NO300772B1 - Benzimidazoles, drugs containing these compounds, and their use - Google Patents

Description

Foreliggende oppfinnelse angår nye benzimidazoler med den generelle formel The present invention relates to new benzimidazoles with the general formula

deres tautomerer og deres salter, spesielt for farmasøytisk anvendelse, deres fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser, som utgjør verdifulle angiotensin-antagonister, særlig angiotensin-II-antagonister, medikamenter som inneholder disse forbindelser, og anvendelsen av disse for fremstilling av legemidler. their tautomers and their salts, especially for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids or bases, which constitute valuable angiotensin antagonists, in particular angiotensin-II antagonists, medicaments containing these compounds, and the use thereof for the preparation of medicines.

I den generelle formel I ovenfor betyr: In the general formula I above means:

Rx en metylgruppe i 4-stilling, Rx a methyl group in the 4-position,

R2 en imidazo[1, 2-a]pyridin-2-yl-, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 3-klor-5,6,7,8-tetrahydro-imidazo [1 , 2-a] pyridin-2 -yl- , l-metyl-benzimidazol-2-yl-, 1-metyl-5-fluor-benzimidazol-2-yl- eller butansultam-l-yl- R 2 an imidazo[1, 2-a]pyridin-2-yl-, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 3-chloro-5,6, 7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, l-methyl-benzimidazol-2-yl-, 1-methyl-5-fluoro-benzimidazol-2-yl- or butansultam-l -yl-

gruppe, group,

R3 en alkylgruppe med 2 til 4 karbonatomer, en cyklopropylgruppe eller en alkoksygruppe med 2 eller 3 karbonatomer og R3 an alkyl group with 2 to 4 carbon atoms, a cyclopropyl group or an alkoxy group with 2 or 3 carbon atoms and

R4 en i 1- eller 2-stilling med en Ra - CO-0-CH2-gruppe substituert tetrazolylgruppe, en Rb-CO-0-(RCCH)-0-CO-, RdO-CO-eller RbO-CO-0-(RCCH)-0-CO-gruppe, idet R4 a in the 1- or 2-position with a Ra - CO-0-CH2 group substituted tetrazolyl group, a Rb-CO-0-(RCCH)-0-CO-, RdO-CO- or RbO-CO-0- (RCCH)-O-CO group, in that

Ra utgjør en rettkjedet eller forgrenet alkylgruppe med 1 til 6 karbonatomer, en cykloalkylgruppe med 5 til 7 karbonatomer, en benzyl-, l-fenyletyl-, 2-fenyletyl-, 3-fenylpropyl-, metoksymetyl- eller cinnamylgruppe, Ra constitutes a straight-chain or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 5 to 7 carbon atoms, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group,

Rb utgjør en rettkjedet eller forgrenet alkylgruppe med 1 til 6 karbonatomer, en cykloalkylgruppe med 5 til 7 karbonatomer, en fenyl-, benzyl-, l-fenyletyl-, 2-fenyletyl- eller 3-fenylpropylgruppe, Rb constitutes a straight-chain or branched alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group,

Rc utgjør et hydrogenatom eller en metylgruppe, Rc constitutes a hydrogen atom or a methyl group,

Rd utgjør en rettkjedet eller forgrenet alkylgruppe med 5-6 karbonatomer, en cykloalkylgruppe med 5-7 karbonatomer, Rd constitutes a straight-chain or branched alkyl group with 5-6 carbon atoms, a cycloalkyl group with 5-7 carbon atoms,

en benzyl-, l-fenyletyl-, 2-fenyletyl-, 3-fenylpropyl-, a benzyl-, 1-phenylethyl-, 2-phenylethyl-, 3-phenylpropyl-,

metoksymetyl- eller cinnamylgruppe. methoxymethyl or cinnamyl group.

Dessuten omfatter oppfinnelsen forbindelsene Furthermore, the invention includes the compounds

4'-[(2-cyklopropyl-4-metyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a] pyridin-2-yl)-benzimidazol-l-yl)-metyl] -bifenyl-2-karboksylsyre, 4'-[(2-cyclopropyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl ] -biphenyl-2-carboxylic acid,

4'-[(2-etoksy-4-metyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-biphenyl-2-carboxylic acid,

4'-[(2-etoksy-4-metyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl,

4'-[(2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4'-[(2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4'-[(2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4'-[(2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4 ' -[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl , 4 ' -[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5 -yl)-biphenyl,

4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and

4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre, 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

deres tautomerer og deres salter. their tautomers and their salts.

Særlig foretrukket er følgende forbindelser: 4 ' - [ (2-cyklopropyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre 4'-[(2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4 '- [ (2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl) -metyl]-2- (lH-tetrazol-5-yl)-bifenyl, 4 '-[(2-etyl-4-metyl-6-(1-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4 '-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre, Particularly preferred are the following compounds: 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol- 1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl) -methyl]-biphenyl-2-carboxylic acid, 4'-[ (2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-( 1H-tetrazol-5-yl)-biphenyl, 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl, 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl] -biphenyl-2-carboxylic acid,

deres tautomerer og deres salter. their tautomers and their salts.

Av disse er sistnevnte forbindelse spesielt foretrukket. Of these, the latter compound is particularly preferred.

Forbindelsene kan fremstilles etter følgende fremgangsmåter: The compounds can be produced according to the following methods:

a) cyklisering av en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel a) cyclization of an optionally formed compound of the general formula in the reaction mixture

hvor where

R-l og R2 er som innledningsvis definert, R-1 and R2 are, as initially defined,

en av restene X,, eller Y1 utgjør en gruppe med den generelle formel one of the residues X,, or Y1 constitutes a group of the general formula

og den andre av restene Xx eller Yx utgjør en gruppe med den generelle formel and the second of the residues Xx or Yx constitutes a group of the general formula

hvor R3 og R4 er som innledningsvis definert, where R3 and R4 are as initially defined,

R5 er et hydrogenatom eller en R3CO-gruppe, hvor R3 er som definert ovenfor, R5 is a hydrogen atom or an R3CO group, where R3 is as defined above,

Zi og Z2, som kan være like eller forskjellige, utgjør eventuelt med alkylgrupper, med 1 til 6 karbonatomer, substituerte amino-, hydroksy- eller merkaptogrupper, eller zi og Z2 sammen, et oksygen- eller svovelatom, en iminogruppe som eventuelt er substituert med en alkylgruppe med 1 til 3 karbonatomer, en alkylendioksy- eller alkylenditiogruppe som hver har 2 eller 3 karbonatomer. Zi and Z 2 , which may be the same or different, optionally with alkyl groups, with 1 to 6 carbon atoms, constitute substituted amino, hydroxy or mercapto groups, or zi and Z 2 together, an oxygen or sulfur atom, an imino group optionally substituted with an alkyl group of 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms.

Cykliseringen foretas hensiktsmessig i et oppløsnings-middel eller i en oppløsningsmiddelblanding som etanol, isopropanol, iseddik, benzen, klorbenzen, toluen, xylen, glykol, glykolmonometyleter, dietylenglykol-dimetyleter, sulfolan, dimetylformamid, tetralin eller i et overskudd av det acyleringsmiddel som benyttes for fremstilling av forbindelsen med den generelle formel II, f.eks. i det tilsvarende nitril, anhydrid, syrehalogenid, ester eller amid, eksempelvis ved temperaturer mellom 0 og 250°C, men fortrinnsvis ved reaksjonsblandingens kokepunkt, eventuelt i nærvær av et kondensasjonsmiddel som fosforoksyklorid, tionylklorid, sulfurylklorid, svovelsyre, p-toluensulfonsyre, metan-sulfonsyre, saltsyre, fosforsyre, polyfosforsyre, eddiksyre-anhydrid, eller eventuelt også i nærvær av en base som kalium-etylat eller kalium-tert-butylat. Cykliseringen kan imidlertid også foretas uten oppløsningsmiddel og/eller kondensasjonsmiddel . The cyclization is conveniently carried out in a solvent or in a solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess of the acylating agent used for preparation of the compound of the general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250°C, but preferably at the boiling point of the reaction mixture, possibly in the presence of a condensation agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulfuric acid, p-toluenesulfonic acid, methane sulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or optionally also in the presence of a base such as potassium ethylate or potassium tert-butylate. However, the cyclization can also be carried out without a solvent and/or condensing agent.

Særlig fordelaktig foretas omsetningen slik at en forbindelse med den generelle formel II fremstilles i reaksjonsblandingen ved reduksjon av en tilsvarende o-nitroamino-forbindelse, eventuelt i nærvær av en karboksylsyre med den generelle formel R3COOH, eller ved acylering av en tilsvarende o-diaminoforbindelse. Ved å stanse reduksjonen av nitrogruppen på hydroksylamintrinnet, oppnår man ved den påfølgende cyklisering N-oksydet av en forbindelse med den generelle formel I. Det således oppnådde N-oksyd overføres deretter ved reduksjon i en tilsvarende forbindelse med den generelle formel I. Particularly advantageously, the reaction is carried out so that a compound of the general formula II is produced in the reaction mixture by reduction of a corresponding o-nitroamino compound, optionally in the presence of a carboxylic acid of the general formula R3COOH, or by acylation of a corresponding o-diamino compound. By stopping the reduction of the nitro group in the hydroxylamine step, the N-oxide of a compound of the general formula I is obtained in the subsequent cyclization. The N-oxide thus obtained is then transferred by reduction into a corresponding compound of the general formula I.

Den påfølgende reduksjon av det oppnådde N-oksyd med formel I, overføres fortrinnsvis, i et oppløsningsmiddel som vann, vann/etanol, metanol, iseddik, eddiksyreetylester eller dimetylformamid, med hydrogen i nærvær av en hydreringskatalysator som Raney-nikkel, platina eller palladium/kull, med metaller som jern, tinn eller sink i nærvær av en syre som eddiksyre, saltsyre eller svovelsyre, med salter som jern(II)-sulfat, tinn(II)klorid eller natriumditionitt, eller med hydrazin i nærvær av Raney-nikkel, ved temperaturer mellom 0 og 50°C, men fortrinnsvis ved romtemperatur. The subsequent reduction of the obtained N-oxide of formula I is preferably carried out, in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/ charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulfuric acid, with salts such as iron(II) sulphate, tin(II) chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel, at temperatures between 0 and 50°C, but preferably at room temperature.

b) Omsetning, av et benzimidazol med den generelle formel b) Reaction, of a benzimidazole with the general formula

hvor where

Rx til R3 er som innledningsvis definert, Rx to R3 are, as initially defined,

med en bifenylforbindelse med den generelle formel with a biphenyl compound of the general formula

hvor where

R4 er som innledningsvis definert og R4 is as initially defined and

Z3 utgjør en nukleofil utgående gruppe, så som et halogenatom, f.eks. et klor-, brom- eller jodatom, eller en substituert sulfonyloksygruppe, f.eks. en metansulfonyloksy-, fenyl-sulfonyloksy- eller p-toluensulfonyloksygruppe. Z 3 constitutes a nucleophilic leaving group, such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy group.

Omsetningen foretas hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som metylenklorid, dietyleter, tetrahydrofuran, dioksan, dimetylsulfoksyd, dimetylformamid eller benzen, eventuelt i nærvær av et syrebindende middel som natriumkarbonat, kaliumkarbonat, natriumhydroksyd, kalium-tert-butylat, natriumhydrid, trietylamin eller pyridin, hvorunder de to sistnevnte samtidig også kan benyttes som oppløsningsmiddel, fortrinnsvis ved temperaturer mellom 0 og 100°C, f.eks. ved temperaturer mellom romtemperatur og 50°C. The reaction is conveniently carried out in a solvent or a solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzene, possibly in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butylate, sodium hydride, triethylamine or pyridine, during which the latter two can simultaneously also be used as a solvent, preferably at temperatures between 0 and 100°C, e.g. at temperatures between room temperature and 50°C.

Ved omsetningen oppnår man fortrinnsvis en blanding av 1-og 3-isomerene- som deretter eventuelt kan spaltes i den tilsvarende 1- og 3-isomer ved kromatografi under bruk av et bærermateriale som kiselgel eller aluminiumoksyd. During the reaction, a mixture of the 1- and 3-isomers is preferably obtained, which can then possibly be resolved into the corresponding 1- and 3-isomer by chromatography using a carrier material such as silica gel or aluminum oxide.

c) For fremstilling av en forbindelse med den generelle formel I, hvor R4 utgjør en karboksygruppe: overføring av en forbindelse med den generelle formel c) For the preparation of a compound of the general formula I, where R4 constitutes a carboxy group: transfer of a compound of the general formula

hvor where

Rx til R3 er som innledningsvis definert, og Rx to R3 are as initially defined, and

R4 ' utgjør en gruppe som ved hydrolyse, termolyse eller hydrogenolyse kan overføres i en karboksygruppe. R 4 ' forms a group which, by hydrolysis, thermolysis or hydrogenolysis, can be transferred into a carboxy group.

Eksempelvis kan funksjonelle derivater av karboksygruppen i likhet med deres usubstituerte eller substituerte amider, estere, tiolestere, ortoestere, iminoetere, amidiner eller anhydrider, nitrilgruppen eller tetrazolylgruppen, ved hydrolyse overføres i en karboksygruppe, estere med tertiære alkoholer, f.eks. tert-butylester, ved termolyse overføres i en karboksygruppe og estere med aralkanoler, f.eks. benzyl-esteren, ved hydrogenolyse overføres i en karboksygruppe. For example, functional derivatives of the carboxyl group, like their unsubstituted or substituted amides, esters, thiol esters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group or the tetrazolyl group, can by hydrolysis be transferred in a carboxyl group, esters with tertiary alcohols, e.g. tert-butyl ester, by thermolysis a carboxy group is transferred and esters with aralkanols, e.g. the benzyl ester, by hydrogenolysis is transferred in a carboxy group.

Hydrolysen utføres hensiktsmessig i nærvær av en syre som saltsyre, svovelsyre, fosforsyre, trikloreddiksyre eller trifluoreddiksyre, i nærvær av en base som natriumhydroksyd eller kaliumhydroksyd, i et egnet oppløsningsmiddel som vann, vann/metanol, etanol, vann/etanol, vann/isopropanol, vann/dioksan, metylenklorid eller kloroform ved temperaturer mellom -10°C og 120°C, f.eks. ved temperaturer mellom romtemperatur og reaksjonsblandingens kokepunkt. Ved hydrolyse i nærvær av en organisk syre som trikloreddiksyre eller trifluoreddiksyre, kan eventuelt forekommende alkoholiske hydroksygrupper samtidig overføres i en tilsvarende acyloksy-gruppe, som f.eks. trifluoracetoksygruppen. The hydrolysis is suitably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, water/dioxane, methylene chloride or chloroform at temperatures between -10°C and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture. During hydrolysis in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups that may occur can be simultaneously transferred into a corresponding acyloxy group, such as e.g. the trifluoroacetoxy group.

Betyr R4 ' i en forbindelse med den generelle formel V en cyano- eller aminokarbonylgruppe, kan disse gruppene også overføres i karboksygruppen med et nitritt, f.eks. natrium-nitritt, i nærvær av en syre som svovelsyre, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom 0 og 50°C. If R 4 ' in a compound of the general formula V is a cyano or aminocarbonyl group, these groups can also be transferred in the carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, which can also serve as a solvent, at temperatures between 0 and 50°C.

Betyr R4 ' i en forbindelse med den generelle formel V for eksempel den tertiære butyloksykarbonylgruppe, kan den tertiære butylgruppen også avspaltes termisk, eventuelt i et egnet oppløsningsmiddel som metylenklorid, kloroform, benzen, toluen, tetrahydrofuran eller dioksan, og fortrinnsvis i nærvær av en katalytisk mengde av en syre som p-toluensulfonsyre, svovelsyre, fosforsyre eller polyfosforsyre, fortrinnsvis ved kokepunktet for det anvendte oppløsningsmiddel, f.eks. ved temperaturer mellom 40°C og 100°C. If R 4 ' in a compound of the general formula V is for example the tertiary butyloxycarbonyl group, the tertiary butyl group can also be cleaved off thermally, optionally in a suitable solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, e.g. at temperatures between 40°C and 100°C.

Betyr R4 ' i en forbindelse med den generelle formel V for eksempel benzyloksykarbonylgruppen, kan benzylgruppen også avspaltes hydrogenlytisk i nærvær av en hydreringskatalysator som palladium/kull, i et egnet oppløsningsmiddel som metanol, etanol, etanol/vann, iseddik, eddiksyreetylester, dioksan eller dimetylformamid, fortrinnsvis ved temperaturer mellom 0 og 50°C, f.eks. ved romtemperatur, og under et hydrogentrykk på 1 til 5 bar. Ved hydrogenolysen kan samtidig andre rester, f.eks. en nitrogruppe, med-reduseres til en aminogruppe, en benzyloksygruppe til en hydroksygruppe, en vinylidengruppe til en tilsvarende alkylidengruppe eller en kanelsyregruppe til en tilsvarende fenylpropionsyregruppe, eller erstattes med hydrogenatomer, f.eks. et halogenatom med et hydrogenatom. d) For fremstilling av en forbindelse med den generelle formel I, hvor R4 utgjør en lH-tetrazolylgruppe: avspaltning av en beskyttelsesrest fra en forbindelse med den generelle formel If R 4 ' in a compound of the general formula V for example the benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide , preferably at temperatures between 0 and 50°C, e.g. at room temperature, and under a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, other residues, e.g. a nitro group, is co-reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group or a cinnamic acid group to a corresponding phenylpropionic acid group, or replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom. d) For the preparation of a compound of the general formula I, where R 4 constitutes a 1H-tetrazolyl group: cleavage of a protecting residue from a compound of the general formula

hvor where

Rlt R2 og R3 er som innledningsvis definert og R4" utgjør en lH-tetrazolylgruppe som i 1- eller 3-stilling er beskyttet med en beskyttelsesrest. R 1 R 2 and R 3 are as initially defined and R 4" constitutes a 1H-tetrazolyl group which is protected in the 1- or 3-position with a protective residue.

Som beskyttelsesrest kommer eksempelvis trifenylmetyl-, tributyltinn- eller trifenyltinn-gruppen i betraktning. As a protective residue, for example, the triphenylmethyl, tributyltin or triphenyltin group comes into consideration.

Avspaltningen av en benyttet beskyttelsesrest skjer fortrinnsvis i nærvær av et hydrogenhalogenid, fortrinnsvis i nærvær av hydrogenklorid, i nærvær av en base som natriumhydroksyd eller alkoholisk ammoniakk i et egnet oppløsnings-middel som metylenklorid, metanol, metanol/ammoniakk, etanol eller isopropanol, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved romtemperatur, eller eventuelt, dersom omsetningen foretas i nærvær av alkoholisk ammoniakk, ved forhøyet temperatur, f.eks. temperaturer mellom 100 og 150°C, fortrinnsvis ved temperaturer mellom 120 og 140°C. e) For fremstilling av en forbindelse med den generelle formel I, hvor R4 utgjør en IH-tetrazolylgruppe: The cleavage of a used protective residue preferably takes place in the presence of a hydrogen halide, preferably in the presence of hydrogen chloride, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100°C, preferably at room temperature, or possibly, if the reaction is carried out in the presence of alcoholic ammonia, at an elevated temperature, e.g. temperatures between 100 and 150°C, preferably at temperatures between 120 and 140°C. e) For the preparation of a compound of the general formula I, where R4 constitutes an IH-tetrazolyl group:

omsetning av en forbindelse med den generelle formel turnover of a compound with the general formula

hvor where

Rx til R3 er som innledningsvis definert, Rx to R3 are, as initially defined,

med hydrogenazidsyre eller salter av denne. with hydrogenazide acid or salts thereof.

Omsetningen foretas fortrinnsvis i et oppløsningsmiddel som benzen, toluen eller dimetylformamid ved temperaturer mellom 80 og 150°C, fortrinnsvis ved 125°C. Herunder frigjøres hydrogenazidsyren enten under omsetningen fra et alkaliazid, f.eks. fra natriumazid i nærvær av en svak syre, f.eks. ammoniumklorid, eller ved at tetrazolidsaltet, oppnådd i reaksjonsblandingen ved omsetning med et salt av hydrogenazidsyren, fortrinnsvis med aluminiumazid eller tributyltinnazid, som dessuten hensiktsmessig fremstilles i reaksjonsblandingen ved omsetning av aluminiumklorid eller tributyltinnklorid med et alkaliazid, så som natriumazid, deretter surgjøres med en fortynnet syre, så som 2N saltsyre eller 2N svovelsyre. The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150°C, preferably at 125°C. Here, the hydrogenazide acid is released either during the reaction from an alkali azide, e.g. from sodium azide in the presence of a weak acid, e.g. ammonium chloride, or in that the tetrazolid salt, obtained in the reaction mixture by reaction with a salt of hydrogen azide acid, preferably with aluminum azide or tributyltin azide, which is also conveniently produced in the reaction mixture by reaction of aluminum chloride or tributyltin chloride with an alkali azide, such as sodium azide, is then acidified with a dilute acid , such as 2N hydrochloric acid or 2N sulfuric acid.

f) For fremstilling av forbindelser med den generelle formel I, hvor R4 utgjør en i 1- eller 2-stilling med en Ra-CO-0-CH2-gruppe substituert tetrazolylgruppe, en RaO-CO-, Rb-CO-0-(RCCH)-0-CO- eller en RbO-CO-0- (RCCH) -O-CO-gruppe : omsetning av en forbindelse med den generelle formel f) For the preparation of compounds of the general formula I, where R4 constitutes a tetrazolyl group substituted in the 1- or 2-position with a Ra-CO-0-CH2 group, a RaO-CO-, Rb-CO-0-( RCCH)-0-CO- or a RbO-CO-0- (RCCH)-O-CO group : reaction of a compound of the general formula

hvor where

Rx til R3 er som innledningsvis definert og Rx to R3 are as initially defined and

R4"' betyr en karboksy-, lH-tetrazolyl- eller 2H-tetrazolylgruppe, R4"' means a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group,

med en forbindelse med den generelle formel with a compound of the general formula

hvor where

Y2 betyr en Ra-C0-0-CH2-, Rb-CO-0-(RCCH) -, Rb0-C0-0-(RCCH) - eller Y2 means a Ra-C0-0-CH2-, Rb-CO-0-(RCCH) -, Rb0-C0-0-(RCCH) - or

Ra-gruppe, hvor Ra til Rc er som innledningsvis definert og Ra group, where Ra to Rc are as initially defined and

Z4 betyr en nukleofil utgående gruppe, så som et halogenatom, f.eks. et klor- eller bromatom, eller også, dersom Y utgjør en Ra-gruppe, en hydroksygruppe. Z 4 means a nucleophilic leaving group, such as a halogen atom, e.g. a chlorine or bromine atom, or, if Y constitutes a Ra group, a hydroxy group.

Omsetningen skjer hensiktsmessig ved forestring med en tilsvarende alkohol eller med et tilsvarende reaktivt derivat, som f.eks. halogenidet, i et oppløsningsmiddel eller en opp-løsningsmiddelblanding som vann, metylenklorid, kloroform, eter, tetrahydrofuran, dioksan eller dimetylformamid, eller i et overskudd av acyleringsmidlet som oppløsningsmiddel, eventuelt i nærvær av et middel som virker aktiverende eller vanntiltrekkende på syren, så som tionylklorid, med deres anhydrider, estere eller halogenider, eventuelt i nærvær av en uorganisk eller tertiær organisk base som natriumhydroksyd, kaliumkarbonat, trietylamin eller pyridin, idet de to sistnevnte samtidig også kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 og 100°C, fortrinnsvis ved temperaturer mellom -10 og 80°C. The reaction conveniently takes place by esterification with a corresponding alcohol or with a corresponding reactive derivative, such as e.g. the halide, in a solvent or a solvent mixture such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide, or in an excess of the acylating agent as a solvent, optionally in the presence of an agent which has an activating or water-attracting effect on the acid, such as thionyl chloride, with their anhydrides, esters or halides, optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, the latter two of which can simultaneously also serve as a solvent, at temperatures between -25 and 100°C, preferably at temperatures between -10 and 80°C.

I de ovenfor beskrevne omsetninger kan eventuelt forekommende reaktive grupper som hydroksy- eller iminogrupper, beskyttes under omsetningen ved hjelp av vanlige beskyttelsesgrupper som avspaltes igjen etter omsetningen. In the reactions described above, reactive groups that may occur, such as hydroxy or imino groups, can be protected during the reaction by means of common protective groups which are split off again after the reaction.

Aktuelle beskyttelsesrester for en hydroksygruppe er trimetylsilyl-, acetyl-, benzoyl-, metyl-, etyl-, tert-butyl-, benzyl- eller tetrahydropyranylgruppen, og for en iminogruppe, acetyl-, benzoyl-, etoksykarbonyl- eller benzylgruppen. Relevant protecting residues for a hydroxy group are the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and for an imino group, the acetyl, benzoyl, ethoxycarbonyl or benzyl group.

Den eventuelt påfølgende avspaltning av en benyttet beskyttelsesrest skjer fortrinnsvis hydrolytisk i et vandig oppløsningsmiddel, f.eks. i vann, isopropanol/vann, tetrahydrofuran /vann eller dioksari/vann, i nærvær av en syre, så som saltsyre eller svovelsyre, eller i nærvær av en alkalibase som natriumhydroksyd eller kaliumhydroksyd, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved reaksjonsblandingens kokepunkt. Avspaltningen av en benzylrest skjer imidlertid fortrinnsvis hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator som palladium/kull i et oppløsningsmiddel som under tilsetning av en syre, så som saltsyre, ved temperaturer mellom 0 og 50°C, men fortrinnsvis ved romtemperatur, og under et hydrogentrykk på 1 til 7 bar, fortrinnsvis på 3 til 5 bar. The possibly subsequent cleavage of a used protective residue preferably takes place hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxarium/water, in the presence of an acid, such as hydrochloric acid or sulfuric acid, or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at the reaction mixture's boiling point. However, the cleavage of a benzyl residue preferably takes place hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as under the addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50°C, but preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably at 3 to 5 bar.

En således oppnådd isomerblanding av en forbindelse med den generelle formel I kan eventuelt spaltes, fortrinnsvis kromatografisk ved bruk av en bærer, så som kiselgel eller aluminiumoksyd. A thus obtained mixture of isomers of a compound of the general formula I can optionally be resolved, preferably chromatographically using a carrier, such as silica gel or aluminum oxide.

De oppnådde forbindelsene med den generelle formel I kan dessuten overføres i deres syreaddisjonssalter, spesielt for farmasøytisk anvendelse, i deres fysiologisk akseptable salter, med uorganiske eller organiske syrer. Som syrer for formålet kommer eksempelvis saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, fumarsyre, ravsyre, melkesyre, sitronsyre, vinsyre eller maleinsyre i betraktning. The obtained compounds of the general formula I can also be transferred in their acid addition salts, especially for pharmaceutical use, in their physiologically acceptable salts, with inorganic or organic acids. Acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Dessuten lar de således oppnådde nye forbindelser med den generelle formel I, dersom de inneholder en karboksy- eller IH-tetrazolylgruppe, seg deretter eventuelt overføre i deres salter med uorganiske eller organiske baser, spesielt for farmasøytisk anvendelse, i deres fysiologisk akseptable salter. Som baser kommer herunder eksempelvis natriumhydroksyd, kaliumhydroksyd, cyklogheksylamin, etanolamin, dietanolamin og trietanolamin i betraktning. Moreover, the thus obtained new compounds of the general formula I, if they contain a carboxy or IH-tetrazolyl group, can subsequently optionally be transferred into their salts with inorganic or organic bases, especially for pharmaceutical use, into their physiologically acceptable salts. Examples of bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

De anvendte utgangsforbindelser med den generelle formel II til XIII er tildels kjent fra litteraturen eller kan oppnås ifølge fremgangsmåter kjent fra litteraturen. The starting compounds with the general formula II to XIII used are partly known from the literature or can be obtained according to methods known from the literature.

Således oppnås eksempelvis en forbindelse med den generelle formel II ved alkylering av en tilsvarende o-amino-acylamino-forbindelse med en forbindelse med den generelle formel IV. Den til formålet nødvendige o-aminoacylamino-forbindelse oppnås ved reduksjon av en tilsvarende o-nitro-acylamino-forbindelse, som på sin side oppnås ved nitrering av et tilsvarende acylaminoacetofenon, påfølgende overføring av det oppnådde, tilsvarende o-nitroacylaminoacetofenon i det tilsvarende 6-bromacetofenon, påfølgende cyklisering av w-bromacetofenonet med et tilsvarende syreamid og påfølgende reduksjon av nitrogruppen. Før reduksjonen av nitrogruppen kan en således oppnådd oksazol-4-yl-forbindelse ved hjelp av et tilsvarende amin, fortrinnsvis med ammoniakk, under trykk, overføres i den tilsvarende imidazol-4-yi-forbindelse, eller en således oppnådd i 1-stilling usubstituert imidazol-4-yl-forbindelse, ved alkylering overføres i en tilsvarende i 1-stilling alkylert imidazol-4-yl-forbindelse. Thus, for example, a compound of the general formula II is obtained by alkylating a corresponding o-amino-acylamino compound with a compound of the general formula IV. The o-aminoacylamino compound required for the purpose is obtained by reduction of a corresponding o-nitro-acylamino compound, which in turn is obtained by nitration of a corresponding acylaminoacetophenone, subsequent transfer of the obtained, corresponding o-nitroacylaminoacetophenone in the corresponding 6- bromoacetophenone, subsequent cyclization of the w-bromoacetophenone with a corresponding acid amide and subsequent reduction of the nitro group. Before the reduction of the nitro group, an oxazol-4-yl compound thus obtained can be transferred by means of a corresponding amine, preferably with ammonia, under pressure, into the corresponding imidazol-4-yl compound, or a thus obtained in the 1-position unsubstituted imidazol-4-yl compound, by alkylation is transferred into a corresponding imidazol-4-yl compound alkylated in the 1-position.

En utgangsforbindelse med den generelle formel III oppnås ved reduksjon og cyklisering av en av de foran beskrevne o-nitro-acylamino-forbindelser. A starting compound with the general formula III is obtained by reduction and cyclization of one of the o-nitro-acylamino compounds described above.

En utgangsforbindelse med den generelle formel V, VI, VII og VIII oppnås ved omsetning av en forbindelse med den generelle formel III med en tilsvarende forbindelse med den generelle formel IV. A starting compound of the general formula V, VI, VII and VIII is obtained by reacting a compound of the general formula III with a corresponding compound of the general formula IV.

De nye forbindelsene med den generelle formel I og deres fysiologisk akseptable salter, oppviser verdifulle farmakologiske egenskaper. De utgjør angiotensin-antagonister, spesielt angiotensin-II-antagonister. The new compounds of the general formula I and their physiologically acceptable salts exhibit valuable pharmacological properties. They constitute angiotensin antagonists, especially angiotensin-II antagonists.

Eksempelvis ble forbindelsene: For example, the connections were:

A = 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2- yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, A = 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2- yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

B = 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre, B = 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

C = 4'-[(2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, C = 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

D = 4'-[(2-cyklopropyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo-Ll ,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og D = 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-L1,2-a]pyridin-2-yl)-benzimidazol-1-yl)- methyl]-biphenyl-2-carboxylic acid and

E = 4'-[(2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, E = 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl) -biphenyl,

undersøkt med henblikk på deres biologiske virkninger på følgende måte: examined for their biological effects as follows:

Angiotensin- II- reseptorbinding, metodebeskrivelse Angiotensin II receptor binding, method description

Vev (rottelunge) homogeniseres i Tris-buffer (50 mmol Tris, 150 mmol NaCl, 5 mmol EDTA, pH 7,40) og sentrifugeres to ganger, hver gang i 20 min. ved 20.000 x g. Den endelige pellet resuspenderes i inkubasjonsbuffer (50 mmol Tris, 5 mmol MgCl2, 0,2% BSA, pH 7,40) 1:75, beregnet på basis av vekten av det fuktige vev. Porsjoner på 0,1 mL homogenat inkuberes i 60 min. ved 37°C med 50 pM [<125>I]-angiotensin II (NEN, Dreieich, Tyskland) og tiltagende konsentrasjoner av testforbindelsen i et totalvolum på 0,25 mL. Inkubasjonen avsluttes ved hurtig filtrering gjennom glassfiberfilter-matte. Filterne vaskes med 4 mL iskald buffer (25 mmol Tris, 2,5 mmol MgCl2, 0,1% BSA, pH 7,40). Den bundne radioaktivitet fastslås ved måling i en gamma-teller. Ut fra dose/virkningskurven bestemmes den tilsvarende ICS0-verdi. Tissue (rat lung) is homogenized in Tris buffer (50 mmol Tris, 150 mmol NaCl, 5 mmol EDTA, pH 7.40) and centrifuged twice, each time for 20 min. at 20,000 x g. The final pellet is resuspended in incubation buffer (50 mmol Tris, 5 mmol MgCl2, 0.2% BSA, pH 7.40) 1:75, calculated on the basis of the weight of the moist tissue. Portions of 0.1 mL homogenate are incubated for 60 min. at 37°C with 50 pM [<125>I]-angiotensin II (NEN, Dreieich, Germany) and increasing concentrations of the test compound in a total volume of 0.25 mL. The incubation is terminated by rapid filtration through a glass fiber filter mat. The filters are washed with 4 mL ice-cold buffer (25 mmol Tris, 2.5 mmol MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity is determined by measurement in a gamma counter. Based on the dose/effect curve, the corresponding ICS0 value is determined.

I den beskrevne test oppviser forbindelsene A til E følgende IC50-verdier: In the test described, the compounds A to E exhibit the following IC50 values:

På grunn av deres farmakologiske egenskaper egner de nye forbindelsene og deres fysiologisk akseptable salter, seg til behandling av hypertoni og hjerteinsuffisiens, til behandling av ischemiske perifere sirkulasjonsforstyrrelser, ved myokardischemi (angina), til forebyggelse av hjerte-insuf f isiensutvikling etter myokardinfarkt, til behandling av diabetisk nefropati, av glaukom, gastrointestinale sykdommer og blærelidelser. Due to their pharmacological properties, the new compounds and their physiologically acceptable salts are suitable for the treatment of hypertension and heart failure, for the treatment of ischemic peripheral circulatory disorders, for myocardial ischemia (angina), for the prevention of heart failure development after myocardial infarction, for the treatment of diabetic nephropathy, of glaucoma, gastrointestinal diseases and bladder disorders.

Dessuten egner de nye forbindelsene og deres fysiologisk akseptable salter seg til behandling av pulmonale sykdommer, f.eks. lungeødemer og kronisk bronkitt, til forebyggelse av arteriell re-stenose etter angioplastikk, av fortykninger av karveggen etter karoperasjoner, arteriosklerose og diabetisk angiopati. På grunn av påvirkningen av acetylcholin- og dopamin-frigjøringen gjennom angiotensin i hjernen, egner de nye angiotensin-antagonistene seg også til å oppheve sentral-nervøse forstyrrelser, f.eks. ved depresjoner, ved Alzheimers sykdom, Parkinson-syndromet, bulemi, samt ved forstyrrelser av kognitive funksjoner. Moreover, the new compounds and their physiologically acceptable salts are suitable for the treatment of pulmonary diseases, e.g. pulmonary edema and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, of thickening of the vessel wall after coronary operations, arteriosclerosis and diabetic angiopathy. Due to the influence of acetylcholine and dopamine release through angiotensin in the brain, the new angiotensin antagonists are also suitable for reversing central nervous disorders, e.g. in depression, in Alzheimer's disease, Parkinson's syndrome, bulemia, as well as in disorders of cognitive functions.

Den nødvendige dosering for å oppnå en ønsket virkning hos voksne utgjør ved intravenøs tilførsel hensiktsmessig 0,5 til 100 mg, fortrinnsvis 1 til 70 mg, og ved peroral administrasjon 0,1 til 200 mg, fortrinnsvis 1 til 10 0 mg, gitt 1 til 3 ganger daglig. Forbindelser med den generelle formel I lar seg herunder innarbeide, eventuelt i kombinasjon med andre virkestoffer, som f.eks. blodtrykkssenkende midler, ACE-hemmere, diuretika og/eller kalsiumantagonister, sammen med én eller flere inerte vanlige bærerstoffer og/eller fortynnings-midler, f.eks. med maisstivelse, melkesukker, rørsukker, mikrokrystallinsk cellulose, magnesiumstearat, polyvinyl-pyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/glycerol, vann/sorbitol, vann/polyetylenglykol, propylen-glykol, cetylstearylalkohol, karboksymetylcellulose eller fettholdige substanser som hårdfett eller egnede blandinger av disse, i vanlige galeniske tilberedninger som tabletter, drasjéer, kapsler, pulvere, suspensjoner eller stikkpiller. The necessary dosage to achieve a desired effect in adults amounts to an appropriate amount of 0.5 to 100 mg, preferably 1 to 70 mg for intravenous administration, and for oral administration 0.1 to 200 mg, preferably 1 to 100 mg, given 1 to 3 times daily. Compounds with the general formula I can be incorporated below, possibly in combination with other active substances, such as e.g. blood pressure lowering agents, ACE inhibitors, diuretics and/or calcium antagonists, together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

I de ovennevnte kombinasjoner kan det således ytterligere inngå virkestoffer, så som bendroflumetiazid, klortiazid, hydroklortiazid, spironolaktdn, benztiazid, cyklotiazid, etakrynsyre, furosemid, metoprolol, prazosin, atenolol, propranolol (di)hydralazin-hydroklorid, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin, nitrendipin, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril og ramipril. Dosen for disse virkestoffene utgjør herunder hensiktsmessig 1/5 av den ellers anbefalte laveste dosering opp til l/l av den vanligvis anbefalte dosering, hvilket vil si for eksempel 15 til 200 mg hydroklortiazid, 125 til 2000 mg klortiazid, 15 til 200 mg etakrynsyre, 5 til 80 mg furosemid, 20 til 480 mg propranolol, 5 til 60 mg felodipin, 5 til 60 mg nifedipin eller 5 til 60 mg nitrendipin. The above-mentioned combinations may thus further include active substances, such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactdn, benzthiazide, cyclothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, propranolol (di)hydralazine hydrochloride, diltiazem, felodipine, nicardipine, nifedipine , nisoldipine, nitrendipine, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dose for these active substances is appropriately 1/5 of the otherwise recommended lowest dosage up to l/l of the usually recommended dosage, which means for example 15 to 200 mg hydrochlorothiazide, 125 to 2000 mg chlorothiazide, 15 to 200 mg ethacrynic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipine, 5 to 60 mg nifedipine, or 5 to 60 mg nitrendipine.

De etterfølgende eksempler skal belyse oppfinnelsen ytterligere. The following examples shall further illustrate the invention.

Eksempel 1 Example 1

4'- [ (2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol- l- yl)- metyll- bifenyl- 2- karboksylsyre 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl-biphenyl-2-carboxylic acid

a) 2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol a) 2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole

En blanding av 4,5 g (21 mmol) l-metylamino-2-amino-4-fluorbenzen-dihydroklorid og 4,3 g (21 mmol) 2-etyl-4-metyl-benzimidazol-6-yl-karboksylsyre omrøres i 100 g polyfosforsyre ved 140°C i 4 timer og røres deretter inn i ca. 300 g isvann, hvorpå den gjøres alkalisk med konsentrert ammoniakk-oppløsning. Det utfelte råprodukt suges av, tørkes og renses deretter ved kolonnekromatografi (3 00 g kiselgel; metylenklorid/etanol = 95:5). A mixture of 4.5 g (21 mmol) of 1-methylamino-2-amino-4-fluorobenzene dihydrochloride and 4.3 g (21 mmol) of 2-ethyl-4-methyl-benzimidazol-6-yl-carboxylic acid is stirred in 100 g of polyphosphoric acid at 140°C for 4 hours and then stirred in for approx. 300 g of ice water, after which it is made alkaline with concentrated ammonia solution. The precipitated crude product is suctioned off, dried and then purified by column chromatography (300 g silica gel; methylene chloride/ethanol = 95:5).

Utbytte: 3,1 g (48% av det teoretiske) Yield: 3.1 g (48% of theoretical)

Rf-verdi: 0,24 (kiselgel; metylenklorid/etanol = 19:1) Rf value: 0.24 (silica gel; methylene chloride/ethanol = 19:1)

b) 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert- butylester b) 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid-tert - butyl ester

En oppløsning av 1,55 g (5 mmol) 2-etyl-4-metyl-6-(1-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol i 30 mL dimetylsulfoksyd tilsettes 616 mg (5,5 mmol) kalium-tert-butylat og omrøres i 15 minutter ved romtemperatur. Deretter tilsettes 1,9 g (5,5 mmol) 4 '-brommetyl-bifenyl-2-karboksylsyre-tert-butylester og omrøringen fortsettes i ytterligere 20 timer ved romtemperatur. Deretter røres blandingen inn i ca. 80 mL mettet natriumkloridoppløsning, hvoretter det utfelte råprodukt avsuges og renses ved kolonnekromatografi (150 g kiselgel; eluent: metylenklorid/etanol = 98:2). A solution of 1.55 g (5 mmol) of 2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole in 30 mL of dimethyl sulfoxide is added to 616 mg (5.5 mmol ) potassium tert-butylate and stirred for 15 minutes at room temperature. 1.9 g (5.5 mmol) of 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester are then added and stirring is continued for a further 20 hours at room temperature. The mixture is then stirred into approx. 80 mL saturated sodium chloride solution, after which the precipitated crude product is filtered off with suction and purified by column chromatography (150 g silica gel; eluent: methylene chloride/ethanol = 98:2).

Utbytte: 1,4 g (50% av det teoretiske) Yield: 1.4 g (50% of the theoretical)

Rf-verdi: 0,4 7 (kiselgel; metylenklorid/etanol = 19:1) Rf value: 0.4 7 (silica gel; methylene chloride/ethanol = 19:1)

c) 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-vl)- benzimidazol- l- yl)- metyl]- bifenyl- 2- karboksylsyre c) 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

En oppløsning av 1,4 g (2,4 mmol) 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert-butylester og 15 mL trifluoreddiksyre i 3 0 mL metylenklorid omrøres i 14 timer ved romtemperatur, hvoretter den inndampes og residuet tilsettes ca. 3 0 mL vann og gjøres alkalisk med 2N natronlut. Etter ekstrahering to ganger med 30 mL porsjoner dietyleter, sur-gjøres den vandige fase med 20% sitronsyre. Det derved utfelte råprodukt suges av og renses ved kolonnekromatografi (100 g kiselgel; eluent: metylenklorid/etanol = 96:4). A solution of 1.4 g (2.4 mmol) of 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl) -methyl]-biphenyl-2-carboxylic acid tert-butyl ester and 15 mL of trifluoroacetic acid in 30 mL of methylene chloride are stirred for 14 hours at room temperature, after which it is evaporated and the residue is added approx. 30 mL of water and made alkaline with 2N caustic soda. After extraction twice with 30 mL portions of diethyl ether, the aqueous phase is acidified with 20% citric acid. The thus precipitated crude product is sucked off and purified by column chromatography (100 g silica gel; eluent: methylene chloride/ethanol = 96:4).

Utbytte: 850 mg (69% av det teoretiske) Yield: 850 mg (69% of the theoretical)

Smeltepunkt: 246-248°C Melting point: 246-248°C

C32<H>27FN402 (518, 60) C32<H>27FN402 (518, 60)

Beregnet: C, 74,11 H, 5,25 N, 10,80 Calculated: C, 74.11 H, 5.25 N, 10.80

Funnet: 73,95 5,34 10,80 Found: 73.95 5.34 10.80

Massespektrum: m/e = 518 Mass spectrum: m/e = 518

Eksempel 2 Example 2

4 ' - [ (2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-1-yl)- metvll- bifenyl- 2- karboksylsvre 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 87% av det teoretiske Yield: 87% of the theoretical

Smeltepunkt: 269-271°C Melting point: 269-271°C

C29H31N304S (517,65) C29H31N304S (517.65)

Beregnet: C, 67,29 H, 6,04 N, 8,12 Calculated: C, 67.29 H, 6.04 N, 8.12

Funnet: 67,56 6,12 8,28 Found: 67.56 6.12 8.28

Rf-verdi: 0,39 (kiselgel; metylenklorid/etanol = 9:1) Massespektrum: m/e = 517 Rf value: 0.39 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 517

Eksempel 3 Example 3

4 ' -t(2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol- l- vl)- metyl]- bifenyl- 2- karboksvlsyre 4'-t(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[(2-cyklo-propyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 4'-[(2-cyclo-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.

Utbytte: 50% av det teoretiske Yield: 50% of the theoretical

Smeltepunkt: 245-248°C Melting point: 245-248°C

C32<H>26<N>402 (498,59) C32<H>26<N>402 (498.59)

Beregnet: C, 77,09 H, 5,26 N, 11,24 Calculated: C, 77.09 H, 5.26 N, 11.24

Funnet: 76,88 5,37 11,30 Found: 76.88 5.37 11.30

Rf-verdi: 0,63 (kiselgel; metylenklorid/etanol = 9:1) Massespektrum: m/e = 498 Rf value: 0.63 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 498

Eksempel 4 Example 4

4'- [ (2-cyklopropyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[ (2-cyklo-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 4'-[(2-cyclo-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazole -1-yl)-methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 53% av det teoretiske Yield: 53% of the theoretical

Smeltepunkt: 310-312°C Melting point: 310-312°C

C32<H>30N4O2 (502,62) C32<H>30N4O2 (502.62)

Beregnet: C, 76,47 H, 6,02 N, 11,15 Calculated: C, 76.47 H, 6.02 N, 11.15

Funnet: 76,23 5,97 10,85 Found: 76.23 5.97 10.85

Rf-verdi: 0,17 (kiselgel; metylenklorid/etanol = 9:1) Massespektrum: m/e = 502 Rf value: 0.17 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 502

Eksempel 5 Example 5

4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol- l- yl)- metyl]- 2-( lH- tetrazol- 5- yl)- bifenyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1- yl)- methyl]- 2-(1H- tetrazole-5- yl)-biphenyl

a) 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)- benzimidazol- l- yl)- metyl]- 2- cyano- bifenvl a) 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl

En oppløsning av 1,55 g (5 mmol) 2-etyl-4-metyl-6-(1-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol i 30 mL dimetylsulfoksyd tilsettes 616 mg (5,5 mmol) kalium-tert-butylat og omrøres i 15 minutter ved romtemperatur. Deretter tilsettes 1,5 g (5,5 mmol) 4'-brommetyl-2-cyano-bifenyl og omrøringen fortsettes i ytterligere 2 0 timer ved romtemperatur. Blandingen røres derpå inn i ca. 80 mL mettet natriumklorid-oppløsning, hvoretter det utfelte råprodukt suges av og renses ved kolonnekromatografi (150 g kiselgel; eluent: metylenklorid/etanol = 97:3) . A solution of 1.55 g (5 mmol) of 2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole in 30 mL of dimethyl sulfoxide is added to 616 mg (5.5 mmol ) potassium tert-butylate and stirred for 15 minutes at room temperature. 1.5 g (5.5 mmol) of 4'-bromomethyl-2-cyano-biphenyl is then added and stirring is continued for a further 20 hours at room temperature. The mixture is then stirred for approx. 80 mL saturated sodium chloride solution, after which the precipitated crude product is sucked off and purified by column chromatography (150 g silica gel; eluent: methylene chloride/ethanol = 97:3).

Utbytte: 1,9 g (76% av det teoretiske) Yield: 1.9 g (76% of theoretical)

Rf-verdi: 0,43 (kiselgel; metylenklorid/etanol = 19:1) Rf value: 0.43 (silica gel; methylene chloride/ethanol = 19:1)

b) 4 '-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl b) 4 '-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl

En oppløsning av 1,9 g (3,8 mmol) 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-cyano-bifenyl, 4,1 g (76 mmol) ammoniumklorid og 4,9 g (76 mmol) natriumazid i 30 mL dimetylformamid oppvarmes til 140°C i 15 timer, hvorpå ytterligere 2,0 g ammoniumklorid og 2,4 g natriumazid tilsettes og oppvarmingen til 14 0°C fortsettes i ytterligere 4 timer. Deretter røres oppløsningen inn i ca. 80 mL mettet natriumkloridoppløsning, hvorpå det utfelte råprodukt suges av og renses ved kolonnekromatografi (150 g kiselgel; eluent: metylenklorid/etanol = 19:1). A solution of 1.9 g (3.8 mmol) of 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl) -methyl]-2-cyano-biphenyl, 4.1 g (76 mmol) ammonium chloride and 4.9 g (76 mmol) sodium azide in 30 mL dimethylformamide are heated to 140°C for 15 hours, after which a further 2.0 g ammonium chloride and 2.4 g of sodium azide are added and heating to 140°C is continued for a further 4 hours. The solution is then stirred into approx. 80 mL saturated sodium chloride solution, after which the precipitated crude product is sucked off and purified by column chromatography (150 g silica gel; eluent: methylene chloride/ethanol = 19:1).

Utbytte: 1,25 g (61% av det teoretiske) Yield: 1.25 g (61% of theoretical)

Smeltepunkt: 267-269°C Melting point: 267-269°C

C32<H>27FN8 (542,60) C32<H>27FN8 (542.60)

Beregnet: C, 70,84 H, 5,02 N, 20,65 Calculated: C, 70.84 H, 5.02 N, 20.65

Funnet: 70,52 5,04 20,82 Found: 70.52 5.04 20.82

Rf-verdi: 0,6 0 (kiselgel; metylenklorid/etanol = 9:1) Massespektrum: m/e = 542 Rf value: 0.6 0 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 542

Eksempel 6 Example 6

4'-[(2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl) - benzimidazol- l- vl)- metvll- 2-( lH- tetrazol- 5- yl)- bifenyl 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-vl)-methyl-2-(1H-tetrazol-5-yl)- biphenyl

a) 4'-[(2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(2-trifenylmetyl-tetrazol-5-yl)- bifenyl a) 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5- yl)-biphenyl

En oppløsning av 570 mg (1,86 mmol) 2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol i 20 mL dimetylsulfoksyd tilsettes 224 mg (2,0 mmol) kalium-tert-butylat og omrøres i 15 minutter ved romtemperatur. Deretter tilsettes 1,11 g (2,0 mmol) 4'-brommetyl-2-(2-trifenylmetyl-tetrazol-5-yl)-bifenyl, hvoretter omrøringen fortsettes 3 timer til ved romtemperatur. Blandingen røres deretter inn i ca. 50 mL mettet natriumkloridoppløsning, hvoretter det utfelte råprodukt suges av og renses ved kolonnekromatografi (10 0 g kiselgel; eluent: etylacetat/petroleter = 4:1). A solution of 570 mg (1.86 mmol) 2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazole in 20 mL dimethylsulfoxide is added to 224 mg (2.0 mmol) potassium ter -butylate and stirred for 15 minutes at room temperature. 1.11 g (2.0 mmol) of 4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are then added, after which stirring is continued for a further 3 hours at room temperature. The mixture is then stirred in for approx. 50 mL saturated sodium chloride solution, after which the precipitated crude product is sucked off and purified by column chromatography (100 g silica gel; eluent: ethyl acetate/petroleum ether = 4:1).

Utbytte: 860 mg (59% av det teoretiske) Yield: 860 mg (59% of the theoretical)

Rf-verdi: 0,56 (kiselgel; etylacetat/petroleter = 4:1) Rf value: 0.56 (silica gel; ethyl acetate/petroleum ether = 4:1)

b) 4'-[(2-etoksy-4-metyl-6- (1-metyl-benzimidazol-2-yl)-benzimidazol- l- vl)- metvll- 2-( lH- tetrazol- 5- vl)- bifenyl b) 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-vl)-methyl-2-(1H-tetrazol-5-vl)- biphenyl

En blanding av 830 mg (1,06 mmol) 4'- [ (2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(2-trifenylmetyl-tetrazol-5-yl)-bifenyl, 2,5 mL IN natronlut og 20 mL etanol omrøres i 2 timer ved 80°C. Oppløsningen inndampes og residuet tilsettes 30 mL vann og gjøres svakt surt med iseddik. Blandingen ekstraheres deretter tre ganger med 20 mL porsjoner metylenklorid, hvorpå de samlede organiske ekstraktene vaskes med 20 mL vann og inndampes. Det således oppnådde råprodukt renses ved kolonnekromatografi (50 g kiselgel; metylenklorid/etanol = 97:3). A mixture of 830 mg (1.06 mmol) of 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2- (2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 2.5 mL 1N caustic soda and 20 mL ethanol are stirred for 2 hours at 80°C. The solution is evaporated and the residue is added to 30 mL of water and made slightly acidic with glacial acetic acid. The mixture is then extracted three times with 20 mL portions of methylene chloride, after which the combined organic extracts are washed with 20 mL of water and evaporated. The crude product thus obtained is purified by column chromatography (50 g silica gel; methylene chloride/ethanol = 97:3).

Utbytte: 430 mg (75% av det teoretiske) Yield: 430 mg (75% of the theoretical)

Smeltepunkt: 194-197°C Melting point: 194-197°C

C32<H>28N80 (540,60) C32<H>28N80 (540.60)

Beregnet: C, 71,10 H, 5,22 N, 20,73 Calculated: C, 71.10 H, 5.22 N, 20.73

Funnet: 69,99 5,36 20,54 Found: 69.99 5.36 20.54

Massespektrum: m/e = 54 0 Mass spectrum: m/e = 54 0

Eksempel 7 Example 7

4 ' - [ (2-etoksy-4-metyl-6- (imidazo [1, 2-a] pyridin-2-yl) - benzimidazol- l- yl)- metyl]- bifenvl- 2- karboksylsyre- hydrat 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid hydrate

Fremstillet analogt med Eksempel 1 fra 4 '-[(2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl) - metyl] -bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[(2-ethoxy-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.

Utbytte: 72% av det teoretiske Yield: 72% of the theoretical

Smeltepunkt: 207-209°C Melting point: 207-209°C

C31H2SN403 x H20 (520,60) C31H2SN403 x H20 (520.60)

Beregnet: C, 71,52 H, 5,42 N, 10,76 Calculated: C, 71.52 H, 5.42 N, 10.76

Funnet: 71,22 5,37 10,76 Found: 71.22 5.37 10.76

Rf-verdi: 0,3 6 (kiselgel; metylenklorid/etanol = 19:1) Rf value: 0.3 6 (silica gel; methylene chloride/ethanol = 19:1)

Eksempel 8 Example 8

Blanding av 4 '- [ (2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) "-metyl] -2- [1- (pivaloyloksymetyl) -tetrazol-5-yl] -bifenyl og 4 '- [ (2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-1-yl)- metyl]- 2-\ 2 -( pivaloyloksymetyl)- tetrazol- 5- vl]- bifenyl Mixture of 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)"-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5 -yl]-biphenyl and 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-\ 2-(pivaloyloxymethyl)- tetrazole-5-vl]-biphenyl

En oppløsning av 400 mg (0,74 mmol) 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl)-metyl]-2-(1H-tetrazol-5-yl)-bifenyl, 0,16 mL (1,1 mmol) pivalinsyre-klormetylester og 194 mg (1,1 mmol) kaliumkarbonat-dihydrat i 10 mL dimetylformamid omrøres i 14 timer ved romtemperatur, røres deretter inn i ca. 50 mL mettet natriumkloridoppløsning og ekstraheres tre ganger med 2 0 mL porsjoner metylenklorid. De samlede organiske ekstraktene vaskes med vann og inndampes. Det således oppnådde råprodukt renses ved kolonnekromatografi (50 g kiselgel; eluent: metylenklorid/etanol = 98:2). A solution of 400 mg (0.74 mmol) 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H -tetrazol-5-yl)-biphenyl, 0.16 mL (1.1 mmol) pivalic acid chloromethyl ester and 194 mg (1.1 mmol) potassium carbonate dihydrate in 10 mL dimethylformamide are stirred for 14 hours at room temperature, then stirred into about. 50 mL saturated sodium chloride solution and extracted three times with 20 mL portions of methylene chloride. The combined organic extracts are washed with water and evaporated. The crude product thus obtained is purified by column chromatography (50 g silica gel; eluent: methylene chloride/ethanol = 98:2).

Utbytte: 400 mg (82% av det teoretiske) Yield: 400 mg (82% of the theoretical)

Smeltepunkt: amorft Melting point: amorphous

C35H41N704S (655,80) C35H41N704S (655.80)

Beregnet: C, 64,10 H, 6,30 N, 14,95 S, 4,88 Calculated: C, 64.10 H, 6.30 N, 14.95 S, 4.88

Funnet: 63,99 6,22 14,80 5,03 Found: 63.99 6.22 14.80 5.03

Rf-verdi: 0,46 (kiselgel; metylenklorid/etanol = 19:1) Rf value: 0.46 (silica gel; methylene chloride/ethanol = 19:1)

Eksempel 9 Example 9

Blanding av Mixture of

4'- [ (2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] - pyridin-2-yl) -benzimidazol-l-yl)-metyl]-2-[1-(pivaloyloksy-metyl) -tetrazol-5-yl]-bifenyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl) -methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl

og and

4 ' - [ (2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl) -benzimidazol-l-yl)-metyl]-2-[2-(pivaloyloksy-metyl) - tetrazol- 5- yll - bifenvl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl) -methyl]-2-[2-(pivaloyloxy-methyl)-tetrazol-5-yl-biphenyl

Fremstillet analogt med Eksempel 8 fra 4'-[ (2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl] -2-(lH-tetrazol-5-yl)-bifenyl og pivalinsyre-klormetylester. Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazole -1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and pivalic acid chloromethyl ester.

Utbytte: 75% av det teoretiske Yield: 75% of the theoretical

Smeltepunkt: 203-205°C Melting point: 203-205°C

C38<H>42N8<0>2 (642,80) C38<H>42N8<0>2 (642.80)

Beregnet: C, 71,00 H, 6,59 N, 17,43 Calculated: C, 71.00 H, 6.59 N, 17.43

Funnet: 70,85 6,63 17,43 Found: 70.85 6.63 17.43

Rf-verdi: 0,43 (kiselgel; metylenklorid/etanol = 19:1) Massespektrum: m/e = 642 Rf value: 0.43 (silica gel; methylene chloride/ethanol = 19:1) Mass spectrum: m/e = 642

Eksempel 10 Example 10

4 ' - [ (2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl] -2-[1-(cykloheksyloksy-karbonyloksy)- etvloksykarbonyll- bifenyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl) -methyl] -2-[1-(cyclohexyloxy-carbonyloxy)-ethloxycarbonyl-biphenyl

En oppløsning av 504 mg (1,0 mmol) 4'-[(2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 600 mg 1-(cykloheksyloksykarbonyloksy)-etyljodid og 350 mg kaliumkarbonat i 25 mL dimetylsulfoksyd omrøres i 14 timer ved romtemperatur, røres deretter inn i ca. 70 mL mettet natrium-kloridoppløsning og ekstraheres tre ganger med 3 0 mL porsjoner etylacetat. De samlede organiske ekstraktene vaskes med vann og inndampes. Det således oppnådde råprodukt renses ved kolonnekromatografi (100 g kiselgel; eluent: metylenklorid/etanol = 98:2). A solution of 504 mg (1.0 mmol) 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2 -yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, 600 mg of 1-(cyclohexyloxycarbonyloxy)-ethyl iodide and 350 mg of potassium carbonate in 25 mL of dimethylsulfoxide are stirred for 14 hours at room temperature, then stirred into approx. 70 mL saturated sodium chloride solution and extracted three times with 30 mL portions of ethyl acetate. The combined organic extracts are washed with water and evaporated. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluent: methylene chloride/ethanol = 98:2).

Utbytte: 325 mg (48% av det teoretiske) Yield: 325 mg (48% of the theoretical)

Smeltepunkt: 162-164°C Melting point: 162-164°C

C41H46N40s (674,85) C41H46N40s (674.85)

Beregnet: C, 72,97 H, 6,87 N, 8,30 Calculated: C, 72.97 H, 6.87 N, 8.30

Funnet: 72,63 6,77 ' 8,17 Found: 72.63 6.77 ' 8.17

Rf-verdi: 0,52 (kiselgel; metylenklorid/etanol = 19:1) Massespektrum: m/e = 674 Rf value: 0.52 (silica gel; methylene chloride/ethanol = 19:1) Mass spectrum: m/e = 674

Eksempel 11 Example 11

4'-[(2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-(pivaloyloksymetyl-oksykarbonvl)- bifenyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl) -methyl]-2-(pivaloyloxymethyl-oxycarbonyl)-biphenyl

Fremstillet analogt med Eksempel 8 fra 4'-[(2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og pivalinsyre-klormetylester i dimetylformamid. Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazole -1-yl)-methyl]-biphenyl-2-carboxylic acid and pivalic acid chloromethyl ester in dimethylformamide.

Utbytte: 76% av det teoretiske Yield: 76% of the theoretical

Smeltepunkt: 142-144°C Melting point: 142-144°C

C38H42N404 (618,79) C38H42N404 (618.79)

Beregnet: C, 73,76 H, 6,84 N, 9,09 Calculated: C, 73.76 H, 6.84 N, 9.09

Funnet: 73,60 6,92 9,17 Found: 73.60 6.92 9.17

Rf-verdi: 0,40 (kiselgel; metylenklorid/etanol = 19:1) Massespektrum: m/e = 618 Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1) Mass spectrum: m/e = 618

Eksempel 12 Example 12

4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-1-vl)- metvll- 2-( pivaloyloksymetyloksvkarbonvl)- bifenyl 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl-2-(pivalyloxymethyloxycarbonyl)-biphenyl

Fremstillet analogt med Eksempel 8 fra 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og pivalinsyre-klormetylester i dimetylformamid. Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and pivalic acid chloromethyl ester in dimethylformamide.

Utbytte: 70% av det teoretiske Yield: 70% of the theoretical

Smeltepunkt: olje Melting point: oil

C35H41<N>306S (631,80) C35H41<N>306S (631.80)

Beregnet: C, 66,54 H, 6,54 N, 6,65 S, 5,08 Calculated: C, 66.54 H, 6.54 N, 6.65 S, 5.08

Funnet: 66,21 6,67 6,54 5,34 Found: 66.21 6.67 6.54 5.34

Rf-verdi: 0,49 (kiselgel; metylenklorid/etanol = 19:1) Massespektrum: m/e = 631 Rf value: 0.49 (silica gel; methylene chloride/ethanol = 19:1) Mass spectrum: m/e = 631

Eksempel 13 Example 13

4'-[(2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-[1-(etoksykarbonyl-oksymetyloksy)- karbonyl]- bifenyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl) -methyl]-2-[1-(ethoxycarbonyl-oxymethyloxy)-carbonyl]-biphenyl

Fremstillet analogt med Eksempel 8 fra 4'-[(2-n-propyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og 1-(etoksykarbonyloksy)-metylklorid i dimetylformamid. Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazole -1-yl)-methyl]-biphenyl-2-carboxylic acid and 1-(ethoxycarbonyloxy)-methyl chloride in dimethylformamide.

Utbytte: 38,5% av det teoretiske Yield: 38.5% of the theoretical

Smeltepunkt: 123-125°C Melting point: 123-125°C

C37<H>40<N4O>5 (62 0,76) C37<H>40<N4O>5 (62 0.76)

Beregnet: C, 71,59 H, 6,50 N, 9,03 Calculated: C, 71.59 H, 6.50 N, 9.03

Funnet: 71,57 6,58 9,03 Found: 71.57 6.58 9.03

Rf-verdi: 0,33 (kiselgel; metylenklorid/etanol = 19:1) Massespektrum: m/e = 620 Rf value: 0.33 (silica gel; methylene chloride/ethanol = 19:1) Mass spectrum: m/e = 620

Eksempel 14 Example 14

4'-[(2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol- l- yl)- metvll - 2-( lH- tetrazol- 5- yl)- bifenyl 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl-2-(1H-tetrazol-5-yl) )- biphenyl

Fremstillet analogt med Eksempel 6 fra 4 ' - [ (2-etoksy-4-metyl-6-(imidazo [1,2-a]pyridin-2-yl-benzimidazol-l-yl) -metyl] - 2-(2-trifenylmetyl-tetrazol-5-yl)-bifenyl og natronlut i etanol. Prepared analogously to Example 6 from 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl-benzimidazol-1-yl)-methyl]-2-(2 -triphenylmethyl-tetrazol-5-yl)-biphenyl and caustic soda in ethanol.

Eksempel 15 Example 15

4 ' - [ (2-etoksy-4-metyl-6 - (5,6,7, 8-tetrahydro-imidazo [1, 2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl 4'-[(2-ethoxy-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

Fremstillet analogt med Eksempel 6 fra 4 ' - [ (2-etoksy-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl) - benzimidazol-l-yl)-metyl]-2-(2-trifenylmetyl-tetrazol-5-yl) - bifenyl og natronlut i etanol. Prepared analogously to Example 6 from 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1 -yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and caustic soda in ethanol.

Eksempel 16 Example 16

4'-[(2-etoksy-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksy 1 syre 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-biphenyl-2-carboxy 1 acid

Fremstillet analogt med Eksempel 1 fra 4 '- [ (2-etoksy-4-metyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl) - benz imidazol - 1 -yl) -metyl] -bifenyl - 2 - karboksylsyre - tert -butyl - ester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benz imidazole - 1-yl)-methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 63% av det teoretiske Yield: 63% of the theoretical

Smeltepunkt: 238-240°C Melting point: 238-240°C

Rf-verdi: 0,62 (kiselgel; metylenklorid/etanol = 9:1) Rf value: 0.62 (silica gel; methylene chloride/ethanol = 9:1)

Eksempel 17 Example 17

4'-[(2-etyl-4-metyl-6- (butansultam-l-yl)-benzimidazol-l-yl)-metyl]- bifenvl- 2- karboksylsyre 4'-[(2-ethyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4 ' -[(2-etyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl)-metyl] -bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[(2-ethyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 68% av det teoretiske Yield: 68% of the theoretical

Smeltepunkt: >24 0°C Melting point: >24 0°C

C28<H>29N304S (503,60) C28<H>29N304S (503.60)

Beregnet: C, 66,77 H, 5,80 N, 8,34 Calculated: C, 66.77 H, 5.80 N, 8.34

Funnet: 66,57 5,69 8,30 Found: 66.57 5.69 8.30

Rf-verdi: 0,36 (kiselgel; metylenklorid/etanol = 9:1) Rf value: 0.36 (silica gel; methylene chloride/ethanol = 9:1)

Eksempel 18 Example 18

4'-[(2-etyl-4-metyl-6-(3-klor-5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksvlsvre 4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1- yl)-methyl]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[(2-etyl-4-metyl-6-(3-klor-5, 6,7,8-tetrahydro-imidazo[1,2-a] pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert-butylester og trifloreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl) -benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 43% av det teoretiske Yield: 43% of the theoretical

Smeltepunkt: 295-297°C Melting point: 295-297°C

<C>3l<H>29ClN402 (525,06) <C>3l<H>29ClN4O2 (525.06)

Beregnet: C, 70,91 H, 5,57 N, 10,67 Cl, 6,75 Calculated: C, 70.91 H, 5.57 N, 10.67 Cl, 6.75

Funnet: 70,81 5,54 10,55 6,83 Found: 70.81 5.54 10.55 6.83

I de etterfølgende farmasøytiske anvendelseseksempler kan enhver egnet forbindelse med formel I, spesielt slike hvor R4 utgjør en i 1- eller 2-stilling med en Ra-CO-0-CH2-gruppe substituert tetrazolylgruppe, en karboksy-, lH-tetrazolyl-, Ra-0-C0-, Rb-C0-0-(RCCH)-O-CO- eller en R5-0-C0-0-(RCCH)-0-CO-gruppe, benyttes som virkestoff: In the following pharmaceutical application examples, any suitable compound of formula I, especially those where R4 constitutes a tetrazolyl group substituted in the 1- or 2-position with a Ra-CO-0-CH2 group, a carboxy-, 1H-tetrazolyl-, Ra -0-C0-, Rb-C0-0-(RCCH)-O-CO- or an R5-0-C0-0-(RCCH)-0-CO group, is used as active ingredient:

Eksempel I Example I

Ampuller, inneholdende 50 mg virkestoff per 5 ml Ampoules, containing 50 mg of active ingredient per 5 ml

Frems t i11ina: Forward t i1ina:

I en del av vannet oppløses buffer-forbindelsene og isotoniseringsmidlet. Virkestoffet tilsettes og etter full-stendig oppløsning, tilsettes vann til det angitte volum. In part of the water, the buffer compounds and the isotonizing agent are dissolved. The active substance is added and after complete dissolution, water is added to the indicated volume.

Eksempel II Example II

Ampuller, inneholdende 100 mg virkestoff per 5 ml Ampoules, containing 100 mg of active ingredient per 5 ml

Fremstilling:Manufacturing:

I en del av vannet oppløses metylglukamin, hvoretter virkestoffet under omrøring og oppvarming, bringes til opp-løsning. Etter tilsetning av oppløsningsmidlet påfylles vann til det angitte volum. Methylglucamine is dissolved in part of the water, after which the active ingredient is brought into solution while stirring and heating. After adding the solvent, water is added to the indicated volume.

Eksempel III Example III

Tabletter, inneholdende 50 mg virkestoff Tablets, containing 50 mg of active ingredient

Fremsti11ing: Progress:

Virkestoffet, CaHP04, melkesukker og maisstivelse fuktes jevnt med en vandig PVP-oppløsning. Massen siktes gjennom en 2 mm sikt, tørkes i omlufts-tørkeskap ved 50°C og siktes på nytt. The active substance, CaHP04, milk sugar and cornstarch are evenly moistened with an aqueous PVP solution. The mass is sieved through a 2 mm sieve, dried in a circulating air drying cabinet at 50°C and sieved again.

Etter innblanding av glattemidlet, presses granulatet på en tabletteringsmaskin. After mixing in the smoothing agent, the granulate is pressed on a tableting machine.

Eksempel IV Example IV

Drasjéer, inneholdende 50 mg virkestoff Dragees, containing 50 mg of active ingredient

Fremstilling: Manufacturing:

Virkestoffet blandes med hjelpestoffene og fuktes med en vandig gelatinoppløsning. Etter sikting og tørking, blandes The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After sieving and drying, mix

granulatet med magnesiumstearat og presses til kjerner. the granulate with magnesium stearate and pressed into cores.

De således fremstillede kjerner drasjéres etter kjente fremgangsmåter. Drasjéringssuspensjonen eller -oppløsningen kan tilsettes farvestoff. The cores produced in this way are coated according to known methods. Dye can be added to the coating suspension or solution.

Eksempel V Example V

Drasjéer, inneholdende 100 mg virkestoff Dragees, containing 100 mg of active ingredient

Fremstilling: Manufacturing:

Virkestoffet blandes med hjelpestoffene og fuktes med en vandig PVP-oppløsning. Den fuktige masse siktes gjennom en 1,5 mm sikt og tørkes ved 45°C. Etter tørkingen foretas ny sikting, hvorpå magnesiumstearatet blandes inn. Blandingen presses til kjerner. The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is sieved through a 1.5 mm sieve and dried at 45°C. After drying, new sieving is carried out, after which the magnesium stearate is mixed in. The mixture is pressed into cores.

De således fremstillede kjerner drasjéres deretter etter kjente fremgangsmåter. Drasjéringssuspensjonen eller The cores produced in this way are then coated according to known methods. The coating suspension or

-oppløsningen kan tilsettes farvestoffer. - dyes can be added to the solution.

Eksempel VI Example VI

Kapsler, inneholdende 250 mg virkestoff Capsules, containing 250 mg active ingredient

Fremstilling: Manufacturing:

Virkestoffet og maisstivelse blandes og fuktes med vann. Den fuktige masse siktes og tørkes. Det tørre granulat siktes og blandes med magnesiumstearat. Sluttblandingen fylles over på hård-gelatin-kapsler av størrelse 1. The active substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is poured into size 1 hard gelatin capsules.

Eksempel VII Example VII

Peroral suspensjon, inneholdende 50 mg virkestoff per 5 ml Oral suspension, containing 50 mg of active ingredient per 5 ml

Fremstilling: Manufacturing:

Destillert vann oppvarmes til 70°C. I dette oppløses hydroksyetylcellulose under omrøring. Ved tilsetning av sorbitoloppløsning og glycerol avkjøles blandingen til romtemperatur. Ved romtemperatur tilsettes sorbinsyre, aroma- og virkestoff. For å oppnå utlufting av suspensjonen foretas evakuering under omrøring. En dose = 50 mg inngår i 5,0 ml. Distilled water is heated to 70°C. Hydroxyethyl cellulose is dissolved in this while stirring. When sorbitol solution and glycerol are added, the mixture is cooled to room temperature. At room temperature, sorbic acid, aroma and active ingredient are added. To achieve venting of the suspension, evacuation is carried out while stirring. A dose = 50 mg is included in 5.0 ml.

Eksempel VIII Example VIII

Suppositorier, inneholdende 100 mg virkestoff Suppositories, containing 100 mg of active ingredient

Fremstilling:Manufacturing:

Hårdfettet smeltes og ved 40°C dispergeres det oppmalte virkestoff homogent i smeiten. Blandingen avkjøles til 38°C og støpes i svakt avkjølte suppositorieformer. The hard fat is melted and at 40°C the ground active substance is homogeneously dispersed in the melt. The mixture is cooled to 38°C and cast into slightly cooled suppository forms.

Claims (6)

1. Benzimidazoler, karakterisert ved at de har den generelle formel hvor Rx i 4-stilling betyr en metylgruppe, R2 betyr en imidazo[1,2-a]pyridin-2-yl-, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 3-klor-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 1-metyl-benzimidazol-2-yl-, 1-metyl-5-fluor-benzimidazol-2-yl- eller butansultam-l-yl-gruppe, R3 betyr en alkylgruppe med 2 til 4 karbonatomer, en cyklopropylgruppe eller en alkoksygruppe med 2 eller 3 karbonatomer og R4 betyr en i 1- eller 2-stilling med en Ra-CO-0-CH2-gruppe substituert tetrazolylgruppe, en Rb-CO-0- (RCCH) -0-CO-, RdO-CO- eller Rb0-CO-0- (RCCH) -0-CO-gruppe, idet Ra utgjør en rettkjedet eller forgrenet alkylgruppe med 1 til 6 karbonatomer, en cykloalkylgruppe med 5 til 7 karbonatomer, en benzyl-, l-fenyletyl-, 2-fenyletyl-, 3-fenylpropyl-, metoksymetyl- eller cinnamylgruppe, Rb utgjør -en rettkjedet eller forgrenet alkylgruppe med 1 til 6 karbonatomer, en cykloalkylgruppe med 5 til 7 karbonatomer, en fenyl-, benzyl-, l-fenyletyl-, 2-fenyletyl- eller 3-fenylpropylgruppe, Rc utgjør et hydrogenatom eller en metylgruppe, og Rd utgjør en rettkjedet eller forgrenet alkylgruppe med 5-6 karbonatomer, en cykloalkylgruppe med 5-7 karbonatomer, en benzyl-, l-fenyletyl-, 2-fenyletyl-, 3-fenylpropyl-, metoksymetyl- eller cinnamylgruppe, eller en forbindelse valgt fra1. Benzimidazoles, characterized in that they have the general formula where Rx in the 4-position means a methyl group, R 2 means an imidazo[1,2-a]pyridin-2-yl-, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 3-chloro-5,6 ,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl-, 1-methyl-benzimidazol-2-yl-, 1-methyl-5-fluoro-benzimidazol-2-yl- or butan- 1-yl group, R3 means an alkyl group with 2 to 4 carbon atoms, a cyclopropyl group or an alkoxy group with 2 or 3 carbon atoms and R4 means a tetrazolyl group substituted in the 1- or 2-position with a Ra-CO-0-CH2 group, a Rb-CO-0-(RCCH)-0-CO-, RdO-CO- or Rb0-CO-0 - (RCCH) -0-CO group, in that Ra constitutes a straight-chain or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 5 to 7 carbon atoms, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb is - a straight-chain or branched alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group, Rc constitutes a hydrogen atom or a methyl group, and Rd represents a straight-chain or branched alkyl group with 5-6 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, or a connection chosen from 4 ' - [ (2-cyklopropyl-4-metyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-etoksy-4-metyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-etoksy-4-metyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a] - pyridin-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl,4'-[(2-cyclopropyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-biphenyl-2-carboxylic acid, 4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-biphenyl-2-carboxylic acid, 4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl, 4'- [ (2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre,4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, 4 '-[ (2-etoksy-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl) - benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl,4 '-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl, 4 '- [ (2-etoksy-4-metyl-6-(1-metyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre og 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre, deres tautomerer og deres salter.4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl , 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl, 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and 4'- [(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, their tautomers and their salts. 2. Forbindelser ifølge krav 1, karakterisert ved at de er valgt fra 4'-[(2-cyklopropyl-4-metyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a] pyridin-2-yl)-benzimidazol-l-yl)-metyl] -bifenyl-2-karboksylsyre 4'-[(2-cyklopropyl-4-metyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre, 4'-[(2-etoksy-4-metyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-l-yl) -metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-etyl-4-metyl-6-(l-metyl-5-fluor-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[(2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl) -metyl]-bifenyl-2-karboksylsyre, deres tautomerer og deres salter.2. Compounds according to claim 1, characterized in that they are selected from 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazole -1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl )-methyl]-biphenyl-2-carboxylic acid, 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl , 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl, 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, their tautomers and their salts. 3. Forbindelse ifølge krav 1, karakterisert ved at den er 4'-[ (2-n-propyl-4-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl)-metyl]-bifenyl -2-karboksylsyre, og tautomerer og salter derav.3. Connection according to claim 1, characterized in that it is 4'-[(2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, and tautomers and salts thereof. 4. Forbindelse ifølge et av kravene 1 til 3, karakterisert ved at den er et fysiologisk akseptabelt salt av en forbindelse med formel I ifølge et av kravene 1-3.4. Compound according to one of claims 1 to 3, characterized in that it is a physiologically acceptable salt of a compound of formula I according to one of claims 1-3. 5. ' Legemiddel, karakterisert ved at det inneholder en forbindelse ifølge minst et av kravene 1 til 3, eller et fysiologisk akseptabelt salt derav sammen med ett eller flere fysiologisk akseptable bærerstoffer og/eller fortynnings-midler.5. ' Medicine, characterized in that it contains a compound according to at least one of claims 1 to 3, or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers and/or diluents. 6. Anvendelse av en forbindelse med formel I ifølge minst et av kravene 1 til 3 eller et fysiologisk akseptabelt salt derav for fremstilling av et legemiddel med angiotensin-antagonis-tisk virkning.6. Use of a compound of formula I according to at least one of claims 1 to 3 or a physiologically acceptable salt thereof for the production of a medicinal product with an angiotensin-antagonistic effect.