FI105547B - Process for the preparation of pharmaceutically useful benzimidazoles - 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

, 105547

The process for the preparation of pharmaceutically usable benzimidazoles EP-A-0392317 already discloses benzimidazoles which are valuable angiotensin antagonists.

It has now been found that benzimidazoles of general formula I can be prepared

RrC jC Vr »» 15 wherein Rή is a chlorine atom, an alkyl group of 1 to 3 carbon atoms or a trifluoromethyl group, R 2 is a 5-, 6- or 7-membered alkyleneimino group in which the methylene group may be replaced by a carbonyl or sulfonyl group, optionally an alkyl group having 1 to 3 carbon atoms or a maleic acid imido group mono- or disubstituted with a phenyl group, the substituents may be the same or different, optionally in the 1-position with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group 4,5,6,7-tetrahydrobenz-25-imidazol-2-yl, wherein the phenyl nucleus in the above benzimidazole groups may additionally be substituted by a fluorine atom, a methyl or trifluoromethyl group, an imidazo [2,1-b] thiazol-6-yl; -, imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2-yl, , imidazo [1,2-c] pyrimidin-2-30 yl, imidazo [1,2-a] pyrazin-2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8 -yl, imidazo [4,5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl or imidazo [4,5-d] pyridazin-2-yl, • pyridyl group or 2,105,547 at the 1-position with an imidazol-1-yl alkyl group substituted with 1 to 3 carbon atoms or with a benzyl group which may additionally be substituted on its carbon ring with an alkyl group having 1 to 3 carbon atoms, 5 R 3 is an alkyl group having 1 to 5 carbon atoms a cycloalkyl group having 3 to 5 carbon atoms and R4 being a carboxy or 1H-tetrazolyl group, their physiologically acceptable salts with inorganic or organic acids or bases.

For the meanings already indicated in the definition of R 1 to R 3, for example, R is a hydrogen, or chlorine atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or trifluoromethyl group, R 2 is 2-carboxyphenylmethylamino, 2-Carboxyphenylmethylenecarbo-20-ylamino, pyrrolidino, 2-methylpyrrolidino, 3-ethylpyrrolidino, 3-isopropylpyrrolidino, piperidino, 3-methylpiperidino, 4-methylpiperidino, 4-ethylpiperino, isopropylpiperidino, hexamethyleneimino, 3-methylhexamethyleneimino, 4-methylhexamethyleneimino, 3-ethylhexamethyleneimino, 4-isopropylhexamethyleneimino, 3,3-dimethylpyrrolidino, 3,4-dime -25-style-pyrrolidino-, 3,3-dimethyl-piperidino, 3,4-dimethyl-piperidino, 4,4-dimethyl-piperidino, 3,3-dimethyl-hexamethylene-imino, 3,4-dimethyl-hexamethylene-imino, 4,4- dimethylhexamethyleneimino, 3,5-dimethylhexamethylene. imino, 3,3-tetramethylene-pyrrolidino, 3,3-pentamethylene-pyrrolidino, 3,3-tetramethylene-piperidino, 3,3-pentamethylene-piperidino, 4,4-tetramethylene-piperidino, 4,4-pentamethylene-piperidino -, 3,3-tetramethylenehexamethyleneimino, 3,3-pentamethylenehexamethyleneimino, 4,4-tetramethylenehexamethyleneimino, 4,4-pentamethylenehexamethyleneimino, 2-oxopyrrolidino, • 2-oxopiperidino- , 2-oxohexamethyleneimino, propane sultam-1-yl, 3 105547 butane sultam-1-yl, pentane sultam-1-yl, maleic acid amido, maleic acid imido, 2-methyl maleic acid amido, 3-methyl maleic acid amide, -methyl maleic acid imido, 2-phenyl maleic acid amido, 3-phenyl maleic acid amido, 2-phenyl maleic acid amido, 2,3-dimethyl maleic acid amido, 5 3-methyl-2-phenyl maleic acid amido, 2-methyl-3-phenyl -methyl-3-phenylmaleic acid imido, 2,3-diphenylmaleic acid amido, 2,3-diphenylmaleic acid amido, 1-methylimidazol-4-yl- , 1-Benzyl-imidazol-4-yl, 1,2-dimethyl-imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-4-yl, 1-benzyl-2- methylimidazol-4-yl, benzimidazol-2-yl, 10-methylbenzimidazol-2-yl, 1-ethylbenzimidazol-2-yl, 1-n-propylbenzimidazol-2-yl, 1- isopropylbenzimidazol-2-yl, 1-n-butylbenzimidazol-2-yl, 1-isobutylbenzimidazol-2-yl, 1-n-pentylbenzimidazol-2-yl, 1-n-hexylbenzimidazol-2-yl- , 1-cyclopropylbenzimidazol-2-yl, 1-cyclobutylbenzimidazol-2-yl, 1-cyclopentylbenzimidazol-2-yl, 1-cyclohexylbenzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 1,5 -dimethylbenzimidazol-2-yl, 1,6-dimethylbenzimidazol-2-yl, 1,4-dimethylbenzimidazol-2-yl, 5,6-dimethylbenzimidazol-2-yl, 1,5,6- trimethylbenzimidazol-2-yl, 5-fluoro-1-methylbenzimidazol-2-yl, 6-fluoro-1-methylbenzimidazol-2-yl, 5-trifluoromethylbenzimidazol-2-yl, 5-trifluoromethyl- 20 1-methylbenzimidazol-2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyrimidin-2-yl, imidazo [1,2-a] pyrimidin-2-yl, imidazo [ 4,5-b] 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, imidazo [5S] -pyridin-4-yl, purin-8-yl, imidazo [4,5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, imidazo-25 [4,5-d] pyridazin-2-yl, and R3 is methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopropyl, cyclobutyl or cyclopentyl .

30

The compounds according to the invention are obtained by the following processes: a) Cyclization of a compound of general formula (II) 4 105547

• -0C

Wherein R 1 and R 2 are as defined above, one of X 1 or Y 1 is a group of general formula 10 -NR 6 -CH 3 - (Y) and the other of X and Y 1 is a group of general formula z, z2 - nh1, R10 and R10 are as defined above,

Re is a hydrogen atom or a group R3CO- wherein R3 is as defined above, Z1 and Z2, which may be the same or different, are optionally substituted amino groups or optionally substituted by lower alkyl groups, hydroxy-20 or mercapto groups, or Z1 and Z1 are together an oxygen or sulfur atom , optionally an imino group substituted with a C 1-6 alkyl group, an alkylenedioxy or an alkylenedithio group having 2 or 3 carbon atoms in each case, but one of the groups Xt or Y must be a group of the general formula

25 Rs

COR3 V - Q is Z1 z2 30 - / - NH - C - R3

The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, nitrile, anhydride, acid halide, ester or amide, e.g. in the presence of phosphoric acid, polyphosphoric acid, acetic anhydride, or optionally in the presence of a base such as potassium methylate or potassium tert-butylate. However, the cyclization can also be carried out in the absence of solvent and / or condensation reagent.

However, it is particularly preferred to carry out the reaction by preparing the compound of general formula II in a reaction mixture by reduction of the corresponding o-nitroamino compound 15, optionally in the presence of a carboxylic acid of general formula R 3 COOH or by acylation of the corresponding o-diamino compound. By interrupting the reduction of the nitro group to the hydroxylamine step, the next cyclization yields the oxide of the compound of general N-formula I. The N-oxide thus obtained is subsequently reduced by reduction to the corresponding compound of general formula I.

The subsequent reduction of the N-oxide of the resulting compound 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-25 nickel, platinum or Pd / C. such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulfuric acid,. salts such as iron (11) sulfate, tin (II) chloride or sodium dithionite, or hydrate. cine in the presence of Raney nickel at temperatures between 0 and 50 ° C, but preferably at room temperature.

B) Reaction of benzimidazole of general formula III 6 105547

Ri '-όφ-' "

5 H

wherein R 1 to R 3 are as defined above, with a biphenyl compound of the general formula IV: wherein R 4 is as defined above and Z 3 is a nucleophilic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or substituted a sulfonyloxy group, for example 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, dimethyl sulphoxide, dimethylformamide or benzene, optionally in the presence of at the same time also as a solvent, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.

In particular, the reaction provides a mixture of the 1 and 3 isomers which, if desired, is subsequently separated into the corresponding 1 and 3 isomers, preferably by chromatography using a support such as silica gel or alumina.

C) For the preparation of a compound of general formula I wherein R 4 is a carboxy group: 7 105547

Conversion of a compound of general formula V 0.1 wherein R 1 to R 3 are as defined above and R 4 'is a group which can be converted to a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

10

For example, functional derivatives of a carboxy group, such as their unsubstituted or substituted amides, esters, thiol esters, orthoesters, imino ethers, amidines or anhydrides, nitrile group or tetrazolyl group, and esters with aralkanols, for example benzyl ester, can be converted to a carboxy group by hydrogenolysis.

The hydrolysis is conveniently carried out in the presence of either an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol / at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture. In hydrolysis, in the presence of organic acids such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present at the same time may simultaneously be converted to the corresponding acyloxy group, such as trifluoroacetoxy.

If R4 'in the compound of general formula V has a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group by nitrite, for example sodium nitrite in the presence of an acid such as sulfuric acid, where appropriate used simultaneously as a solvent at temperatures between 0 and 50 ° C. .

For example, if R 4 'in the compound of general formula V has a tert -butyloxy-5carbonyl group, the tert-butyl group may also be cleaved in a thermally optionally inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, for example at temperatures between 40 and 100 ° C.

For example, if R 4 'in the compound of general formula V has a benzyloxycarbonyl group, then the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as Pd / C in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, , dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, for example at room temperature and hydrogen pressure of 100 to 500 kPa. Hydrogenolysis may simultaneously reduce other groups, 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 cinnamic acid group to a corresponding phenylpropionic acid group, or substituted with hydrogen atoms, e.g.

• · d) For the preparation of a compound of general formula I, wherein R 4 is a 1H-tetra-25 solyl group:

Cleavage of a protecting group from a compound of general formula VI

Av 30 Ri-Il Vr 3 r (U) - (VI): wherein 9 105547

Ru R 2 and R 3 are as defined above and R 4 "is a 1-position or 3-position protected 1H-tetrazolyl group.

Suitable protecting groups include, for example, triphenylmethyl, tributyl lithium or triphenyltinyl.

The protecting group used is preferably cleaved in the presence of halogen hydrogen, 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 room temperature, or also, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, for example, between 100 and 150 ° C, preferably between 120 and 140 ° C.

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

Reaction of a compound of general formula VII with 20 fc - µ - <Q> - m

NC

Wherein R 1 to R 3 are as defined above with hydrogen azide 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 125 ° C. Herein, either the hydrogen azide is suitably liberated during the reaction from an alkali azide, e.g. in the reaction mixture by reaction of aluminum chloride or tributyltin chloride with an alkali azide such as sodium azide, is subsequently liberated by adjusting to an acidic pH with a dilute acid such as 2N hydrochloric acid or 2N sulfuric acid.

5 f) For the preparation of compounds of general formula I wherein R 2 is one of the aforementioned benzimidazol-2-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4,5-c] pyridin-2 -yl, imidazo [4,5-b] pyrazin-2-yl, imidazo [4,5-c] pyridazin-2-yl, imidazo [4,5-d] pyridazin-2-yl or purine Of the -8-yl groups: 10

Cyclization of a compound of general formula X

bX'y '** cWdAy, x »15 D1 Y2 wherein 0, 1 or 2 of the groups A, C, or D has a nitrogen atom and the remainder of the groups A, C, or D! are methine groups, R "is hydrogen, fluoro, chloro or bromo, alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl, and one of X2 or Y2 is a group R13-NH2, and the other of X2 is X, is of the general formula 30 '-' - 'wherein R 1 R 3 and R 4 are as defined above, one of R 13 or R 14 is a hydrogen atom and the other of R 13 or R 14 is a hydrogen atom, C 1 -C 6 alkyl group or cycloalkyl group;

Zg and Zg, which may be the same or different, are optionally substituted amino groups or optionally substituted hydroxy or mercapto groups by lower alkyl groups, or

Zg and Zg together are an oxygen or sulfur atom, an imino group optionally substituted by a C 1 -C 3 alkyl group, an alkylenedioxy or alkylenedithio group having 2 or 3 carbon atoms in each case and optionally subsequent hydrolysis.

The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethylether, diethylene glycol dimethyl ether, anhydrous, , in an acid halide, ester or amide, for example at temperatures between 0 and 250 ° C, but preferably at the boiling point of the reaction mixture, optionally with a condensing reagent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic in the presence of acetic anhydride, or optionally also in the presence of a base such as potassium methylate or potassium tert-butylate. However, the cyclization can also be carried out without solvent and / or condensation reagent.

However, it is particularly preferred that the reaction be carried out such that the compound of general formula X is prepared by reduction of the corresponding o-nitroamino compound in the reaction mixture, optionally in the presence of a carboxylic acid of general formula XI are as defined above, or by acylation of the corresponding o-diamino compound with a carboxylic acid of general formula XI.

12 105547

By interrupting the reduction of the nitro group to the hydroxylamine step, the next cyclization yields the N-oxide of the compound of general formula I. The N-oxide thus obtained is subsequently converted by reduction to the corresponding compound of general formula I.

The subsequent reduction of the N-oxide thus obtained is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide in the presence of a hydrogenation catalyst such as Raney nickel, platinum or Pd / C, such as iron. , tin or zinc in the presence of an acid such as acetic acid, 10 hydrochloric acid or sulfuric acid, salts such as iron (II) sulfate, tin (II) chloride or sodium dithionite, or hydrazine in the presence of Raney nickel at temperatures between 0 and 50 .

The following hydrolysis is conveniently carried out in the presence of either 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, water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture. In the case of hydrolysis in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups which may be present may be simultaneously converted to a corresponding acyloxy group such as a trifluoroacetoxy group.

In the reactions described above, any reactive groups present, such as hydroxy, amino or alkylamino groups, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, protecting groups for a hydroxy group include a trimethyl-silyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and a protecting group for an amino, alkylamino or imino group, for example, acetyl, benzoyl , ethoxycarbonyl or benzyl group.

13 105547

The subsequent subsequent cleavage of the protecting group is preferably carried out hydrolytically in an aqueous solvent, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as hydrochloric or sulfuric acid, or an alkali base such as sodium hydroxide or hydroxide. And 100 ° C, preferably at the boiling point of the reaction mixture. However, the cleavage of the benzyl group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst such as Pd / C in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with an acid such as hydrochloric acid at 0 to 50 ° C. and at a hydrogen pressure of 100 to 700 kPa, but preferably of 300 to 500 kPa.

The mixture of isomers of the compound of general formula I thus obtained can, if desired, be advantageously chromatographically resolved using a carrier such as silica gel or alumina.

In addition, the resulting compounds of general formula I may be converted into their acid addition salts, in particular, for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids.

Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the novel compounds of general formula I so obtained, if they contain a carboxy or 1H-tetrazolyl group, are subsequently converted into their salts with inorganic or organic bases, especially their physiologically acceptable salts for pharmaceutical use. As bases. for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulas II to XIII used as starting materials are partly known in the literature or can be obtained by methods known in the literature.

14 105547.

For example, the compound of general formula II is obtained by alkylation of the corresponding o-aminonitro compound and subsequent reduction of the nitro group.

The compound of general formula III, V, VI, VII, IX, X or XII used as starting material is obtained by acylation of the corresponding o-phenylenediamine or corresponding o-aminonitro compound, subsequent reduction of the nitro group and subsequent cyclization of the o-diaminophenyl compound thus obtained cyclization of the corresponding substituted benzimidazole with the corresponding amine or alkylation of the corresponding 1H-benzimidazole NH-10, whereby the mixture of isomers thus obtained can be next separated by conventional methods, for example, chromatography. The above-mentioned starting compound compounds are described in part in EP-A-0392317.

For example, 2-n-butyl-5- (imidazo [1,2-a] pyridin-2-yl) -3H-benzimidazole is obtained by reaction of p-aminoacetophenone with butyric acid chloride, followed by nitration, bromination, ring closure with 2-aminopyridine, 6 -butanoylamido-3- (imidazo [1,2-a] pyridin-2-yl) -nitrobenzene, which is converted after the reduction of the nitro group by cyclization to the desired compound, or 2-n-butyl-4-methyl-6- ( 1-methylbenzimidazol-2-yl) -1H-benzimidazole by nitration of 3-methyl-4-n-butanoylamido-benzoic acid methyl ester, followed by reduction of the nitro group and cyclization to 2-n-butyl-4-methyl-6-methoxycarbonyl-1H-benzimidazole, is subsequently converted by cyclization with 2-methylaminoaniline to the desired compound.

Benzimidazole in which the alkoxy group at the 2-, 3-, 4- or 5-position is substituted. *. imidazole group, for example, by reaction with the corresponding 7-hydroxybenzimidazole described in EP-A-0392317, reaction with the corresponding α, ω-dihaloalkane, and subsequent reaction with the corresponding imidazole.

"105547 15

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

For example, from A = 4 '- [[2-n-butyl-7- [3- (imidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid, 10B = 4 '- [[2-n-Butyl-7- [3- (benzimidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid trifluoroacetate, C = 4'- [[2-n-Butyl-4-methyl-7- [4- (tetrahydrobenzimidazol-1-yl) butyloxy] benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, 15 D = 4 '- [[2 -n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, E = 4 '- [[2-n-propyl-4-methyl -6- (1-methylbenzimidazol-2-yl) benzimidazol-20-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, F = 4 '- [[2-n-propyl-4 -methyl-6- (1-oxoisoindolin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, 25 G - 4 '- [[2-n- propyl 4-methyl-6- (butanesulfam-1-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl, N -. H = 4, - [[2-n-Butyl-6- (2,3-dimethyl-maleic acidamino) -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid semihydrate, 30 L = 4 '- [[2 -n-Butyl-6- (isopropylcarbonylamino) -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, J = 4 '- [[2-n-butyl-4-methyl-6- (morpholinocarbonylamino) benzimidazole -1-yl] methyl] biphenyl-2-carboxylic acid, 16 105547 K = 4 '- [[2-n-butyl-6- (cyclohexylaminocarbonylamino) -4-methylbenz-5-imidazol-1-yl] methyl] biphenyl-2 -carboxylic acid semitrifluoroacetate, L = 4 '- [[2-n-butyl-7- [3- (imidazol-1-yl) propyloxy] -4-methylbenzimidazol-1-yl] methyl] -2- (1H- tetrazol-5-yl) biphenyl, 10 M = 4 '- [(2-cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid , N = 4 '- [(2-n-Propyl-4-methyl-6- (1-methyl-5-fluorobenzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, 15 O = 4 '- [(2-n-propyl-4-methyl-6- (im idazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl, P = 4 '- [( 2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-20-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, Q = 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl, 25 R = 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl ] -2- (1H-tetrazol-5-yl) biphenyl hydrochloride and η 5, S = 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1-b] thiazol-6) -yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid was studied for their biological effects as follows:

DESCRIPTION OF THE METHODS Binding to the anaiotensin II receptor 17 105547

Tissue (rat lung) is homogenized in Tris buffer (50 mM Tris, 150 mM NaCl, 5 mM EDTA, pH 7.40) and centrifuged twice at 20,000 x g for 20 min each. The final pellet is resuspended in incubation buffer (50 mM Tris, 5 mM MgCl 2, 0.2% BSA, pH 7.40) 1:75, based on wet weight of tissue. In each case, 0.1 ml of homogenate is incubated for 60 min at 37 ° C with increasing concentrations of 50 µM [125 I] -angiotensin II (NEN, Dreieich, FRG) and test substance in a total volume of 0.25 ml. The incubation is terminated by rapid filtration through a glass fiber filter mat. The filters are each washed with 4 mL of ice-cold buffer (25 mM Tris, 2.5 mM MgCl 2, 0.1% BSA, pH 7.40). Bound radioactivity is measured with a gamma counter. The IC 50 value is determined from the dose-response curve.

Substances A to S show the following IC50 values in the following test: 15 substance IC · *, [nM] A 510.0 B 52.0 C 130.0 D 3.7 20 E 14.0 F 5.0 G 1.2 H 20.0 I 6.6 25 J 3.5 K 17.0 L 240.0 M 12.0 ,. N, 26.0. 30 O 3.4 P 1.2 Q 1.7 R 20.0 S 7.8 35 ie 105547

In addition, compounds D, E, F, G, H, M, and O were tested for activity in awake renal hypertensive rats following oral administration by methods known in the literature. At a dose of 10 mg / kg, these compounds showed an antihypertensive effect.

In addition, administration of the above compounds to a dose of 30 mg / kg i.v. no toxic side effects could be observed, for example no negative inotropic effect or any cardiac arrhythmia. Accordingly, the compounds are very acceptable.

10

Based on their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the treatment of hypertension and cardiac insufficiency, for the treatment of ischemic peripheral blood flow disorders, for myocardial infarction, for the treatment of diseases.

Further, the novel compounds and their physiologically acceptable salts are useful in the treatment of pulmonary diseases, for example, pulmonary edema and chronic bronchial tubes, to prevent vasoconstriction after vascular molding, vascular wall thickening after vascular surgery, arterial wall disease, and hardening of the artery wall. For the release of acetylcholine and dopamine via angiotensin action in the brain, new angiotensin antagonists are also useful in the treatment of central nervous system disorders such as depression, Alzheimer's disease, Parkinson's. syndrome, bulimia, as well as impaired consciousness.

In order to achieve the same effect in adults, the dosage required is suitably 30-100 mg for intravenous administration, preferably 30-70 mg, and for oral administration 50-200 mg, preferably 75-150 mg, 1-3 times daily. For this purpose, the compounds of general formula I prepared according to the invention may optionally be processed in combination with other active substances, such as antihypertensives, diuretics and / or calcium antagonists, together with 1 or more inert conventional media and / or diluents, e.g. starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, carbylene glycol, propylene glycol, propylene glycol, vegetable fat or suitable mixtures thereof, for conventional galenical preparations such as tablets, granules, capsules, powders, suspensions or lozenges.

Thus, for the above combinations, other active ingredients include, for example, bendoflumethiazide, chlorothiazide, hydrochlorothiazide, spirololactone, benzthiazide, cyclothiazide, ethacrylic acid, furosemide, metoprolol, prazosin, atenolipol, , nisoldipine and nitrendipine. The dosage of these active ingredients is conveniently between 1/5 of the lowest dose normally used and 1/1 of the dose normally used, for example 15-200 mg hydrochlorothiazide, 125-2000 mg 20 chlorothiazide, 15-200 mg ethacrylic acid, 5-80 mg furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg of nitredipine.

The following examples further illustrate the invention:

Example 1 4,4 -if2-n-Butyl-7- [5- (imidazole-1-vin-pentyloxy-4-methyl-benzimidazol-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-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2- Carboxylic acid tert.-butyl ester • Dissolve in 35 ml of methylene chloride, add 5 ml of trifluoroacetic acid and stir for 12 hours at room temperature. Dilute with methylene chloride and shake with water and saturated sodium bicarbonate solution. 0.063-0.02 mm, 5 ethyl acetate / ethanol / ammonia = 90.10: 0.1) and crystallized from acetone.

Yield: 0.19 g (29.9% of theory),

Melting point: 185-187 ° C.

Calc'd: C 71.81 H 7.09 N 9.85 10 Found: 72.03 7.19 9.71

Mass spectrum: m / e = M + 550

According to Example 1, the following compounds are obtained: 4 '- [[2-n-Butyl-4-methyl-6- (4,5-dihydro-2H-pyridazin-3-one-6-yl) -benzimidazole-1] -yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (4,5-dihydro-2H-pyridazin-3-one-6-yl) -benzimid - azol-1-yl] -methyl] -biphenyl-2-carboxylic acid 20 '- [[2-Ethyl-4-methyl-6- (4,5-dihydro-2H-pyridazin-3-one-6-yl) ) Benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Butyl-4-methyl-6- (phenylaminocarbonylamino) -benzimidazol-1-25-yl] -methyl] -biphenyl- 2-carboxylic acid; 4, - [[2-Ethyl-4-methyl-6- (cyclohexylaminocarbonylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 30 '- [[2-n-Propyl-4- methyl 6- (cyclohexylaminocarbonylamino) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-Butyl-4-methyl-6- (cyclohexylaminocarbonylamino) benzimidazol-1] -yl] -methyl] -biphenyl-2-carboxylic acid 21 105547 4 '- [[2-n-Propyl-4-methyl-6- (methylaminocarbonylmethyl-amino) -benzimid-5-azol-1-yl] -methyl] -biphenyl-2 -carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (n-pentynaminocarbonyl-methylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 10 4' - [[ 2-n-Propyl-4-methyl-6- (n-pentylaminocarbonylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (n-Butylaminocarbonylmethylamino) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 15 4 '- [[2-n-Propyl-4-methyl-6- (benzylaminocarbonylamino) -benzimidate sol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (allylaminocarbonylamino) -benzimidazol-1-20-yl] -methyl] -biphenyl-2 -carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (cyclohexylaminocarbonyl-methylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 25' - [[2-n- Propyl 4-methyl-6- (dimethylaminocarbonylmethylamino) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid ·. · 4 '- [[2-n-Propyl-4-methyl-6- (dimethylaminocarbonylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 30 4' - [[2-n-Propyl-4 -methyl-6- (cyclohexylaminocarbonyl-n-butylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-propyl-4-methyl-6- (methylaminocarbonyl-cyclohexylamino) -benzimidazole -1-yl] -methyl] -biphenyl-2-carboxylic acid 22 105547 4 '- [[2-n-Propyl-4-methyl-6- (methylaminocarbonyl-benzylamino) -benz-5-imidazol-1-yl] -methyl] -biphenyl -2-Carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (n-hexylaminocarbonyl-cyclohexylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 10 4' - [[2- n-Propyl-4-methyl-6- (cyclohexylaminocarbonyl-ethylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (Dimethylaminocarbonyl-n-pentylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 15 4 '- [[2-n-Propyl-4-methyl-6- (morphol) inocarbonylamino) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (pyrrolidinocarbonylamino) benzimidazol-1-20 yl] methyl] - biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (pyrrolidinocarbonyl-methylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 25' - [[ 2-n-Propyl-4-methyl-6- (piperidinocarbonylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (3) -Benzyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinon-1-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 30 23 105547

Example 2 4MT2-n-Butyl-7-β-imidazol-1-yl-propyloxy-4-methyl-benzimidazole-1-vin-methyl-biphenyl-2-carboxylic acid 5

Prepared according to Example 1 4 '- [[2-n-Butyl-7- [3- (imidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2 -carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 69.4% of theory, Melting point: 208-210 ° C C 32 H 34 N 4 O 3 (522.64)

Calc'd: C, 73.54; H, 6.56; N, 10.72. Found: 73.45, 6.62, 10.60

Rf Value: 0.50 (silica gel; acetic ester / ethanol / ammonia = 50: 45: 5)

Example 3 4, -R 2 -N-Butyl-7- [3- (benzimidazol-1-yl) -propyloxy] -4-methyl-benzimidazole-1-yl] -methyl-biphenyl-2-carboxylic acid trifluoroacetate

Prepared according to Example 1 4 '- [[2-n-Butyl-7- [3- (benzimidazol-1-yl) -propyloxy) -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid. acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 87.8% of theory,

Melting point: 221-223 ° C

CNA x CF3COOH (686.72)

H, 5.43; N, 8.15. Found: 66.58 5.62 8.31

Rf Value: 0.45 (silica gel; acetic ester / ethanol / ammonia = 50: 45: 5)

Example 4 105547 4 - [[2- (N-Butyl) -7- [4- (imidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid hydrate

Prepared according to Example 1 4 '- [[2-n-Butyl-7- [4- (imidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl -acid tert-butyl ester and trifluoroacetic acid in methylene chloride. Yield: 68.5% of theory, Melting point: 126-128 ° C CssHseNAxHaO (554.68)

Calc'd: C 71.46 H 6.91 N 10.10 Found 71.63 7.02 9.98

Mass spectrum: m / e = 53615

Example 5 4'-η 2 -N-Butyl-7- [2- (benzimidazol-1-yl) -ethoxyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared according to Example 1 4 '- [[2-n-butyl-7- [2- (benzimidazol-1-yl) ethoxy] -4-methylbenzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 78.1% of theory, Melting point: 167-169 ° C C35H34N403 (558.68)

Calcd: C 75.25 H 6.13 N 10.03. Found: 75.03 6.17 9.95 25 105547

Example 6 4'-tR-2-n-Butyl-7- [5- (Benzimidazol-1-yl) -pentloxy] -4-methyl-benzimidazole-1-methyl-methyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 4 '- [[2-n-Butyl-7- [5- (benzimidazol-1-yl) -pentyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxyl -acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 7 4, - [2-n-Butyl] -7- [4- (benzimidazol-1-yl] butyloxy] -methyl-benzimidazole-1-yl] -biphenyl] -2-carboxylic acid Prepared according to example 1 4 '- [[2-n- butyl 7- [4- (benzimidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 8 20 4 - [[2-n-Butyl] -4-methyl-7- [4- (tetrahydro-benzimidazol-1-yl) -butyloxy] -benzimidazol-1-yl] -methyl] -biphenyl} -carboxylic acid

Prepared according to Example 1 4 '- [[2-n-Butyl-4-methyl-7- [4- (tetrahydro-25-benzimidazol-1-yl) -butyloxy] -benzimidazol-1-yl] -methyl] -biphenyl- From 2-carboxylic acid tert-butyl ester and trifluoroacetic acid from methylene chloride. tetrachloride.

Yield: 86% of theory,

Melting point: 229-231 ° C 30 C37H42N403 (590.76)

Calcd: C 75.23 H 7.17 N 9.48 Found: 75.34 7.06 9.38 t m 26 105547

Example 9 4I-β2-n-ProDIII-4-methyl-6-ylmethyl-benzimidazol-2-yl-phenylimidazol-1-yl-methyl-biphenyl-2-carboxylic acid 5

Prepared according to Example 1 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 theory, Melting point: 261-263 ° C C 33 H 30 N 4 O 2 (514.60)

Calcd: C 77.02 H 5.87 N 10.89 Found: 76.90 5.85 10.99 The following compounds are obtained according to Example 9: 4 '- [[2-n-Propyl-4-methyl-6] - (1-n-Propyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 20 4 '- [[2-n-Propyl-4-methyl-6- (1-n) -hexylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (1-cyclopropylbenzimidazol-2-yl) benzimidazole - azol-1-yl] -methyl] -biphenyl-2-carboxylic acid 25 '- [[2-n-Propyl-4-methyl-6- (1-cyclohexyl-benzimidazol-2-yl) -benzimidazol-1-yl] ] -methyl] -biphenyl-2-carboxylic acid 27 105547

Example 10 4'-η 2 -N-Propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl]

To a solution of 1.60 g (3.3 mmol) of 4 '- [[2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-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. Thereafter, water is added and the precipitate is removed by suction. The crude product thus obtained is purified by chromatography on silica gel (300 g silica gel, methylene chloride + 6% ethanol).

Yield: 900 mg (51% of theory),

Melting point: 228-230 ° C 15 C 33 H 30 N 8 (538.70)

Found: C 73.58 H 5.61 N 20.80 Found: 73.48 5.55 20.70

According to Example 10, the following compounds are obtained: 4 - [[2-n-Propyl-4-methyl-6- (1-n-hexyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- ( 1H-Tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-4-methyl-6- (1-cyclobutyl-benzimidazol-2-yl) -benzimid-25-azol-1-yl] - methyl] -2- (1H-tetrazol-5-yl) biphenyl; 4 '- [[2-n-Propyl-4-methyl-6- (1-cyclohexylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) ) -Biphenyl 30 4 '- [[2-n-Butyl-4-methyl-7- [2- (imidazol-1-yl) -ethoxy] -benzimidazol-1-yl] -methyl] -2- (1H- tetrazol-5-yl) -biphenyl 28 105547 4'-t [2-n-Butyl-7- [3- (imidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -2 - (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-7- [4- (imidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-5-yl Methyl] -2- (1 H -tetrazol-5-yl) benzenyl 4 '- [[2-n-butyl-4-methyl-7- [5 - (imidazol-1-yl) -pentyloxy] benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 10 4 '- [[2-n-Butyl -7- [2- (Benzimidazol-1-yl) -ethoxy] -4-methyl-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n -Butyl-4-methyl-7- [3- (benzimidazol-1-yl) -propyloxy] -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-7- (4- (ben Zimidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-4-methyl] -7- [5- (Benzimidazol-1-yl) -pentyloxy] -benzimid-20-azol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-7- [2- (4,5,16,7-tetrahydrobenzimidazol-1-yl) ethoxy] -4-methylbenzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl 25 '- [[2-n-Butyl-4-methyl-7- [3- (tetrahydrobenzimidazol-1-yl) propyloxy] benzimidazol-1-yl] methyl ] -2- (1H-tetrazol-5-yl) biphenyl-4 '- [[2-n-Butyl-7- [4- (tetrahydrobenzimidazol-1-yl) -butyloxy] -4-methyl-benzimidazol-1-one. yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 30 9 4 '- [[2-n-Butyl-4-methyl-7- [5- (tetrahydrobenzimidazol-1-yl) pentyloxy] ] - Benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl 4 '- [[2-n-Butyl-4-methyl-6- (phenylaminocarbonylamino) -benzimidazol-1- yy) i -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 29 1 05547 4 '- [[2-Ethyl-4-methyl-6- (cyclohexylaminocarbonylamino) -benzoimidazol-1-5-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4' - [[ 2-Propyl-4-methyl-6- (cyclohexylaminocarbonylamino) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 10 4 '- [[2-n-Butyl -4-Methyl-6- (cyclohexylaminocarbonylamino) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-4- methyl 6- (methylaminocarbonylmethylamino) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 15 4 '- [[2-n-Propyl-4-methyl-6 - (n-Pentylaminocarbonyl-methylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -benzenyl 4 '- [[2 -n-Propyl-4-methyl-6- (n-pentylaminocarbonylamino) -benzimidazol-20'-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [ [2-n-Propyl-4-methyl-6- (n-butylaminocarbonylmethyl-amino) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 25 '- [[ 2-n-propyl-4-methylene over-6- (benzylaminocarbonylamino) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl. ·. 4 '- [[2-n-Propyl-4-methyl-6- (allylaminocarbonylamino) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 30 4' - [[ 2-n-Propyl-4-methyl-6- (cyclohexylaminocarbonyl-methylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 105547 4 '- [[2-n -Propyl-4-methyl-6- (dimethylaminocarbonylmethylamino) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 30 4 - [[2-n-Propyl-4 -methyl-6- (dimethylaminocarbonylamino) -benzimidazol-5-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-4-methyl-6 - (cyclohexylaminocarbonyl-n-butylamino) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl 10 4 '- [[2-n-Propyl-4-methyl-6 - (Methylaminocarbonylcyclohexylamino) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 4 '- [[2-n-Propyl-4-methyl-6- (methylaminocarbonylbenzylamino) benz -imidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 15 4 '- [[2-n-Propyl-4 -methyl-6- (n-hexylaminocarbonyl-cyclohexylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-4-methyl-6 - (cyclohexylaminocarbonyl-ethylamino) -benz-20-imidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-4-methyl-6 - (dimethylaminocarbonyl-n-pentylamino) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 25 4, - [[2-n-Propyl-4-methyl -6- (morpholinocarbonylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl ». 4 '- [[2-n-Propyl-4-methyl-6- (pyrrolidinocarbonylamino) -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) -biphenyl [[2-n-Propyl-4-methyl-6- (pyrrolidinocarbonylmethylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2- n-Propyl-4-methyl-6- (pipendinocarbonylmethylamino) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 31 105547 4 '- [[2-N -Propyl-4-methyl-6- (3-benzyl-3,4,5,6-tetrahydro-2- (1H) pyrimidinon-5-yl) benzimidazol-1-yl) methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl

Example 11 4'-Rf-2-n-Propyl-4-methyl-6-phthalimino-benzimidazol-1-yl) -methyl-2- (1H-10-tetrazole-5-yl-biphenyl)

Prepared according to Example 10 from 4 '- [(2-n-propyl-4-methyl-6-phthalimino-benzimidazol-1-yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 6.8% of theory,

Melting point: from 160 ° C sintered C33H27N702 (553.60)

Calc'd: C 71.59 H 4.92 N 17.71 Found: 71.39 4.88 17.54 20

Example 12 4'- (2-n-Butyl-4-methyl-6-phthalimino-benzimidazol-1-yl) -methyl-2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [(2-n-butyl-4-methyl-6-phthalimino-benzimidazol-1-yl) -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 7.1% of theory, Melting point: From 150 ° C, sintered C34H29N702 (567.70)

Calc'd: C 71.94 H 5.15 N 17.27 • Found: 71.75 5.19 17.22 32 105547

Example 13 4'-fr2-n-Propyl-4-methyl-6- (1-oxo-isoindolin-2-yl-benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-methyl-6- (1-oxo-isoindolin-2-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 25.0% of theory, Melting point: From 170 ° C sintered C33H29N70 (539.60)

H, 5.42; N, 18.17

Found: 73.20 5.41 18.33 Example 14 4l-trans-2-n-Butyl-4-methyl-6- (1-oxo-isoindolin-2-yl) -benzimidazol-1-yl-methyl] -2- (1H) -tetrazol-5-yl) -biphenyl Prepared according to example 10 4 '- [[2-n-butyl-4-methyl-6- (1-oxo-isoindolin-2-yl) -benzimidazol-1-yl] - methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

Yield: 21.0% of theory,

Melting point: from 165 ° C to 2534 ° C to 31 ° C (553.70)

Calc'd: C, 73.76; H, 5.64; N, 17.71

Found: 73.58 5.33 17.41 33 105547

Example 15 4, -R 2 -N-Propyl-4-methyl-6- (butane-sultam-1-yl-benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-methyl-6- (butanesulfonyl-Tam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide dimethylformamide.

Yield: 49.0% of theory, Melting point: From 186 ° C sintered C29H31N702S (541.70)

H, 5.77; N, 18.10; S, 5.92

Found: 64.10 5.39 18.01 5.98 Example 16 4 - [[2-Ethyl-4-methyl-6- (butane-sultam-1-yl] -benzimidazol-1-yl] -methyl] -2- (1H) -tetrazol-5-yl-biphenyl Prepared according to Example 10 from 4 '- [[2-ethyl-4-methyl-6- (butanesulfam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide Yield: 60.0% of theory,

Melting point: amorph, from 194 ° C sintered C28H29N702S (527.70) 25 Calc'd: C 63.74 H 5.54 N 18.58 S 6.08

Found: 63.83 5.66 18.41 5.82 34 105547

Example 17 4, N -butyl-4-methyl-e- (butane-sultam-1-win-benzimidazol-1-win-methyl-2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4, [[2-n-butyl-4-methyl-6- (butanesulfam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide. Yield: 48.0% of theory,

Melting point: amorph, from 183 ° C sinter 10 C 30 H 33 N 7 O 2 S (555.70)

H, 5.99; N, 17.64; S, 5.77

Found: 64.53 5.66 17.63 5.55

Example 18 15R-N-Propyl-m-ethyl-e-f-butanesulfam-1-win-benzimidazol-1-ylmethyl] -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to example 10 from 4 '- [[2-n-propyl-4-ethyl-6- (butanesulfam-20-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide. Yield: 27.0% of theory,

Melting point: amorph, from 189 ° C sintered with C 30 H 33 N 7 O 2 S (555.70)

Calc'd: C 64.84 H 5.99 N 17.64 S 5.77 25 Found: 64.81 5.68 17.87 5.31 35 105547

Example 19 4'-trans-4-ethyl-4-ethyl-6- (butanesulfam-1-yl-benzimidazol-1-ylmethyl) -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [[2-ethyl-4-ethyl-6- (butanesulfam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 39.0% of theory, Melting point: amorph, from 212 ° C sintered with C29H31N702S (541.70)

H, 5.77; N, 18.10; S, 5.92

Found: 64.30 5.51 17.99 5.59 Example 20 4, -IT2-n-Propyl-4-isopropyl-6- (butane-sultam-1-phenyl-benzimidazol-1-yl) -methyl] -2- MH-Tetrazol-5-yl-10-biphenyl Prepared according to Example 10 4 '- [[2-n-propyl-4-isopropyl-6- (butane-sultam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide Yield: 22.0% of theory.

Melting point: amorph C ^ HH ^N ((569.70) 25 Calc .: C 65.35 H 6.19 N 17.21 S 5.63

Found: 65.13 6.10 17.54 5.40 36 105547

Example 21 4'-β-Ethyl-4-isopropyl-β- (butane-sultam-1-yl-benzimidazol-1-ylmethyl) -2- (1H-tetrazol-5-yl) -biphenyl

Prepared according to Example 10 from 4 '- [[2-ethyl-4-isopropyl-6- (butanesulfonyl-Tam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide. Yield: 24.0% of theory,

Melting point: amorph, from 209 ° C, sintered with 10

Calc'd: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.99 5.71 17.43 5.71

Example 22 4, 4-T2-n-Propyl-4-trifluoromethyl-6 - (, butane-sultam-1-yl) -benzimidazole-1-methyl-methyl-2- (1H-tetrazol-5-yl) -biphenyl

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-trifluoromethyl-6-20 (butane-sultam-1-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 17.0% of theory,

Melting point: 199-203 ° C C29H28F3N702S (595.70) 25 Calc .: C 58.48 H 4.74 N 16.46 Found: 58.28 4.43 16.22 37 105547

Example 23 N-Propyl-N-methyl-N-benzenesulfonyl-methylaminol-benzimidazol-1-yl] -methyl-2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-methyl-6- (N-benzenesulfonyl-methylamino) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 42.0% of theory, Melting point: 161-163 ° C C 32 H 31 N 7 O 2 S (577.70)

Calcd: C 66.53 H 5.41 N 16.97 S 5.55 Found: 66.32 5.36 16.70 5.31 Example 24 4, -ff 2-n-Butyl-4-methyl-6 - (N-Benzenesulfonyl-methylamino) -benzimidazole-1-yl] -methyl-2- (1H-tetrazol-5-yl) -biphenyl Prepared according to Example 10 4 '- [[2-n-butyl-4-methyl-6- (N- benzenesulfonyl-methyl-amino) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 37.0% of theory,

Melting point: 150-153 ° C 25 C33H33N702S (591.70)

Calc'd: C, 66.98; H, 5.62; N, 16.57

Found: 66.71 5.38 16.39

According to Example 24, the following compounds are obtained: 4 '- [[2-Ethyl-4-methyl-6- (4,5-dihydro-2H-pyridazin-3-one-6-yl) benzimidazol-1-yl] methyl ] -2- (1H-tetrazol-5-yl) -biphenyl 38 105547 4 '- [[2-n-Propyl-4-methyl-6- (4,5-dihydro-2H-pyridazin-3-one) 6-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 4 - [[2-n-Butyl-4-methyl-6- (4 , 5-Dihydro-2H-pyridazin-3-one-6-yl) -benzimid-5-azol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[ 2-n-Propyl-4-methyl-6- (3-benzyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinon-1-yl) -benzimidazol-1-yl] -methyl] -2- (1H-Tetrazol-5-yl) -biphenyl 10 - [(4-ethyl-4-methyl-6S-benzyl-5S, 6S-tetrahydro-1H) -pyrimidinon-1-yl] -benzimidazol-1 yl) methyl] -2- (1 H-tetrazol-5-yl) biphenyl

Example 25 4'-ΓΓ2-η-Βιι1ννϋ-4-ηηΘΐννΙί-β- (1-methylbenzimidazol-2-yl) benzimidazole-1-ylmethyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 4 '- [[2-n-Butyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid-20 tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 48.0% of theory,

Melting point: 233-235 [deg.] C. [deg.] C. (528.70)

Calc'd: C 77.25 H 6.10 N 10.60 25 Found: 77.10 5.98 10.46 39 105547

Example 26 4'-IT2-n-Butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] -C1H-tetrazol-5-yl] biphenyl]

Prepared according to Example 10 from 4 '- [[2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2-cyano-biphenyl and sodium azide dimethylformamide.

Yield: 41.0% of theory, Melting point: 235-237 ° C C34H32N8 (552.70)

Calcd: C, 73.89; H, 5.84; N, 20.28. Found: 73.67; 5.81; 19.93. Example 26 gives the following compounds: 4 '- [[2-n-Butyl-4-methyl-6] - (1-Ethylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) -biphenyl 20 4 '- [[2-n-Butyl-4-methyl- 6- (1-Cyclopropyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-4- methyl 6- (1-n-pentylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 25 '- [[2-n-Butyl -4-Methyl-6- (1-cyclopentyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 40 105547

Example 27 4, -R 2 -N-Propyl-4-methyl-e- (2-oxo-piperidin-1-yl) -benzimidazole-1-vinyl-methyl-2- (1H-tetrazol-5-yl) - bifenwli 5

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-methyl-6- (2-oxo-piperidin-1-yl) -benzimidazol-1-yl] -methyl] -2-cyanobiphenyl and sodium azide -dist in dimethylformamide.

Yield: 51.0% of theory, Melting point: amorph, from 140 ° C sintered with C30H31N7O (505.60)

Calc'd: C, 71.26; H, 6.18; N, 19.39. Found: 71.08, 6.22, 19.47. Example 28 4, -? - n -Butyl-4-methyl-6- (2-oxo-piperidine). -1-methyl) benzimidazole-1-vinylmethyl-2- (1H-tetrazol-5-yl) biphenyl Prepared according to Example 10 4 '- [[2-n-butyl-4-methyl6- (2-oxo) piperidin-1-yl) benzimidazol-1-yl] methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.

*

Yield: 39.0% of theory,

Melting point: amorph, from 128 ° C sinter 25 C31H33N70 (519.70)

Calc'd: C 71.65 H 6.40 N 18.87 Found: 71.44 6.23 18.59

Example 29 41 105547 4'-Fr 2 -N-Pro-Dyl-4-methyl-6- (2-oxo-piperidin-1-yl-benzimidazole-1-yl-methyl--2- (1H-tetrazol-5-fluoro-biphenyl) 5

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

Yield: 51.0% of theory, Melting point: amorph, from 115 ° C sintered with C30H31N7O (505.60)

Calcd: C 71.26 H 6.18 N 19.39 Found: 71.51 6.39 19.09 Example 30 4'-η 2 -N-propyl-6- (imidazor. 2-a-pyridin-2-yl). Benzimidazol-1-ylmethyl-biphenyl-2-carboxylic acid Prepared according to example 1 4 '- [[2-n-propyl-6- (imidazo [1,2-a] pyridin-2-yl) -benzimidazole] 1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

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Yield: 54.0% of theory,

Melting point: 202-204 ° C 25 C 31 H 26 N 4 O 2 (486.60)

Calc'd: C 76.52 H 5.39 N 11.52 Found: 76.33 5.32 11.30

The following compounds are obtained according to Example 30: 4 '- [[2-n-Propyl-6- (8-methyl-imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl -2-Carboxylic acid 105547 42 4 '- [[2-n-Butyl-6- (6-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] biphenyl -2-Carboxylic acid 4, - [[2-n-Propyl-6- (5,7-dimethylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-5 yl] methyl] biphenyl -2-Carboxylic acid 4 '- [[2-n-Propyl-6- (6-aminocarbonyl-imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl 1-2-Carboxylic acid 10 4 '- [[2-n-Butyl-6- (6-chloroimidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] methyl] - biphenyl-2-carboxylic acid 4, - [[2-n-Propyl-6- (imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4' - [[2 -n-Butyl-6- (2,3-dimethylimidazo [2,1-b] thiazol-6-yl) benzene simidazol-1 -20-yl] -methyl] -biphenyl-2-carboxylic acid

Example 31 • '4'-f [2-n-Butyl-6- (imidazor-2-a] pyridin-2-yl') - benzimidazole-1-yl] -methyl] -25-biphenyl-2-carboxylic acid

Prepared according to Example 1 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 theory,

Melting point: 193-195 ° C C 32 H 28 N 4 O 2 (500.60) »43 105547

Calc'd: C 76.78 H 5.64 N 11.19 Found 76.73 5.48 11.00

Example 32 5'-tert-2-n-Propyl-6- (imidazol-2-atovidin-2-yl) -benzinnidazole-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - Biphenyl

Prepared according to Example 10 from 4 '- [[2-n-propyl-6- (imidazo [1,2-a] pyridin-10 2-yl) -benzimidazol-1-yl] methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 28.0% of theory,

Melting point: 187-189 ° C C 31 H 26 N 8 (510.60) 15 Calc .: C 72.92 H 5.13 N 21.95

Found: 72.80 4.97 21.74

According to Example 32, the following compounds are obtained: 20 4 '- [[2-n-Propyl-6- (7-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Propyl-6- (5-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1] - yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 25 4 - [[2-n-Butyl-6- (6-bromoimidazo [1,2-a] pyridin-2) -yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl-4 '- [[2-n-Propyl-6- (5,7-dimethyl-imidazo] [1,2-a] Pyrimidin-2-yl) -benzimidazol-30'-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n- Butyl 6- (3-methylimidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 44 105547 4 '- [[2-n-propyl-6- (2-phenyl-imidazo [2,1-b] thiazol-6-yl) -benzimidazol-1-yl] -methyl] -2- ( 1H-tetrazol-5-yl) biphenyl

Example 33 5 '- [[2-n-Butyl] -6-imidazor-2-a-pyridin-2-yl] benzimidazol-1-yl] -methyl-2H-tetrazol-5-yl] -biphenyl

Prepared according to Example 10 from 4, - [[2-n-butyl-6- (imidazo [1,2-a] pyridin-2-10 yl) -benzimidazol-1-yl] methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide . Yield: 23.0% of theory,

Melting point: 170-173 ° C C 32 H 28 Ne (524.60)

Calc'd: C 73.26 H 5.38 N 21.36 Found: 73.09 5.32 21.20

Example 34 N -proteinv-M-methyl-e-flmidazo [1,2-a] benzyl-2-yl] benzimidazole-1 -20 [mu] l-methyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 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 theory,

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

Melting point: 299-303 ° C (methylene chloride / ethanol = 20: 1). C32H28N402 (500.60)

Calc'd: C 76.78 H 5.64 N 11.19 30 Found: 76.55 5.61 10.87

According to Example 34, the following compounds are obtained: 45 105547 4 '- [[2-n-Propyl-4-methyl-6- (8-methylimidazo [1,2-a] pyridin-2-yl) -benzimidazole] 1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Butyl-4-methyl-6- (7-methyl-imidazo [1,2-a] pyridin-2-yl) -benzimidate- 5-Azol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 - [[2-n-Butyl-4-methyl-6- (6-methyl-imidazo [1,2-a] pyridin-2-yl) -Benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 10 4 '- [[2-n-Propyl-4-methyl-6- (5-methyl-imidazo [1,2-a] pyridine) -2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl-6- (5,7-dimethyl-imidazo [1 , 2-a] Pyridin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 15 '- [[2-Ethyl-4-methyl-6- (6-aminocarbonyl) - Imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-Ethyl-4-methyl-6- (6-chloro) imidazo [1,2-a] pyridin-2-yl) benzimidazol-1-20 yl) methyl] biphenyl-2-carb acid A

Example 35 4 · 4'-η 2 -N-Propyl-4-methyl-ε - (imidazo [1,2-a] pyridine-2-naphthyl-benzimidazole-1 -25 η 1 -methyl-2- (1H-tetrazol-5-η 10 - Biphenyl

Prepared according to Example 10 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 theory,

Melting point: from 181 ° C sintered C32H28N8 (524.60), c 105547 46

Calc'd: C 73.26 H 5.38 N 21.36 Found: 73.10 5.24 21.13

According to Example 35 the following compounds are obtained: 5 '- [[2-n-Propyl-4-methyl-6- (5-methylimidazo [1,2-a] pyridin-2-yl) -benzimidazole-1]. -yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 44 - [2H] -propyl-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) -benzimidazol-1-yl] 10-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Example 36 4,4-N-Butyl-4-methyl-6-imidazo [1,2-a] pyridin-2-yl-benzimidazol-1-yl] -15-methyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 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 theory,

Melting point: 194-197 ° C C33H30NA (514.60)

Calc'd: C 77.02 H 5.88 N 10.89 Found: 76.81 5.78 10.64 25

According to Example 36, the following compounds are obtained: 4, - [[2-n-Propyl-6- (pyrrolidin-2-on-5-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 4'- [[2-n-Propyl-6- (pyrrolidin-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 47 105547 4 '- [[2-n-Propyl-6- (quinoline) -2-yl) -benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid 4 '- [[2-n-Butyl-6- (quinolin-2-yl) -benzimidazol-1-yl] -methyl] biphenyl-2-carb-5 -oxylic acid 4 '- [[2-n-Propyl-6- (isoquinolin-3-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 10 4' - [[ 2-Ethyl-6- (isoquinolin-3-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Example 37 4'- [[2-n-Butyl] -4-methyl-6-fimidazo [1,2-a] pyridin-2-yl] benzimidazole-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 4 '- [[2-n-Butyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano. biphenyl and sodium 20 azide in dimethylformamide.

Yield: 26.0% of theory, C33H30N8 (538.60)

Calc'd: C 73.58 H 5.61 N 20.80 Found: 73.39 5.40 20.92 25

According to Example 37, the following compounds are obtained: 4 '- [[2-n-Propyl-6- (pyrrolidin-2-one-5-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazole). 5-yl) -biphenyl 30 4 '- [[2-n-Propyl-6- (pyrrolidin-2-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) - biphenyl 48 105547 4 '- [[2-n-Propyl-6- (pipericlin-2-one-6-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-6- (piperidin-2-one-6-yl) -benzimidazol-1-yl] methyl] -2- (1H-5-tetrazol-5-yl) - biphenyl 4 - [[2-n-Propyl-6- (piperidin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 10 4 '- [ [2-n-Butyl-6- (piperidin-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-Ethyl- 6- (Pyridin-2-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 15 4 '- [[2-n-Propyl-6- (pyridin- 2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [[2-n-Butyl-6- (pyridin-2-yl) - benzimidazol-1-yl] -Met yl] -2- (1H-tetrazol-20-yl) -biphenyl 4 '- [[2-n-Propyl-6- (quinolin-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 25 '- [[2-n-Butyl-6- (quinolin-2-yl) -benzimidazol-1-yl] -methyl] -> 2- (1H) -tetrazol-5-yl) -biphenyl: 4 '- [[2-n-Propyl-6- (isoquinolin-3-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5) -yl) -biphenyl 30 '- [[2-Ethyl-6- (isoquinolin-3-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 49 105547

Example 38 4, 4-N-Butyl-4-methyl-6- (2,2-dimethyl-lipo-propionylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 5

Prepared according to Example 1 4 '- [[2-n-Butyl-4-methyl-6- (2,2-dimethyl-propienylamino) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid ester. butyl ester and trifluoroacetic acid in methylene chloride.

Example 39 4'-trans-2-n-Butyl-7- [2- (tetrahydrobenzimidazol-1-vin-ethoxy] -4-methyl-benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid Prepared according to Example 1 4 '- [[2-n-butyl-7- [2- (tetrahydrobentsimid-imidazol-1-yl) -ethoxy] -4-methyl-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert butyl ester and trifluoroacetic acid in methylene chloride Yield: 81% of theory.

Melting point: 236-237 ° C 2035-353 ° (562.71)

Calcd: C 74.71 H 6.81 N 9.96 Found: 74.51 6.79 9.98

Example 40 4- [4- (N-Butyl) -4-methyl-7- [5- (tetrahydrobenzimidazol-1-yl) pentoxy] benzimidazole-1-yl] methyl-biphenyl] -2-carboxylic acid

Prepared according to Example T 4 '- [[2-n-Butyl-4-methyl-7- [5- (tetrahydro-30-benzimidazol-1-yl) -pentyloxy] -benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

50 105547

EXAMPLE 41 4- [4- (N-Butyl) -7- [3- (Tetrahydrobenzimidazol-1-yl) -propyloxy] -methyl-benzimidazole-1-vin-methyl-biphenyl] -2-carboxylic acid

Prepared according to Example 1 4 '- [[2-n-Butyl-7- [3- (tetrahydrobenzimidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2 -carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

10

Example 42 4, - [[2-n-Propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl] -benzimidazol-1-ylmethyl] -biphenyl-2-carboxylic acid.

Prepared according to Example 1 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 theory, 20 Melting point. 224-226 ° C (after evaporation of the solvent)

Melting point: 294-297 ° C (methylene chloride / ethanol = 20: 1) C31H27N502 (501.60)

Calcd: C 74.23 H 5.43 N 13.96 Found: 74.10 5.31 13.66 25

Example 43 4,4-N-Propyl-4-methyl-6-fimidazo [2,1-b] thiazol-6-yl) benzimidazole-1-vinylmethyl] -biphenyl-2-carboxylic acid.

Prepared according to Example 1 4 '- [[2-n-propyl-4-methyl6- (imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2- carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

"105547 51

Yield: 43% of theory,

Melting point: 192-195 ° C (after evaporation of the solvent)

Melting point:> 300 ° C (methylene chloride / ethanol = 20: 1) C 30 H 26 N 4 O 2 S (506.64) δ Calc .: C 71.12 H 5.17 N 11.06 S 6.33 Found: 70.97 5.19 10 , 88 6.09

According to Example 43, the following compounds are obtained: 10 4 '- [[2-n-Propyl-4-methyl-6- (3-methylimidazo [2,1-b] thiazol-6-yl) -benzimidazole-1]. -yl] -methyl] -biphenyl-2-carboxylic acid 4, - [[2-n-Propyl-4-methyl-6- (2,3-dimethylimidazo [2,1-b] thiazol-6-yl) -Benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 15 4 '- [[2-n-Butyl-4-methyl-6- (2,3-trimethylene-imidazo [2,1-b] ] Thiazol-6-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 - [[2-n-Propyl-4-methyl-6- (2,3-tetramethylene-imidazo] [2,1-b] Thiazol-6-yl) -20-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 4 '- [[2-Ethyl-4-methyl-6- (2-phenyl) - imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid Example 44 4'-trans-n-Propyl-4-methyl-6- (imidazor2. 1-Bis-thiazol-6-yl-benzimidazol-1-yl] -methyl-2-fH-tetrazol-5-yl] -biphenyl Prepared according to Example 10 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 theory, 52-105547

Melting point: amorph, from 196 ° C sintered with C 30 H 26 N 8 S (530.67)

Calc'd: C 67.90 H 4.94 N 21.12 S 6.04 Found: 67.77 4.84 21.00 5.87 5

According to Example 44, the following compounds are obtained: 4 '- [[2-n-Propyl-4-methyl'6- (3-methylimidazo [2,1-b] thiazol-6-yl) benzimidazole-1- ylmethyl] -2- (1H-tetrazol-5-yl) benzenyl] -4 '- [[2-n-Butyl-4-methyl-6- (2,3-dimethyl) imidazo [2,1-b] thiazol-6-yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 4 - [[2-n- Butyl 4-methyl-6- (2,3-trimethyleneimidazo [2,1-b] thiazol-6-yl) benz-15-imidazol-1-yl] methyl] -2- (1H-tetrazole) -5-yl) -biphenyl 4 '- [[2-Ethyl-4-methyl-6- (2,3-tetramethyleneimidazo [2,1-b] thiazol-6-yl) benzimidazole-1- yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl 20 4 - [[2-n-Propyl-4-methyl-6- (2-phenylimidazo [2,1-b] ] thiazol-6-yl) benz-imidazol-1-yl] methyl] -2- (1 H-tetrazol-5-yl) biphenyl

Example 45 4'- [T2-n-Propyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-win-biphenyl) »

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] methyl-2-cyano-biphenyl and sodium azide dimethylformamide.

Yield: 28% of theory,

Melting point: 202-205 ° C - C 32 H 28 N 8 (524.64) 53 105547

Calcd: C 73.26 H 5.38 N 21.36 Found: 73.01 5.22 21.56

According to Example 45, the following compounds are obtained: 5,4, - [[2-Ethyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2- (1H-tetrazole-5) -yl) biphenyl 4 '- [[2-n-Butyl-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl] -10 methyl] -2- (1 H-Tetrazol-5-yl) -Benzenyl 4 '- [[2-n-Propyl-4-methyl-6- (1-n-hexyl-benzimidazol-2-yl) -benzimidazole] 1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl 15 4 '- [[2-n-Propyl-4-methyl-6- (1-cyclopropyl-benzimidazole) -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- (1H-tetrazol-5-yl) -biphenyl 20

Example 46 4'-fr2-n-ProD16-4-methyl-6- (benzimidazol-2-yl) benzimidazol-1-yl]

metwlil-Biphenyl-2-karbokswlihaDPQ

25

Prepared according to example 1 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, Melting point: 239-242 ° C C 32 H 28 N 4 O 2 (500.61)

Calc'd: C 76.78 H 5.64 N 11.19 'Found: 76.55 5.60 11.41 54 105547

According to Example 46, the following compounds are obtained: 4, - [[2-Ethyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid 5 4 '- [ [2-n-Butyl-4-methyl-6- (benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl] -6- (1-n-Hexyl-benzimidazol-2-yl) -benzimid-10-azol-1-yl] -methyl] -biphenyl-2-carboxylic acid 4 '- [[2-n-Propyl-4-methyl- 6- (1-Cyclopropyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid 15 4 '- [[2-n-Propyl-4-methyl-6- (1) -cyclohexyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Example 47 20 4 - ((2-n-Butyl-7-β-imidazol-1-yl) -propyl-oxy-4-methyl-benzimidazol-1-ylmethyl-2-yl] -H-tetrazol-5-yl) - Biphenyl

Prepared from 4 '- [[2-n-Butyl-7- [3- (imidazol-1-yl) -propyloxy] -4-methyl-benzimidazol-1-yl] -methyl] -2- (1 -triphenylmethyltetrazol-5-yl) -biphenyl by cleavage of the 1-triphenylmethane group with ethanol / hydrochloric acid.

Yield: 89.8% of theory,

Melting point: 83-87 ° C 'C 32 H 34 N 80 x 1.5 H 2 O (573.69)

Calc'd: C 66.99 H 6.50 N 19.53 30 Found: 66.83 6.52 19.43 55 105547

Example 48 4'4f6- (N-Benzosulfonyl-methylamino-2-n-butyl-4-methyl-benzimidazole-1-yl-methyl) -biphenyl-2-carboxylic acid 5

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

Yield: 95.6% of theory, Melting point: 211-212 ° C C33H33N304S (567.70)

Calc'd: C 69.80 H 5.86 N 7.40 S 5.65

Found: 69.52 5.92 7.33 5.84 Example 49 4'-1- [4- (N-Benzosulfonyl-n-pentylamino) -2-n-butyl-4-methyl-benzimidazol-1-yl] -methyl] -yl- biphenyl-2-carboxylic acid Prepared according to example 1 4 '- [[6- (N-benzosulfonyl-n-pentylamino) -2-n-butyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 81.8% of theory,

Melting point: 232-233 ° C 25 C37H41N304S (623.81)

Calc'd: C, 71.24; H, 6.62; N, 6.74; S, 5.14

Found: 71.30 6.77 6.68 5.33 56 56 105547

Example 50 4'-trans-n-Butyl-6- (isopropylcarbonylamino) -methyl-benzimidazole-1-ylmethyl-biphenyl-2-carboxylic acid 5

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

Yield: 86.3% of theory, Melting point: 313-315 ° C.

Calc'd: C, 74.51; H, 6.88; N, 8.69

Obtained: 74.37 7.10 8.74 Example 51 4l-η 2 -N-Butyl-6- (2,3-dimethyl-malic acid) -N-methyl-benzimidazole-1-yl-methyl-biphenyl-2-carboxylic acid semihydrate Example 1 according to 4 '- [[2-n-butyl-6- (2,3-dimethyl-maleic acid amino) -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid methylene chloride.

Yield: 88.9% of theory,

Melting point: 321-322 ° C 25 C 32 H 31 N 3 O 4 x 0.5 H 2 O (530.62)

Calc'd: C 72.43 H 6.08 N 7.92

Found: 72.89 6.16 7.89 t 57 105547

EXAMPLE 52 4'-R6- (2,3-Dimethyll-maleic acid) -Pino-N2-n-Dro-DW1-4-methyl-benzimidazole-1-yl-methyl-biphenyl-2-carboxylic acid semihydrate 5

Prepared according to Example 1 from the 4 '- [[6- (2,3-dimethyl-maleic acid function) -2-n-propyl-4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride. Yield: 75.4% of theory,

Melting point: 329-331 ° C

C31H29N3O4x0.5H2O (516.60)

Calc'd: C 72.08 H 5.85 N 8.13

Obtained: 72.04 5.84 7.96 Example 53 4'- (6-Acetamino-2-n-butyl-4-methyl-benzimidazole-1-yl) -methyl-biphenyl-2-carboxylic acid trifluoroacetate semihydrate Prepared according to Example 1 from 4 '- [(6-acetamino-2-n-butyl-4-methyl-benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 95.7% of theory,

Melting point: 112-114 ° C (amorph) 25 C28H29N303 x CF3COOH x 0.5 H2O (578.59)

Calc'd: C, 62.28; H, 5.40; N, 7.26

Found: 62.57 5.46 7.21 * 58 105547

Example 54 4'-Rf-2-n-Butyl-4-methyl-6-methyl-morpholinocarbonylamino) -benzimidazole-1-methyl-methyl-biphenyl-2-carboxylic acid DPo 5

Prepared according to example 1 from 4 '- [[2-n-butyl-4-methyl-6- (morpholinocarbonylamino) -benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid methylene chloride.

Yield: 80.9% of theory, Melting point: 279-281 ° C C31H34N404 (526.64)

Calc'd: C 70.70 H 6.51 N 10.64

Obtained: 70.48 6.50 10.51 Example 55 4, N-Butyl-6- (cyclohexylaminocarbonylamino) -4-methyl-benzimidazol-1-yl] -methyl-biphenyl-2-carboxylic acid -Semitrifluoroacetate Prepared according to Example 1 from 4 '- [[2-n-butyl-6- (cyclohexylaminocarbonylamino) -4-methyl-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 76.9% of theory,

Melting point: 288-289 ° C 25 C 33 H 38 N 4 O 3 x 0.5 CF 3 COOH (595.70)

Calc'd: C 68.55 H 6.51 N 9.41

Found: 69.08 7.02 9.65 t> | 59 105547

Example 56 4-, -R 2 -N-Propyl-4-isopropyl-6-H-oxo-isoindoline-2-yl] -benzimidazole-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -bifenvvl i 5

Prepared according to Example 10 from 4 '- [[2-n-propyl-4-isopropyl-6- (1-oxo-isoindolin-2-yl) -benzimidazol-1-yl] -methyl] -2-cyano-biphenyl and nat. sodium azide in dimethylformamide.

Yield: 14% of theory, Melting point: amorph C35H33N7O (567.71)

Calc'd: C 74.05 H 5.86 N 17.27

Found: 73.97 5.82 17.26

Mass Spectrum: M + = 567 15

Example 57 4, N-Propyl-5-imidazor-2-ylpyridin-2-yl) -benzimidazole-1-yl] -methyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 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 theory, Melting point: 250-253 ° C C 31 H 26 N 4 O 2 (486.60)

Calc'd: C 76.52 H 5.39 N 11.52 Found: 76.28 5.47 11.27 so 105547

Example 58 4- [2- (2-n-Propyl-4-ethyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid

Prepared according to example 1 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 theory,

Melting point: 217-219 ° C

C34H32N4O2 (528.70)

Calc'd: C 77.24 H 6.10 N 10.60

Found: 77.12 6.09 10.75 Example 59 4'- [(2-n-Propyl-4-ethyl-6- (1-methyl-benzimidazol-2-yl] -benzimidazol-1-yl) -methyl] -2- (1H-Tetrazol-5-yl) -biphenyl Prepared according to Example 10 4 '- [(2-n-propyl-4-ethyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-one). yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 15% of theory,

Melting point: 215-217 ° C 25 C34H32N8 (552.70)

Calc'd: C, 73.89; H, 5.84; N, 20.28

Found: 73.66 6.02 20.56 61 61 105547

Example 60 4'-f (2-Cyclopropyl-4-methyl-6- (1-methyl-benzimidazol-2-yl-benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid 5

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

Yield: 52% of theory, Melting point: 244-246 ° C 033Η28Ν 02 02 (512.60)

Calc'd: C 77.32 H 5.51 N 10.93

Found: 77.75 5.71 10.94 Example 61 4 ', 4' - (2-Methylpropyl-4-methyl-6-n-methylbenzimidazole-2-vinylbenzimidazole-1-ylmethyl) -2- (1H-tetrazole). Prepared according to Example 10 4 '- [(2-cyclopropyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -2- cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 59% of theory,

Melting point: 245-247 ° C 25 C 33 H 28 N 8 (536.65)

Calc'd: C, 73.86; H, 5.26; N, 20.88

Found: 73.95 5.42 20.90

Example 62 62 105547 4R- (2-Methyl-butyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl] -methyl-biphenyl-2-carboxylic acid 5

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

Yield: 63% of theory, Melting point: 189-191 ° C.

H, 5.74; N, 10.64

Found: 77.35 5.92 10.40 Example 63 4'-i (2-Butyl-4-methyl-6- (1-methyl-benzimidazol-2-yl-benzimidazol-1-yl) -methyl-fl-2- (1H) -tetrazol-5-yl) -biphenyl Prepared according to Example 10 4 '- [(2-cyclobutyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide Yield: 61% of theory,

Melting point: 197-199 ° C.

Calc'd: C, 74.16; H, 5.49; N, 20.35

Found: 74.12 5.74 20.67h «

'V

63 105547

Example 64 4'-f (2-n-Propyl-4-methyl-6- (1-methyl-5-fluorobenzimidazol-2-vinyl-benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid 5

Prepared according to Example 1 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 theory, Melting point: 250-252 ° C C33H29FN402 (532.60)

Calcd: C 74.42 H 5.49 N 10.52 Found: 74.14 5.64 10.54 Example 64 gives the following compounds: 4 '- [(2-n-Propyl-4-methyl-6) - (Pyridin-2-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid 20 4 '- [(2-n-Propyl-4-methyl-6- (quinolin-2-yl) -benzimidazole) -1-yl) -methyl] -biphenyl-2-carboxylic acid 4 '- [(2-n-Propyl-4-methyl-6- (isoquinolin-3-yl) -benzimidazol-1-yl) -methyl] -biphenyl -2-Carboxylic acid 25 4 '- [(2-n-Propyl-4-methyl-6- (isoquinolin-1-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid 64 105547

Example 65 N-Propyl-methyl-η-imidazol-1-yl-pyrimidine-4-yl-benzimidazol-1-yl) -methyl-2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 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 theory, Melting point: from 275 ° C (dec) C31H27N9xH2O (543.65)

Calculated: C 68.49 H 5.38 N 23.19 Found: 68.25 5.50 23.37 The following compounds are obtained according to Example 65: 4 '- [(2-n-Propyl-4-methyl-6) - (pyndin-2-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 20 4 '- [(2-n-Propyl-4-methyl-6- (quinolin-2-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl 4 '- [(2-n-Propyl-4-methyl- 6- (isoquinolin-3-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 25 '- [(2-n-Propyl-4-methyl-) 6- (isoquinolin-1-yl) benzimidazol-1-yl) methyl] -2-, (1H-tetrazol-5-yl) biphenyl 65 105547

Example 66

RF2-4'-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-imidatsoM.2-alpvhdin-2-vvliV

Benzimidazole-1-methyl-methyl-biphenyl-2-carboxylic acid 5

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

Yield: 67% of theory,

Melting point: from 240 ° C (sintering) C32H32N402 (504.64)

Calc'd: C 76.16 H 6.39 N 11.10 Found: 75.94 6.46 11.20 15

According to Example 66, the following compounds are obtained: 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 20 - [[4- (Ethyl) -methyl] -6,6-tetrahydro-imidazol-1-yl] -pyridin-4-yl] -benzimidazole-1- yl) methyl] biphenyl-2-carboxylic acid

Example 67 25 4 - [(2-n-Propyl-4-methyl-6- (5.6.7.8-tetrahydro-imidazo [1,2-a] pyridin-2-vinyl-benzimidazol-1-yl) -methyl] -2- f 1 H -tetrazol-5-wlhbifenwli * ·

Prepared according to Example 10 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetra-30-hydroimidazo [1,2-a] pyridin-2-yl)) -Benzimidazol-1-yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 73.5% of theory, Melting point: from 275 ° C (dec.) 66 105547 C32H32N8 (528.67)

Calcd: C, 72.70; H, 6.10; N, 21.20 Found: 72.40; 6.07, 21.48. In accordance with Example 67, the following compounds are obtained: - (5,6,7,8-Tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl 10 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 68 15 4 - [(2-n-Propyl-4-methyl-6- (1-methyl-6-fluorobenzimidazol-2-yl] benzimidazol-1-ylmethyl) -biphenyl-2-carboxylic acid

Prepared according to Example 1 4 '- [(2-n-prepyl-4-methyl-6- (1-methyl-6-fluoro-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2 -carboc · · 20 from succinic acid tert-butyl ester and trifluoroacetic acid in methylene chloride. Yield: 76% of theory,

Melting point: 243-245 ° C C33H29FN4O2 (532.60)

Calc'd: C 74.42 H 5.49 N 10.52 Found: 74.74 5.52 10.77

Mass Spectrum: m / e = 532 67 105547

Example 69 4'- (2-n-Propyl-4-chloro-6- (1-oxo-isoindoline-2-yl) -benzimidazole-1-yl] -methyl-biphenyl-2-carboxylic meat DPQ 5

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

Yield: 7.5% of theory, Melting point: 209-210 ° C C 32 H 26 ClN 3 O 3 (536.04).

Mass spectrum: m le = 535/537

Rf Value: 0.25 (silica gel; methylene chloride / ethanol = 9: 1) Example 70 4'-f (2-n-Propyl-4-chloro-6- (1-methylbenzimidazole-2-yl) benzimidazole-1 - (wli) -methyl] -biphenyl-2-carboxylic acid Prepared according to example 1 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazole-1-yl). yl) -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 52.7% of theory,

Melting point: 292-295 ° C 25 C32H27CN402 (535.06)

R f Value: 0.30 (silica gel; methylene chloride / ethanol = 19: 1)

Calc'd: C 71.90 H 5.08 N 10.45 Cl 6.63 Found: 71.29 5.21 10.40 6.76

Example 71 ee 105547 N-Propyl-m-chloro-e-n-methyl-benzimidazol-4-yl-benzimidazole-1- (10-methyl-methyl) -2- (1H-tetrazol-5-yl) -biphenyl] -hydrochloride

Prepared according to Example 10 from 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2-cyano-biphenyl and sodium azide dimethylformamide.

Yield: 54.8% of theory, Melting point: from 204 ° C sintered with C32H27ClN8 x HCl (595.55)

Rf Value: 0.20 (silica gel; petroleum ether / ethyl acetate = 1: 1 and 1% glacial acetic acid) Calcd: C 62.55 H 4.71 N 18.85 Cl 11.85 Found: 62.34 4.97 18 , 84 11.57 15

Example 72 4 '- [(2-η-ΡΓθρννΙι'-4-ηοπ-6- (1-oxo-isoindolin-2-yl) -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -bifenwli 20

Prepared according to Example 10 from 4 '- [(2-n-propyl-4-chloro-6- (1-oxoisoindolin-2-yl) benzimidazol-1-yl) methyl] -2-cyanobiphenyl and sodium azide dimethylformamide. Yield: 24.6% of theory,

Melting point: 246-248 ° C 25 C 32 H 26 ClN 70 (560.08)

Rf Value: 0.15 (silica gel; methylene chloride / ethanol = 9: 1)

Calcd: C, 69.00; H, 4.67; N, 17.55; Cl, 6.40. Found: 68.26; 4.75; 17.73; 6.97. Example 72 gives the following compound: 4 '- [(2-n- Propyl 4-chloro-6- (4,5,6,7-tetrahydrobenzimidazol-2-yl) benzimidazole-1-yl) methyl] -2- (1H-tetrazol-5-yl) - biphenyl 105547 69

Example 73 4 '- [(2-n-Propyl-4-chloro-e- (cyclohexyl) aminocarbonyl] amino] benzimidazole-1-yl] -methyl] -biphenyl-2-carboxylic acid

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

Yield: 75% of theory,

Melting point: 222-224 ° C

C ^ CINA (545.09)

R f Value: 0.15 (silica gel; methylene chloride / ethanol = 19: 1)

Calc'd: C 68.50 H 6.10 N 10.30 Cl 6.48 Found: 68.89 5.98 10.02 7.04 15

Example 74 4'-f (2-n-Propyl-4-methyl-6-amidinobenzimidazol-1-ylmethyl-biphenyl-2-carboxylic acid hydrate 20a) 4 '- [(2-n-Propyl-4-methyl- 6-Amino-benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid methyl ester 2.1 g (5 mmol) of 4 '- [(2-n-propyl-4-methyl-6-cyanobenzimidazole). 1-yl) -methyl] -biphenyl-2-carboxylic acid methyl ester is dissolved in 250 ml of methanol at room temperature with stirring. At 10-20 ° C, hydrogen chloride is introduced into the mixture under ice-cooling for 3 hours. It is then stirred for a further 3 hours at room temperature. Soluble. The tin is removed by distillation in vacuo, 2 x ether is added to the residue and evaporated. The imino ether formed is dissolved in 250 ml of methanol and 10.0 g of ammonium carbonate are added. The reaction mixture is stirred for 12 hours at room temperature. After removal of the solvent in vacuo, the residue is purified on a silica gel column (particle size: 0.063-0.032 mm), eluting with a mixture of methylene chloride and methanol with increasing polarity (9: 1 and: 8: 2). The uniform fractions are evaporated in vacuo.

70 105547

Yield: 1.5 g (58% of theory)

Rf Value: 0.15 (silica gel; eluent: methylene chloride / methanol = 9: 1) b) 4 '- [(2-n-Propyl-4-methyl-6-amidinobenzimidazol-1-yl) methyl) buff -5-yl-2-carboxylic acid 0.51 g (1.0 mmol) of 4 '- [(2-n-Propyl-4-methyl-6-amidinobenzimidazol-1-yl) methyl] biphenyl-2- the carboxylic acid methyl ester is dissolved in 6 ml of tetrahydrofuran, 2.8 ml of 1.4 M aqueous lithium hydroxide solution and 3 ml of water are added and stirred for 2 days at room temperature. A solution of 300 mg of ammonium chloride in 4 ml of water is then added.

The mixture is stirred for 5 minutes, the precipitate formed is filtered off with suction, washed with acetone and dried over potassium hydroxide.

Yield: 0.25 g (59% of theory),

Melting point: 270-271 ° C (dec) C26H26N4O2 x H2O (426.53) Calc'd: C 70.25 H 6.35 N 12.60 Found: 70.04 6.23 12.50 fVvalue: 0, 55 (silica gel; eluent: methylene chloride / methanol / ammonia = 2: 1: 0.25) 20 Example 74 gives the following compound: 4 '- [(2-n-Propyl-4-chloro-6- (4,5, 6,7-Tetrahydrobenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid Example 75 4, -f (2-n-Pro-dimethyl-4-methyl-6- (1-methyl) (a) 3-Methyl-4-butyrylamino-5-nitro-acetophenone 32.6 g (148 mmol) of 3-methyl-imidazol-4-yl) -benzimidazole-1-ylmethyl-biphenyl-2-carboxylic acid. 4-Butyrylamino-acetophenone is added portionwise with stirring at -15 ° C to 300 ml of fuming nitric acid and stirred for an additional 30 minutes at -15 ° C. The reaction mixture is poured with stirring into 3 ice 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 theory), Rf value: 0.32 (silica gel; methylene chloride).

Rf Value: 0.48 (silica gel; methylene chloride / methanol = 50: 1) b) 3-Methyl-4-butyrylamino-5-nitro-1-bromoacetophenone To a solution of 23.8 g (90 mmol) in 3 of methyl 4-butyrylamino-5-nitroaceto-phenone in 900 ml of dichloromethane, a solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane is added dropwise with stirring so that the color of the reaction mixture completely disappears. After stirring for a further two hours, the reaction mixture is evaporated to dryness in vacuo, the residue thus obtained is triturated with about 20 ml of dichloromethane / diethyl ether (1: 1), filtered off with suction and then dried. This gives 23 g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-omega-bromoacetophenone, which still contains about 10% of starting material. The product is further reacted without further purification.

Rf Value: 0.69 (silica gel; methylene chloride / methanol = 50: 1)

Rf Value: 0.84 (silica gel; methylene chloride / methanol = 9: 1) c) 2-Butyrylamino-3-nitro-5- (imidazo-4-yl) -toluene A solution of 6.8 g (20 mmol) 3-Methyl-4-butyrylamino-5-nitro-omega-bromoacetophenone in 20 ml of formamide is heated for 2 hours at 140 ° C. The cooled solution is then poured into about 50 mL of 1N ammonia and stirred for about 15 minutes. The precipitated crude product is suctioned off, washed with about 50 ml of water and dried. 4.4 g (75% of theory) of the product are obtained, which is reacted further without further purification.

R f Value: 0.29 (silica gel; methylene chloride / methanol = 9: 1) * 105547 72 d) 2-Butyrylamino-3-nitro-5- (1-methylimidazol-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) of potassium carbonate dihydrate in 30 ml of 5 dimethylsulfoxide, 1.3 g (9.5 mmol) of methyl iodide are added dropwise at room temperature and then stirred for 2 hours. The reaction mixture is then mixed with about 150 ml of water and then extracted four times with 25 ml of ethyl acetate each time. The organic extract is washed with about 30 ml of water, dried and evaporated. The crude product thus obtained is purified by flash chromatography (300 g of silica gel, eluent: 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 15 640 mg (2.1 mmol) 2-Butyrylamino-3-nitro-5- (1-methylimidazol-4-yl) toluene is hydrogenated in 30 ml of methanol after addition of about 200 mg of palladium on carbon (20%) at room temperature and hydrogen pressure 5 bar. After complete hydrogen uptake, the catalyst is removed by filtration and the filtrate is concentrated. The crude product thus obtained is reacted without further purification. Rule. 600 mg (100% of theory),

Rf Value: 0.23 (silica gel; methylene chloride / methanol = 9: 1) f) 2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) -benzimidazole 600 mg (2 , 1 mmol) 2-Butyrylamino-3-amino-5- (1-methylimidazol-4-yl)-toluene is heated in 10 ml of glacial acetic acid for slowly refluxing. Then evaporate. dry in vacuo, add about 15 ml of water to the residue, make anal by ammonia and extract four times with about 10 ml of ethyl acetate each time.

The organic extract is washed with about 15 mL of water, dried, and finally evaporated. The crude product thus obtained is reacted without further purification. Yield: 420 mg (79% of theory),

Rf Value: 0.37 (silica gel; methylene chloride / methanol = 9: 1) * 105547 73 g) 4 '- [(2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) - Benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid tert-butyl ester

To a solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6- (1-methyl-5-imidazol-4-yl) -benzimidazole and 90 mg (0.8 mmol) of potassium tert- butylate in 5 mL of dimethyl sulfoxide, add 280 mg (0.8 mmol) of 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester and stir the mixture for 90 minutes at room temperature, then stir in about 40 mL of water, is extracted four times each time with about 10 ml of acetic ester, then the organic extract is washed with 10 times 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel, mobile solvent; dichloromethane / methanol = 30: 1).

Yield: 230 mg (56% of theory),

Rf Value: 0.61 (silica gel; methylene chloride / methanol = 9: 1) for 15 h) 4 '- [(2-n-Propyl-4-methyl-6- (1-methylimidazol-4-yl) - benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid

A solution of 230 mg (0.44 mmol) of 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-20-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 is dissolved in about 5 ml of dilute sodium hydroxide solution, the solution is neutralized with acetic acid, then the precipitate is suctioned off, washed with water and dried. Yield: 120 mg (59% of theory),

Melting point: 293-295 ° C

Rf Value: 0.39 (silica gel; methylene chloride / methanol = 9: 1) 1 ·

According to Example 75, the following compounds are obtained: 4 '- [(2-n-Propyl-4-methyl-6- (1-ethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2- carboxylic acid 30 74 105547 4 '- [(2-n-Propyl-4-methyl-6- (1-n-hexyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid 4 '- [(2-n-Propyl-4-methyl-6- (1-benzylimidazol-4-yl) benzimidazol-1-5 yl) 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 10 4 '- [(2-n-Propyl) -4-Methyl-6- (1-cyclohexyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid

Example 76 15 4, -I- (2-n-Pro-Dwl-4-methyl-e- (1-methyl-imidazol-4-yl) -benzimidazole-1-10-methyl-dl-2- (1H-tetrazol-5-yl-biphenyl)

Prepared according to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl) methyl] -2-cyano-biphenyl and nat. -20 rhodium azide in dimethylformamide.

Yield: 24% of theory Melting point: 255-257 ° C

Value: 0.24 (silica gel; methylene chloride / methanol = 9: 1) C 29 H 28 N 8 x H 2 O (506.62) Calc'd: C 68.76 H 5.97 N 22.12 Found 68.90 5.97 22, 03 • • According to Example 76, the following compounds are obtained: 4 '- [(2-n-Propyl-4-methyl-6- (1-ethylimidazol-4-yl) benzimidazol-1-yl) methyl] - 2- (1H-tetrazol-5-yl) -biphenyl «105547 75 4 '- [(2-n-Propyl-4-methyl-6- (1-n-hexyl-imidazol-4-yl) -benzimidazol-1] - (yl) -methyl] -biphenyl-2-carboxylic acid 4 - [(2-n-Propyl-4-methyl-6- (1-benzyl-imidazol-4-yl) -benzimidazol-1-5-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] -4 '- [(2-n-Propyl-4-methyl-6- (1-cyclohexyl-imidazol-4-yl) -benzimidazol-1-yl) ) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Example 77 15 4 - [(2-Ethyl-4-methyl-6- (5,6,7,7,8-tetrahydro-imidazol-1,2-a] pyridin-2-yl-benzimidazol-1-yl) -methyl] -2-1H-tetrazole -5-winbifenvvli

Prepared according to Example 10 4 '- [(2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1] -yl) -methyl] -2-cyano-20-biphenyl and sodium azide in dimethylformamide.

Yield: 21% of theory Melting point: amorphous

Rf value: 0.27 (silica gel; methylene chloride / ethanol = 9: 1) C31H30Ne (514.54) Calc'd: C 72.35 H 5.88 N 21.78 Found: 72.01 5.82 21, 44 »♦ 105547 76

EXAMPLE 78 4R- (2-n-ProDIII-4-methyl-6- (8-methyl-imidazo [1,2-a] pyridin-2-yl-benzimidazol-1-yl) -methyl] -biphenyl-1,2-carboxylic acid wl fatty acid 5

Prepared according to Example 1 4 '- [(2-n-propyl-4-methyl-6- (8-methylimidazo [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 theory Melting point: 295-297 ° C

F value: 0.34 (silica gel; methylene chloride / ethanol = 9: 1) C 33 H 30 N 4 O 2 x H 2 O (532.65)

Calc .; C 74.41 H 6.06 N 10.52 Found: 74.81 6.05 10.43

Example 79 4, - (2-n-Propyl-4-methyl-6- (2-pyridyl-benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl

Prepared according to Example 10 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 theory, Melting point: from 136 ° C (dec.) C 30 H 27 N 7 x 0.5 H 2 O (494.60)

Calc'd: C 72.85 H 5.71 N 19.83 Found: 72.45 6.01 19.83 77 105547

Example 80 4, -f (2-n-Propyl-4-methyl-η 8 -methyl-imidazo [1,2-a] pyridin-2-yl) -benzimidazol-1-yl-methwin-2- (1H- tetrazole-5-wlh-bifenwli 5

Prepared according to Example 10 4 '- [(2-n-propyl-4-methyl-6- (8-methylimidazo [1,2-a] pyridin-2-yl) benzimidazol-1-yl) methyl] - 2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 19% of theory 10 Melting point: amorphous CaaHaoNe (538.61)

Mass spectrum: m / e = 538

Example 81 4'-f2-Ethyl-4-methyl-6- (5.6.7.8-tetrahydro-imidazol-2-yl-benzimidazol-1-yl) -methyl-biphenyl-2-carboxylic acid

Prepared according to Example 1 4- [2-Ethyl-4-methyl-6- (5,6,7,8-tetrahydro-20-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 theory Melting point:> 300 ° C

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

Example 82: 4'-R- (2-n-Propyl-4-methyl-6- (1-isopropyl-imidazol-4-yl-benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid

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

105547 78

Yield: 84% of theory Melting point: 285-286 ° C

Rf value: 0.55 (silica gel; methylene chloride / methanol = 9: 1). Example 83 4l- [(2-n-Pro-dimethyl-4-methyl-6- (1-isopropyl-imidazole-4-vin-benzimidazole)] Prepared according to Example 10 4 '- [(2-n-propyl-4-methyl-6- (1-isopropyl-imidazole) - 1-methyl-methyl-6- (1H-tetrazol-5-yl) -biphenyl] 4-yl) -benzimidazol-1-yl) methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.

Yield: 18% of theory Melting point: Amorph 15 Value: 0.29 (silica gel; methylene chloride / methanol = 9: 1) C 31 H 32 N 8 (516.66).

Mass spectrum: m le = 516

Example 84 20 4 - [(2-n-Propyl-4-methyl-6- (1-n-hexyl-imidazol-4-yl] -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid

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

V

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Example 85 79 105547 4'- (2-n-Propyl-4-methyl-6- (1-benzyl-imidazol-4-yl) -benzimidazole-1-yl-methyl-biphenyl-2-carboxylic acid 5

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

Example 86 4'-r (2-n-Propyl-4-methyl-6-f-n-hexyl-imidazol-4-yl-benzimidazol-1-10-methyl-2- (1H-tetrazol-5-yl) -biphenyl Prepared according to Example 10 4 '- [(2-n-propyl-4-methyl-6- (1-n-hexylimidazol-4-yl) benzimidazol-1-yl) methyl] -2- cyano-biphenyl and sodium azide in dimethylformamide.

Example 87 20 4 - [(2-n-Propyl-4-methyl-6 - [(benzyl) imidazole-4-yl] -benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -biphenyl]

Prepared according to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (1-benzyl-25-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2-cyanobiphenyl and nat. rium azide in dimethylformamide.

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Example 88 So 105547 4'-Methyl-2-n-propyl-4-methyl-6- (1-methyl-1H-benzimidazol-2-yl) -benzimidazole-1-ylmethyl-biphenyl-2-carbonihaDPo-tert-butyl ester 5 a) 4-Butyrylamino-3-methyl-5-nitro-benzoic acid 2.80 g (10.0 mMol) of 4-butyrylamino-3-methyl-5-nitro-benzoic acid methyl ester are stirred in a mixture of 20 ml. 1N sodium hydroxide solution, 40 ml ethanol, 10 ml and 5 ml dichloromethane overnight at room temperature. Finally, the organic solvent was distilled off, the residue was diluted with about 30 ml of water and acidified with glacial acetic acid. The precipitated crude product was filtered off with suction, washed with a little water and dried.

Yield: 2.08 g (78% of theory), 15 C 12 N 14 N 2 O 5 (266.25).

Rf value: 0.14 (silica gel, dichloromethane / ethanol = 19: 1)

Mass Spectrum: (MH) '= 165 b) 4-Butyrylamino-3-methyl-N- (2-methylamino-phenyl) -5-nitrobenzamide 1.33 g (5.0 mMol) of 4-butyrylamino-3-methyl- 5-Nitro-benzoic acid was dissolved in 20 ml of absolute dimethylformamide, then 1.61 g (5.0 mMol) of O-benzotriazol-1-yl] -NNN'.N'-tetramethyluronium tetrafluoroborate (TBTU) and 2.0 ml (14.4 mMol) of triethylamine and stirred at room temperature for 15 minutes. Finally, 1.00 g (5.0 mMol) of 2-methylamino-phenylamine-monophosphate was added and stirred overnight at room temperature. It was then evaporated to dryness, the residue was dissolved in about 40 ml of water, the insoluble solids were removed by suction and washed with a little water. Purification was performed by column chromatography over silica gel (eluent: dichloromethane containing 30% -10% ethanol).

Yield: 0.76 g (41.4% of theory), C19N22N404 (370.40) ··· Rf. 0.28 (silica gel, dichloromethane / ethanol = 19: 1) no 105547

Mass Spectrum: (MH) '= 369 (M + Na) + = 393 c) N- [2-Methyl-4- (1-methyl-1H-benzimidazol-2-yl) -6-nitrophenyl] -butyramiam-5 0.74 g (2.0 mMol) of 4-butyrylamino-3-methyl-N- (2-methylamino-phenyl) -5-nitrobenzamide was heated with 10 ml of glacial acetic acid at 100 ° C for 30 minutes. It was then evaporated to dryness, the residue was stirred in about 10 ml of water and made weakly basic with concentrated ammonia solution.

Thereafter, it was extracted three times with 15 ml of glacial acetic acid each time and the extracts were evaporated after drying. The crude product thus obtained was purified by column chromatography (silica gel; dichloromethane containing 1-5% ethanol).

Yield: 0.64 g (91% of theory), 15 C 19 N 2 O 4 O 3 (352.38)

Rf value: 0.24 (silica gel, dichloromethane / ethanol = 19: 1)

Mass Spectrum: (MH) '= 351 (M + Na) + = 375 ° d) N- [2-Amino-6-methyl-4- (1-methyl-1H-benzimidazol-2-yl) -phenyl-butyr amide 0.56 g (1.6 mMol) of N- [2-methyl-4- (1-methyl-1H-benzimidazol-2-yl) -6-nitrophenyl] -butyramide was hydrogenated in 40 ml of ethanol / dichloromethane (3: 1) by addition of 10% palladium on carbon at room temperature. The catalyst was removed by filtration, the solvent was distilled off in vacuo and the crude product thus obtained was reacted further without purification.

Yield: 0.54 g (crude)

C 19 N 22 N 4 O (322.40) 30 R f = 0.18 (silica gel, dichloromethane / ethanol = 19: 1) 105547 82 e) 4 '- {[2-butyrylamino-3-methyl-5- (1-methyl-1) H-Benzimidazol-2-yl) -phenylamino] -methyl} -diphenyl-2-carboxylic acid tert-butyl ester 0.48 g (1.5 mMol) N- [2-amino-6-methyl-4- (1-methyl) -1H-benzimidazol-2-yl) -5-phenyl] -butyramide and 0.52 g (1.5 mMol) of 4'-bromomethyl-diphenyl-2-carboxylic acid tert-butyl ester were stirred in 5 mL of N-ethyl diisopropylamine for 2 hours at 100 ° C. It was then evaporated to dryness in vacuo and the product was purified by column chromatography over silica gel (eluent: petroleum ether containing 20-40% acetic ester).

Yield: 0.39 g (44% of theory), C37N40N4O3 (588.72)

Rf value: 0.23 (silica gel, dichloromethane / ethanol = 19: 1)

Mass Spectrum: (MH) '= 587 (M + Na) + = 6115 f) 4' [[2-n-Propyl-4-methyl-6- (1-methyl-1H-benzimidazol-2-yl) - Benzimidazol-1-yl] -methyl] -diphenyl-2-carboxylic acid tert-butyl ester 0.35 g (0.6 mMol) 4 '- {[2-butyrylamino-3-methyl-5- (1-methyl-1 H-Benzimidate-20-sol-2-yl) -phenylamino] -methyl} -diphenyl-2-carboxylic acid tert-butyl ester was heated in 10 ml of glacial acetic acid for 30 minutes at 100 ° C. It was then evaporated to dryness, the residue was dissolved in about 10 ml of water and made slightly weakly alkaline with concentrated ammonia solution. This mixture was extracted 3 times with 10 ml each of ethyl acetate, the extracts were dried over sodium sulfate and evaporated.

Yield: 0.27 g (78% of theory) of an amorphous solid, C37N3eN402 (570.74)

Rf value: 0.26 (silica gel, dichloromethane / ethanol = 19: 1)

Mass Spectrum: (M-H) '= 569 30 (M + Na) + = 593 (Μ + ΗΓ = 571 (M + Cl)) - = 605/607 ·

Claims (3)

1. Process for the Preparation of Pharmaceutically Useful Benzimidazoles with the General Pharmaceutical 5R, Rr Wherein R 1 is a chlorine atom, alkyl group having 1-3 carbon atoms or trifluoromethyl group, R 2 is a 5-, 6- or 7-membered alkyleneimino group, wherein methylene group may be replaced by a carbonyl or sulfonyl group, a optionally having an alkyl group having 1-3 carbon atoms or phenyl group mono- or disubstituted maleic acid imido group, the substituents may be the same or different, optionally having an alkyl group having 1-6 carbon atoms, or cycloalkyl group substituted by benzimidazol-2-yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl group, wherein the phenyl core of the above-mentioned benzimidazole groups thereto may be substituted by a fluorine atom, methyl or trifluoromethyl group, an imidazo [2,1-b] thiazol-6-yl group. -, 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 yl-, imidazo [1,2-a] -25 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 pyridyl group or one having an alkyl group of 1-3 carbon atoms, or benzyl group in 1-position substituted imidazol-4-yl group, which can be further substituted in the carbon body by an alkyl group of 1-3 carbon atoms, R3 is an alkyl group of 1- 5 carbon atoms or cycloalkyl group having 3-5 carbon atoms and go 105547 R4 is a carboxy or 1 H-tetrazolyl group, their pharmacologically acceptable salts with inorganic or organic acids or bases, characterized in that a) a compound of the general formula -A where Rt and R2 are the same as above, one of the groups or Υλ is a group of the general formula -NRg-CHf- general formula Z1 Z, - / - NH - C - R3 wherein R3 and R4 are the same as above, R8 is a hydrogen atom or an R3CO group, wherein R3 is defined above , Z-, and Z2, which are the same or different, are an optionally substituted amino group or an optionally with a lower alkyl group substituted hydroxy or mercapto group or Z, and Z2 together is an oxygen or sulfur atom, optionally with an alkyl group having 1 to 3 carbon atoms substituted imino group, an alkylenedioxy or alkylenediothio group having 2 or 3 carbon atoms, however one of the groups X X or Y Y is a group of the general formula cor3 ) Is cyclized and optionally the so obtained corresponding to the N-oxide is reduced or b) a benzimidazole of the general formula RH 20 where R 1 - R 3 is the same as above, is reacted with a biphenyl compound of the general formula Z 2 -CH 2 - P% - / (IV) wherein R 4 is as defined above and Z 3 is a nucleophilic leaving group, or c) to prepare a compound of the general formula Formula I, wherein R4 is a carboxy group, a compound of general formula 92. Rr0 R '(V) R'4 where R, - R3 is the same as above and R4 is a group transferable by hydrolysis, thermolysis or hydrogenolysis to a carboxy group, converted to the corresponding carboxy compound or d) to produce a compound having the general formula I, wherein R 4 is a 1 H-tetrazolyl group, from a compound of the general formula U 1 - <V 1) wherein R 1, R 2 and R 3 are the same as above and R 4 or 3-position with a protecting group protected 1 H-tetrazolyl group, the protecting group is split off or e) to prepare a compound of general formula I, wherein R 4 is a 1 H-tetrazolyl group, a compound of the general formula 30. M NC "where R 10 - R 3 is the same as above, reacted with hydrochloric acid or its salts or f) to produce compounds of general formula I wherein R 2 is a benzimidazol-2-yl-, imidazo defined above. [4,5-b] pyridin-2-yl-, imidazo [4,5-c] pyridin-2-yl-, imidazo [4,5-b] pyrazin-2-yl-, imidazo [4,5 -c] pyridazin-2-yl-, imidazo [4,5-d] pyridazin-2-yl or purin-8-yl group, a compound of the general formula 10 \B B <1'Ττ / ΧζCL in IX) where none, one or two of the groups A1t B1f C1 or D1 is a nitrogen atom and the other groups Of C1 or D- are methane groups, R 2 is a hydrogen or fluorine atom, a methyl or trifluoromethyl group and the one of groups X2 or Y2 is an R13-NH group and the other of groups X2 or Y2 is a group of the general formula r, <R4 wherein R1t R3 and R4 are the same as above, one of groups R13 and R 14 is a hydrogen atom and the other of the groups R 13 and R 14 is a hydrogen atom, alkyl group pp having 1-6 carbon atoms or cycloalkyl group having 3-7 carbon atoms, Z5 and Zq which are the same or different are an optionally substituted amino group or an optionally with a lower alkyl group substituted hydroxy or mercapto group or Z5 and Zq together are an oxygen or sulfur atom, optionally with an alkyl group having 1-3 carbon atoms substituted imino group, an alkylene or alkylenediothio group having 2 or 3 carbon atoms, are cyclized and any optionally corresponding to N-oxide is reduced and the compound so obtained is optionally subsequently hydrolyzed or, if necessary, the reactions a) - f) protecting groups used as protection for reactive groups are cleaved and / or optionally then the resulting compound of the general formula 11 -, 3-isomer mixture with isomer separation is separated into its 1- and 3-isomers or the so-called compound of the general formula I, is converted into its salt, especially for pharmaceutical use, into its physiologically acceptable salt with an inorganic or organic acid or base. 2. A process according to claim 1 for the preparation of 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 20 or its salt, characterized in that the corresponding starting materials are used. A process according to claim 1 for the preparation of 4 '- [2-n-ethyl-4-methyl-6- (4,5,6,7-tetrahydro-imidazole [1,2-a] pyridin-2-yl) (benzimidazol-1-yl) methyl] -biphenyl-2-carboxylic acid or its site, characterized in that the corresponding starting materials are used.