NO301585B1 - Benzimidazoles and drugs containing these - Google Patents

Abstract

1-Biphenylylmethyl-benzimidazole derivs. of formula (I) and their salts are new. (A) where: R1 = F, Cl, Br, 1-4C alkyl, cycloalkyl, CH2F, CHF2 or CF3 and is in the 4 position; R2 = R2 or may also be R2 when R4 = 1H-tetrazolyl; R'2 = 3-5C alkoxy substd. in the 3, 4 or 5 position by imidazolyl, or 2-5C alkoxy substd. in the 2, 3, 4 or 5 position by benzimidazolyl or tetrahydrobenzimidazolyl; R2 = e.g. (a) 2-(1-imadazolyl)ethoxy, 1-4C alkylsulphonyloxy, OSO2Ph or phenylalkylsulphonyloxy; (b) acylamino opt. N-substd. by 1-6C alkyl, Ph, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenylyl, where acyl is 1-7C alkanoyl, 2-4C alkoxycarbonyl, 1-6C alkylsulphonyl, benzoyl, phenylsulphonyl, phenylalkylsulphonyl, naphthylsulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl, where phenyl rings are opt. substd. by 1-2 of F, Cl, Br, Me and OMe, or 3-oxopyridazylinyl or (l) 3-oxodihydropyridazinyl, opt. 2-substd. by alkyl or phenylalkyl and opt. further C-substd. by 1-2 alkyl gps., Het = a C- or imino-bonded 5-membered heteroaromatic ring or a C-bonded 6-membered heteroaromatic ring. (B) where: R1 = H or F, Cl, Br, 1-4C alkyl, CH2F, CHF2 or CF3 in the 5, 6 or 7 position; R2 = Het or a gp. as defined in (l) above; R3 and R4 are as defined in (A); provided that: (a) R2 is not 3-methylimidazo (4,5-b)pyridin-2-yl or 3-n-hexylimidazo(4,5-b) pyridin-2-yl in the 6 position when R1 = H, R3 = n-Pr and R4 = COOH; (b) R2 is not benzoxazol-2-yl in the 5 or 6 position when R1 = H, R3 = n-Pr or n-Bu and R4 = 1H-tetrazolyl; (c) R2 is not 1-methyl-2-benzimidazolyl in the 5 or 6 position or 1-n-butyl-2-benzimidazolyl, 1,5-dimethyl-2-benzimidazolyl or 1-methyl-5-trifluoromethyl -2-benzimidazolyl in the 6 postion when R1 = H, R3 = n-Pr and R4 = COOH; (d) R2 is not 1-methyl-2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH or 1H-tetrazolyl; (e) R2 is not 2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH; unless otherwise stated, alkanoyl, alkyl and alkoxy gps. are 1-3C and cycloalkyl gps. are 3-7C.

Description

In EP-A-0 392 317, EP-A-0 400 835, EP-A-0 399 732 and US-A-

4,880,804, benzimidazoles have already been described which constitute valuable angiotensin antagonists. It has now been shown that the new benzimidazoles with it general formula

as well as their salts, especially for pharmaceutical use, their physiologically acceptable salts, with inorganic or organic acids or bases, constitute even more valuable angiotensin antagonists, especially angiotensin-II antagonists.

In the general formula I above means:

R1 in 4-position, a fluorine, chlorine or bromine atom, a

alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and also a hydrogen atom, when R 2 is an imidazo[1,2-a]pyrimidin-2-yl group,

R2 is a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group which is optionally substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, and where a methylene group may be replaced by a carbonyl or sulfonyl group,

a maleic acid imido group which is optionally mono- or disubstituted with an alkyl or phenyl group, where the substituents may be the same or different,

a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 6 carbon atoms or with a

cycloalkyl group, where the phenyl nucleus in one of the above-mentioned benzimidazole groups can also be substituted with a fluorine atom or with a methyl or trifluoromethyl group, an imidazo[2,1-b]thiazol-6-yl-, imidazo[1,2-a]pyridine -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]pyrazine -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 group,

a pyridine ring linked via a carbon atom,

an imidazolyl group bound via a carbon atom which is optionally substituted in the 1-position with an alkyl or benzyl group, and which in the carbon skeleton can also be substituted with an alkyl group, or

also an 8-methyl-imidazo[1,2-a]pyridin-2-yl group in the 6-position, when R-1 is a methyl group and R3 simultaneously an n-propyl group,

R3an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms, and

R4 a carboxy or 1H-tetrazolyl group,

and their salts with inorganic or organic acids or bases,

wherein, unless otherwise stated, one of the aforementioned alkyl moieties may contain 1 to 3 carbon atoms and one of the above-mentioned cycloalkyl moieties may contain 3 to 7 carbon atoms.

Examples of the meaning of the residues R-j_ to R3 as defined above are for

R-1: a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl group,

R2: a 2-oxo-pyrrolidino-, 2-oxo-piperidino-, 2-oxohexa-methyleneimino-, propanesultam-1-yl-, butansultam-1-yl-, pentane-sultam-1-yl-, maleic imido-, 2-methyl-maleic imido-, 2-phenyl-maleic imido-, 2-methyl-3-phenyl-maleic imido-, pyridin-2-yl-, 4-methyl-imidazol-2-yl-, l-methyl-imidazol-4 -yl-, 1-methyl-imidazol-5-yl-, 1-benzyl-imidazol-4-yl-, 1-benzyl-imidazol-5-yl-, 1,2-dimethyl-iaridazol-4-yl-, 1,2-dimethyl-imidazol-5-yl-, l-benzyl-2-methyl-imidazol-4-yl, 1-benzyl-2-methyl-imidazol-5-yl-, benzimidazol-2-yl-, l -methyl-benzimidazol-2-yl-, l-ethyl-benzimidazol-2-yl-, l-n-propyl-benzimidazol-2-yl-, l-isopropyl-benzimidazol-2-yl-, l-n-butyl-benzimidazol-2 -yl-, l-isobutyl-benzimidazol-2-yl-, l-n-pentyl-benzimidazol-2-yl-, 1-n-hexyl-benzimidazol-2-yl-, l-cyclopropyl-benzimidazol-2-yl-, l-cyclobutyl-benzimidazol-2-yl-, 1-cyclopentyl-benzimidazol-2-yl-, l-cyclohexyl-benzimidazol-2-yl-, 5-methyl-benzimidazol-2-yl-, 1,5-dimethyl- benzimidazol-2-yl-, 1,6-dimethyl-benzimidazol-2-yl-, 1,4-dimethyl-b enzimidazol-2-yl-, 5-fluoro-1-methyl-benzimidazol-2-yl-, 6-fluoro-1-methyl-benzimidazol-2-yl-, 5-trifluoromethyl-benzimidazol-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-l-ethyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-l-n-butyl-benzimidazol-2-yl-, 4,5,6 ,7-tetrahydro-l-n-hexyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-l-cyclopropyl-benzimidazol-2-yl-, 4,5,6,7-tetrahydro-l-cyclohexyl -benzimidazol-2-yl-, imidazo[1,2-a]pyrimidin-2-yl-, 8-methyl-imidazo[1,2-a]pyridin-2-yl-, 5,6,7,8- tetrahydro-imidazo[1,2-a]pyridin-2-yl-, imidazo[4,5-c]pyridin-2-yl-, imidazo[2,1-b]thiazol-6-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 group, and

R3: a methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, iso-butyl-, tert-butyl-, n-pentyl-, 1-methyl-butyl-, 2-methyl-butyl- , 3-methyl-butyl, cyclopropyl, cyclobutyl or cyclopentyl group.

Particularly preferred compounds with the general formula I stated above are, however, those where

in the 4-position means a chlorine atom, an alkyl group with 1 to 3 carbon atoms or a trifluoromethyl group, or also a hydrogen atom when R2 means an imidazo[1,2-a]pyrimidin-2-yl group,

R2 is a 5-, 6- or 7-membered alkyleneimino group, where a methylene group may be replaced by a carbonyl or sulfonyl group,

a maleic acid imido group which is optionally mono- or disubstituted with an alkyl group with 1-3 carbon atoms or with a phenyl group, where the substituents may be the same or different,

a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group, where the phenyl nucleus in a of the benzimidazole groups mentioned above can also be substituted with a fluorine atom or with a methyl or trifluoromethyl group, an imidazo[2,1-b]thiazol-6-yl-, imidazo[1,2-a]pyridin-2-yl- , 5,6,7,8-tetra-hydro-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]pyridazine -2-yl or imidazo-[4,5-d]pyridazin-2-yl group,

a pyridine ring linked via a carbon atom or

an imidazol-4-yl group which is substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms or with a benzyl group, and which in the carbon skeleton can also be substituted with an alkyl group with 1 to 3 carbon atoms,

R3 means an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms and

R4 means a carboxy or 1H-tetrazolyl group,

especially those compounds of the general formula I, where

R1 in the 4-position means a methyl group or a chlorine atom or also a hydrogen atom when R2 means an imidazo[1,2-a]-pyrimidin-2-yl group,

R2 is a 5-, 6- or 7-membered alkyleneimino group, in which a methylene group is replaced by a carbonyl or sulfonyl group,

a maleic acid imido group which is optionally mono- or disubstituted with an alkyl or phenyl group, where the substituents may be the same or different,

a benzimidazol-2-yl or a 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms, where the phenyl nucleus in one of the above said benzimidazole groups can also be substituted with a fluorine atom, an 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-b]thiazol-6-yl group, or

an imidazol-4-yl group which is substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms,

R3 means an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms and

R4 means a carboxy or 1H-tetrazolyl group,

and their salts with inorganic or organic acids or bases.

Particularly preferred compounds are illustrated in Examples 1, 2, 3, 4, 12, 18, 20, 21, 25, 26, 29, 34, 38, 39, 40, 41, 42, 44 and 51, especially 1 and 51.

The compounds can be produced according to the following methods:

a) cyclization of a compound of the general formula

where

and R2 is as initially defined,

one of the residues X.^ or Y.sub.1 forms a group with the general formula

and the other of the residues or Y1 constitutes a group of the general formula

where R^ and R^ are as initially defined,

Rg is a hydrogen atom or an R3CO group, where R3 is as defined above,

Z1 and Z2> which may be the same or different, constitute optionally substituted amino groups or hydroxy or mercapto groups which are optionally substituted with lower alkyl groups, or

and Z2 together constitute an oxygen or sulfur atom, an imino group which is optionally substituted with an alkyl group with 1 to 3 carbon atoms, an alkylene dioxy or alkylene dithio group each having 2 or 3 carbon atoms, where however one of the residues X.^ or Y 1 must constitute a group with the general formula

The cyclization is conveniently carried out in a solvent or in a solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess of the acylating agent used for preparation of the compound of the general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250°C, but preferably at the boiling point of the reaction mixture, possibly in the presence of a condensation 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 also in the presence of a base such as potassium ethylate or potassium tert.butylate. However, the cyclization can also be carried out without a solvent and/or condensing agent.

Particularly advantageously, the reaction is carried out so that a compound of the general formula II is produced in the reaction mixture by reduction of a corresponding o-nitroamino compound, optionally in the presence of a carboxylic acid with the general formula R^COOH, or by acylation of a corresponding o-diamino compound . By stopping the reduction of the nitro group in the hydroxylamine step, the N-oxide of a compound of the general formula I is obtained in the subsequent cyclization. The N-oxide thus obtained is then transferred by reduction into a corresponding compound of the general formula I.

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

b) Reaction of a benzimidazole with the general formula

where

R 1 to R 4 are as initially defined, with a biphenyl compound of the general formula

where

R4 is as initially defined and

Z^ constitutes a nucleophilic leaving group, such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy group.

The reaction is conveniently carried out in a solvent or a solvent mixture, such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzene, possibly in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butylate, triethylamine or pyridine , whereby the latter two can also be used as a solvent at the same time, preferably at temperatures between 0 and 100°C, e.g. temperatures between room temperature and 50°C.

The reaction preferably yields a mixture of the 1- and 3-isomers which can then optionally be resolved into the corresponding 1- and 3-isomer, preferably chromatographically using a carrier material such as silica gel or aluminum oxide. c) For the preparation of a compound of the general formula I, where R4 constitutes a carboxy group: transfer of a compound of the general formula

where

R]L to R3 are as initially defined, and

R4' constitutes a group which can be transferred into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

For example, functional derivatives of the carboxy group, like their unsubstituted or substituted amides, esters, thiol esters, ortho esters, imino ethers, amidines or anhydrides, the nitrile group or the tetrazolyl group can be transferred by hydrolysis in a carboxy group, esters with tertiary alcohols, e.g. tert.butyl ester, by thermolysis a carboxy group is transferred and esters with aralkanols, e.g. the benzyl ester, by hydrogenolysis is transferred in a carboxy group.

The hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric 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, e.g. at temperatures between room temperature and the boiling point of the reaction mixture. During hydrolysis in the presence of an organic acid, such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups that may be present can be simultaneously transferred into a corresponding acyloxy group, such as e.g. the trifluoroacetoxy group.

If R 4 ' in a compound of the general formula V is a cyano or aminocarbonyl group, these groups can also be transferred with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, which can simultaneously serve as a solvent, at temperatures between 0 and 50°C, in the carboxy group.

If R' in a compound of the general formula V is for example the tertiary butyloxycarbonyl group, the tertiary butyl group can also be cleaved off thermally, optionally in a suitable solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, e.g. at temperatures between 40°C and 100°C.

If R4' in a compound of the general formula V is for example the benzyloxycarbonyl group, the benzyl group can also be cleaved off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide , preferably at temperatures between 0 and 50°C, e.g. at room temperature, and under a hydrogen pressure of

1 to 5 bars. During the hydrogenolysis, other residues, e.g. a nitro group, is co-reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group or a cinnamic acid group to a corresponding phenylpropionic acid group, or replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom. d) For the preparation of a compound of the general formula I, where R4 constitutes a 1H-tetrazolyl group: removal of a protecting residue from a compound of the general formula

where

Rl'R2°^R3 are as inle<^nin9sv:'-s defined and

R4" constitutes a 1H-tetrazolyl group in the 1- or 3-position which is protected with a protecting residue.

As a protective residue, for example, the triphenylmethyl, tributyltin or triphenyltin group comes into consideration.

The cleavage of a used protective residue preferably takes place in the presence of a hydrogen halide, 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 isopropanol, at temperatures between 0 and 100°C, preferably at room temperature, or possibly, if the reaction is carried out in the presence of alcoholic ammonia, at an elevated temperature, e.g. temperatures between 100 and 150°C,

preferably at temperatures between 120 and 140°C,

e) For the preparation of a compound of the general formula I, where R4 constitutes a 1H-tetrazolyl group: reaction of a compound of the general formula

where

R1 to R3 are, as initially defined, with hydrogen azide acid or salts thereof.

The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150°C, preferably at 125°C. During the reaction, the hydrogenazide acid is suitably liberated from an alkali azide, e.g. from sodium azide in the presence of a weak acid, e.g. ammonium chloride, or in that the tetrazolid salt, obtained in the reaction mixture by reaction with a salt of hydrogen azide acid, preferably with aluminum azide or tributyltin azide, which is also conveniently produced in the reaction mixture by reaction of aluminum chloride or tributyltin chloride with an alkali azide, such as sodium azide, is then acidified with a dilute acid , such as 2N hydrochloric acid or 2N sulfuric acid.

f) For the preparation of compounds with the general formula I, where R2 is one of those mentioned at the outset

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-, groups:

turnover of a compound with the general formula

where

one of the residues A, B, C or D is a methine group or a nitrogen atom and the rest of the residues A, B, C or D constitute methine groups or

A and B constitute a methine group and the -C=D group a sulfur atom, Rg is a hydrogen, fluorine, chlorine or bromine atom, an alkyl-, alkoxy-, hydroxy-, phenyl-, nitro-, amino-, alkylamino -, dialkylamino-, alkanoylamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, trifluoromethyl-, alkanoyl-, aminosulfonyl-, alkylaminosulfonyl or dialkylaminosulfonyl group and R10 means a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group, whereby if Rg and R1 are adjacent methyl groups, these can be linked together with a methylene or ethylene group,

with a compound of the general formula

where

R 1 , R 3 and R 4 are as initially defined, and

Z 4 constitutes a nucleophilic leaving group, such as a halogen atom, e.g. a chlorine or bromine atom.

The reaction is conveniently carried out in a solvent or a solvent mixture such as ethanol, isopropanol, benzene, glycol, glycol monomethyl ether, dimethylformamide or dioxane, for example at temperatures between 0 and 150°C, preferably at temperatures between 20 and 100°C. However, the turnover can also be carried out without a solvent.

g) For the preparation of compounds of the general formula I, where R2 constitutes one of the initially mentioned benzimidazol-2-yl-, imidazo[4,5-b]pyridin-2-yl-, imidazo[4,5-c]pyridine -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 groups: cyclization of a compound of the general formula

where

none, one or two of the residues A^, P^, C1 or D1 constitutes a nitrogen atom and

the remaining residues of the residues A^ B^, C or D.^ constitute met ingroups,

R is hydrogen, fluorine, chlorine or bromine, an alkyl-, alkoxy-, hydroxy-, phenyl-, nitro-, amino-, alkylamino-, dialkylamino-, alkanoylamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl group and

R^2 is a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group,

one of the residues X2 or Y2 constitutes an R 3 -NH group and the other of the residues X2 or Y2 constitutes a group with the general formula

where

R1, R3 and R4 are as initially defined,

one of the residues R 13 or R 14 is a hydrogen atom and the other of the residues R 13 or R 4 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a cycloalkyl group,

Zr, and Zc, which may be the same or different, mean optionally substituted amino groups or optionally hydroxy or mercapto groups which are substituted with lower alkyl groups, or

Zb c and Zc b together with an oxygen or sulfur atom mean an •imino group which is optionally substituted with an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, and optionally subsequent hydrolysis.

The cyclization is suitably carried out in a solvent or a solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulphonane, dimethylformamide, tetralin or in an excess of the acylating agent used to prepare the compound with the general formula X, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250°C, preferably at the boiling point of the reaction mixture, possibly in the presence of a condensation agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid , phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium ethylate or potassium tert.butylate. However, the cyclization can also be carried out without solvent and/or condensing agent.

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

where

R 1 , R 3 and R 4 are as initially defined, or by acylation of a corresponding o-diamino compound with a carboxylic acid of the general formula XI.

By interrupting the reduction of the nitro group in the hydroxyl-amine step, the N-oxide of a compound of the general formula I is obtained in the subsequent cyclization. The N-oxide thus obtained is then transferred by reduction into a corresponding compound of the general formula I .

The subsequent reduction of an N-oxide thus obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals 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 with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, preferably at room temperature.

The subsequent hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric 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, e.g. at temperatures between room temperature and the boiling point of the reaction mixture. During hydrolysis in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups that may occur can be simultaneously transferred into a corresponding acyloxy group, such as the trifluoroacetoxy group. h) For the preparation of compounds with the general formula I, where R2 constitutes a dihydropyridazin-3-one or pyridazin-3-one group which in the 2-position may have an alkyl group with 1 to 3 carbon atoms which is substituted with a phenyl group, or in the carbon skeleton may be substituted with one or two alkyl groups with 1 to 3 carbon atoms:

reaction of a carboxylic acid with the general formula

where

R1#R3 and R4 are as initially defined and

E represents an ethylene or ethenylene group optionally substituted with one or two alkyl groups of 1 to 3 carbon atoms, or reactive acid derivatives thereof, such as their esters, amides or halides, with a hydrazine of the general formula

where

R 15 constitutes a hydrogen atom or an alkyl group with 1 to 3 carbon atoms which is optionally substituted with a phenyl group.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or in an excess of the hydrazine used, resp. hydrazine hydrate, at temperatures between 0 and 200°C, e.g. at temperatures between 20 and 150°C, preferably at the boiling point of the reaction mixture, and optionally in the presence of an acid such as sulfuric acid or p-toluenesulfonic acid as condensation agent. However, the turnover can also be carried out without a solvent.

In the reactions described above, any reactive groups that may occur, such as hydroxy, amino or alkyl-amino groups, can be protected during the reaction by means of normal protective groups which are cleaved off again after the reaction.

Relevant protective residues for a hydroxy group are, for example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and for an amino, alkylamino or imino group, acetyl, benzoyl, the ethoxycarbonyl or benzyl group.

The possibly subsequent cleavage of a used protective residue preferably takes place hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as hydrochloric acid or sulfuric acid, or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at the reaction mixture's boiling point. However, the removal of a benzyl residue preferably takes place hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, optionally with the addition of an acid, e.g. hydrochloric acid, at temperatures between 0 and 50°C, preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably of 3 to 5 bar.

A thus obtained mixture of isomers of a compound of the general formula I can optionally be resolved, preferably chromatographically using a carrier, such as silica gel or aluminum oxide.

The obtained compounds of the general formula I can also be transferred in their acid addition salts, especially for pharmaceutical use, in their physiologically acceptable salts, with inorganic or organic acids. Acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, the thus obtained new compounds of the general formula I, if they contain a carboxy or 1H-tetrazolyl group, can subsequently optionally be transferred into their salts with inorganic or organic bases, especially for pharmaceutical use, into their physiologically acceptable salts. Examples of bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The starting compounds of the general formula II to XIII are partly known from the literature or are obtained according to methods known from the literature.

Thus, for example, a compound with the general formula II is obtained by alkylation of a corresponding o-amino-nitro compound and subsequent reduction of the nitro group.

A starting compound with the general formula III, V, VI, VII, IX, X or XII is obtained by acylation of a corresponding o-diamine or a corresponding o-amino-nitro compound, subsequent reduction of the nitro group and subsequent cyclization of a thus obtained o-diamino compound, optionally with subsequent cleavage of a used protective residue, or by cyclization of a corresponding substituted benzimidazole with a corresponding amine, or by NH-alkylation of a corresponding 1H-benzimidazole, whereby the isomer mixture thus obtained is then separated by means of usual methods, e.g. by chromatography. The aforementioned output compounds are partly 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 reacting p-amino-acetophenone with butyric acid chloride, subsequent nitration, bromination, ring closure with 2- aminopyridine to the 6-n-butanoyl-amido-3-(imidazo[1,2-a]pyridin-2-yl)-nitrobenzene, which then, after reduction of the nitro group, is transferred by cyclization into the desired compound, or

2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1H-benzimidazole by nitration of 3-methyl-4-n-butanoylamido-benzoic acid methyl ester, subsequent reduction of the nitro group and cyclization to 2-n-propyl-4-methyl-6-methoxycarbonyl-1H-benzimidazole, which then, during cyclization with 2-methylamino-aniline, is transferred into the desired compound.

A benzimidazole in which the alkoxy group in the 2-, 3-, 4- or 5-position is substituted with an imidazole residue is obtained, for example, by reacting a corresponding 7-hydroxy-benzimidazole, which is described in EP-A-0 392 317 , by reaction with a corresponding a-, w-dihaloalkane and subsequent reaction with a corresponding imidazole.

The new compounds of the general formula I and their physiologically acceptable salts exhibit valuable pharmacological properties. They constitute angiotensin antagonists, especially angiotensin-II antagonists.

For example, the connections were:

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-(butansultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl ,

D = 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazol-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-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-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1- yl)-methyl]-biphenyl-2-carboxylic acid,

I = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[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-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)- methyl]-biphenyl-2-carboxylic acid investigated for their biological effects as follows:

Anaiotensin II receptor binding, method description

Rat lung tissue was homogenized in Tris buffer (50 mMol Tris, 150 mMol NACl, 5 mMol EDTA, pH 7.40) and centrifuged twice, each time for 20 min. at 20,000 x g. The final centrifuge button was resuspended in incubation buffer (50 mMol Tris, 5 mMol MgCl2, 0.2% BSA, pH 7.40) 1:75, calculated on the basis of the weight of the wet tissue. Portions of 0/1 ml homogenate

125

was incubated for 60 min. at 37°C with 50 pM [ I]-angiotensin II (NEN, Dreieich, Germany) and increasing concentrations of the test compound in a total volume of 0.25 ml. The incubation was terminated by rapid filtration through a glass fiber filter mat. The filters were washed with 4 ml of ice-cold buffer (25 mMol Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity was measured in a gamma counter. Out from

dose/response curve, the corresponding IC5Q value was determined.

In the test described, the compounds A to S showed the following IC^q values:

In addition, compounds A, B, C, D, E and G were tested for their effects on conscious, renally hypertensive rats after oral administration, according to methods known from the literature. At a dose of 10 mg/kg, these compounds showed a blood pressure-lowering effect.

Upon administration of the above-mentioned compounds up to a dose of 30 mg/kg i.v. no toxic side effects could be observed, e.g. no negative inotropic effect and no heart rhythm disturbances. The connections are thus well tolerable.

Due to their pharmacological properties, the new compounds and their physiologically acceptable salts are suitable for the treatment of hypertension and heart failure, for the treatment of ischemic peripheral circulatory disorders, in myocardial ischemia (angina), for the prevention of heart failure development after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

Moreover, the new compounds and their physiologically acceptable salts are suitable for the treatment of pulmonary diseases, e.g. pulmonary edema and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, of thickening of the vessel wall after coronary operations, arteriosclerosis and diabetic angiopathy. Due to the influence of acetylcholine and dopamine release through angiotensin in the brain, the new angiotensin antagonists are also suitable for removing central nervous disorders, e.g. in depression, in Alzheimer's disease, Parkinson's syndrome, bulemia, as well as in disorders of cognitive functions.

The dosage required to achieve a desired effect is suitably 20 to 100 mg, preferably 30 to 70 mg for intravenous administration, and 50 to 200 mg, preferably 75 to 150 mg for oral administration, given 1 to 3 times a day. Compounds with the general formula I can be incorporated below, possibly in combination with other active substances, e.g. blood pressure lowering agents, diuretics and/or calcium antagonists, together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The above-mentioned combinations may thus further include active substances, such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, propranolol (di)hydralazine hydrochloride, diltiazem, felodipine, nicardipine, nifedipine , nisoldipine and nitrendipine. The dose for these active substances is appropriately 1/5 of the otherwise recommended lowest dosage up to l/l of the usually recommended dosage, which means for example 15 to 200 mg hydrochlorothiazide, 125 to 2000 mg chlorothiazide, 15 to 200 mg ethacrynic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipine, 5 to 60 mg nifedipine, or 5 to 60 mg nitrendipine.

The following examples shall further illustrate the invention.

Example A

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

0.7 g (1.15 mmol) 4'-[[2-n-butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methylbenzimidazol-1-yl]methyl]biphenyl-2 -carboxylic acid tert-butyl ester is dissolved in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid is added and stirred for 12 hours at room temperature. The mixture is diluted with methylene chloride and decanted with water and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated in vacuo. The crude product thus obtained is purified over a silica gel column (particle size: 0.063-0.02 mm, ethyl acetate/ethanol/ammonia = 90:10:0.1) and crystallized from acetone. Yield: 0.19 g (29.9% of the theoretical),

Melting point: 185-187°C

<C>34<H>38<N>4°3X H2° (550'70)

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

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

Yield: 63.9% of the theoretical

Melting point: 261-263°C

<C>33<H>30<N>4°2 (<5>14.60)

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) 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl] -2-cyano-biphenyl in 50 ml of dimethylformamide, 4.3 g (66 mmol) of sodium azide and 3.5 g (66 mmol) of ammonium chloride are added and the mixture is stirred for 24 hours at 140°C. Water is then added, after which the precipitate is sucked off. The crude product thus obtained is purified chromatographically on silica gel (300 g silica gel, methylene chloride + 6% ethanol).

Yield: 900 mg (51% of the theoretical)

Melting point: 228-23 0°C

<C>33H30<N>8 (<5>38.70)

Example 3

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

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

Yield: 49.0% of the theoretical

Melting point: sinters from 186°C

<C>29<H>31N7°2<S>(541'70>

Example 4

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

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

Yield: 60.0% of the theoretical

Melting point: amorphous, sinters from 194°C

<C>28<H>29N7°2<S>(527.70)

Example 5

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

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

Yield: 48.0% of the theoretical,

Melting point: amorphous, sinters from 183°C

<C>30<H>33N7°2S (555'70>

Example 6

4'-[[2-n-<p>rop<y>1-4-et<y>1-6-(butansultam-1-(<y>1)-benzimidazol-1-yl]-methyl]-2 -(1H-tetrazol-5-yl)-biphenyl

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

Yield: 27.0% of the theoretical

Melting point: amorphous, sinters from 189°C

<C>3Q<H>33N702<S>(555.70)

Example 7

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

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

Yield: 3 9.0% of the theoretical

Melting point: amorphous, sinters from 212°C

<C>29<H>31N7°2<S>(541'70)

Example 8

4'-[[2-n-propyl-4-isopropyl-6-(butansultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

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

Yield: 22.0% of the theoretical

Melting point: amorphous

<C>31<H>35N7°2<S>(569'70)

Example 9

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

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

Yield: 24.0% of the theoretical

Melting point: amorphous, sinters from 20 9°C

<C>30<H>33N7°2<S>(555.70)

Example 10

4'-[[2-n-propyl-4-trifluoromethyl-6-(butansultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

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

Yield: 17.0% of the theoretical

Melting point: 199-203°C

<C>29<H>28<F>3N7°2<S>(595.70)

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-tert .butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 48.0% of the theoretical

Melting point: 233-235°C

<C>34<H>32<N>4°2 (<5>28'70>).

Example 12

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

Prepared analogously to Example 2 from 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 the theoretical

Melting point: 235-237°C

<C>34<H>32<N>8 (<5>52.70)

Example 13

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

Prepared analogously to Example 2 from 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 the theoretical

Melting point: amorphous, sinters from 140°C

<C>30H31N7<O>(505.60)

Example 14

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

Prepared analogously to Example 2 from 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: 3 9.0% of the theoretical

Melting point: amorphous, sinters from 128°C

<C>31H33<N>7<0>(519.70)

Example 15

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

Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol- 5-yl)-biphenyl by cleavage of the triphenylmethyl group using methanolic hydrochloric acid.

Yield: 51.0% of the theoretical

Melting point: amorphous, sinters from 115°C

<C>30<H>31<N>7° (<5>05'6°)

Example 16

4'-[[2-n-propyl-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-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid -tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 54.0% of the theoretical

Melting point: 202-204°C

<C>31<H>26<N>4°2 (<4>86<60>).

Example 17

4 '-[[2-n-butyl-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-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid -tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 41.0% of the theoretical

Melting point: 193-195°C

<C>32<H>28<N>4°2 (<5>00.60)

Example 18

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

Yield: 28.0% of the theoretical

Melting point: 187-189°C

<C>31<H>26<N>8 (<5>10.60)

Example 19

4'-[[2-n-butyl-6-(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-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 23.0% of the theoretical

Melting point: 170-173°C

<C>32H28<N>8 (<5>24.60)

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-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl -2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 38.0% of the theoretical

Melting point: 195-197°C (after evaporation of the solvent)

Melting point: 299-303°C (methylene chloride/ethanol = 20:1) C32<H>28<N>4°2 (<5>00.60)

Example 21

4'-[[2-n-propyl-4-methyl-6-(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-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 the theoretical

Melting point: sinters from 18l°C

<C>32<H>28N8(524.60)

Example 22

4'-[[2-n-butyl-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-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl -2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 51.0% of the theoretical

Melting point: 194-197°C

<C>33<H>30<N>4°2 (<5>14.60)

Example 23

4'-[[2-n-butyl-4-methyl-6-(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-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 the theoretical

<C>33<H>30<N>8 (<5>38,60)

Example 24

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

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

Yield: 47% of the theoretical

Melting point: 224-226°C (after evaporation of the solvent)

Melting point: 294-297°C (methylene chloride/ethanol =20:1)<C>31<H>27<N>5°2 (<5>01.60)

Example 25

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

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

Yield: 43% of the theoretical

Melting point: 192-195°C (after evaporation of the solvent) Melting point: >300°C (methylene chloride/ethanol = 20:1)

<C>30<H>26N4°2S (506.64)

Example 2 6

4 '-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl

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

Yield: 21% of the theoretical

Melting point: amorphous, sinters from 196°C

<C>30H26<N>8<S>(530.67)

Example 27

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 from 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 the theoretical

Melting point: 202-205°C

<C>32H28<N>8 (<5>24.64)

Example 28

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 the theoretical

Melting point: 239-242°C

<C>32<H>28<N>4°2 (<5>00.61)

Example 29

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

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

Yield: 88.9% of the theoretical

Melting point: 321-322°C

<C>32<H>31<N>3°4X 0.5 H2° (530'62)

Example 3 0

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

Prepared analogously to Example A from 4'-[[6-(2,3-dimethylmaleic acid imino)-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 the theoretical

Melting point: 329-331°C

C31H29N3°4 x 0.5 H2°(516'6°)

Example 31

4 '-[[2-n-propyl-5-(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-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid -tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 32% of the theoretical

Melting point: 250-253°C

<C>31<H>26<N>4°2<<4>86.60)

Example 32

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-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid-tert .butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 64% of the theoretical

Melting point: 217-219°C

<C>34<H>32<N>4°2 (<5>28'7°)

Example 33

4 '-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-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 the theoretical

Melting point: 215-217°C

<C>34H32<N>8 (<5>52'70>).

Example 34

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-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: 52% of the theoretical

Melting point: 244-246°C

<C>33<H>28<N>4°2 (<5>12.60)

Example 35

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

Prepared analogously to Example 2 from 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 the theoretical

Melting point: 245-247°C

<C>33H28<N>8<<5>36'65>

Example 3 6

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

Prepared analogously to Example A from 4'-[(2-cyclobutyl-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: 63% of the theoretical

Melting point: 189-191°C

C34<H>30<N>4°2(526'60>

Example 37

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

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

Yield: 61% of the theoretical

Melting point: 197-199°C

<C>34H30<N>8 (<5>50.70)

Example 3 8

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

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

Yield: 34% of the theoretical

Melting point: 250-252°C

C33H29FN402 (532.60)

Example 3 9

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

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

Yield: 16.5% of the theoretical

Melting point: from 275°C (decomp.)

C31H2?Ng x H2O (543.65)

Example 4 0

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

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

Yield: 67% of the theoretical

Melting point: from 240°C (sinters)

<C>32<H>32<N>4°2 (<5>04.64)

Example 41

4'-[(2-n-propyl-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-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 the theoretical

Melting point: from 275°C (decomp.)

<C>32<H>32<N>8 (<5>28.67)

Example 42

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

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

Yield: 76% of the theoretical

Melting point: 243-245°C

C33H29FN4°2(532.60)

Mass spectrum: m/e = 532

Example 43

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-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid-tert .butyl ester and trifluoroacetic acid i

methylene chloride.

Yield: 52.7% of the theoretical

Melting point: 292-295°C

C32H27CN4°2 <535'06)

-value: 0.3 0 (Silica gel; methylene chloride/ethanol = 19:1)

Example 44

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

Prepared analogously to Example 2 from 4'-[(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 the theoretical

Melting point: sinters from 204°C

C32H27C1N8 x HC1 (595.55)

R^-value: 0.20 (Silica gel; petroleum ether/ethyl acetate = 1:1 and

1% glacial acetic acid)

Example 45

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-nitro-acetophenone

32.6 g (148 mmol) 3-methyl-4-butyrylamino-acetophenone

is added in portions while stirring at -15°C in 300 ml fuming nitric acid and stirred further for 30 minutes at -15°C. The reaction mixture is then poured with stirring over 3 liters of ice. The precipitated crude product is suctioned off, washed with 400 ml of water, dried and purified by recrystallization from ethanol/diethyl ether (1:1).

Yield: 23.8 g (61.0% of the theoretical)

R^-value: 0.32 (Silica gel; methylene chloride)

R^-value: 0.48 (Silica gel; methylene chloride/methanol = 50:1)

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

Into a solution of 23.8 g (90 mmol) 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml dichloromethane, a solution of 16.0 g (200 mmol) bromine in 140 ml of dioxane so slowly that a decolorization of the reaction mixture occurs all the time. It is then stirred for a further two hours, after which the reaction mixture is evaporated to dryness in vacuo. The thus obtained residue is rubbed out with approx. 20 ml of dichloromethane/diethyl ether (1:1), suction off and dry. 23 g (74% of the theoretical) of 3-methyl-4-butyrylamino-5-nitro-co-bromoacetophenone is thereby obtained, which still contains approx. 10% starting material. The product is traded on without further purification.

R^-value: 0.69 (Silica gel; methylene chloride/methanol = 50:1) R^-value: 0.84 (Silica gel; methylene chloride/methanol = 9:1)

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

A solution of 6.8 g (20 mmol) of 3-methyl-4-butyrylamino-5-nitro-w-bromoacetophenone in 20 ml of formamide is heated for 2 hours at 140°C. The cooled solution is then poured over for approx. 50 ml IN ammonia and stir for approx. 15 minutes. The precipitated crude product is suctioned off, 50 ml of water is added and dried. 4.4 g (75% of the theoretical) of the product is thereby obtained, which is converted further without further purification.

R^-value: 0.29 (Silica gel; methylene chloride/methanol = 9:1)

d) 2-butyrvlamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene

To a solution of 2.5 g (8.7 mmol) 2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mmol) potassium carbonate dihydrate in 30 ml dimethylsulfoxide is added dropwise 1.3 g (9.5 mmol) methyl iodide at room temperature, after which the mixture is stirred for 2 hours. The reaction mixture is then stirred into approx. 150 ml of water and extracted 4 times with 25 ml portions of ethyl acetate. The organic extracts are washed with approx. 30 ml of water, dried and evaporated. The crude product thus obtained is purified by column chromatography (300 g silica gel, eluent: methylene chloride/methanol = 30:1).

Yield: 640 mg (24% of the theoretical)

R^-value: 0.54 (Silica gel; methylene chloride/methanol = 9:1)

e) 2-butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene 640 mg (2.1 mmol) 2-butyrylamino-3-nitro-5-(1-methyl-imidazol- 4-yl)-toluene in 30 ml of methanol is hydrogenated while adding approx. 200 mg palladium/charcoal (20%) at room temperature and under a hydrogen pressure of 5 bar. After complete hydrogen absorption, the catalyst is filtered off, after which the filtrate is evaporated. The raw product thus obtained is traded on without further purification.

Yield: 600 mg (100% of the theoretical)

Rf value: 0.23 (Silica gel; methylene chloride/methanol = 9:1)

f) 2- n- propyl- 4- methyl- 6-( l- methyl- imidazol- 4- vl)- benzimidazole 600 mg (2.1 mmol) 2-butyrylamino-3-amino-5-(1-methyl- imidazol-4-yl)-toluene in 10 ml of glacial acetic acid is boiled under reflux for 1 hour. The mixture is then evaporated to dryness in a vacuum, after which the residue is added approx. 15 ml of water, made alkaline with ammonia and extracted 4 times with approx. 10 ml portions of ethyl acetate. The organic extracts are washed with approx. 15 ml of water, dried and evaporated. The raw product thus obtained is processed further without further purification.

Yield: 420 mg (79% of the theoretical)

R^-value: 0.37 (Silica gel; methylene chloride/methanol = 9:1)

g) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl-biphenyl-2-carboxylic acid tert. butyl ester

To a solution of 200 mg (0.79 mmol) 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg

(0.8 mmol) potassium tert.butylate in 5 ml of dimethyl sulfoxide is added to 280 mg (0.8 mmol) 4'-bromomethyl-biphenyl-2-carboxylic acid tert.butyl ester, after which the mixture is stirred for 90 minutes at room temperature. It is then stirred in for approx. 40 ml of water, extracted 4 times with approx. 10 ml portions of ethyl acetate, after which the organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The thus obtained product

purified by column chromatography (100 g silica gel, eluent: dichloromethane/methanol = 30:1).

Yield: 230 mg (56% of theoretical)

R^-value: 0.61 (Silica gel; methylene chloride/methanol = 9:1)

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

A solution of 230 mg (0.44 mmol) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl] - biphenyl-2-carboxylic acid tert-butyl ester and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane are stirred at room temperature overnight and then evaporated to dryness. The residue dissolves in approx. 5 ml of diluted caustic soda and the solution is neutralized with ethyl acetate, after which the precipitate that has formed is sucked off, washed with water and dried.

Yield: 120 mg (59% of the theoretical)

Melting point: 293-295°C

Rj value: 0.3 9 (Silica gel; methylene chloride/methanol = 9:1)

Example 46

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

Melting point: 255-257°C

R^ value: 0.24 (Silica gel; methylene chloride/methanol = 9:1)<C>29<H>28N8X H2° (506'62)

Example 47

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

Yield: 21% of the theoretical

Melting point: amorphous

R^ value: 0.27 (Silica gel; methylene chloride/ethanol = 9:1)<C>31H30<N>8<<5>14'64>

Example 48

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)-benzimidazol-1-yl)- methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 87% of the theoretical

Melting point: 295-297°C

R^-value: 0.34 (Silica gel; methylene chloride/ethanol = 9:1)<C>33<H>30N4°2X H2° <532'65>

Example 4 9

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-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 56% of the theoretical

Melting point: from 136°C (decomp.)

<C>3Q<H>27<N>7x 0.5 H20 (494.60)

Example 50

4'-[(2-n-propyl-4-methyl-6-(8-methyl-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-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 the theoretical

Melting point:, amorphous

Rf value: 0.36 (Silica gel; methylene chloride/ethanol = 9:1)<C>33H30<N>8 (<5>38.61)

Mass spectrum: m/e = 538

Example 51

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

Prepared analogously to Example A from 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 tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 50% of the theoretical

Melting point:. >300°C

R^-value: 0.16 (Silica gel; methylene chloride/ethanol = 9:1)

Example 52

4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-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-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid -tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 84% of the theoretical

Melting point: 285-286°C

R^-value: 0.55 (Silica gel; methylene chloride/methanol = 9:1)

Example 53

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

Prepared analogously to Example 2 from 41 -[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 18% of the theoretical

Melting point: amorphous

R^ value: 0.29 (Silica gel; methylene chloride/methanol = 9:1)<C>31<H>32<N>8<<5>16'66)

Mass spectrum: m/e = 516

Example 54

4'-[(2-n-propyl-4-methyl-6-(1-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 55

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

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

In the following pharmaceutical application examples, any suitable compound of formula I, especially those where R4 constitutes a carboxy or 1H-tetrazolyl group, can be used as active ingredient:

Example I

Ampoules, containing 50 mg of active ingredient per 5 ml

Manufacturing:

In part of the water, the buffer compounds and the sodium chloride that is added to give an isotonic solution are dissolved. The active ingredient is added and after complete dissolution, water is added to the indicated volume.

Example II

Ampoules, containing 100 mg of active ingredient per 5 ml

Manufacturing:

Methylglucamine is dissolved in part of the water, after which the active ingredient is brought into solution while stirring and heating. After adding the solvent, water is added to the specified volume.

Example III

Tablets, containing 50 mg of active ingredient

Manufacturing:

The active substance, CaHP04, milk sugar and cornstarch are evenly moistened with an aqueous PVP solution. The pulp is pressed through a 2 mm sieve, dried in a recirculated air drying cabinet at 50°C and sieved again.

After mixing in the smoothing agent, the granulate is pressed on a tableting machine.

Example IV

Dragees, containing 50 mg of active ingredient

Manufacturing:

The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After sieving and drying, the granules are mixed with magnesium stearate and pressed into cores.

The cores produced in this way are coated according to known methods. Dye can be added to the coating suspension or solution.

Example V

Dragees, containing 100 mg of active ingredient

Manufacturing:

The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm sieve and dried at 45°C. After drying, new sieving is carried out, after which the magnesium stearate is mixed in. The mixture

pressed to cores.

The cores produced in this way are then coated according to known methods. The coating suspension or

- dyes can be added to the solution.

Example VI

Capsules, containing 250 mg active ingredient

Manufacturing:

The active substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is poured into size 1 hard gelatin capsules.

Example VII

Oral suspension, containing 50 mg of active ingredient per 5 ml

Manufacturing:

Distilled water is heated to 70°C. Hydroxyethyl cellulose is dissolved in this while stirring. When sorbitol solution and glycerol are added, the mixture is cooled to room temperature. At room temperature, sorbic acid, aroma and active ingredient are added. To free the suspension from air, evacuation is carried out while stirring. A dose = 50 mg is included in 5.0 ml.

Example VIII

Suppositories, containing 100 mg of active ingredient

Manufacturing:

The hard fat is melted and at 40°C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and cast into slightly cooled suppository forms.

Claims (9)

1. Benzimidazoles, characterized by the general formula where R1 in 4-position means a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and also a hydrogen atom, when R2 means an imidazo[1,2-a]pyrimidin-2-yl- group, R2 is a 5-, 6- or 7-membered alkylenimino or alkenylenimino group which is optionally substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, and where a methylene group can be replaced by a carbonyl or sulfonyl group, a maleic acid imido group which is optionally mono- or disubstituted with an alkyl or phenyl group, where the substituents may be the same or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group, where the phenyl nucleus in a of the above-mentioned benzimidazole groups may also be substituted with a fluorine atom or with a methyl or trifluoromethyl group, an imidazo[2,1-b]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]pyridazin-2-yl group, a pyridine ring linked via a carbon atom, an imidazolyl group bound via a carbon atom which is optionally substituted in the 1-position with an alkyl or benzyl group, and which in the carbon skeleton can also be substituted with an alkyl group, or also an 8-methyl-imidazo[1,2-a]pyridin-2-yl group in the 6-position, when R-j_ is a methyl group and R3 simultaneously an n-propyl group, R 3 means an alkyl group of 1 to 5 carbon atoms or a cycloalkyl group of 3 to 5 carbon atoms, and R 3 means a carboxy or 1H-tetrazolyl group, and their salts with inorganic or organic acids or bases, wherein, unless otherwise stated, one of the aforementioned alkyl moieties may contain 1 to 3 carbon atoms and one of the above-mentioned cycloalkyl moieties may contain 3 to 7 carbon atoms. 2. Benzimidazoles with the general formula I according to claim 1, characterized in that R 2 in the 4-position means a chlorine atom, an alkyl group with 1 to 3 carbon atoms or a trifluoromethyl group, or also a hydrogen atom when R 2 means an imidazo[1,2-a] pyrimidin-2-yl group, R2 is a 5-, 6- or 7-membered alkyleneimino group, where a methylene group may be replaced by a carbonyl or sulfonyl group, a maleic acid imido group which is optionally mono- or disubstituted with an alkyl group with 1-3 carbon atoms or with a phenyl group, where the substituents may be the same or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group, where the phenyl nucleus in a of the aforementioned benzimidazole groups can also be substituted with a fluorine atom or with a methyl or trifluoromethyl group, an imidazo[2,1-b]thiazol-6-yl-, imidazo[1,2-a]pyridin-2-yl- , 5,6,7,8-tetra-hydro-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]pyridazine -2-yl or imidazo-[4,5-d]pyridazin-2-yl group, a pyridine ring linked via a carbon atom or an imidazol-4-yl group which is substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms or with a benzyl group, and which in the carbon skeleton can also be substituted with an alkyl group with 1 to 3 carbon atoms, R3 means an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms and R4 means a carboxy or 1H-tetrazolyl group, and their salts with inorganic or organic acids or bases. 3. Benzimidazoles with the general formula I according to claim 1, characterized in that R.^ in the 4-position means a methyl group or a chlorine atom or also a hydrogen atom when R.sub.2 means an imidazo[1,2-a]-pyrimidin-2-yl group, R2 is a 5-, 6- or 7-membered alkyleneimino group, in which a methylene group is replaced by a carbonyl or sulfonyl group, a maleic acid imido group which is optionally mono- or disubstituted with an alkyl or phenyl group, where the substituents may be the same or different, a benzimidazol-2-yl or a 4,5,6,7-tetrahydro-benzimidazol-2-yl group which is optionally substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms, where the phenyl nucleus in one of the above said benzimidazole groups can also be substituted with a fluorine atom, an 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-b]thiazol-6-yl group, or an imidazol-4-yl group which is substituted in the 1-position with an alkyl group with 1 to 3 carbon atoms, R means an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms and R4 means a carboxy or 1H-tetrazolyl group, and their salts with inorganic or organic acids or bases. 4. Benzimidazole with the general formula I according to claim 1, characterized in that it is selected from (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-(butansultam-1-yl)-benzimidazol-1-yl ] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (d) 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazole-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-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-n-propyl-4-methyl-6-(4,5,6,7-tetrahydro- imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl -2-carboxylic acid, (i) 4 ' - [ (2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo-[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-methylbenzimidazole) -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, (1) 4'-[[2-ethyl-4-methyl-6-(butansultam-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-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H -tetrazol-5-yl)-biphenyl, (o) 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1- yl]-methyl]-biphenyl-2-carboxylic acid, (p) 4 ' -[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol- 1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (q) 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b ]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and (r) 4'-t(2-n-propyl-4-methyl- 6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid (s) 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 or bases. 5. Benzimidazole according to claim 1, characterized in that it is 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, and its salts with inorganic or organic acids or bases. 6. Benzimidazole according to claim 1, characterized in that it is 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 or bases. 7. Physiologically acceptable salts, characterized in that they are salts of compounds according to at least one of claims 1 to 6, with inorganic or organic acids or bases. 8. Medicine, characterized in that it contains a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7, possibly together with one or more inert carriers and/or diluents. 9. Use of a compound according to at least one of claims 1 to 7, for the production of a medicinal product with an angiotensin-antagonistic effect.