3-methyl-4-butyrylamino-acetophenone were added portionwise with stirring at -15 ° C to 300 ml of fuming nitric acid and stirred for 30 min at -15 ° C. Then, with stirring, the reaction mixture was poured onto ice, the separated crude product was sucked off, washed with 400 ml of water, dried and recrystallized from ethanol (diethyl ether / 1: 1).

Yield: 23.8 g / 61.0% of theory /

R _f value: 0.32 (silica gel, methylene chloride)

R _f value: 0.48 (silica gel, methylene chloride / methanol = 50: 1) in 3-methyl-4-butyrylamino-5-nitro-bromoacetophenone

To a solution of 23.8 g (90 mmol) of 3-methyl-4-butyryl-amino-5-nitro-acetophenone in 900 ml of dichloromethane was added at room temperature and a solution of 16.0 g / 200 mmol / bromine in 140 was added. ml of dioxane so slowly that complete discoloration of the reaction mixture is achieved. Finally, it was stirred for a further 2 h, then the reaction mixture was concentrated to dryness in vacuo. The resulting residue was triturated with about 20 ml of dichloromethane (diethyl ether (1: 1), aspirated and dried. 23 g (74% of the theol) of 3-methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone are thus obtained, in which about 10% of the starting material is incorporated. The resulting product was further reacted without further purification.

R _f - value: 0.69 / silica gel, methylene chloride / methanol = 50: 1 /

R _f - value: 0.84 (silica gel, methylene chloride / methanol = 9: 1).

with (2-butyrylamino-3-nitro-5- (imidazol-4-yl) -toluene

A solution of 6.8 g / 20 mmol / 3-methyl-4-butyrylamino-5-nitro-co-bromoacetophenone in 20 ml of formamide was heated at 140 ° C for 2 h. The cooled solution was then mixed with about 50 ml of 1N ammonia and stirred for about 15 minutes. The precipitated crude product was sucked off, washed with about 50 ml of water and dried. 4.4 g (75% of theory) of the product are obtained which, without further purification, is further reacted.

R ₍ - value: 0.29 / silica gel, methylene chloride / methanol = 9: 1 / d) 2-butyrylamino-3-nitro-5- (1-methyl imidazol-4-yl) -toluene

To a solution of 2.5 g (8.7 mmol) of 2-butyrylamino-3-nitro-5- (imidazol-4-yl) -toluene and

5.2 g / 30 mmol / potassium carbonate dihydrate in 30 ml of dimethyl sulfoxide were added dropwise at room temperature 1.3 g / 9.5 mmol / methyl iodide and finally stirred for 2 h. The reaction mixture was then stirred in about 150 ml of water and finally extracted four times with 25 ml of glacial acetic acid. The organic extracts were washed with about 30 ml of water, dried and concentrated. The crude product thus obtained was purified by column chromatography (300 g silica gel, solvent: methylene chloride / methanol - 30: 1).

Yield: 640 mg / 24% of theory /

Rf value: 0.54 (silica gel, methylene chloride / methanol = 9: 1) e) 2-butyrylamino-3-amino-5- (1-methylimidazol-4-yl) -toluene

640 mg (2.1 mmol) of 2-butyrylamino-nitro-5- (1-methyl-imidazol-4-yl) -toluene are hydrogenated in 30 ml of methanol after the addition of about 200 mg of palladium / charcoal / 20% at room temperature. and a hydrogen pressure of 5 bar /. After complete absorption of hydrogen, the catalyst is filtered off and the filtrate is concentrated. The crude product thus obtained is further reacted without further purification.

Yield: 600 mg / 100% of theory /

Rf value: 0.23 (silica gel, methylene chloride / methanol = 9: 1) f / 2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazole

600 mg (2.1 mmol) of 2-butyrylamino-amino-5- (1-methyl-imidazol-4-yl) -toluene were heated for 1 hour in 10 ml of glacial acetic acid as counter-current. It is then evaporated to dryness in vacuo, the residue is mixed with about 15 ml of water, basified with ammonia and extracted four times with 10 ml of ethyl acetate. The organic extracts were washed with about 15 ml of water, dried and concentrated. The crude product thus obtained is further reacted without further purification.

Yield: 420 mg / 79% of theory /

Rf value: 0.37 (silica gel, methylene chloride / methanol = 9: 1 / g / tert-butyl ester of 4 '- // 2-n-propyl-4-methyl-6- / 1-methyl-imidazole-4 -yl (-benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic acid

To a solution of 200 mg (0.79 mmol) of 2n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazole and 90 mg (0.8 mmol) of potassium tert. butylate in 5 ml of dimethyl sulfoxide was added 280 mg (0.8 mmol) of 4'bromomethyl-biphenyl-2-carboxylic acid tert -butyl ester and the mixture was stirred at room temperature for 90 min, then stirred for about 40 min. ml of water and extracted four times with 10 ml of acetic anhydride each. The organic extracts were then washed with 10 ml of water, dried and concentrated to dryness. The crude product thus obtained is purified on a chromatographic column (100 g silica gel, solvent: dichloromethane / methanol = 30: 1).

Yield: 230 mg / 56% of theory /

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1 / h) 4'-2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) -benzimidazol-1-yl (b-methyl) 18 biphenyl-2-carboxylic acid

Solution of 230 mg (0.44 mmol) 4 '- (2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl tert-butyl ester -biphenyl-2-carboxylic acid and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane were stirred overnight at room temperature and finally concentrated to dryness. The residue was dissolved in dilute sodium hydroxide solution, about 5 ml, and the solution was neutralized with acetic acid, the resulting precipitate was sucked off, washed with water and dried.

Yield: 120 mg / 59% of theory / mp: 293-295 ° C

Rf value: 0.39 / silica gel, methylene chloride / methanol = 9: 1 /

The following compounds were prepared analogously to Example 40:

4 '- // 2-n-propyl-4-methyl-6- (1-ethyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

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

4 '- // 2-n-propyl-4-methyl-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Example 41. 4 '- // 2-n-propyl-4-methyl-6/1-methyl-imidazol-4-yl] -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5- or N-biphenyl

Prepared analogously to Example 2 from 4 '- // 2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl) -2-cyano- biphenyl and sodium azide in dimethylformamide.

Yield: 24% of theory.

Mp: 255 - 257 ° C

Rf value: 0.24 (silica gel, methylene chloride / methanol = 9: 1 / ^C 29 ^H 28 ^N 8 ^{X H} 2 ⁰ / 506.62)

Calc .: C, 68.75; H, 5.97; N, 22.12;

The following compounds were prepared analogously to Example 41:

4 '- // 2-n-propyl-4-methyl-6- (1-ethyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl) -2- (1H-tetrazol-5-yl) / -biphenyl

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-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) / -biphenyl

Example 42. 4 '- // 2-ethyl-4-methyl-6- /

5,6,7,8-tetrahydro-imidazo (1,2-a) pyridin-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl-biphenyl)

Prepared analogously to Example 2 from 4 '- // 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo (1,2-a) pyridin-2-yl) -benzimidazol-1-yl) -methyl / -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 21% of theory.

Melting point: amorphous

Rf value: 0.27 (silica gel, methylene chloride / ethanol = 9: 1)

C ₃₁ H _z N _g / 514.64 /

Calc'd: C 72.35 H 5.88 N 21.78

Ht .: 72.01 5.82 21.44

Example 43 4 '- // 2-n-propyl-4-methyl-6/8-methyl-imidazo [1,2-a] pyridin-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl -2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-n-propyl-4-methyl-6- (8-methyl-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: 87% of theory.

Mp: 295 - 297 ° C

Rf value: 0.34 (silica gel, methylene chloride / ethanol = 9: 1)

C ₃₃ Η _Μ N ₄ 0 ₂ x H ₂ O / 532.65 /

Calc'd: C 74.41 H 6.06 N 10.52

Ht .: 74.81 6.05 10.43

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

Prepared analogously to Example 2 from 4 '- [(2-n-propyl-4-methyl-6- (2-pyridyl) -benzimidazol-Kil] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 56% of theory.

Melting point: from 136 ° C (decomposition)

C _x H ₂₇ N, x H ₂ O / 494.60 /

Calcd: C, 72.85; H, 5.71; N, 19.83

Lat: 72.45 6.01 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-tetrazole- 5-yl / -biphenyl

Prepared analogously to Example 2 of 4 '- // 2-n-propyl-4-methyl-6- (8-methyl-imidazo)

1,2-a (pyridin-2-yl) -benzimidazol-1-yl] -methyl) -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 19% of theory.

M.P. amorphous 5

Rf value: 0.36 (silica gel, methylene chloride / ethanol = 9: 1)

C3 ^H3 N, (538.61) Mass spectrum: m / e = 538

Example 46. 4 '- / 2-ethyl-4-methyl-6- (5.6, 10)

7,8-tetrahydro-imidazo (1,2-a) -pyridin-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- / 2-ethyl-4-methyl-6- / 15 tert-butyl ester

5,6,7,8-tetrahydro-imidazo (1,2-a) pyridin-2yl) -benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 50% of theory. 20

M.p .:> 300 ° C

Rf value: 0.16 (silica gel, methylene chloride / ethanol = 9: 1)

Example 47 4 '- // 2-n-propyl-4-methyl-6/1-isopropyl-imidazol-4-yl] -benzimidazol-1-yl} -methyl) -biphenyl-2-carboxylic acid analogously to Example A of 4 '- // 2-n-propyl-4-methyl6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic ester acid 30 and trifluoroacetic acid in methylene chloride.

Yield: 84% of theory.

Mp: 285-286 ° C

Rf value: 0.55 / silica gel, methylene chloride / methanol = 9: 1/35

Example 48 4 '- // 2-n-propyl-4-methyl-6/1-isopropyl-imidazol-4-yl] -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) N-biphenyl Prepared analogously to Example 2 of 4 '- // 2-n-propyl-4-methyl-6- (1-isopropyl-imi-40-dazol-4-yl) -benzimidazol-1-yl] -methyl N-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 18% of theory.

M.p .: amorphous 45

Rf value: 0.29 / silica gel, methylene chloride / methanol = 9: 1 /

C ₃ H ₃₂ N, / 516,66 / MS: m / e = 516

Example 49. 4 '- // 2-n-Propyl-4-methyl-6-50 S -benzyl-imidazol-4-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared analogously to Example A from 4 '- [2-n-propyl-4-methyl-6- (1-benzyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -biphenyl-tert. butyl ester and trifluoroacetic acid in methylene chloride.

Example 50 4 '- [(2-n-propyl-4-methyl-6/1-benzyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazole-5- or N-biphenyl

Prepared analogously to Example 2 of 4 '- [2-n-propyl-4-methyl-6- (1-benzyl-imidazol-4-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Example 51 Ampoules containing 50 mg of active substance per 5 ml

Active substance 50 mg KN ₂ PO ₄ 2 mg Na ₂ NRO ₄ x 2H _a O 50 mg Sodium chloride 12 mg

Water for injection of more than ml

Receiving. Powders and isotopes are dissolved in some of the water. The active substance is added and the solution is brought to the indicated volume with water.

Example 52 Ampoules containing 100 mg of active substance per 5 ml

Active substance 100 mg Methylglucamine 35 mg Glycofural 1000 mg

Polyethylene glycol-polypropylene glycol-block polymer 250 mg

Water for injection of 5 ml or more

Receiving. Methylglucamine is dissolved in some of the water and the active substance is added to the solution with stirring and heating. After the solvent was added with water, the solution was adjusted to the indicated volumes.

Example 53 Tablets containing 50 mg of active substance

Calcium phosphate 70,0 mg Milk sugar 40,0 mg Cornstarch 35,0 mg Polyvinylpyrrolidone 3,5 ml Magnesium stearate 1.5 mg

200,0 mg

Receiving. The active substance, calcium phosphate, milk sugar and corn starch are wetted simultaneously with an aqueous solution of polyvinylpyrrolidone. The mixture was fed to a 2 mm sieve and dried in a drying oven with circulating air at 50 ° C and filtered again.

After blending the lubricants, the granulate is compressed into tablets.

Example 54 Dragees containing 50 mg of active substance and corn starch and moistened with water. The wet mass is filtered and dried. The dried granulate is filtered and mixed with magnesium stearate. The final mixture was placed in hard capsules of size 1.

Example 57 Oral suspensions containing 50 mg of active substance per 5 ml

Active substance 50,0 mg Lysine 25,0 mg Milk sugar 60,0 mg Cornstarch 34,0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mg 180,0 mg

Receiving. The active substance is mixed with an auxiliary agent and moistened with an aqueous solution of gelatin. After drying and drying, the granulate is mixed with magnesium stearate and pressed onto dragees.

The dragees thus obtained can be coated in a known manner. Suspensions and solutions can also be added a dye.

Example 55 Dragees containing 100 mg of active substance

Active substance 100.0 mg

Lysine 50.0 mg

Milk sugar / lactose / 86.0 mg

Corn starch 50.0 mg

Polyvinylpyrrolidone 2.8 mg

Microcrystalline cellulose 60.0 mg

Magnesium stearate 1.2 mg

350,0 mg

Receiving. The active substance is mixed with an auxiliary agent and wetted with an aqueous solution of polyvinylpyrrolidone. The wetted mass was filtered through a 1.5 mm sieve and dried at 45 ° C. After drying, it is filtered again and mixed with magnesium stearate. The resulting mixture was pressed onto dragees.

The dragees thus obtained can be coated in a known manner. Suspensions and solutions can also be added a dye.

Example 56 Capsules containing 250 mg of active substance

Active substance 250.0 mg

Corn starch 68.5 mg

Magnesium stearate 1.5 mg

320,0 mg

Receiving. Mix the active ve-

Active substance 50,0 mg Hydroxyethyl cellulose 50,0 mg Sorbic acid 5.0 mg Sorbitol 70% 600,0 mg Glycerin 200,0 mg Aroma 15.0 mg Water 5,0 ml Receiving. Distilled water is heated

thaw to 70 ° C. Hydroxymethylcellulose is dissolved therein with stirring. By adding sorbitol solution and glycerin, it was cooled to room temperature. At room temperature, sorbic acid, aroma and active substance are added. In order to vent, the suspension is aspirated with stirring. One dose = 50 mg is contained in 5.0 ml.

Example 58 Suppositories containing 100 mg of active substance

Active substance 100.0 mg

Adeps solidus 1600.0 mg

1700.0 mg

Receiving. The solid fat melts. The milled active substance is added to the melt at 40 ° C and dispersed. Cool to 38 ° C and pour into pre-cooled suppository molds.

Claims (11)

Claims 1. Benzimidazoles of the general formula wherein R 1 represents a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl-, fluoromethyl-, difluoromethyl- or trifluoromethyl group, R ₂ means optionally substituted by one or two alkyl groups or by one tetramethylene or pentamethylene group, 5-, 6 or 7-membered alkyleneimino or alkenylene21 group, in which one methylene group is substituted with one carbonyl or sulfonyl group, one optionally substituted with one alkyl or phenyl group, mono- or a disubstituted maleincarboxyimido group, wherein 5 the substituents may be the same or different, one optionally substituted at the 1- position by an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group, benzimidazol-2-yl or 4,5,6,7-tetrahydro-benz- 10 a zimidazol-2-yl group, wherein the phenyl core of the benzimidazole groups mentioned above is further substituted with a fluorine atom, one methyl or trifluoromethyl group, one imidazo (1,2-c) triazol-6-yl-, im - 15 Dazo (1,2-a) pyridin-2-yl-, 5,6,7,8-tetrahydroimidazo (1,2-a) pyridin-2-yl, imidazo (1,2-a) pyridin-2 -yl, imidazo (4,5-c) pyridin-2-yl-, imidazo / 4,5-c / py idin-2-yl-, imidazo (1,2-c) pyridin-2-yl-, imidazo (1,2-a) pyrazin-2-yl-, 20-imidazo (1,2-c) pyridazin-2- yl-, purine-8-yl-, imidazo (4,5-c) pyrazin-2-yl-, imidazo (4,5-c) pyridazin-2-yl- or imidazo (4,5-d) pyridazine A 2-yl group, one pyridine group, or one optionally substituted first with a single alkyl group or a benzyl group linked to a carbon atom by an imidazole group, which may be further substituted in the carbon skeleton by one alkyl group, R 1 represents an alkyl group of 1 to 5 carbon atoms or a cycloalkyl group of 3 to 5 carbon atoms and R ₄ represents a carboxy or lH-tetrazolilgrupa, and salts thereof with inorganic or organic acids and bases, wherein, unless otherwise stated, one referred to in 35 above alkyl portion typically contains 1 to 3 carbon atoms, and one cycloalkyl moiety above typically contains 3 to 7 carbon atoms. Benzimidazole of general formula I according to claim 1, wherein R1 represents a chlorine atom, an alkyl group of 1 to 3 carbon atoms or one trifluoromethyl group, R1 represents a 5-, 6-, or 7-membered alkyleneimino group , in which one methylene group is 45 substituted with one carbonyl or sulfonyl group, one mono- or disubstituted with one alkyl group having 1 to 3 carbon atoms, or with one phenyl group a maleincarboximidogroup, wherein the substituents may be 50 identical or different, one substituted with 1 to one alkyl group of 1 to 6 carbon ether atoms or one cycloalkyl group of benzimidazol-2-yl- or 4,5,6,7-tetrahydro-benzimidazol-2-yl group, wherein the phenyl nucleus of one of the above benzimidazyl groups can be further substituted by fluorine atom, one methyl group or trifluoromethyl group, one imidazo (1,2-c) thiazol-6-yl-, imidazo (1,2-a) pyridin-2-yl-, 5,6,7,8-tetrahydroimidazole) 1,2-a) pyridin-2-yl-, imidazo (1,2-a) -pyrimidin-2-yl-, imidazo (4,5-c) 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 (1,2b) pyridazin-2-yl -, pyridin-8-yl, midazo (4,5-c) pyridin-2-yl-, imidazo (4,5-c) pyridazin-2-yl- or imidazo (4,5-d) pyridazin-2-yl group, one pyridyl group, or one substituted at the 1-position with one alkyl group of 1 to 3 carbon atoms or with one benzyl ί group, an imidazol-4-yl group, which may be further substituted in the carbon skeleton by one alkyl group with 1 to 3 carbon atom, R1 denotes one alkyl group having 1 dof 5 carbon atoms or one cycloalkyl group of 3 to 5 carbon atoms, and R ₄ meansί, one carboxy group or 1H-tetrazolyl group, ί and their salts with inorganic or organic acids and bases. Benzimidazoles of the general formula I according to claim 1, in which R _t represents one methyl group or one chlorine atom, R ₁ means one 5-, 6- or 7-membered alkyleneimino group in which one methylene group can be substituted by one carbonyl group or sulfonyl group, one optionally mono- or di-substituted alkyl group of 1 to 3 carbon atoms or one phenyl group, maleicarboximidogroup wherein the substituents may be the same or different, one optionally substituted by 1 place with one alkyl group having 1 to 3 carbon a ohm, benzimidazol-2-yl- or 4,5,6,7-tetrahydro-benzimidazol-2-yl-group, wherein the phenyl nucleus of one of the above-mentioned benzimidazole groups can be further substituted by one fluorine atom, with one imidazo (1,2-a) pyridin-2-yl-, 5,6,7,8tetrahydro-imidazo (1,2-a) -pyridin-2-yl-, imidazo (1,2-a) pyrimidine -2-yl- or imidazo (1,2-c) triazol-6-yl-group, or one substituted at the 1-position by an alkyl group of 1 to 3 carbon atoms, imidazol-4-yl-group, R ₃ I means one alkyl group of 1 to 5 carbon atoms or one cycloalkyl group of 3 to 5 carbon atoms and R ₄ denotes aa a carboxylic or 1H-tetrazolyl group, and salts thereof with inorganic or organic acids or bases. 4. Benzimidazoles of general formula I according to claim 1, as follows: 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) N-tetrazol-5-biphenyl, c (4 '- [(2-n-propyl-4-methyl-6- (butanesultam-1-yl) -benzimidazol-1-yl) -methyl] -2- -yl) -biphenyl, d / 4 '- // 2-n-butyl-6- (2,3-dimethylmaleinecarboximino) -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- p-propyl-4-methyl-6- [1-methyl- 5-fluoro-benzimidazol-2-yl] -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid, g (4 '- [2-n-propyl-4-methyl-6- (imidazo) - 1,2-a (pyrimidin-2-yl) -benzimidazol-1-yl (methyl) -2- (1H-tetrazol-5-yl) -biphenyl, h / 4 '- // 2-p-propyl- 4-methyl-6- (5,6,7,8tetrahydro-imidazo- (1,2-a) pyridin-2-yl) benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic acid, i / 4 '- // 2-n-propyl-4-methyl-6- (5,6,7,8tetrahydro-imidazo- (1,2-a) pyridin-2-yl) benzimidazol-1-yl) -methyl) - 2- / 1H-tetrazole- 5-yl] -biphenyl, N-4 '- [(2-p-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1) N-tetrachol-5-yl] -biphenyl, k (4 '- // 2-n-propyl-4-methyl-6- (imidazo) 2,1-c (thiazol-6-yl) benzimidazol-1-yl] -methyl) -biphenyl-2-2-carboxylic acid, 1/4 '- // 2-ethyl-4-methyl-6- (butanesultan-1-yl) -benzimidazol-1-yl] -methyl) -2- (1H-tetrazol-5-yl) -biphenyl, m / 4' - // 2-n-butyl-4-methyl-6- (1-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-yl) -biphenyl, p / 4 '- // 2-p-propyl-4 -methyl-6- (imidazo) 1.2- [(thiazol-6-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl, q / 4 '- [(2-p-propyl-4-) methyl-6- / 1-methyl- 6-fluoro-2-yl] -benzimidazol-1-yl] -methyl) biphenyl-2-carboxylic acid and N / 4 '- [2-ethyl-4-methyl-6- (5,6,7,8) -tetrahydro-imidazo- (1,2-a) pyridin-2-yl] -benzimidazol-1-yl] -methyl) -biphenyl-2-carboxylic acid, and their salts with inorganic or organic acids and bases. 5. 4 '- // 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid and its inorganic salts or organic acids and bases. 6. 4 '- // 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo (1,2-a) -pyridin-2-yl) -benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid. 7. Physiologically tolerated salts of compounds according to at least one of the above claims 1 to 6 with inorganic or organic acids and bases. A medicament comprising one compound according to at least one of claims 1 to 6 or one physiologically tolerated salt according to claim 7 simultaneously with optionally one or more carriers and / or diluents. Use of a compound according to at least one of claims 1 to 7 for the preparation of drugs with angiotensin-antagonistic action. A method for the preparation of a medicament according to claim 8, characterized in that in a non-chemical way a compound according to at least one of claims 1 to 7 is treated with one or more carriers and / or diluents. A process for the preparation of benzimidazoles according to claims 1 to 7, characterized in that a / a compound of the general formula wherein R 1 and R ₂ have the meanings given in claims 1 to 6, one of the residues X ₍ or Y] denote one group of general formula and the other residue X 1 or Y 1 denote one group of general formula V - nor Λξ - R _v wherein Rj and R ₄ have the meanings given in claims 1 to 6, R ₈ means a hydrogen atom or one R ₃ CO-rpyna, wherein R ₃ has the meanings indicated above, Zj and Z ₂ , which may be the same or different, denote optionally substituted amino groups or optionally substituted by a lower alkyl group a hydroxy or mercapto group or T _x and Z ₂ together denote an oxygen or sulfur atom, one in a given a case substituted with an alkyl group of one to 3 carbon atoms, an imino group, an alkylenedioxy or alkylenedithio group with typically 2 or 3 carbon atoms, wherein the residues are X! and W! denote one group of the general formula or ^z and ^z 2 - LV V. is cyclized, and optionally the corresponding N-oxide thus obtained is reduced, or in / a benzimidazole of the general formula wherein R 1 and R ₃ have the meanings given in claims 1 to 6, reacted with a compound of the general formula nucleophilic starting group, or c / to produce one compound of general formula I in which R ₄ means one carboxyl group, one compound of general formula in which R 1 to R ₃ have the meanings given in claims 1 to 6, R ₄ 'means a carboxyl group converted by hydrolysis, thermolysis or hydrogenolysis which combines ynene is converted to the corresponding carboxy compound or d) to obtain a compound of general formula I, in which R ₄ represents one 1H-tetrazolyl group, one protecting group from a compound of general formula in which R _p R ₂ and R 1 are as claimed in claims from 1 to 6 meanings and R ₄ stands for 1-protected or 3-position with one protecting group 1H-tetrazolyl group, cleaves or is / for the preparation of a compound of general formula I, in which R ₄ stands for 1H-tetrazolyl group, a compound of general formula "4 in which R ₄ has the abovementioned meanings claimed ii from 1 to 6 and Z ₃ represents a in which R, to Rj are as defined in claims 1 to 6, is reacted with hydrazoic acid or salts thereof or f / for the preparation of compounds of general formula I, in which R ₂ has the meanings indicated in claims 1 to 6, imidazo (1,2-a) pyridin-2-yl, imidazo (1,2-a) -2-yl-, imidazo / 1,2-c) pyrimidin-2-yl-, imidazo (1,2-a) pyrazin-2-yl-, imidazo (1,2-c) pyridazin-2-yl- or imidazo) 1,2- c) thiazol-6-yl-groups, a compound of the general formula (VIII) nh ₂ in which the radicals A, B, C and D denote one optionally substituted by one methyl group, methylene group or nitrogen atom and the methylene groups usual for the radicals A, B, C and D or A and B usually mean one methylene group and -C = D- group 15 means a sulfur atom, reacts with a compound of the general formula in which R _p Rj and R ₄ have the meanings specified in claims 1 to 6 and Z ₄ denotes a halogen and cm, such as chlorine or bromine, or 30 g / for the preparation of compounds of general formula I, wherein R ₂ is as defined in claims 1 to 6 meanings benzimidazol-2il-, imidazo / 4,5-c / pyridine-2 -or-, imidazo / 4,5-c / -pyridin-2-yl-, imidazo (4,5-c) pyrazin-35 2-yl-, imidazo / 4,5-c) -pyridazin-2-yl-, imidazo / 4, 5-d / pyridazin-2-yl- or purin-8-yl-groups, one compound of the general formula wherein one or two of the radicals A _p Bp Cj or D denote one nitrogen atom and the rest of the radicals A _p B _p C or D denote a methylene group and R _H denote a hydrogen or fluorine atom, one methyl or trifluoromethyl group, one of the radicals X ₂ or Y ₂ represents an R _J3 -NH-rpyna, and the other X ₂ or Y ₂ represents a group of general formula wherein R _p Rj and R ₄ have the meanings given in claims 1 to 6, one of the radicals R ₁₃ or R _{] 4} represents a hydrogen atom and the other radical R ₁₃ or R ₁₄ represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group with 3 to 7 carbon atoms, Ζ ₅ and Z ₆ , which may be the same or different, denote substituted amino groups, or optionally substituted by alkyl groups, hydroxy or mercapto groups, or Ζ ₃ and Ζ ₆ denote together an oxygen or sulfur group an atom, optionally substituted by one alkyl group of 1 to 3 carbon atoms, an imino group, an alkylenedioxy group or an alkylenediothio group with typically 2 to 3 carbon atoms, is cyclized, and optionally the corresponding N-oxide thus obtained is reduced, and the compound thus obtained is finally chi and if necessary, the reagent group used to react during the reaction in the cases a / to g / is cleaved off, and / or if necessary, the isomer mixture thus obtained is separated into the constituent isomers thereof, and / or the compound of the general formula I thus obtained is converted into a salt thereof, especially in a pharmaceutical application it is converted into a physiologically acceptable salt thereof with inorganic or organic acids and bases.