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NO178927B - Analogous Process for the Preparation of Therapeutically Active Benzimidazoles - Google Patents

Analogous Process for the Preparation of Therapeutically Active Benzimidazoles Download PDF

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NO178927B
NO178927B NO912859A NO912859A NO178927B NO 178927 B NO178927 B NO 178927B NO 912859 A NO912859 A NO 912859A NO 912859 A NO912859 A NO 912859A NO 178927 B NO178927 B NO 178927B
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methyl
benzimidazol
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biphenyl
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NO912859A
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NO178927C (en
NO912859L (en
NO912859D0 (en
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Berthold Narr
Norbert Hauel
Jacques Van Meel
Wolfgang Wienen
Michael Entzeroth
Uwe Ries
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Thomae Gmbh Dr K
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Publication of NO912859L publication Critical patent/NO912859L/en
Publication of NO178927B publication Critical patent/NO178927B/en
Publication of NO178927C publication Critical patent/NO178927C/en

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Abstract

The invention relates to benzimidazoles of the general formula <IMAGE> in which R1 to R4 are as defined in Claim 1, mixtures of their 1-, 3-isomers, and their salts, which have valuable properties. The novel compounds are, in particular, angiotensin antagonists.

Description

I US-patent 4.880.804 beskrives blant annet 4'-[(2-alkyl-benzimidazol-l-yl)metyl]bifenyl-2-karboksylsyrer og 4'-[(2-alkyl-benzimidazol-l-yl)metyl]-2-(lH-tetrazol-5-yl)bifenyler som i benzimidazolringen er substituert med en alkanoylaminometylgruppe og utgjør angiotensin-II-antagonister. US patent 4,880,804 describes, among other things, 4'-[(2-alkyl-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acids and 4'-[(2-alkyl-benzimidazol-1-yl)methyl] -2-(1H-tetrazol-5-yl)biphenyls which are substituted in the benzimidazole ring with an alkanoylaminomethyl group and constitute angiotensin-II antagonists.

I norsk ansøkning 90.1571 (patent 177533) med prioritet fra 8. april 1989 beskrives likedes benzimidazoler som er angiotensin-II-antagonister. Den nevnte ansøkning ble imidlertid gjort allmenn tilgjengelig etter de to første prioriteter for foreliggende ansøkning. Som det vil fremgå av den nedenstående forsøksrapport utmerker forbindelsene ifølge eksempel 96 til 122 seg overfor de strukturelt nærmest beslektede kjente forbindelser. In Norwegian application 90.1571 (patent 177533) with priority from 8 April 1989, benzimidazoles which are angiotensin-II antagonists are also described. However, the aforementioned application was made publicly available after the first two priorities for the present application. As will be apparent from the test report below, the compounds according to examples 96 to 122 excel compared to the structurally most closely related known compounds.

Det har nå vist seg at de nye benzimidazolene med den generelle formel It has now been shown that the new benzimidazoles with the general formula

deres 1-, 3-isomerblandinger, samt deres salter, spesielt ved farmasøytisk anvendelse, deres fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser, utgjør enda mer verdifulle angiotensinantagonister, spesielt angiotensin-II-antagonister. their 1-, 3-isomer mixtures, as well as their salts, especially in pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids or bases, constitute even more valuable angiotensin antagonists, especially angiotensin-II antagonists.

I den ovenfor angitte generelle formel betyr R1 en tetra-hydrobehzimidazolyl- eller imidazopyridinylgruppe eller en benzimidazolyl- eller benzoksazolylgruppe som i~fenylkjernen eventuelt er substituert med et fluor-, klor- eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, hvor NH-gruppen i den foran nevnte imidazolring dessuten kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en aminogruppe som er substituert med en bicykloheksylkarbonyl- eller bifenylkarbonylgruppe, eller en hydroksycykloalkylaminokarbonylgruppe med 5 til 7 karbonatomer i cykloalkyldelen, som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, In the general formula given above, R1 means a tetrahydrobezimidazolyl or imidazopyridinyl group or a benzimidazolyl or benzoxazolyl group in which the phenyl nucleus is optionally substituted with a fluorine, chlorine or bromine atom, with an alkyl group of 1 to 3 carbon atoms, with an alkoxy group with 1 to 3 carbon atoms or with a trifluoromethyl group, where the NH group in the aforementioned imidazole ring can also be substituted with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group with 3 to 7 carbon atoms, an amino group which is substituted with a bicyclohexylcarbonyl- or biphenylcarbonyl group, or a hydroxycycloalkylaminocarbonyl group with 5 to 7 carbon atoms in the cycloalkyl part, which may also be substituted on the N atom with an alkyl group with 1 to 3 carbon atoms,

en bicykloheksyl- eller bifenyl-substituert aminokarbonylaminogruppe som dessuten på N-atomet kan være substituert med én eller to alkylgrupper som hver har 1 til 3 karbonatomer, a bicyclohexyl- or biphenyl-substituted aminocarbonylamino group which can also be substituted on the N atom by one or two alkyl groups each having 1 to 3 carbon atoms,

dessuten, med unntak av 2-okso-3,4-tetrametylen-pyrrolidin-1-yl-gruppen, en 5-, 6- eller 7-leddet alkylenimino- eller furthermore, with the exception of the 2-oxo-3,4-tetramethylene-pyrrolidin-1-yl group, a 5-, 6- or 7-membered alkyleneimino- or

alkenyleniminogruppe, hvor en metylengruppe kan-være erstattet med en karbonyl- eller sulfonylgruppe, og som eventuelt er substituert med én eller to alkylgrupper med 1 til 3 karbonatomer eller med en tetrametylen- eller pentametylengruppe, alkenylenimino group, where a methylene group can be replaced by a carbonyl or sulfonyl group, and which is optionally substituted with one or two alkyl groups with 1 to 3 carbon atoms or with a tetramethylene or pentamethylene group,

en 3,4,5,6-tetrahydro-2(1H)-pyrimidinongruppe som eventuelt kan være substituert med en alkyl- eller fenylalkylgruppe med 1 til 3 karbonatomer i hver alkyldel, a 3,4,5,6-tetrahydro-2(1H)-pyrimidinone group which may optionally be substituted with an alkyl or phenylalkyl group with 1 to 3 carbon atoms in each alkyl part,

en rettkjedet eller forgrenet hydroksyalkylaminokarbonylgruppe med 4 til 6 karbonatomer i alkyldelen, a straight-chain or branched hydroxyalkylaminocarbonyl group with 4 to 6 carbon atoms in the alkyl part,

en maleinsyreamido- eller maleinsyreimidogruppe som eventuelt kan være mono- eller, disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med en fenylgruppe, hvor substituentene kan være like eller forskjellige, a maleic amido or maleic imido group which may optionally be mono- or disubstituted with an alkyl group with 1 to 3 carbon atoms or with a phenyl group, where the substituents may be the same or different,

en imidazolin- eller imidazolgruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, an imidazoline or imidazole group which may optionally be substituted with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group with 3 to 7 carbon atoms,

en imidazolidindiongruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, med en fenylalkylgruppe med 1 til 3 karbonatomer i alkyldelen, med en tetrametylen-, pentametylen- eller heksametylengruppe, an imidazolidinedione group which may optionally be substituted with an alkyl group with 1 to 3 carbon atoms, with a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, with a tetramethylene, pentamethylene or hexamethylene group,

en alkylsulfonyloksygruppe med 1 til 6 karbonatomer, an alkylsulfonyloxy group of 1 to 6 carbon atoms,

en benzensulfonyloksygruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, a benzenesulfonyloxy group which may optionally be substituted with an alkyl group with 1 to 3 carbon atoms,

en alkylamino- eller fenylalkylaminogruppe som er substituert med en alkylsulfonylgruppe med 4 til 6 karbonatomer eller med en fenylalkylsulfonylgruppe, hvori hver alkyldel kan inneholde 1 til 3 karbonatomer, an alkylamino or phenylalkylamino group which is substituted with an alkylsulfonyl group of 4 to 6 carbon atoms or with a phenylalkylsulfonyl group, in which each alkyl moiety may contain 1 to 3 carbon atoms,

en amino- eller alkylaminogruppe som er substituert med en naftalensulfonylgruppe, som i naftalenringen kan være substituert med en.^iialkylaminogruppe eller med én eller to "alkoksygrupper, hvori hver alkyldel kan inneholde 1 til 3 karbonatomer, an amino or alkylamino group which is substituted with a naphthalenesulfonyl group, which in the naphthalene ring may be substituted with an alkylamino group or with one or two alkoxy groups, in which each alkyl part may contain 1 to 3 carbon atoms,

en alkoksygruppe med 3 til 5 karbonatomer som i 3-, 4- eller 5-stillingen er substituert med en imidazolylgruppe, an alkoxy group with 3 to 5 carbon atoms which is substituted in the 3-, 4- or 5-position with an imidazolyl group,

en alkoksygruppe med 2 til 5 karbonatomer som i 2-, 3-, 4-eller 5-stilling er substituert med en benzimidazolyl- eller tetrahydrobenzimidazolylgruppe, an alkoxy group with 2 to 5 carbon atoms which is substituted in the 2-, 3-, 4- or 5-position with a benzimidazolyl or tetrahydrobenzimidazolyl group,

en pyridazin-3-on- eller dihydro-pyridazin-3-on-gruppe, som a pyridazin-3-one or dihydro-pyridazin-3-one group, which

i 2-stillingen kan være substituert med en eventuelt fenyl-substituert alkylgruppe med 1 til 3 karbonatomer, og som i karbonskjelettet ytterligere kan være substituert med 1 eller 2 alkylgrupper med 1 til 3 karbonatomer, in the 2-position may be substituted with an optionally phenyl-substituted alkyl group with 1 to 3 carbon atoms, and which in the carbon skeleton may further be substituted with 1 or 2 alkyl groups with 1 to 3 carbon atoms,

en pyrrolidino-, piperidino- eller heksametyleniminogruppe som er substituert med 2 alkylgrupper som hver har 1 til 3 karbonatomer, a pyrrolidino, piperidino or hexamethyleneimino group substituted by 2 alkyl groups each having 1 to 3 carbon atoms,

en 7-nitro-benzofurazan-4-yl-aminoalkanoylaminogruppe, hvor alkanoyldelen kan inneholde 2 eller 3 karbonatomer, a 7-nitro-benzofurazan-4-yl-aminoalkanoylamino group, where the alkanoyl part may contain 2 or 3 carbon atoms,

en heptametylen-imino-, 1H,3H-kinazolin-2,4-dion-3-yl-, pentametylen-oksazolin-2-yl-, benzofurankarbonylamino- eller 7-nitro-benzofurazan-4-yl-aminogruppe, a heptamethylene-imino-, 1H,3H-quinazolin-2,4-dion-3-yl-, pentamethylene-oxazolin-2-yl-, benzofurancarbonylamino- or 7-nitro-benzofurazan-4-yl-amino group,

eller når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, betyr R1 i 6-stilling dessuten er en aminogruppe som er substituert med en fenylsulfonyl-, cykloheksylmetylaminokarbonyl-, 2-karboksycykloheksylmetylkarbonyl-, 2-tert.butoksy-karbonyl-cykloheksylmetylkarbonyl-, 2-karboksy-3,4,5,6-tetra-hydrobenzoyl-, N-metyl-fenylaminokarbonyl- eller 3-cykloheksylpropylgruppe; en metylaminogruppe som er substituert med en propylsulfonyl-, fenylsulfonyl-, metylfenylsulfonyl- eller klorfenylsulfonylgruppe; en n-pentylaminogruppe som er substituert med en fenylsulfonyl- eller metoksyfenylsulfonylgruppe; en n-propylaminogruppe som er substituert med en metylfenylsulfonyl-eller metoksyfenylsulfonylgruppe; en isopropylaminogruppe som er substituert med en benzoyl- eller klorfenylsulfonylgruppe; en N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydrohomoftalimido-, N-metansulfonyl-2-fenyletylamino-, N-klorfenylsulfonyl-benzylamino-, piperidino-, "4-metyl-piperidino-eller heksametyleniminogruppe, or when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in the 6-position also means an amino group which is substituted with a phenylsulfonyl-, cyclohexylmethylaminocarbonyl-, 2-carboxycyclohexylmethylcarbonyl-, 2-tert.butoxy-carbonyl-cyclohexylmethylcarbonyl- , 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3-cyclohexylpropyl group; a methylamino group substituted with a propylsulfonyl, phenylsulfonyl, methylphenylsulfonyl or chlorophenylsulfonyl group; an n-pentylamino group substituted with a phenylsulfonyl or methoxyphenylsulfonyl group; an n-propylamino group substituted with a methylphenylsulfonyl or methoxyphenylsulfonyl group; an isopropylamino group substituted with a benzoyl or chlorophenylsulfonyl group; an N-acetyl-cyclohexylmethylamino-, 3,4,5,6-tetrahydrophthalimido-, hexahydrohomophthalimido-, N-methanesulfonyl-2-phenylethylamino-, N-chlorophenylsulfonyl-benzylamino-, piperidino-, "4-methyl-piperidino- or hexamethyleneimino group ,

e-lier, når R3 utgjør en karboksygruppe og f€ z utgjør en n-butylgruppe, R1 i 5- eller 6-stilling er en 2-okso-l,2-dihydro- e-lier, when R3 constitutes a carboxy group and f€ z constitutes an n-butyl group, R1 in the 5- or 6-position is a 2-oxo-1,2-dihydro-

3,4-tetrametylen-pyrrolidin-l-yl-, 3-karboksypropionyl- eller 3-karboksy-2-metyl-propionylgruppe, 3,4-tetramethylene-pyrrolidin-1-yl-, 3-carboxypropionyl- or 3-carboxy-2-methyl-propionyl group,

eller, når R3 er en karboksygruppe og R2 utgjør en metyl-, etyl-, n-propyl-, n-butyl- eller metylmerkaptogruppe, R1 i 6-stilling er en pyrrolidinokarbonylaminogruppe, or, when R3 is a carboxy group and R2 is a methyl, ethyl, n-propyl, n-butyl or methyl mercapto group, R1 in the 6-position is a pyrrolidinocarbonylamino group,

eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en n-butylgruppe, R1 i 5- eller 6-stilling er en n-pentylaminogruppe som er substituert med en metylaminokarbonyl- eller cykloheksylaminokarbonylgruppe, eller i 6-stilling er en 3,3-dimetyl-glutar-syreimido- eller 4,4-tetrametylen-glutarsyreimidogruppe, or also, when R 3 constitutes a tetrazolyl group and R 2 constitutes an n-butyl group, R 1 in the 5- or 6-position is an n-pentylamino group which is substituted by a methylaminocarbonyl or cyclohexylaminocarbonyl group, or in the 6-position is a 3,3- dimethyl glutaric acid imido or 4,4-tetramethylene glutaric acid imido group,

eller når R3 utgjør en tetrazolylgruppe og R2 utgjør en or when R 3 constitutes a tetrazolyl group and R 2 constitutes a

etyl- eller n-propylgruppe, R, i 6-stilling dessuten står for en N-benzensulfonyl-metylaminogruppe, ethyl or n-propyl group, R, in the 6-position also stands for an N-benzenesulfonyl-methylamino group,

eller når R3 utgjør en tert-butoksykarbonylgruppe og R2 utgjør en N-butylgruppe, R1 i 6-stilling også kan være en 2-karboksycykloheksylmetylkarbonylamino- eller pyrrolidinokarbonylaminogruppe, or when R3 constitutes a tert-butoxycarbonyl group and R2 constitutes an N-butyl group, R1 in the 6-position can also be a 2-carboxycyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group,

R2 er et hydrogenatom eller en rettkjedet eller forgrenet alkylgruppe med 1 til 5 karbonatomer, hvori en metylengruppe kan være erstattet med et svovelatom, R2 is a hydrogen atom or a straight-chain or branched alkyl group of 1 to 5 carbon atoms, in which a methylene group may be replaced by a sulfur atom,

R3 er en karboksy-, lH-tetrazolyl- eller en alkoksykarbonylgruppe med tilsammen 2 til 5 karbonatomer og R3 is a carboxy, 1H-tetrazolyl or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms and

R4 er et hydrogen-, fluor-, klor- eller bromatom. R 4 is a hydrogen, fluorine, chlorine or bromine atom.

Foreliggende oppfinnelse omfatter således de nye ovenfor nevnte benzimidazoler, hvor de tilsvarende cyano-, tert.butoksy-karbonyl- og trifenylmetyl-forbindelsene utgjør særlig verdifulle mellomprodukter. The present invention thus includes the new benzimidazoles mentioned above, where the corresponding cyano-, tert-butoxy-carbonyl and triphenylmethyl compounds constitute particularly valuable intermediates.

Gjennom foreliggende oppfinnelse kan det således fremstilles nye legemidler som inneholder en av de ovenfor nevnte farmako-logisk virksomme forbindelser med den generelle formel I eller et tilsvarende fysiologisk akseptabelt salt og som særlig er egnet til behandling av hypertoni og hjerteinsuffisiens, dessuten til behandling av ischemiske perifere gjennomblødningsforstyrrelser, myokardieischemi (angina), til forebyggelse av "hjerte-insuffisiens-progresjon etter myokardieinfarkt, til behandling av diabetisk nefropati, glaukom, samt gastrointestinale sykdommer og blære-lidelser. Through the present invention, new pharmaceuticals can thus be produced which contain one of the above-mentioned pharmacologically active compounds of the general formula I or a corresponding physiologically acceptable salt and which are particularly suitable for the treatment of hypertension and heart failure, also for the treatment of ischemic peripheral circulatory disturbances, myocardial ischemia (angina), for the prevention of "heart failure progression after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, as well as gastrointestinal diseases and bladder disorders.

Aktuelle betydninger for de innledningsvis nevnte definisjoner av restene R1 og R2 er for eksempel Current meanings for the initially mentioned definitions of the residues R1 and R2 are, for example

for R, benzimidazol-2-yl-, l-metyl-benzimidazol-2-yl-, 1-etyl-benzimidazol-2-yl-, l-n-propyl-benzimidazol-2-yl-, 1-isopropyl-benzimidazol-2-yl-, l-n-butyl-benzimidazol-2-yl-, 1-n-pentyl-benzimidazol-2-yl-, l-n-heksyl-benzimidazol-2-yl-, l-cyklopropyl-benzimidazol-2-yl-, l-cyklopentyl-benzimidazol-2-yl-, 1-cykloheksyl-benzimidazol-2-yl-, l-cykloheptyl-benzimidazol-2-yl-, 1,5-dimetyl-benzimidazol-2-yl-, 1,6-dimetyl-benzimidazol-2-yl-, l-metyl-5-metoksy-benzimidazol-2-yl-, 1-metyl-5-fluor-benzimidazol-2-yl-, l-metyl-5-klor-benzimidazol-2-, l-metyl-5-brom-benzimidazol-2-yl-, 1- metyl-5-trifluormetyl-benzimidazol-2-yl-, tetrahydro-benzimidazol-2-yl-, l-metyl-tetrahydro-benzimidazol-2-yl-, 1-etyl-tetrahydro-benzimidazol-2-yl-, 1-n-propyl-tetrahydro-benzimidazol-2- yl~, l-isopropyl-tetrahydro-benzimidazol-2-yi-, 1-n-butyl-tetra-hydrobenzimidazol-2-yl-, l-n-pentyl-tetrahydro-benzimidazol-2-yl-, 1- n-heksyl-tetrahydro-benzimidazol-2-yl-, l-cyklopropyl-tetra-hydrb-benzimidazol-2-yl-, l-cyklopentyl-tetrahydro-benzimidazol-2-yl-, l-cykloheksyl-tetrahydro-benzimidazol-2-yl-, 1-cykloheptyl-tetrahydro-benzimidazol-2-yl-, benzoksazol-2-yl-, 5-met.yl-benzoksazol-2-yl-, 5-metoksy-benzoksazol-2-yl-, 5-trifluormetyl-benzoksazol-2-yl-, 5-fluor-benzoksazol-2-yl-, 5-klor-benzoksazol-2- yl-, 5-brom-benzoksazol-2-yl-, 4-bifenylylkarbonylamino-, 4-cykloheksylkarbonylamino-, N-metyl-4-bifenylylkarbonylamino-, N-etyl-4-cykloheksylkarbonylamino-, N-n-propyl-4-bifenylylkarbonylamino- , N-isopropyl-4-cykloheksylkarbonylamino-, 2-hydroksy-cyklopentylamino-, 2-hydroksycykloheksylamino-, 2- hydroksy-cykloheptyl-amino-, 3-hydroksy-cyklopentylamino-, 3- hydroksy-cykloheksylamino-, 3-hydroksy-cykloheptylamino-, 4- hydroksy-cykloheksylamino-, 4-hydroksy-cykloheptylamino-, N-metyl-2-hydroksy-cyklopentylamino-, N-etyl-2-hydroksy-cykloheksylamino-, N-isopropyl-2-hydroksy-cykloheptylamino-, N-metyl-3-hydroksy-cyklopentylamino-, N-etyl-3-hydroksy-cykloheksylamino-, N-n-propyl-3-hydroksy-cykloheptyl-amino-, N-metyl-4-hydroksy-cykloheksylamino-, N-etyl-4-hydroksy-cykloheptylamino-, 4-bifenylylaminokarbonylamino-, 4-bicykloheksylalninokarbonyl-amino-, N-(4-bifenylylaminokarbonyl)metylamino-, N-(4-bicyklo- for R, benzimidazol-2-yl-, l-methyl-benzimidazol-2-yl-, 1-ethyl-benzimidazol-2-yl-, l-n-propyl-benzimidazol-2-yl-, 1-isopropyl-benzimidazol-2 -yl-, l-n-butyl-benzimidazol-2-yl-, 1-n-pentyl-benzimidazol-2-yl-, l-n-hexyl-benzimidazol-2-yl-, l-cyclopropyl-benzimidazol-2-yl-, l-cyclopentyl-benzimidazol-2-yl-, 1-cyclohexyl-benzimidazol-2-yl-, l-cycloheptyl-benzimidazol-2-yl-, 1,5-dimethyl-benzimidazol-2-yl-, 1,6- dimethyl-benzimidazol-2-yl-, l-methyl-5-methoxy-benzimidazol-2-yl-, 1-methyl-5-fluoro-benzimidazol-2-yl-, l-methyl-5-chloro-benzimidazol-2 -, l-methyl-5-bromo-benzimidazol-2-yl-, 1- methyl-5-trifluoromethyl-benzimidazol-2-yl-, tetrahydro-benzimidazol-2-yl-, l-methyl-tetrahydro-benzimidazol-2 -yl-, 1-ethyl-tetrahydro-benzimidazol-2-yl-, 1-n-propyl-tetrahydro-benzimidazol-2-yl~, 1-isopropyl-tetrahydro-benzimidazol-2-yl-, 1-n-butyl -tetra-hydrobenzimidazol-2-yl-, l-n-pentyl-tetrahydro-benzimidazol-2-yl-, 1- n-hexyl-tetrahydro-benzimidazol-2-yl-, l-cyclopropyl-tetra-hydrb-benzimidazol-2- yl-, l-cyclopent yl-tetrahydro-benzimidazol-2-yl-, 1-cyclohexyl-tetrahydro-benzimidazol-2-yl-, 1-cycloheptyl-tetrahydro-benzimidazol-2-yl-, benzoxazol-2-yl-, 5-meth.yl- benzoxazol-2-yl-, 5-methoxy-benzoxazol-2-yl-, 5-trifluoromethyl-benzoxazol-2-yl-, 5-fluoro-benzoxazol-2-yl-, 5-chloro-benzoxazol-2-yl- , 5-bromo-benzoxazol-2-yl-, 4-biphenylylcarbonylamino-, 4-cyclohexylcarbonylamino-, N-methyl-4-biphenylylcarbonylamino-, N-ethyl-4-cyclohexylcarbonylamino-, N-n-propyl-4-biphenylylcarbonylamino-, N -isopropyl-4-cyclohexylcarbonylamino-, 2-hydroxy-cyclopentylamino-, 2-hydroxycyclohexylamino-, 2- hydroxy-cycloheptyl-amino-, 3-hydroxy-cyclopentylamino-, 3- hydroxy-cyclohexylamino-, 3-hydroxy-cycloheptylamino-, 4-hydroxy-cyclohexylamino-, 4-hydroxy-cycloheptylamino-, N-methyl-2-hydroxy-cyclopentylamino-, N-ethyl-2-hydroxy-cyclohexylamino-, N-isopropyl-2-hydroxy-cycloheptylamino-, N-methyl -3-hydroxy-cyclopentylamino-, N-ethyl-3-hydroxy-cyclohexylamino-, N-n-propyl-3-hydroxy-cycloheptyl-amino-, N -methyl-4-hydroxy-cyclohexylamino-, N-ethyl-4-hydroxy-cycloheptylamino-, 4-biphenylylaminocarbonylamino-, 4-bicyclohexylalninocarbonyl-amino-, N-(4-biphenylylaminocarbonyl)methylamino-, N-(4-bicyclo-

heksylaminokarbonyl)-metylamino-, N-(metyl-4-bifenylylamino-karbonyl)-metylamino-, N-(metyl-4-bicykloheksylaminokarbonyl)-metylamino-, N-(4-bifenylylaminokarbonyl)-etylamino-, N-(4-bi-cykloheksylaminokarbonyl)-isopropylamino-, N-(etyl-4-bifenylyl-aminokarbonyl ) -metylamino-, N-(metyl-4-bicykloheksylamino-karbonyl") -etylamino-, pyrrolidin-2-on-l-yl-, piperidin-2-on-l-yl-, heksametylenimin-2-on-l-yl-, propansuitam-l-yl-, butansultam-1-yl-, pentansultam-l-yl-, 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-metyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-etyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3-(2-fenyletyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 3- (3-fenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl-, 4- hydroksybutylamino-, 5-hydroksypentylamino-, 6-hydroksyheksyl-amino-, maleinsyreimido-, 2-metyl-maleinsyreimido-, 2-fenyl-maleinsyreimido-, 2,3-dimetyl-maleinsyreimido-, 2,3-difenylmaleinsyreimido-, 2-metyl-maleinsyreamido^, 3-metyl-maleinsyreamido-, 2,3-dimetyl-maleinsyreamido-, 2-fenyl-maleinsyreamido-, 3-fenyl-maleinsyreamido-, 2,3-difenyl-maleinsyreamido-, 3-metyl-2-fenyl-maleinsyreamido-, 2-metyl-3-fenyl-maleinsyreamido-, imidazolin-2-yl-, l-metyl-imidazolin-2-yl-, 1-etyl-imidazolin-2- yl-, l-propyl-imidazolin-2-yl-, imidazolidin-2,4-dion-3-yl-, 5- metyl-imidazolidin-2,4-dion-3-yl-, 5-etyl-imidazolidin-2,4-dion-3- yl-, 5-n-propyl-imidazolidin-2,4-dion-3-yl-, 5-benzyl-imidazolidin-2,4-dion-3-yl-, 5-(2-fenyletyl)-imidazolidin-2,4-dion-3-yl-, 5-(3-fenylpropyl)-imidazolidin-2,4-dion-3-yl-, 5,5-tetrametylen-imidazolidin-2,4-dion-3-yl-, 5^5-pentametylen-imidazolidin-2,4-dion-3-yl-, 5,5-heksametylen-imidazolidin-2,4-dion-3-yl-, 5,5-dimetyl-imidazolidin-2,4-dion-3-yl-, 5,5-dietyl-imidazolidin-2,4-dion-3-yl-, metansulfonyloksy-, etansulfonyloksy-, propansulfonyloksy-, butansulfonyloksy-, pentansulfonyloksy-, heksansulfonyloksy-, benzensulfonyloksy-, p-toluensulfonyloksy-, N-n-butansulfonyl-metylamino-, N-n-pentansulfonyl-metylamino-, N-n-heksansulfonyl-metylamino-, N-fenylmetansulfonyl-metylamino-, N-(2-fenyletansulfonyl)-metylamino-, N-(3-fenylpropansulfonyl)-metylamino-, N-n-butansulfonyl-etylamino-, N-n-pentansulfonyl-isopropylamino-, N-n-heksansulfonyl-etylamino-, N-fenylmetansulfonyl-etylamino-, N-(2-fenyletansulfonyl)-n-propylamino-, N-(3-fenylpropansulfonyl)-etylamino-, naftalen-l-sulfonylamino-, naftalen-2-sulfonylamino-, 5-dimetylamino-naftalen-l-sulfonylamino-, N-(naftalen-l-sulfonyl)-metylamino-, N-(naftalen-2-sulfonyl)-etylamino-, N-(5-dimetylamino-naftalen-1-sulfonyl)-metylamino-, N-(5-metoksy-naftalen-l-sulfonyl)-metylamino-, N-(5,6-dimetoksynaftalen-2-sulfonyl)-etylamino-, 3-(imidazol-1-yl)propoksy-, 4-(imidazol-l-yl)butoksy-, 5-(imidazol-l-yl)-pentoksy-, 2-(benzimidazol-l-yl)-etoksy-, 3-(benzimidazol-l-yl)-propoksy-, 4-(benzimidazol-l-yl)-butoksy-, 5-(benzimidazol-l-yl)-pentoksy-, 2-(tetrahydrobenzimidazol-l-yl)-etoksy-, 3-(tetrahydro-benzimidazol-l-yl)-propoksy-, 4-(tetrahydrobenzimidazol-l-yl)-butoksy-, 5-(tetrahydrobenzimidazol-l-yl)-pentoksy-, 4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-metyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-etyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-n-propyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-,. 2-isopropyl—4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-(2-fenyletyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-(3-fenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4-metyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 5-metyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4,4-dimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 5,5-dimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4,5-dimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,4-dimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,5-dimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,4,5-trimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,4,4-trimetyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,5,5-tri-metyl-4 , 5-dihydro-2H-pyridazin-3-on-6-yl-, 2H-py_ridazin-3-on-6-yl-, 2-metyl-2H-pyridazin-3-on-6-yl-, 2-etyl-2H-pyridazin-3-on-6-yl-, 2-n-propyl-2H-pyridazin-3-on-6-yl-, 2-isopropyl-2H-pyridazin-3- on-6-yl-, 2-benzyl-2H-pyridazin-3-on-6-yl-, 2-(2-fenyletyl)-2H-pyridazin-3-on-6-yl-, 2-(3-fenylpropyl)-2H-pyridazin-3-on-6-yl-, hexylaminocarbonyl)-methylamino-, N-(methyl-4-biphenylylamino-carbonyl)-methylamino-, N-(methyl-4-bicyclohexylaminocarbonyl)-methylamino-, N-(4-biphenylylaminocarbonyl)-ethylamino-, N-(4- bi-cyclohexylaminocarbonyl)-isopropylamino-, N-(ethyl-4-biphenylyl-aminocarbonyl)-methylamino-, N-(methyl-4-bicyclohexylamino-carbonyl")-ethylamino-, pyrrolidin-2-on-l-yl-, piperidin-2-on-l-yl-, hexamethyleneimin-2-on-l-yl-, propanesuitam-l-yl-, butansultam-1-yl-, pentasultam-l-yl-, 3,4,5,6 -tetrahydro-2(1H)-pyrimidon-1-yl-, 3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-ethyl-3,4,5 ,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-isopropyl-3 ,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-( 2-phenylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl-, 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)- pyrimidon-1-yl-, 4-hydroxybutylamino-, 5-hydroxypentylamino-, 6-hydroxyhexyl-amino-, maleic imido-, 2-methyl-maleic imido-, 2 -phenyl-maleic acid imido-, 2,3-dimethyl-maleic acid imido-, 2,3-diphenyl-maleic acid imido-, 2-methyl-maleic acid amido^, 3-methyl-maleic acid amido-, 2,3-dimethyl-maleic acid amido-, 2-phenyl-maleic acid amido -, 3-phenyl-maleic amido-, 2,3-diphenyl-maleic amido-, 3-methyl-2-phenyl-maleic amido-, 2-methyl-3-phenyl-maleic amido-, imidazolin-2-yl-, l-methyl -imidazolin-2-yl-, 1-ethyl-imidazolin-2-yl-, l-propyl-imidazolin-2-yl-, imidazolidin-2,4-dion-3-yl-, 5-methyl-imidazolidin-2 ,4-dion-3-yl-, 5-ethyl-imidazolidin-2,4-dion-3-yl-, 5-n-propyl-imidazolidin-2,4-dion-3-yl-, 5-benzyl- imidazolidin-2,4-dion-3-yl-, 5-(2-phenylethyl)-imidazolidin-2,4-dion-3-yl-, 5-(3-phenylpropyl)-imidazolidin-2,4-dione- 3-yl-, 5,5-tetramethylene-imidazolidin-2,4-dion-3-yl-, 5^5-pentamethylene-imidazolidin-2,4-dion-3-yl-, 5,5-hexamethylene-imidazolidin -2,4-dion-3-yl-, 5,5-dimethyl-imidazolidin-2,4-dion-3-yl-, 5,5-diethyl-imidazolidin-2,4-dion-3-yl-, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, pentanesulfonyl oxy-, hexanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy-, N-n-butanesulfonyl-methylamino-, N-n-pentanesulfonyl-methylamino-, N-n-hexanesulfonyl-methylamino-, N-phenylmethanesulfonyl-methylamino-, N-(2-phenylethanesulfonyl)- methylamino-, N-(3-phenylpropanesulfonyl)-methylamino-, N-n-butanesulfonyl-ethylamino-, N-n-pentanesulfonyl-isopropylamino-, N-n-hexanesulfonyl-ethylamino-, N-phenylmethanesulfonyl-ethylamino-, N-(2-phenylethanesulfonyl)- n-propylamino-, N-(3-phenylpropanesulfonyl)-ethylamino-, naphthalene-l-sulfonylamino-, naphthalene-2-sulfonylamino-, 5-dimethylamino-naphthalene-l-sulfonylamino-, N-(naphthalene-l-sulfonyl) -methylamino-, N-(naphthalene-2-sulfonyl)-ethylamino-, N-(5-dimethylamino-naphthalene-1-sulfonyl)-methylamino-, N-(5-methoxy-naphthalene-1-sulfonyl)-methylamino- , N-(5,6-dimethoxynaphthalene-2-sulfonyl)-ethylamino-, 3-(imidazol-1-yl)propoxy-, 4-(imidazol-1-yl)butoxy-, 5-(imidazol-1-yl) )-pentoxy-, 2-(benzimidazol-1-yl)-ethoxy-, 3-(benzimidazol-1-yl)-propoxy-, 4-(benzimidazol-1-yl)-butoxy-, 5-(benzimidazol-1 - yl)-pentoxy-, 2-(tetrahydrobenzimidazol-1-yl)-ethoxy-, 3-(tetrahydro-benzimidazol-1-yl)-propoxy-, 4-(tetrahydrobenzimidazol-1-yl)-butoxy-, 5-( tetrahydrobenzimidazol-1-yl)-pentoxy-, 4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl -, 2-ethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-n-propyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, . 2-isopropyl—4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-(2 -phenylethyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 5-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4,4- dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 5,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 4,5- dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,4-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,5- dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,4,5-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2, 4,4-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl-, 2,5,5-tri-methyl-4,5-dihydro-2H-pyridazin-3-one-6 -yl-, 2H-pyridazin-3-on-6-yl-, 2-methyl-2H-pyridazin-3-on-6-yl-, 2-ethyl-2H-pyridazin-3-on-6-yl- , 2-n-propyl-2H-pyridazin-3-on-6-yl-, 2-isopropyl-2H-pyridazin-3-on-6-yl-, 2-benzyl-2H-pyridazin-3-one-6 -yl-, 2-(2-phenylethyl)-2H-pyridazin-3-on-6-yl-, 2-(3-phenylpropyl)-2H-pyridazin-3-on-6-yl-,

4- metyl-2H-pyridazin-3-on-6-yl-, 5-metyl-2H-pyridazin-3-on-6-yl-, 4 , 5-dimetyl-2H-pyridazin-3-on-6-yl-, 2 , 4-dimety-l-2H-pyridazin-3-on-6-yl-, 2,5-dimetyl-2H-pyridazin-3-on-6-yl-, 2,4,5-trimetyl-2H-pyridaz-in-3-on-6-yl-, 3 , 3-dimetyl-pyrrolidino-, -"3 , 4-dimetyl-pyrrolidino-, 3,3-dimetyl-piperidino-, 3,4-dimetyl-piperidino-, 4- methyl-2H-pyridazin-3-on-6-yl-, 5-methyl-2H-pyridazin-3-on-6-yl-, 4, 5-dimethyl-2H-pyridazin-3-on-6- yl-, 2, 4-dimethyl-1-2H-pyridazin-3-on-6-yl-, 2,5-dimethyl-2H-pyridazin-3-on-6-yl-, 2,4,5-trimethyl -2H-pyridaz-in-3-on-6-yl-, 3 , 3-dimethyl-pyrrolidino-, -"3 , 4-dimethyl-pyrrolidino-, 3,3-dimethyl-piperidino-, 3,4-dimethyl -piperidino-,

4,4-dimetyl-piperidino-, 3,3-dimetyl-heksametylenimino-, 3.4- dimetyl-heksametylenimino-, 4,4-dimetylheksametylenimino-, 3.5- dimetylheksametylenimino-, fenylsulfonylamino-, cykloheksyl-metylaminokarbonylamino-, 2-metylamino-benzoylamino-, 2-karboksy-cykloheksylmetylkarbonylamino-, 2-tert.butoksykarbonyl-cykloheksyl metylkarbonylamino-, 2-karboksy-3,4,5,6-tetrahydrobenzoylamino-, 3- cykloheksylpropylamino-, N-propylsulfonyl-metylamino-, N-fenyl-sulf onyl-metylamino-, N-(4-metylfenylsulfonyl)-metylamino-, N-(4-klorfenylsulfonyl)-metylamino-, N-fenylsulfonyl-n-pentylamino-, N-(4-metoksyfenylsulfonyl)-n-pentylamino-, N-(4-metylfenylsulfonyl) -n-propylamino-, N-(4-metoksyfenylsulfonyl)-n-propyl-amino-, N-benzoyl-isopropylamino-, N-(4-klorfenylsulfonyl)-isopropylamino-, N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydroftalimido-, N-metansulfonyl-2-fenyl-etylamino-, N-klorfenylsulfonyl-benzylamino-, piperidino-, 4- metyl-piperidino-, heksametylenimino-, 3-karboksy-propionyl-, 3-karboksy-2-metyl-propionyl-, pyrrolidinkarbonylamino-, N-metylaminokarbonyl-n-pentylamino-, N-cykloheksylaminokarbonyl-n-pentylamino-, 3,3-dimetyl-glutarsyreimido-, 4,4-tetrametylen-glutarsyreimido-, 2-karboksy-cykloheksylmetylkarbonylamino-, l-n-butyl-imidazolin-2-yl-, l-n-pentyl-imidazolin-2-yl-, 1-n-heksyl-imidazolin-2-yl-, l-cyklopropyl-imidazolin-2-yl-, 1-cyklobutyl-imidazolin-2-yl-, l-cykloheksyl-imidazolin-2-yl-, 1-cykloheptyl-imidazolin-2-yl-, imidazol-2-yl-, l-metyl-imidazol-2-yl-, 1-etyl-imidazol-2-yl-, 1-propyl-imidazol-2-yl-, l-n-butyl-imidazol-2-yl-, l-n-pentyl-imidazol-2-yl-, l-n-heksyl-imidazol-2-yl-, 1-cyklo-propyl-imidazol-2-yl-, l-cyklobutyl-imidazol-2-yl-, 1-cykloheksyl-imidazol-2-yl- eller l-cykloheptyl-imidazol-2-yL-gruppe og 4,4-dimethyl-piperidino-, 3,3-dimethyl-hexamethyleneimino-, 3.4-dimethyl-hexamethyleneimino-, 4,4-dimethylhexamethyleneimino-, 3.5-dimethylhexamethyleneimino-, phenylsulfonylamino-, cyclohexyl-methylaminocarbonylamino-, 2-methylamino-benzoylamino -, 2-carboxy-cyclohexylmethylcarbonylamino-, 2-tert.butoxycarbonyl-cyclohexyl methylcarbonylamino-, 2-carboxy-3,4,5,6-tetrahydrobenzoylamino-, 3- cyclohexylpropylamino-, N-propylsulfonyl-methylamino-, N-phenyl- sulfonyl-methylamino-, N-(4-methylphenylsulfonyl)-methylamino-, N-(4-chlorophenylsulfonyl)-methylamino-, N-phenylsulfonyl-n-pentylamino-, N-(4-methoxyphenylsulfonyl)-n-pentylamino-, N-(4-methylphenylsulfonyl)-n-propylamino-, N-(4-methoxyphenylsulfonyl)-n-propyl-amino-, N-benzoyl-isopropylamino-, N-(4-chlorophenylsulfonyl)-isopropylamino-, N-acetyl- cyclohexylmethylamino-, 3,4,5,6-tetrahydrophthalimido-, hexahydrophthalimido-, N-methanesulfonyl-2-phenyl-ethylamino-, N-chlorophenylsulfonyl-benzylamino-, piperidino-, 4- methylpiperidino-, hexamethyleneimino-, 3- carboxy-pro pionyl-, 3-carboxy-2-methyl-propionyl-, pyrrolidinecarbonylamino-, N-methylaminocarbonyl-n-pentylamino-, N-cyclohexylaminocarbonyl-n-pentylamino-, 3,3-dimethyl-glutaric imido-, 4,4-tetramethylene- glutaric acid imido-, 2-carboxy-cyclohexylmethylcarbonylamino-, l-n-butyl-imidazolin-2-yl-, l-n-pentyl-imidazolin-2-yl-, 1-n-hexyl-imidazolin-2-yl-, l-cyclopropyl-imidazolin -2-yl-, 1-cyclobutyl-imidazolin-2-yl-, l-cyclohexyl-imidazolin-2-yl-, 1-cycloheptyl-imidazolin-2-yl-, imidazol-2-yl-, l-methyl- imidazol-2-yl-, 1-ethyl-imidazol-2-yl-, 1-propyl-imidazol-2-yl-, l-n-butyl-imidazol-2-yl-, l-n-pentyl-imidazol-2-yl- , l-n-hexyl-imidazol-2-yl-, 1-cyclo-propyl-imidazol-2-yl-, l-cyclobutyl-imidazol-2-yl-, 1-cyclohexyl-imidazol-2-yl- or l-cycloheptyl -imidazol-2-yl group and

for R2 hydrogenatomet, metyl-, etyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert-butyl-, n-pentyl-, 1-metylpropyl-, 1-metylbutyl-, 2-metylbutyl-, 3-metylbutyl-, 1-etylpropyl-, 1,1-dietyletyl-, metylmerkaptometyl-, 2-metylmerkaptoetyl-, 3-metylmerkaptopropyl- eller 4-metylmerkaptobutyl-gruppe. for R2 the hydrogen atom, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert-butyl-, n-pentyl-, 1-methylpropyl-, 1-methylbutyl-, 2-methylbutyl- , 3-methylbutyl-, 1-ethylpropyl-, 1,1-diethylethyl-, methylmercaptomethyl-, 2-methylmercaptoethyl-, 3-methylmercaptopropyl- or 4-methylmercaptobutyl group.

Foretrukne forbindelser med den ovenfor angitte generelle Preferred compounds with the above stated general

formel er imidlertid slike hvor however, formula are such where

R,^er en tetrahydrobenzimidazolyl- eller iroldazopyridinyl-gruppe, en benzimidazolylgruppe som eventuelt i fenylkjernen er substituert med et fluor-, klor- eller bromatom, eller med en metyl-, metoksy- eller trifluormetylgruppe, hvor NH-gruppen i den nevnte imidazolring dessuten kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 6 karbonatomer, en eventuelt metylsubstituert benzoksazol-2-ylgruppe, en aminogruppe som er substituert med en bicykloheksylkarbonyl-, bifenylkarbonyl- eller benzofuryl-2-karbonylgruppe, en aminokarbonylaminogruppe som i 3-stilling er substituert med en bicykloheksyl- eller bifenylgruppe, en 5-, 6- eller 7-leddet alkylenimino- eller alkenyleniminogruppe, hvor en metylengruppe er erstattet med en karbonyl- eller sulfonylgruppe, og som eventuelt er substituert med én eller to metylgrupper eller med én tetrametylen- eller pentametylengruppe, en eventuelt metyl- eller benzyl-substituert 3,4,5,6-tetrahydro-2(1H)-pyrimidinongruppe, en hydroksyalkylaminokarbonylgruppe med 4 karbonatomer. i alkyldelen, en maleinsyreamido- eller maleinsyreimidogruppe som eventuelt er mono- eller disubstituert med en metylgruppe eller en fenylgruppe, hvor substituehtene kan være like eller forskjellige, en imidazolin-2-yl- eller imidazol-2-yl-gruppe som i 1-stilling er substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en imidazolidindiongruppe som eventuelt er substituert med. en metyl-, benzyl-, tetrametylen- eller pentametylengruppe, en metylamino- eller benzylaminogruppe som eventuelt er substituert med en metyl-, benzyl-, tetrametylen- eller pentametylengruppe, en metylamino-eller benzylaminogruppe som er substituert med en butansulfonyl-gruppe eller med en fenylmetansulfonylgruppe, en amino- eller metylaminogruppe som er substituert med en naftalensulfonylgruppe som i naftalenringen kan være substituert med en dimetylamino-gruppe eller med to metoksygrupper, en eventuelt metyl- eller benzyl-substituert pyridazin-3-on- eller dihydropyridazin-3-on-gruppe, en pyrrolidino-, piperidino- eller heksametyleniminogruppe som er substituert med to metylgrupper, en heptametylenimino-, 1H,3H-kinazolin-2,4-dion-3-yl-, hydroksycykloheksylaminokarbonyl-, 4,5-pentametylen-oksazolin-2-yl-, 7-nitrobenzofurazan-4-ylamino-eller -7—nitro-benzofurazan-4-yl-amino-propionylamino-gruppe, R,^ is a tetrahydrobenzimidazolyl or iroldazopyridinyl group, a benzimidazolyl group which is optionally substituted in the phenyl nucleus with a fluorine, chlorine or bromine atom, or with a methyl, methoxy or trifluoromethyl group, where the NH group in the mentioned imidazole ring also may be substituted with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group with 3 to 6 carbon atoms, an optionally methyl-substituted benzoxazol-2-yl group, an amino group which is substituted with a bicyclohexylcarbonyl, biphenylcarbonyl or benzofuryl-2-carbonyl group, a aminocarbonylamino group that is substituted in the 3-position with a bicyclohexyl or biphenyl group, a 5-, 6- or 7-membered alkylenimino or alkenylenimino group, where a methylene group is replaced by a carbonyl or sulfonyl group, and which is optionally substituted with one or two methyl groups or with one tetramethylene or pentamethylene group, an optionally methyl- or benzyl-substituted 3,4,5,6-tetrahydro-2(1H)- pyrimidinone group, a hydroxyalkylaminocarbonyl group with 4 carbon atoms. in the alkyl part, a maleic amido or maleic imido group which is optionally mono- or disubstituted with a methyl group or a phenyl group, where the substituents may be the same or different, an imidazolin-2-yl or imidazol-2-yl group as in the 1-position is substituted with an alkyl group of 1 to 6 carbon atoms or with a cycloalkyl group of 3 to 7 carbon atoms, an imidazolidinedione group which is optionally substituted with a methyl, benzyl, tetramethylene or pentamethylene group, a methylamino or benzylamino group which is optionally substituted with a methyl, benzyl, tetramethylene or pentamethylene group, a methylamino or benzylamino group which is substituted with a butanesulfonyl group or with a phenylmethanesulfonyl group, an amino or methylamino group which is substituted with a naphthalenesulfonyl group which in the naphthalene ring may be substituted with a dimethylamino group or with two methoxy groups, an optionally methyl- or benzyl-substituted pyridazin-3-one or dihydropyridazin-3-one group, a pyrrolidino-, piperidino- or hexamethyleneimino group substituted with two methyl groups, a heptamethyleneimino-, 1H,3H-quinazolin-2,4-dion-3-yl-, hydroxycyclohexylaminocarbonyl-, 4,5-pentamethylene-oxazoline-2 -yl-, 7-nitrobenzofurazan-4-ylamino-or -7-nitro-benzofurazan-4-yl-amino-propionylamino group,

eller også, når R3 utgjør en karboksygruppe og R2 utgjør en or also, when R 3 constitutes a carboxy group and R 2 constitutes a

n-butylgruppe, R1 i 6-stilling er en aminogruppe som er substituert med en fenylsulfonyl-, cykloheksylmetylaminokarbonyl-, 2- karboksycykloheksylmetylkarbonyl-, 2-tert.butoksykarbonyl-cykloheksylmetylkarbonyl-, 2-karboksy-3,4,5,6-tetrahydrobehzoyl-, N-metyl-fenylaminokarbonyl- eller 3-cykloheksylpropylgruppe, en metylaminogruppe som er substituert med en propylsulfonyl-, fenylsulfonyl-, 4-metylfenylsulfonyl- eller 4-klorfenylsulfonylgruppe, en n-pentylaminogruppe som er substituert med en fenylsulfonyl- eller 4-metoksyfenylsulfonylgruppe, en n-propylaminogruppe som er substituert med 1,4-metylfenylsulfonyl- eller 4-metoksyfenylsulfonylgruppe, en isopropylaminogruppe som er substituert med en benzoyl- eller 4-klorfenylsulfonylgruppe, en N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydrohomoftalimido-, N-metansulfonyl-2-fenyletylamino-, N-(4-klorfenylsulfonyl)-benzylamino-, piperidino-, 4-metyl-piperidino- eller heksametyleniminogruppe, n-butyl group, R1 in the 6-position is an amino group which is substituted with a phenylsulfonyl-, cyclohexylmethylaminocarbonyl-, 2-carboxycyclohexylmethylcarbonyl-, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl-, 2-carboxy-3,4,5,6-tetrahydrobezoyl -, N-methyl-phenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted with a propylsulfonyl, phenylsulfonyl, 4-methylphenylsulfonyl or 4-chlorophenylsulfonyl group, an n-pentylamino group substituted with a phenylsulfonyl or 4-methoxyphenylsulfonyl group , an n-propylamino group substituted with 1,4-methylphenylsulfonyl or 4-methoxyphenylsulfonyl group, an isopropylamino group substituted with a benzoyl or 4-chlorophenylsulfonyl group, an N-acetyl-cyclohexylmethylamino-, 3,4,5,6- tetrahydrophthalimido-, hexahydrohomophthalimido-, N-methanesulfonyl-2-phenylethylamino-, N-(4-chlorophenylsulfonyl)-benzylamino-, piperidino-, 4-methyl-piperidino- or hexamethyleneimino group,

eller, når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, R, i 5- eller 6-stilling er en 2-okso-l,2-dihydro-3,4-tetrametylen-pyrrolidin-l-yl-, 3-karboksy-propionyl- eller 3- karboksy-2-metylpropionylgruppe, or, when R3 is a carboxy group and R2 is an n-butyl group, R, in the 5- or 6-position is a 2-oxo-1,2-dihydro-3,4-tetramethylene-pyrrolidin-1-yl-, 3 -carboxy-propionyl- or 3-carboxy-2-methylpropionyl group,

eller, når R3 utgjør en karboksygruppe og R2 utgjør en metyl-, etyl-, n-propyl-, n-butyl- eller metylmerkaptogruppe, or, when R3 is a carboxy group and R2 is a methyl, ethyl, n-propyl, n-butyl or methylmercapto group,

R1 i 6-stilling er en pyrrolidinokarbonylaminogruppe, R1 in the 6-position is a pyrrolidinocarbonylamino group,

eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en n-butylgruppe, R1 i 5- eller 6-stilling er en n-pentylaminogruppe som er substituert med en metylaminokarbonyl- eller cykloheksylaminokarbonylgruppe, eller i 6-stilling er en 3,3-dimetylglutarsyreimido- eller 4,4-tetrametylenglutarsyreimidogruppe, or also, when R 3 constitutes a tetrazolyl group and R 2 constitutes an n-butyl group, R 1 in the 5- or 6-position is an n-pentylamino group which is substituted by a methylaminocarbonyl or cyclohexylaminocarbonyl group, or in the 6-position is a 3,3- dimethylglutaric acid imido or 4,4-tetramethyleneglutaric acid imido group,

eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en etyl- eller n-propylgruppe, R1 i 6-stilling er en' N-benzen-sulfonylmetylaminogruppe, or also, when R3 constitutes a tetrazolyl group and R2 constitutes an ethyl or n-propyl group, R1 in the 6-position is an N-benzenesulfonylmethylamino group,

eller også, når R3 utgjør en tert.butoksykarbonylgruppe og or also, when R 3 constitutes a tert.butoxycarbonyl group and

R2 utgjør en N-butylgruppe, R, i 6-stilling er en 2-karboksy-cykloheksylmetylkarbonylamino- eller pyrrolidinokarbonylaminogruppe, R2 constitutes an N-butyl group, R, in the 6-position is a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group,

R2 er et hydrogenatom eller en rettkjedet eller forgrenet alkylgruppe med 1 til 4 karbonatomer, hvor en metylengruppe kan være erstattet med et svovelatom, R2 is a hydrogen atom or a straight-chain or branched alkyl group with 1 to 4 carbon atoms, where a methylene group may be replaced by a sulfur atom,

l l

R3 er en karboksy-, cyano-, lH-tetrazolyl- eller l-trifenylmetyl-tetrazolylgruppe eller en alkoksykarbonylgruppe med tilsammen 2 til 5 karbonatomer, og R 3 is a carboxy, cyano, 1H-tetrazolyl or 1-triphenylmethyl-tetrazolyl group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, and

R4 er et hydrogen-, fluor-, klor- eller bromatom, deres 1-, 3-isomerblandinger samt deres fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser. R 4 is a hydrogen, fluorine, chlorine or bromine atom, their 1-, 3-isomer mixtures as well as their physiologically acceptable salts with inorganic or organic acids or bases.

Særlig foretrukne forbindelser med den ovenfor angitte generelle formel I er imidlertid forbindelser hvor Particularly preferred compounds with the general formula I stated above are, however, compounds where

R1 i 6-stilling er en l-metylbenzimidazol-2-yl-, 3,4,5,6-tetrahydroftalimino-, 2,3-difenylmaleinsyreimido-, 2,3-dimetyl-maleinsyreimido-, N-fenylmetansulfonyl-metylamino-, 2-okso-pyrrolidin-l-yl-, 2-okso-piperidin-l-yl-, 2-okso-heksametylenimino-, 2-okso-3,4-tetrametylenpyrrolidin-2-yl-, 3,3-dimetyl-glutarimido-, N-metylaminokarbonyl-n-pentylamino-, propansultam-1-yl- eller butansultam-l-yl-gruppe, R1 in the 6-position is a 1-methylbenzimidazol-2-yl-, 3,4,5,6-tetrahydrophthalimino-, 2,3-diphenylmaleic acid imido-, 2,3-dimethyl-maleic acid imido-, N-phenylmethanesulfonyl-methylamino-, 2-oxo-pyrrolidin-1-yl-, 2-oxo-piperidin-1-yl-, 2-oxo-hexamethyleneimino-, 2-oxo-3,4-tetramethylenepyrrolidin-2-yl-, 3,3-dimethyl- glutarimido, N-methylaminocarbonyl-n-pentylamino, propanesultam-1-yl or butansultam-1-yl group,

R2 er en metyl-, etyl-, n-propyl- eller n-butylgruppe, R3 er en karboksy- eller en lH-tetrazolylgruppe og R2 is a methyl, ethyl, n-propyl or n-butyl group, R3 is a carboxy or a 1H-tetrazolyl group and

R4 er et hydrogenatom, samt deres fysiologisk akseptable salter med organiske eller uorganiske syrer eller baser. R 4 is a hydrogen atom, as well as their physiologically acceptable salts with organic or inorganic acids or bases.

I henhold til oppfinnelsen oppnås forbindelsene etter følgende fremgangsmåter: According to the invention, the compounds are obtained by the following methods:

a) cyklisering av en forbindelse med den generelle formel a) cyclization of a compound of the general formula

hvor where

R1 er som tidligere definert, R1 is as previously defined,

en av restene X1 eller Y1 utgjør en gruppe med den generelle formel one of the residues X1 or Y1 constitutes a group of the general formula

og den andre av restene X1 eller Y1 utgjør en gruppe med den generelle formel and the second of the residues X1 or Y1 constitutes a group of the general formula

hvor R2 til R4 er som innledningsvis definert, where R2 to R4 are as initially defined,

R5 er et hydrogenatom eller en R2CO-gruppe, hvor R2 er som definert ovenfor, R5 is a hydrogen atom or an R2CO group, where R2 is as defined above,

Z1 og Z2, som kan være like eller forskjellige, utgjør eventuelt substituerte aminogrupper eller hydroksy- eller merkaptogrupper som eventuelt er substituert med lavere alkylgrupper, eller Z1 and Z2, which may be the same or different, constitute optionally substituted amino groups or hydroxy or mercapto groups which are optionally substituted with lower alkyl groups, or

Z1 og Z2 sammen utgjør 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, hvor imidlertid en av restene X1 eller Y1 må utgjøre en gruppe med den generelle formel- Z1 and Z2 together constitute an oxygen or sulfur atom, an imino group which is optionally substituted with an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, where however one of the residues X1 or Y1 must constitute a group with the general formula

Cykliseringen foretas hensiktsmessig i et oppløsningsmiddel eller i en oppløsningsmiddelblanding, som etanol, isopropanol, iseddik, benzen, klorbenzen, toluen, xylen, glykol, glykolmono-metyleter, 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, for eksempel ved temperaturer mellom 0 og 250°C, fortrinnsvis ved reaksjonsblandingens kokepunkt, eventuelt i nærvær av et kondensasjonsmiddel som fosforoksyklorid, iionylklorid, sulfurylklorid, svovelsyre, p-toluensulfonsyre, metansulfonsyre, saltsyre, fosforsyre, polyfosforsyre, eddiksyreanhydrid eller eventuelt også i nærvær av en base som kaliumetylat 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 the 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, preferably at the boiling point of the reaction mixture, possibly in the presence of a condensation agent such as phosphorus oxychloride, ionyl chloride, sulphuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium ethylate or potassium tert.butylate. However, the cyclization can also be carried out without solvent and/or condensing agent.

Særlig fordelaktig er det å foreta 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 R2COOH, eller ved acylering av en tilsvarende o-diaminoforbindelse. Ved å avbryte 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. It is particularly advantageous to carry out the reaction so that a compound of the general formula II is produced in the reaction mixture by reduction of a corresponding o-nitroamino compound, possibly in the presence of a carboxylic acid of the general formula R2COOH, or by acylation of a corresponding o- diamino compound. By interrupting 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 således 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, fortrinnsvis ved romtemperatur. The subsequent reduction of the thus obtained N-oxide of formula I is carried out, preferably 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, by temperatures between 0 and 50°C, preferably at room temperature.

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

I1VUI I1VUI

R1 og R2 er som innledningsvis definert, med en bifenylforbindelse med den generelle formel R1 and R2 are, as initially defined, with a biphenyl compound of the general formula

hvor where

R3 og R4 er som innledningsvis definert og R3 and R4 are 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-, fenylsulfonyl-oksy- 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, trietylamin eller pyridin, hvorav de to sistnevnte samtidig også kan benyttes som oppløsningsmiddel, fortrinnsvis ved temperaturer mellom 0 og 100°C, f.eks. 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, optionally in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butylate, triethylamine or pyridine, of which the two latter can simultaneously also be used as a solvent, preferably at temperatures between 0 and 100°C, e.g. temperatures between room temperature and 50°C.

Ved omsetningen oppnår man fortrinnsvis en blanding av 1- og 3-isomerene som deretter kan spaltes i den tilsvarende 1- og 3-isomer, fortrinnsvis, kromatografisk under bruk av en bærer som kiselgel eller aluminiumoksyd. c) For fremstilling av forbindelser med den generelle formel I, hvor R3 utgjør en karboksygruppe: overføring av en forbindelse med den generelle formel The reaction preferably yields a mixture of the 1- and 3-isomers which can then be resolved into the corresponding 1- and 3-isomer, preferably chromatographically using a carrier such as silica gel or aluminum oxide. c) For the preparation of compounds of the general formula I, where R3 constitutes a carboxy group: transfer of a compound of the general formula

hvor where

R2 og R4 er som innledningsvis definert, R2 and R4 are, as initially defined,

R/ har de betydninger som innledningsvis er angitt for R1 og utgjør en 3-alkoksykarbonylpropionyl- eller 3-alkoksykarbonyl-2-metylpropionylgruppe, hvor alkoksydelen kan inneholde 1 til 3 karbonatomer, og R/ has the meanings given at the outset for R1 and constitutes a 3-Alkoxycarbonylpropionyl or 3-Alkoxycarbonyl-2-methylpropionyl group, where the alkoxy part may contain 1 to 3 carbon atoms, and

R3' utgjør en gruppe som ved hydrolyse, termolyse eller hydrogenolyse kan overføres i en karboksygruppe. R3' constitutes a group which can be transferred into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Eksempelvis kan funksjonelle derivater av karboksygruppen samt 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. benzylesteren, ved hydrogenolyse overføres i en karboksygruppe. For example, functional derivatives of the carboxy group as well as their unsubstituted or substituted amides, esters, thiol esters, ortho esters, imino ethers, amidines or anhydrides, the nitrile group or the tetrazolyl group can by hydrolysis be transferred into a carboxy group, esters with tertiary alcohols, e.g. tert-butyl ester, by thermolysis a carboxy group is transferred and esters with aralkanols, e.g. the benzyl ester, by hydrogenolysis is transferred in a carboxy group.

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 eller vann/dioksan, ved temperaturer mellom -10°C og 12 0°C, f.eks. ved temperaturer mellom romtemperatur og reaksjonsblandingens kokepunkt- Ved hydrolyse i nærvær av en organisk syre som trikloreddiksyre eller trifluoreddiksyre, kan eventuelt foreliggende alkoholiske hydroksygrupper. samtidig overføres i en tilsvarende, acyloksygruppe, som f.eks. trifluoracetoksygruppen. The hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10°C and 12 0°C, e.g. at temperatures between room temperature and the reaction mixture's boiling point - By hydrolysis in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present can. at the same time is transferred in a corresponding, acyloxy group, such as e.g. the trifluoroacetoxy group.

Betyr R3' i en forbindelse med den generelle formel V en cyano- eller aminokarbonylgruppe, kan disse gruppene også over-føres med et nitritt, f.eks. natriumnitritt", i nærvær av en syre, f.eks. svovelsyre, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom 0 og 50°C, i karboksygruppen. If R3' in a compound of the general formula V is a cyano or aminocarbonyl group, these groups can also be transferred with a nitrite, e.g. sodium nitrite", in the presence of an acid, e.g. sulfuric acid, which can also serve as a solvent, at temperatures between 0 and 50°C, in the carboxy group.

Betyr R3' i en forbindelse med den generelle formel V for eksempel den tertiære butoksykarbonylgruppe, kan tert-butylgruppen også avspaltes termisk, eventuelt i et egnet oppløsningsmiddel som metylenklorid, kloroform, benzen, toluen, tetrahydrofuran eller dioksan, og fortrinnsvis i nærvær av en katalytrsk mengde av en syre, så som p-toluensulfonsyre, svovelsyre, fosforsyre, polyfosforsyre, fortrinnsvis ved kokepunktet for det anvendte oppløsningsmiddel, f.eks. ved temperaturer mellom 40°C og 100°C. If R3' in a compound of the general formula V is for example the tertiary butoxycarbonyl group, the tert-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, polyphosphoric acid, preferably at the boiling point of the solvent used, e.g. at temperatures between 40°C and 100°C.

Betyr R3' i en forbindelse med den generelle formel V for eksempel benzyloksykarbonylgruppen, kan benzylgruppen også avspaltes hydrogenlytisk i nærvær av en hydreringskatalysator så 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, 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 haldgenatom med et hydrogenatom. If R3' in a compound of the general formula V is 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, can simultaneously be 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 is replaced by hydrogen atoms, e.g. a halogen atom by a hydrogen atom.

Betyr R1 i en forbindelse med den generelle formel V en av de innledningsvis nevnte hydrolyserbare rester, kan disse under omsetningen overføres i en tilsvarende karboksy- eller amino-forbindelse. d) For fremstilling av en forbindelse med den generelle formel I hvor R3 utgjør en lH-tetrazolylgruppe: avspaltning av en beskyttelsesrest fra en forbindelse med den generelle formel If R1 in a compound of the general formula V represents one of the initially mentioned hydrolysable residues, these can be transferred during the reaction into a corresponding carboxy or amino compound. d) For the preparation of a compound of the general formula I where R 3 constitutes a 1H-tetrazolyl group: removal of a protecting residue from a compound with the general formula

R1, R2 og R4 er som innledningsvis definert og R1, R2 and R4 are as initially defined and

R3" utgjør en lH-tetrazolylgruppe i 1- eller 3-stilling som er beskyttet med en beskyttende gruppe. R3" constitutes a 1H-tetrazolyl group in the 1- or 3-position which is protected with a protecting group.

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

Avspaltningen av en benyttet beskyttelsesgruppe 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 oppløsningsmiddel som metylenklorid, metanol, metanol/ammoniakk, etanol eller isopropanol, ved tempraturer 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 R3 utgjør en lH-tetrazolylgruppe: The removal of a used protecting group 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 optionally, 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 R3 constitutes a 1H-tetrazolyl group:

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

hvor where

R1, R2 og R4 er som innledningsvis definert, R1, R2 and R4 are, as initially defined,

med hydrogenazidsyre eller salter derav. 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. Under omsetningen frigjøres hydrogenazidsyren fra et alkaliazid, f.eks. fra natriumazid i nærvær av en svak syre, f.eks. ammoniumklorid, eller ved at tetra-zolidsaltet, oppnådd i reaksjonsblandingen ved omsetning med et salt av hydrogenazidsyren, fortrinnsvis med aluminiumazid eller tributyltinnazid, som dessuten hensiktsmessig fremstilles i reaksjonsblandingen ved å omsette aluminiumklorid eller tributyl-tinnklorid med et alkaliazid, f.eks. natriumazid, deretter sur-gjøres med en fortynnet syre så som 2N saltsyre eller 2N svovelsyre. f) For fremstilling av forbindelser med den generelle formel I, hvor Rv utgjør en pentametylen-oksazolin-2-ylgruppe: The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150°C, preferably at 125°C. During the reaction, the hydrogenazide acid is released 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 the hydrogenazide acid, preferably with aluminum azide or tributyltin azide, which is also conveniently prepared in the reaction mixture by reacting aluminum chloride or tributyltin chloride with an alkali azide, e.g. sodium azide, then acidified with a dilute acid such as 2N hydrochloric acid or 2N sulfuric acid. f) For the preparation of compounds of the general formula I, where Rv constitutes a pentamethylene-oxazolin-2-yl group:

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

hvor where

R2 til R4 er som innledningsvis definert, med 1-aminometyl-cykloheksanol i nærvær av et middel som virker aktiverende på syren. R 2 to R 4 are as initially defined, with 1-aminomethyl-cyclohexanol in the presence of an agent which acts to activate the acid.

Omsetningen utføres fortrinnsvis i et oppløsningsmiddel som tetrahydrofuran eller dioksan, i nærvær av et middel som aktiverer syren, så som karbonylimidazol, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. g) For fremstilling av en forbindelse med den generelle formel I, hvor R., utgjør en 2-okso-3,4-tetrametylen-pyrrolidin-l-ylgruppe: hydrering av en forbindelse med den generelle formel The reaction is preferably carried out in a solvent such as tetrahydrofuran or dioxane, in the presence of an agent which activates the acid, such as carbonyl imidazole, at temperatures between 0 and 50°C, preferably at room temperature. g) For the preparation of a compound of the general formula I, where R. is a 2-oxo-3,4-tetramethylene-pyrrolidin-1-yl group: hydrogenation of a compound of the general formula

hvor where

R2, R3 og R4 er som innledningsvis definert. R2, R3 and R4 are defined as initially.

Den katalytiske hydrering foretas med hydrogen i nærvær av en katalysator, så som palladium/kull i et oppløsningsmiddel som metanol, etanol, eddiksyre-etylester eller iseddik, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur, og under et hydrogentrykk på 1 til 7 bar, fortrinnsvis ved 3 til 5 bar. The catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst, such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, at temperatures between 0 and 50°C, preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably at 3 to 5 bar.

h) For fremstilling av forbindelser med den generelle formel I, hvor R., betyr en aminogruppe som er substituert med en bicykloheksylkarbonyl- eller bifenylkarbonylgruppe og som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en aminokarbonylaminogruppe som er substituert med en bicykloheksyl- eller bifenylgruppe, som dessuten kan være substituert på N-atomet med én eller to alkylgrupper som hver har 1 til 3 karbonatomer, en maleinsyreamido- eller maleinsyreimidogruppe som eventuelt kan være mono- eller disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med -en fenylgruppe, hvor substituentene kan være like eller forskjellige, en alkylam-ino- eller fenylalkylaminogruppe som er substituert med en alkylsulfonylgruppe,med 4 til 6 karbonatomer eller med en h) For the preparation of compounds of the general formula I, where R. means an amino group which is substituted with a bicyclohexylcarbonyl or biphenylcarbonyl group and which on the N atom may also be substituted with an alkyl group with 1 to 3 carbon atoms, an aminocarbonylamino group which is substituted with a bicyclohexyl or biphenyl group, which may also be substituted on the N atom with one or two alkyl groups each having 1 to 3 carbon atoms, a maleic amido or maleic imido group which may optionally be mono- or disubstituted with an alkyl group with 1 to 3 carbon atoms or with -a phenyl group, where the substituents may be the same or different, an alkylamino- or phenylalkylamino group which is substituted with an alkylsulfonyl group, with 4 to 6 carbon atoms or with a

fenylalkylsulfonylgruppe, hvori hver alkyldel kan inneholde 1 phenylalkylsulfonyl group, in which each alkyl moiety may contain 1

til 3 karbonatomer, en amino- eller alkylaminogruppe som er substituert med naftalensulfonylgruppe, som på naftalenringen kan være substituert med en dialkylaminogruppe eller med én eller to alkoksygrupper, hvor hver alkyldel kan inneholde 1 til 3 karbonatomer, "en 7-nitro-benzofurazan-4-ylaminoalkanoylaminogruppe hvor alkanoyldelen kan inneholde 2 eller 3 karbonatomer, en benzofuran-karbonylamino- eller 7-nitro-benzofurazan-4-ylaminogruppe, to 3 carbon atoms, an amino or alkylamino group which is substituted with a naphthalenesulfonyl group, which on the naphthalene ring may be substituted with a dialkylamino group or with one or two alkoxy groups, where each alkyl moiety may contain 1 to 3 carbon atoms, "a 7-nitro-benzofurazan-4 -ylaminoalkanoylamino group where the alkanoyl part may contain 2 or 3 carbon atoms, a benzofuran-carbonylamino- or 7-nitro-benzofurazan-4-ylamino group,

eller også, når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, R1 i 6-stilling, betyr en aminogruppe som er substituert med en fenylsulfonyl-, cykloheksylmetylaminokarbonyl-, 2-karboksycykloheksylmetylkarbonyl-, 2-tert.butoksykarbonyl-cykloheksylmetylkarbonyl-, 2-karboksy-3,4,5,6-tetrahydrobenzoyl-, N-metylfenylaminokarbonyl- eller 3-cykloheksylpropylgruppe, en metylaminogruppe som er substituert med en propylsulfonyl-, fenylsulfonyl-, metylfenylsulfonyl- eller klorfenylsulfonylgruppe, or also, when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in the 6-position means an amino group substituted with a phenylsulfonyl-, cyclohexylmethylaminocarbonyl-, 2-carboxycyclohexylmethylcarbonyl-, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl-, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methylphenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted with a propylsulfonyl, phenylsulfonyl, methylphenylsulfonyl or chlorophenylsulfonyl group,

en n-pentylaminogruppe som er substituert med en fenylsulfonyl- an n-pentylamino group which is substituted with a phenylsulfonyl-

eller metoksyfenylsulfonylgruppe, en n-propylaminogruppe som er substituert med en metylf enylsulf onyl- eller metoksyf enylsulf onyl-^ gruppe, en isopropylaminogruppe som er substituert, med en benzoyl-eller klorfenylsulfonylgruppe, en N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydrohomoftalimido-, N-metan-sulfonyl-2-fenyletylamino- eller N-klorfenylsulfonyl-benzylaminogruppe, or methoxyphenylsulfonyl group, an n-propylamino group substituted with a methylphenylsulfonyl or methoxyphenylsulfonyl group, an isopropylamino group substituted with a benzoyl or chlorophenylsulfonyl group, an N-acetyl-cyclohexylmethylamino-, 3,4,5 ,6-tetrahydrophthalimido-, hexahydrohomophthalimido-, N-methanesulfonyl-2-phenylethylamino- or N-chlorophenylsulfonyl-benzylamino group,

eller, når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, R1 i 5- eller 6-stilling, betyr en 2-okso-l,2-dihydro-3,4-tetrametylen-pyrrolidin-l-yl-gruppe, or, when R3 is a carboxy group and R2 is an n-butyl group, R1 in the 5- or 6-position means a 2-oxo-1,2-dihydro-3,4-tetramethylene-pyrrolidin-1-yl group,

eller, når R3 utgjør en karboksygruppe og R^ en metyl-, or, when R3 constitutes a carboxy group and R^ a methyl,

etyl-, n-propyl-, n-buty1 eller metylmerkaptogruppe, R1 i 6- ethyl, n-propyl, n-buty1 or methylmercapto group, R1 in 6-

stilling, betyr en pyrrolidinokarbonylaminogruppe, position, means a pyrrolidinocarbonylamino group,

eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør or also, when R 3 constitutes a tetrazolyl group and R 2 constitutes

en n-butylgruppe, R1 i 5 - eller 6-stilling, betyr en n-pentylaminogruppe som er substituert med en metylaminokarbonyl- eller cykloheksylaminokarbonylgruppe, eller i 6-still-ing, betyr en 3,3-dimetylglutarsyreimido- eller 4,4-tetrametylenglutarsyreimidogruppe, an n-butyl group, R1 in the 5- or 6-position, means an n-pentylamino group which is substituted with a methylaminocarbonyl or cyclohexylaminocarbonyl group, or in the 6-position, means a 3,3-dimethylglutaric acid imido- or 4,4- tetramethyleneglutaric acid imido group,

eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en or also, when R 3 constitutes a tetrazolyl group and R 2 constitutes a

etyl- eller n-propylgruppe, R, i 6-stilling, betyr en N-benzensulfonyl-metylaminogruppe, ethyl or n-propyl group, R, in the 6-position, means an N-benzenesulfonyl-methylamino group,

eller også, når R3 utgjør en tert-butoksykarbonylgruppe og R2 utgjør en N-butylgruppe, R1 i 6-stilling, betyr en 2-karboksycyklo-heksylmetylkarbonylamino- eller pyrrolidino-karbonylairtinogruppe: or also, when R3 constitutes a tert-butoxycarbonyl group and R2 constitutes an N-butyl group, R1 in the 6-position means a 2-carboxycyclohexylmethylcarbonylamino or pyrrolidinocarbonylairtino group:

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

hvor where

R2, R3 og R4 er som innledningsvis definert, og R2, R3 and R4 are as initially defined, and

R6 betyr et hydrogenatom, en n-pentyl-, cykloheksylmetyl-, alkyl-eller fenylalkylgruppe som hver har 1 til 3 karbonatomer i alkyldelen, med en forbindelse med den generelle formel R6 means a hydrogen atom, an n-pentyl, cyclohexylmethyl, alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl part, with a compound of the general formula

hvor where

Z4 er en nukleofil utgående gruppe, Z4 is a nucleophilic leaving group,

W er en -CO- eller -S02-gruppe og W is a -CO or -SO2 group and

R7 er en 2-hydroksykarbonyl-etenylgruppe, hvor etenyldelen er mono- eller disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med en fenylgruppe, og hvor substituentene kan være like eller forskjellige, en alkylgruppe med 3 til 6 karbonatomer, en fenylalkylgruppe med 1 til 3 karbonatomer i alkyldelen, en naftalengruppe som eventuelt kan være substituert med en dialkyl-■ aminogruppe eller med én eller to alkoksygrupper, hvor hver alkyldel kan inneholde 1 til 3 karbonatomer, en metyl-, fenyl-, metylfenyl-, metoksyfenyl-, klorfenyl-, bifenyl-, bicykloheksyl-, 2- karboksy-cykloheksylmetyl-, 2-karboksy-3,4,5,6-tetrahydrofenyl-, 3- karboksy-l,1-dimetylpropyl-, 3-karboksy-2,2-tetrametylenpropyl-, 7-nitrobenzofurazan-4-ylaminometyl- eller 7-nitrobenzofurazan-4-ylaminoetylgruppe, R7 is a 2-hydroxycarbonyl-ethenyl group, where the ethenyl part is mono- or disubstituted with an alkyl group of 1 to 3 carbon atoms or with a phenyl group, and where the substituents may be the same or different, an alkyl group of 3 to 6 carbon atoms, a phenylalkyl group of 1 to 3 carbon atoms in the alkyl part, a naphthalene group which can optionally be substituted with a dialkyl-■ amino group or with one or two alkoxy groups, where each alkyl part can contain 1 to 3 carbon atoms, a methyl-, phenyl-, methylphenyl-, methoxyphenyl-, chlorophenyl -, biphenyl-, bicyclohexyl-, 2-carboxy-cyclohexylmethyl-, 2-carboxy-3,4,5,6-tetrahydrophenyl-, 3-carboxy-1,1-dimethylpropyl-, 3-carboxy-2,2-tetramethylenepropyl -, 7-nitrobenzofurazan-4-ylaminomethyl or 7-nitrobenzofurazan-4-ylaminoethyl group,

eller også, når W utgjør en -CO-gruppe, en RgNRj-gruppe, hvor or also, when W constitutes a -CO group, an RgNRj group, where

R8 utgjør et hydrogenatom eller en alkylgruppe med 1 til R8 constitutes a hydrogen atom or an alkyl group with 1 more

3 karbonatomer, 3 carbon atoms,

R, utgjør en metyl-, cykloheksyl-, cykloheksylmetyl-, fenyl-, bifenyl- eller bicykloheksylgruppe eller R, constitutes a methyl, cyclohexyl, cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl group or

R8 og R9 sammen med det mellomliggende nitrogenatom utgjør en pyrrolidinogruppe, R8 and R9 together with the intermediate nitrogen atom form a pyrrolidino group,

eller også, Z4 sammen med R, utgjør en ytterligere karbon-nitrogenbinding, or alternatively, Z 4 together with R constitute an additional carbon-nitrogen bond,

eller også, R7 sammen med W, betyr en 7-nitro-benzofurazan-4-yl-aminogruppe. or also, R 7 together with W means a 7-nitro-benzofurazan-4-yl-amino group.

Aktuelle nukleofile utgående grupper for Z4 er eksempelvis klor- eller bromatomet, en alkoksy- eller fenylalkoksy-gruppe som metoksy-, etoksy- eller benzyloksygruppen eller også, når R7 utgjør en av de tidligere nevnte hydrokarboner, en hydroksygruppe. Relevant nucleophilic leaving groups for Z4 are, for example, the chlorine or bromine atom, an alkoxy or phenyl alkoxy group such as the methoxy, ethoxy or benzyloxy group or also, when R7 constitutes one of the previously mentioned hydrocarbons, a hydroxy group.

Omsetningen foretas hensiktsmessig i et oppløsningsmiddel som metylenklorid, kloroform, tetraklormetan, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt i nærvær av et middel som aktiverer syren, eller et vann-tUtrekkende middel, f.eks. i nærvær av klormaursyre-etylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N<1->dicykloheksyl-karbodiimid, N,N<1->dicykloheksylkarbodiimid/N-hydroksysuccinimid, N,N<1->karbonyldiimidazol eller N,N'-tionyldiimidazol eller trifenylfosfin/tetraklormetan eller et middel som aktiverer aminogruppen, f.eks. fosfortriklorid, og eventuelt i nærvær av en uorganisk base, så som natriumkarbonat, eller en tertiær organisk base som trietylamin eller pyridin, og som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 og 150°C, fortrinnsvis ved temperaturer mellom -10°C og kojcepunktet for det anvendte oppløsningsmiddel. The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrachloromethane, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an agent that activates the acid, or a water-extracting agent, e.g. in the presence of chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N<1->dicyclohexylcarbodiimide, N,N<1->dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N<1->carbonyldiimidazole or N,N' -thionyldiimidazole or triphenylphosphine/tetrachloromethane or an agent that activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base, such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, and which can simultaneously serve as a solvent, at temperatures between -25 and 150°C, preferably at temperatures between -10° C and the boiling point of the solvent used.

Betyr Z4 en hydroksygruppe, kan omsetningen foretas på en spesielt fordelaktig måte med reaktive derivater av en karboksylsyre med den generelle formel IX, f.eks. med estere, tioestere, halogenider, anhydrider eller imidazolidiner derav. If Z4 is a hydroxy group, the reaction can be carried out in a particularly advantageous manner with reactive derivatives of a carboxylic acid of the general formula IX, e.g. with esters, thioesters, halides, anhydrides or imidazolidines thereof.

i) For fremstilling av forbindelser med den generelle formel I, hvor R,^ betyr en tetrahydrobenzimidazolyl- eller-imidazopyridinylgruppe eller en benzimidazolylgruppe, som i fenylkjernen eventuelt i) For the preparation of compounds of the general formula I, where R,^ denotes a tetrahydrobenzimidazolyl or imidazopyridinyl group or a benzimidazolyl group, which in the phenyl nucleus optionally

er substituert med et fluor-, klor- eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, hvor NH-gruppen i de ovennevnte imidazolringer dessuten kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en hydroksycykloalkylaminokarbonylgruppe med 5 til 7 karbonatomer i cykloalkyldelen som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, eller en rettkjedet eller forgrenet hydroksyalkylaminokarbonylgruppe med 4 til 6 karbonatomer i alkyldelen: is substituted with a fluorine, chlorine or bromine atom, with an alkyl group with 1 to 3 carbon atoms, with an alkoxy group with 1 to 3 carbon atoms or with a trifluoromethyl group, where the NH group in the above-mentioned imidazole rings can also be substituted with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group of 3 to 7 carbon atoms, a hydroxycycloalkylaminocarbonyl group of 5 to 7 carbon atoms in the cycloalkyl part which may also be substituted on the N atom with an alkyl group of 1 to 3 carbon atoms, or a straight-chain or branched hydroxyalkylaminocarbonyl group of 4 to 6 carbon atoms in the alkyl part:

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

nvor when

R2 til R4 er som innledningsvis definert, eller utgjør reaktive R2 to R4 are as initially defined, or constitute reactive

derivater derav, som syrehalogenider, estere, amider, anhydrider eller nitriler, med et amin med den generelle formel derivatives thereof, such as acid halides, esters, amides, anhydrides or nitriles, with an amine of the general formula

hvor R10 er et hydrogenatom, en cykloalkylgruppe eller en alkylgruppe med 1 til 6 karbonatomer og where R10 is a hydrogen atom, a cycloalkyl group or an alkyl group with 1 to 6 carbon atoms and

Rn betyr en hydroksyalkylgruppe med 4 til 6 karbonatomer, en hydroksycykloalkylgruppe med 5 til 7 karbonatomer eller en 2-aminofenylgruppe som i fenylkjernen kan være substituert med et fluor-, klor- eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, en 2-aminocykIoheksyl- eller 2-aminopyridylgruppe, eventuelt under samtidig dekarboksylering. Rn means a hydroxyalkyl group with 4 to 6 carbon atoms, a hydroxycycloalkyl group with 5 to 7 carbon atoms or a 2-aminophenyl group which in the phenyl nucleus may be substituted with a fluorine, chlorine or bromine atom, with an alkyl group with 1 to 3 carbon atoms, with an alkoxy group with 1 to 3 carbon atoms or with a trifluoromethyl group, a 2-aminocyclohexyl or 2-aminopyridyl group, optionally during simultaneous decarboxylation.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel som metylenklorid, kloroform, tetraklormetan, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt i nærvær av et middel som aktiverer syren, eller et vann-tiltrekkende middel, f.eks. i nærvær av klormaursyre-etylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N<1->dicykloheksylkarbodiimid, N,N'-dicykloheksylkarbodiimid/ N-hydroksysuccinimid, N,N'-karbonyldiimidazol eller N,N'-tionyl-diimidazol eller trifenylfosfin/tetraklormetan, eller et middel som aktiverer aminogruppen, f.eks. fosfortriklorid, og eventuelt i nærvær av en uorganisk base så som natriumkarbonat, eller en tertiær organisk base som trietylamin eller pyridin, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 og 150°C, fortrinnsvis ved temperaturer mellom -10°C og kokepunktet for det anvendte oppløsningsmiddel. The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrachloromethane, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an agent that activates the acid, or a water-attracting agent, e.g. in the presence of chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N<1->dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or triphenylphosphine /tetrachloromethane, or an agent that activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 150°C, preferably at temperatures between -10°C and the boiling point of the solvent used.

En eventuelt således oppnådd orto-benzamidoforbindelse kan deretter om nødvendig overføres i den ønskede benzimidazol-forbindelse ved oppvarming, hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som etanol, isopropanol, iseddik, benzen, klorbenzen, toluen, xylen, glykol, glykolmono-metyleter, dietylenglykol-dimetyleter, sulfolan, dimetylformamid eller tetralin, eventuelt i nærvær av et kondensasjonsmiddel, så som fosforoksyklorid, tionylklorid, sulfurylklorid, svovelsyre, p-toluensulfonsyre, metansulfonsyre, saltsyre, fosforsyre, polyfosforsyre, eddiksyreanhydrid, eller eventuelt også i nærvær av en base som kaliumetylat eller kalium-tert.butylat. Denne cykliseringen kan imidlertid også utføres uten oppløsningsmiddel og/eller kondensasjonsmiddel. An ortho-benzamido compound thus obtained can then, if necessary, be transferred into the desired benzimidazole compound by heating, suitably in a solvent or a solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol mono-methyl ether, diethylene glycol -dimethyl ether, sulfolane, dimethylformamide or tetralin, optionally in the presence of a condensing agent, such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or optionally also in the presence of a base such as potassium ethylate or potassium tert-butylate. However, this cyclization can also be carried out without solvent and/or condensing agent.

Aktuelle beskyttelsesrester for en hydroksygruppe er for eksempel trimetylsilyl-, acetyl-, benzoyl—, metyl-, etyl-, tert.butyl-, benzyl- eller tetrahydropyranylgruppen, og for en amino-, alkylamino- eller iminogruppe, acetyl-, benzoyl-, etoksy-karbonyl-, eller benzylgruppen. Relevant protective residues for a hydroxy group are, for example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and for an amino, alkylamino or imino group, acetyl, benzoyl, the ethoxy-carbonyl 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 dioksan/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 metanol, etanol, eddiksyre-etylester eller iseddik, eventuelt under tilsetning av en syre, f.eks. saltsyre, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur, og under et hydrogentrykk på 1 til 7 bar, fortrinnsvis ved 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 dioxane/water, in the presence of an acid, such as hydrochloric acid or sulfuric acid, or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at the reaction mixture's boiling point. However, the 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 methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, optionally with the addition of an acid, e.g. hydrochloric acid, at temperatures between 0 and 50°C, preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably at 3 to 5 bar.

En således oppnådd isomerblanding av en forbindelse med den generelle formel I kan dersom det er ønskelig, 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, if desired, preferably be resolved chromatographically using a carrier, such as silica gel or aluminum oxide.

De oppnådde forbindelsene med den generelle formel I kan dessuten overføres i sine syreaddisjonssalter, spesielt for farmasøytisk anvendelse, i sine fysiologisk akseptable salter, med uorganiske eller organiske syrer. Egnede syrer til dette formål er for eksempel saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, fumarsyre, ravsyre, melkesyre, sitronsyre, vinsyre og maleinsyre. 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. 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 and maleic acid.

Dessuten lar de således oppnådde nye forbindelser med den generelle formel I, dersom de inneholder en karboksy- eller 1H-tetrazolylgruppe, seg deretter eventuelt overføre i sine salter med uorganiske eller organiske baser, spesielt for farmasøytiske formål, i sine fysiologisk akseptable salter. Som baser kommer herunder eksempelvis natriumhydroksyd, kaliumhydroksyd, cyklo-heksylamin, etanolamin, dietanolamin og trietanolamin i betraktning. Moreover, the thus obtained new compounds of the general formula I, if they contain a carboxy or 1H-tetrazolyl group, can subsequently optionally be transferred in their salts with inorganic or organic bases, especially for pharmaceutical purposes, in their physiologically acceptable salts. Examples of bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Utgangsforbindelsene med den generelle formel II til XV er tildels kjent fra litteraturen, og kan forøvrig oppnås etter fremgangsmåter kjent fra litteraturen. The starting compounds with the general formula II to XV are partly known from the literature, and can otherwise be obtained by methods known from the literature.

Således oppnås eksempelvis en forbindelse med den generelle formel II ved alkylering av en tilsvarende o-am-ino-nitro-forbindelse og påfølgende reduksjon av nitrogruppen. Thus, for example, a compound of the general formula II is obtained by alkylation of a corresponding o-am-ino-nitro compound and subsequent reduction of the nitro group.

En-utgangsforbindelse med den generelle formel III, V, VI, VII, VIII, IX, X eller XII oppnår man ved alkylering av et tilsvarende o-fenylendiamin eller en tilsvarende o-aminonitro-forbindelse, påfølgende reduksjon av nitrogruppen og påfølgende cyklisering av en således oppnådd o-diaminofenylforbindelse, eventuelt med påfølgende avspaltning av en benyttet beskyttelsesrest, eller ved NH-alkylering av et tilsvarende lH-benzimidazol, hvorved 'den således oppnådde isomerblanding deretter skilles ved hjelp av vanlige metoder, f.eks. ved kromatografi. De foran nevnte utgangsforbindelser er tildels beskrevet i EP-A-0 392 317. A starting compound with the general formula III, V, VI, VII, VIII, IX, X or XII is obtained by alkylation of a corresponding o-phenylenediamine or a corresponding o-aminonitro compound, subsequent reduction of the nitro group and subsequent cyclization of a thus obtained o-diaminophenyl compound, optionally with subsequent cleavage of a protective residue used, or by NH-alkylation of a corresponding 1H-benzimidazole, whereby the isomer mixture thus obtained is then separated using usual methods, e.g. by chromatography. The aforementioned output connections are partly described in EP-A-0 392 317.

De nye forbindelsene med den generelle formel I og deres fysiologisk akseptable salter, oppviser verdifulle farmakologiske egenskaper. De utgjør angiotensinantagonister, spesielt angiotensin-II-antagonister. Eksempelvis ble. forbindelsene: A = 4'-[[2-n-prppyl-6-(l-metylbenzimidazol-2-yl)-benz imidazol-l-yl ] metyl ]bifeny1-2-karboksylsyre, The new compounds of the general formula I and their physiologically acceptable salts exhibit valuable pharmacological properties. They constitute angiotensin antagonists, especially angiotensin-II antagonists. For example, became the compounds: A = 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benz imidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

B = 4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-ftalimino)-benzimidazol-l-yl ]metyl]bifenyl-2-karboksylsyre-dihydrat, B = 4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid dihydrate,

C = 4'-[[2-n-butyl-6-(2,3-difenyl-maleinsyreimido)-benzimidazol-l-yl ] metyl ] bif eny 1-2 -karboksylsyre, C = 4'-[[2-n-butyl-6-(2,3-diphenyl-maleic imido)-benzimidazol-1-yl] methyl ] biphenyl 1-2-carboxylic acid,

D = 4'-[[2-n-butyl-6-(2,3-dimetyl-maleinsyreimido)-benzimidazol-l-yl ] metyl ] bif eny 1-2 -karboksylsyre, D = 4'-[[2-n-butyl-6-(2,3-dimethyl-maleic imido)-benzimidazol-1-yl] methyl ] biphenyl 1-2-carboxylic acid,

E = 4'-[[2-n-butyl-6-(N-fenylmetansulfonyl-metylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre, E = 4'-[[2-n-butyl-6-(N-phenylmethanesulfonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

F = 4<1->[[2-n-butyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl ]metyl]-2-(lH-tetrazol-5-yl)-bifenyl F = 4<1->[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)- biphenyl

G = 41 -[[2-n-butyl-6-(2-okso-pyrrolidin-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl G = 41 -[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl

H 4<1->[[2-n-butyl-6-(2-okso-heksametylenimino)-benzimidazol-l-yl] metyl ]-2-(lH-tetrazol-5-yl)-bifenyl, H 4<1->[[2-n-butyl-6-(2-oxo-hexamethyleneimino)-benzimidazol-1-yl] methyl ]-2-(1H-tetrazol-5-yl)-biphenyl,

I = 4'-[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-l-yl ]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, I = 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

J = 41 -[[2-n-butyl-6-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, J = 41 -[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

K = 41 -[[2-n-butyl-6-(cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenylhydrat og K = 41 -[[2-n-butyl-6-(cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl hydrate and

L = 41 -[[2-n-butyl-6-(2-okso-3,4-tetrametylen-pyrrolidin-1-yl)benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre L = 41 -[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-yl)benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid

undersøkt med henblikk på deres biologiske virkninger på følgende måte: Rotter (hanner, 180-220 g) anestetiseres med heksobarbital-natrium (150 mg/kg i.p.). Etter inntrådt narkose innføres en trakealkanyle, hvoretter dyrene despinaliseres og deretter omgående ventileres kunstig med en ventilasjonspumpe. Det arterielle blodtrykk registreres via en kanyle i arteria carotis ved hjelp av en Bell & Howell trykkmåler. Aktuelle forbindelser tilføres i vena jugularis via en kanyle. examined for their biological effects as follows: Rats (males, 180-220 g) are anesthetized with hexobarbital sodium (150 mg/kg i.p.). After induction of anesthesia, a tracheal cannula is introduced, after which the animals are de-spinalized and then immediately ventilated artificially with a ventilation pump. The arterial blood pressure is recorded via a cannula in the carotid artery using a Bell & Howell pressure gauge. Topical compounds are administered into the jugular vein via a cannula.

Testforbindelsene administreres som tre doseringer (10, 20 og 3 0 mg/kg i.v.), idet det per dyr undersøkes en substansdose. The test compounds are administered as three dosages (10, 20 and 30 mg/kg i.v.), with one substance dose being examined per animal.

3 minutter etter den intravenøse tilførsel av testsubstansen 3 minutes after the intravenous administration of the test substance

administreres angiotensin-II intravenøst i tiltagende dosering, hvorved det oppnås et kumulativt dose-virknings-forhold for angiotensin-II i nærvær av testsubstansene. Måleparameteren er økningen av det arterielle blodtrykk. angiotensin-II is administered intravenously in increasing dosage, whereby a cumulative dose-effect relationship is achieved for angiotensin-II in the presence of the test substances. The measurement parameter is the increase in arterial blood pressure.

Denne dose-virknings-kurve sammenlignes med standardkurven for angiotensin-II uten testsubstans. Ved hjelp av et dataprogram beregnes høyreforskyvningen av dose-virkningskurven av angiotensin-II som følge av testsubstansene, hvorpå tilsvarende pA2-verdier for testsubstansene beregnes. This dose-response curve is compared with the standard curve for angiotensin-II without test substance. Using a computer program, the rightward shift of the dose-effect curve of angiotensin-II as a result of the test substances is calculated, after which corresponding pA2 values for the test substances are calculated.

pA^-verdiene av de nevnte testforbindelsene- A til L ligger mellom 6,0 og 7,5. The pA^ values of the mentioned test compounds - A to L lie between 6.0 and 7.5.

Ved tilførsel av de ovennevnte forbindelser opptil en dose på 3 0 mg/kg i.v. kunne det ikke iakttas toksiske bivirkninger, f.eks. ingen negativ inotrop virkning og ingen hjerterytmeforstyrrelser. Forbindelsene er således vel tolererbare. Upon administration of the above-mentioned compounds up to a dose of 30 mg/kg i.v. no toxic side effects could be observed, e.g. no negative inotropic effect and no heart rhythm disturbances. The connections are thus well tolerable.

Forsøksrapport Trial report

Beskrivelse av undersøkelsen for bestemmelse av angiontensin-II-reseptorbinding: Description of the examination for the determination of angiotensin II receptor binding:

Rottelungevev homogeniseres i tris-buffer (50 mMol tris, Rat lung tissue is homogenized in tris buffer (50 mMol tris,

150 mMol NaCl, 5 mMol EDTA, pH 7,40) og sentrifugeres to ganger i 20 minutter hver gang ved 20.0.00 x g. Den oppnådde pellet resuspenderes i inkubasjonsbuffer (50 mMol tris, 5mMol MgCl2, 150 mMol NaCl, 5 mMol EDTA, pH 7.40) and centrifuged twice for 20 minutes each time at 20.0.00 x g. The obtained pellet is resuspended in incubation buffer (50 mMol tris, 5mMol MgCl2,

0.2% BSA; pH 7,40) 1:75, basert på den fuktige vekt av vevet. Prøver på hver 0,1 ml. homogenat inkuberes i 60 minutter ved 37°C med 50 pM [ 1251 ]-Angiontensin II (NEN, Dreieich, Tyskland) og stigende konsentrasjoner av prøveforbindelsen i et samlet volum på 0,25 ml. Inkuberingeh avsluttes ved rask filtrering gjennom glassfiber-filtermatter. Filtrene vaskes i hvert tilfelle med 4 ml iskald buffer (25 mMol tris, 2,5 mMol MgCl2, 0,1% BSA, 0.2% BSA; pH 7.40) 1:75, based on the wet weight of the tissue. Samples of every 0.1 ml. homogenate is incubated for 60 minutes at 37°C with 50 µM [ 1251 ]-Angiontensin II (NEN, Dreieich, Germany) and increasing concentrations of the test compound in a total volume of 0.25 ml. Incubation is terminated by rapid filtration through glass fiber filter mats. The filters are washed in each case with 4 ml ice-cold buffer (25 mMol tris, 2.5 mMol MgCl2, 0.1% BSA,

pH 7,40) Den bundne radioaktivitet bestemmes i en gamma-teller. På grunnlag av dose-virkningskurven bestemmes deji tilsvarende IC50-verdi. Herved ble følgende resultater oppnådd: pH 7.40) The bound radioactivity is determined in a gamma counter. On the basis of the dose-response curve, the corresponding IC50 value is determined. The following results were thereby achieved:

a) Forbindelser ifølge foreliggende oppfinnelse: b) Forbindelser ifølge US-A-4,880,804: a) Compounds according to the present invention: b) Compounds according to US-A-4,880,804:

På grunn av. deres farmakologiske egenskaper egner de nye Because of. their pharmacological properties lend themselves to the new ones

forbindelsene og deres fysiologisk akseptable salter, seg til behandling av hypertoni og hjerteinsuffisiens, til behandling av ischemiske perifere sirkulasjonsforstyrrelser, ved myokardieischemi (angina), til forebyggelse av hjerteinsuffisiensutvikling etter myokardieinfarkt, til behandling av diabetisk nefropati, glaukom, gastrointestinale sykdommer og blæresykdommer. the compounds and their physiologically acceptable salts, 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, glaucoma, gastrointestinal diseases and bladder diseases.

Dessuten egner de nye forbindelsene og deres fysiologiske akseptable salter seg til behandling av pulmonale sykdommer, f.eks. lungeødem og kronisk bronkitt, til forebyggelse av arteriell re-stenose etter angioplastikk, fortykning av karvegger etter karoperasjoner, arteriosklerose og diabetisk angiopati. På grunn av påvirkningen av acetylcholin- og dopamin-frigjøringen gjennom angiotensin i hjernen, egner de nye ang-iotensin-antagonistene seg også til å fjerne sentralnervøse forstyrrelser, f.eks..^ved depresjoner, ved Alzheimers sykdom, Parkinsons 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, thickening of vessel walls after body operations, arteriosclerosis and diabetic angiopathy. Due to the influence of the acetylcholine and dopamine release through angiotensin in the brain, the new angiotensin antagonists are also suitable for removing central nervous disorders, e.g. in depression, in Alzheimer's disease, Parkinson's syndrome, bulemia, as well as in the case of disturbances of cognitive functions.

Den nødvendige dosering for å oppnå en ønsket virkning utgjør ved intravenøs tilførsel hensiktsmessig 20 til 100 mg, fortrinnsvis 30 til 70 mg, og ved oral tilførsel 50 til 200 mg, fortrinnsvis 75 til 150 mg, gitt 1 til 3 ganger daglig. Forbindelser med den generelle formel I lar seg herunder inn-arbeide, eventuelt i kombinasjon med andre virkestoffer, f.eks. blodtrykkssenkende midler, diuretika og/eller kalsiumantagonister, sammen med én eller flere inerte vanlige bærestoffer og/eller fortynningsmidler, f.eks. med maisstivelse, melkesukker, rør-sukker, mikrokrystallinsk cellulose, magnesiumstearat, polyvinyl-pyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/glycerol, vann/sorbitol, vann/polyetylenglykol, propylenglykol, 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 is suitably 20 to 100 mg, preferably 30 to 70 mg for intravenous administration, and 50 to 200 mg, preferably 75 to 150 mg for oral administration, given 1 to 3 times a day. Compounds with the general formula I can be incorporated below, possibly in combination with other active substances, e.g. blood pressure lowering agents, diuretics and/or calcium antagonists, together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, 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, spironolakton, benztiazid, cyklotiazid, etakrinsyre, furosemid, metoprolol, prazosin, atenolol, propranolol (di)hydralazin-hydroklorid, diltiazem, felodipin, nicardipin, nifendipin, nisoldipin og nitrendipin. Dosen for disse virke-stoffene utgjør herunder hensiktsmessig 1/5 av den ellers anbefalte laveste dosering opp til ca. 1/1 av den vanligvis anbefalte dosering, hvilket vil si for eksempel 15 til 200 mg hydroklortiazid, 125 til 2000 mg klortiazid, 15 til 200 mg etakrinsyre, 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. In the above-mentioned combinations, active substances may thus be included, such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, propranolol (di)hydralazine hydrochloride, diltiazem, felodipine, nicardipine, nifendipine , nisoldipine and nitrendipine. The dose for these active substances below is appropriately 1/5 of the otherwise recommended lowest dosage up to approx. 1/1 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

41 -[[2-n-propyl-5-(l-metylbenzimidazol-2-yl)-benzimidazol-1-yl]metyl]bifenyl-2-karboksylsyre og 41 -[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid and

4'-[[2-n-propyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-1-yl1metyl 1 bifenvi- 2- karboksylsyre 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl1methyl 1 bifenvi- 2- carboxylic acid

a) 2- n- propyl- benzimidazol- 5- karboksylsyre- metylester a) 2- n- propyl- benzimidazole- 5- carboxylic acid methyl ester

En oppløsning av 2 3,9 g (100 mmol) 3,4-diaminobenzosyre-metylester-dihydroklorid og 11,7 g (110 mmol) smørsyreklorid i 100 ml fosforoksyklorid ble kokt under tilbakeløpskjøling i 2 timer. Deretter ble ca. 80 ml fosforoksyklorid fradestillert og residuet dekomponert med ca. 150 ml vann. Det utfelte oljeaktige råprodukt ble ekstrahert 3 x 50 ml etylacetat og etter inndampning renset ved søylekromatografi (600 g kiselgel; elueringsmiddel: metylenklorid/metanol (30:1)). A solution of 23.9 g (100 mmol) of 3,4-diaminobenzoic acid methyl ester dihydrochloride and 11.7 g (110 mmol) of butyric acid chloride in 100 ml of phosphorus oxychloride was refluxed for 2 hours. Subsequently, approx. 80 ml of phosphorus oxychloride distilled off and the residue decomposed with approx. 150 ml of water. The precipitated oily crude product was extracted with 3 x 50 ml ethyl acetate and, after evaporation, purified by column chromatography (600 g silica gel; eluent: methylene chloride/methanol (30:1)).

Utbytte: 15,0 g olje (69% av det teoretiske) Yield: 15.0 g of oil (69% of the theoretical)

b) 2- n- propyl- benzimidazol- 5- karboksvlsyre- hemisulfat b) 2- n- propyl- benzimidazole- 5- carboxylic acid hemisulfate

En oppløsning av 15,0 g (73 mmol) 2-n-propyl-benzimidazol-5-karboksylsyre-metylester og 8 g (2 00 mmol) natriumhydroksd i 200 ml vann og 400 ml etanol ble kokt under tilbakeløpskjøling i 2 timer. Deretter ble alkoholen fradestillert, den.vandige oppløsning surgjort med fortynnet med svovelsyre (pH 4-5) og blandingen inndampet på en rotasjonsfordamper. Det derved utkrystalliserte produkt ble suget av, vasket med 50 ml porsjoner aceton og dietyleter og tørket. A solution of 15.0 g (73 mmol) of 2-n-propyl-benzimidazole-5-carboxylic acid methyl ester and 8 g (200 mmol) of sodium hydroxide in 200 ml of water and 400 ml of ethanol was refluxed for 2 hours. The alcohol was then distilled off, the aqueous solution acidified with dilute sulfuric acid (pH 4-5) and the mixture evaporated on a rotary evaporator. The thus crystallized product was sucked off, washed with 50 ml portions of acetone and diethyl ether and dried.

Utbytte: 9,1 g (61% av det teoretiske) Yield: 9.1 g (61% of theoretical)

Smeltepunkt: >220°C Melting point: >220°C

C^H^Oj x 1/2H2S04 (253,26) C^H^Oj x 1/2H 2 SO 4 (253.26)

■Beregnet: C, 52,17; H, 5,17; N, 11,06; S, 6,33 ■Calculated: C, 52.17; H, 5.17; N, 11.06; S, 6.33

Funnet: 51,87; 5,23; 11,11; 6,41 Found: 51.87; 5.23; 11,11; 6.41

c) 2- n- propyl- 5-( l- metylbenzimidazol- 2- yl)- benzimidazol c) 2-n-propyl-5-(1-methylbenzimidazol-2-yl)- benzimidazole

En oppløsning av 6,7 g (25 mmol) 2-n-propy-l-benzimidazol-5-karboksylsyre-hemisulfat og 4,9 g (25 mmol) 2-metylaminoanilin-dihydroklorid i 200 g polyfosforsyre ble omrørtj-i 5 timer ved 150°C og deretter helt over i 600 ml vann og under isavkjøling gjort alkalisk med konsentrert ammoniakk. Den oppnådde oppløsning ble ekstrahert tre ganger med 2 00 ml porsjoner etylacetat og det derved oppnådde råprodukt renset ved søylekromatografi (300 g kiselgel; elueringsmiddel: metylenklorid/metanol = 15:1). A solution of 6.7 g (25 mmol) of 2-n-propyl-1-benzimidazole-5-carboxylic acid hemisulfate and 4.9 g (25 mmol) of 2-methylaminoaniline dihydrochloride in 200 g of polyphosphoric acid was stirred for 5 hours at 150°C and then poured into 600 ml of water and made alkaline with concentrated ammonia under ice cooling. The solution obtained was extracted three times with 200 ml portions of ethyl acetate and the thus obtained crude product purified by column chromatography (300 g silica gel; eluent: methylene chloride/methanol = 15:1).

Utbytte: 2,8 g olje (39% av det teoretiske) Yield: 2.8 g of oil (39% of the theoretical)

C18H18N4 (290,37) C18H18N4 (290.37)

Beregnet: C, 74,46; H, 6,25; N, 19,29 Calculated: C, 74.46; H, 6.25; N, 19,29

Funnet: 73,92; 6,32; 18,96 Found: 73.92; 6.32; 18.96

d) 41 -[[2-n-propyl-5-(1-metylbenzimidazol-2-yl)benzimidazol-l-yl ]metyl]bifeny1-2-karboksylsyre-tert.butylester og d) 41-[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and

41 -[[2-n-propyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-1- ylImety11 bifenyl- 2- karboksylsyre- tert. butylester 41 -[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylmethyl biphenyl-2-carboxylic acid tert. butyl ester

En oppløsning av 2,0 g (6,9 mmol) 2-n-propyl-5-(1-metylbenzimidazol-2-yl)-benzimidazol og 0,91 g (7,5 mmol) kalium-tert.butylat i 50 ml dimetylsulfoksyd ble omrørt i 90. minutter ved romtemperatur og deretter tilsatt 2,6 g (7,5 mmol) 4<1->brom-metyl-bifenyl-2-karboksylsyre-tert.butylester og omrørt videre i 15 timer ved romtemperatur. Blandingen ble deretter helt over i 3 00 ml vann og ekstrahert tre ganger med 50 ml porsjoner etylacetat. Etter inndampning av den organiske fase ble det oppnådde råprodukt renset ved søylekromatografi (300 g kiselgel; elueringsmiddel: metylenklorid/metanol = 30:1). Det ble oppnådd 2,7 g (70% av det teoretiske) av en isomerblanding, som ifølge NMR-spektroskopiske data inneholdt ca. 1,18 g 41 -[(2-n-propyl-5-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl)-metyl]bifeny1-2-karboksylsyre-tert-butylester og ca. 1,52 g 4'-[(2-n-propyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl)metyl]bifeny1-2-karboksylsyre-tert-butylester. A solution of 2.0 g (6.9 mmol) of 2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazole and 0.91 g (7.5 mmol) of potassium tert-butylate in 50 ml of dimethylsulfoxide was stirred for 90 minutes at room temperature and then 2.6 g (7.5 mmol) of 4<1->bromo-methyl-biphenyl-2-carboxylic acid tert-butyl ester were added and stirred further for 15 hours at room temperature. The mixture was then poured into 300 ml of water and extracted three times with 50 ml portions of ethyl acetate. After evaporation of the organic phase, the crude product obtained was purified by column chromatography (300 g silica gel; eluent: methylene chloride/methanol = 30:1). 2.7 g (70% of the theoretical) of an isomer mixture was obtained, which according to NMR spectroscopic data contained approx. 1.18 g of 41-[(2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and approx. 1.52 g of 4'-[(2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl]biphenyl 1-2-carboxylic acid tert-butyl ester.

Rf-verdi: 0,43 (metylenklorid/metanol = 19:1) Rf value: 0.43 (methylene chloride/methanol = 19:1)

e) 4'-[[2-n-propyl-5-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl ]metyl]bifenyl-2-karboksylsyre og e) 4'-[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid and

41 -[[2-n-propyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-1- vl1 metyl] bifeny1- 2- karboksylsyre 41 -[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-vl1 methyl] biphenyl1- 2- carboxylic acid

2,-7 0 g av isomerblandingen oppnådd ifølge Eksempel ld ble oppløst i 100 ml metylenklorid, tilsatt 40 ml trifluoreddiksyre og 2.70 g of the isomer mixture obtained according to Example 1d was dissolved in 100 ml of methylene chloride, 40 ml of trifluoroacetic acid was added and

omrørt i 4 timer ved romtemperatur. Deretter ble blandingen inndampet til tørrhet i vakuum, residuet oppløst i 100 ml 2N natrium-lut, oppløsningen vasket med 50 ml dietyleter og produktblandingen utfelt ved surgjøring av den vandige fase med eddiksyre. Ved søylekromatografi (400 g kiselgel, elueringsmiddel: metylenklorid/ metanol = 15:1) av det således oppnådde faststoffet ble det oppnådd 0,7 g (58% av det teoretiske) 4'-[[2-n-propyl-5-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre med smeltepunkt 219-220°C stirred for 4 hours at room temperature. The mixture was then evaporated to dryness in vacuo, the residue dissolved in 100 ml of 2N sodium hydroxide solution, the solution washed with 50 ml of diethyl ether and the product mixture precipitated by acidifying the aqueous phase with acetic acid. By column chromatography (400 g silica gel, eluent: methylene chloride/methanol = 15:1) of the thus obtained solid, 0.7 g (58% of the theoretical) 4'-[[2-n-propyl-5-( 1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid with melting point 219-220°C

C32H28N4°2 (500,60) C32H28N4°2 (500.60)

Beregnet: C, 7 6,78; H, 5,64; N, 11,19 Calculated: C, 7 6.78; H, 5.64; N, 11,19

Funnet: 76,54; 5,57; 11,01 Found: 76.54; 5.57; 11.01

Rf-verdi: 0,15 (metylenklorid/metanol = 9:1) Rf value: 0.15 (methylene chloride/methanol = 9:1)

og 0,9 g (74% av det teoretiske) 4'-[[2-n-propyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-1-y1]mety1]bifeny1-2-karboksylsyre med smeltepunkt 217-218°C C32H28N4°2 (500,60) and 0.9 g (74% of theory) 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid of m.p. 217-218°C C32H28N4°2 (500.60)

Beregnet: C, 7.6,78; H, 5,64; N;. 11,19 Calculated: C, 7.6,78; H, 5.64; N;. 11,19

Funnet: 76,63 5,55 11,29 Found: 76.63 5.55 11.29

Rf-verdi: 0,40 (metylenklorid/metanol = 9:1) Rf value: 0.40 (methylene chloride/methanol = 9:1)

Eksempel 2 Example 2

4<1->[[2-n-butyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-1-vl1 metyl1bifenyl- 2- karboksvlsyre 4<1->[[2-n-butyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl1 methyl1biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel. 1 fra 41 -[[2-n-butyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Manufactured analogously to Example. 1 from 41 -[[2-n-butyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 4 3% av det teoretiske Yield: 4 3% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C33H3<0N>4°2 (514,60) C33H3<0N>4°2 (514.60)

Beregnet: C, 77,02; H, 5,88; N, 10,89 Calculated: C, 77.02; H, 5.88; N, 10.89

Funnet: 76,88; 5,83; 10,55 Found: 76.88; 5.83; 10.55

Rf-verdi: 0,42 (kiselgel; elueringsmiddel: metylenklorid/ etanol .= 9:1) Rf value: 0.42 (silica gel; eluent: methylene chloride/ ethanol .= 9:1)

Massespektrum: (M + H)<+> = 515 Mass spectrum: (M + H)<+> = 515

Eksempel 3 Example 3

41 -[[6-(bifenyl-4-karbonylamino)-2-n-buty1-benzimidazol-l-yl]-metyl1bifenyl- 2- karboksylsyre x 0, 25 H20 41 -[[6-(biphenyl-4-carbonylamino)-2-n-buty1-benzimidazol-1-yl]-methyl1biphenyl-2-carboxylic acid x 0.25 H20

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(bifenyl-4-karbonylamino)-2-n-butyl-benzimidazol-l-yl]metyl]bifenyl-2-karboksy.lsyre-tert. butylester og trif luoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(biphenyl-4-carbonylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-tert. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 70,6% av det teoretiske Yield: 70.6% of the theoretical

Smeltepunkt: 316-317°C Melting point: 316-317°C

C38H33N3°3 X °'25 H2° (584,20) C38H33N3°3 X °'25 H2° (584.20)

Beregnet: C, 78,13; H, 5,78; N, 7,19 Calculated: C, 78.13; H, 5.78; N, 7.19

Funnet: 7 8,12; 5,79; 7,08 Found: 7 8.12; 5.79; 7.08

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk = 80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 4 Example 4

4'-[[6-(bifenylyl-4-aminokarbonylamino)-2-n-butyl-benzimidazol-1- yl1metyl1bifenvl- 2- karboksylsyre- trifluoracetat- semihydrat 4'-[[6-(biphenylyl-4-aminocarbonylamino)-2-n-butyl-benzimidazol-1- yl1methyl1biphenyl- 2- carboxylic acid- trifluoroacetate- hemihydrate

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(bifenylyl-4-aminokarbonylamino)-2-n-butyl-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(biphenylyl-4-aminocarbonylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 97,0% av det teoretiske Yield: 97.0% of the theoretical

Smeltepunkt: 171-172°C Melting point: 171-172°C

C38<H>34N4°3 X CF3COOH X 1/2 H20 (717,74) C38<H>34N4°3 X CF3COOH X 1/2 H2O (717.74)

Beregnet: C, 66,94; H, 5,06; N, 7,81 Calcd: C, 66.94; H, 5.06; N, 7.81

Funnet: 67,13; 4,99; 7,76 Found: 67.13; 4.99; 7.76

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk = 80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 5 Example 5

4'-[(6-benzensulfonamido-2-n-butyl-benzimidazol-l-yl)metyl] bifeny1- 2- karboksylsyre 4'-[(6-benzenesulfonamido-2-n-butyl-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4<1->[(6-benzensulf onamido-2 -n-buty 1-benz imidazol -1-yl) -metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4<1->[(6-benzenesulfonamido-2-n-butyl 1-benz imidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 75,0% av det teoretiske Yield: 75.0% of the theoretical

Smeltepunkt: 251-252°C Melting point: 251-252°C

C31<H>29N304S (53 9,65) C31<H>29N304S (53 9.65)

Beregnet: C, 69,00; H, 5,42; N, 7,79; S, 5,94 Calculated: C, 69.00; H, 5.42; N, 7.79; S, 5.94

Funnet: 68,96; 5,52; 7,82; 5,86 Found: 68.96; 5.52; 7.82; 5.86

Rf-verdi: 0,50 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 50:45:5) Rf value: 0.50 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 6 Example 6

4 1 -[[6-(N-benzensulfonyl-metylamino)-2-n-butyl-benzimidazol-l- yl 1metyl1bifeny1- 2- karboksylsyre 4 1 -[[6-(N-benzenesulfonyl-methylamino)-2-n-butyl-benzimidazol-1-yl 1-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4<1->[[6-(N-benzensulf onylmetylamino) -2-n-butyl-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4<1->[[6-(N-benzenesulfonylmethylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 7 0,0% av det teoretiske Yield: 7 0.0% of the theoretical

Smeltepunkt: 211-212°C Melting point: 211-212°C

C32<H>31<N>304S (55 3,68) C32<H>31<N>304S (55 3.68)

Beregnet: C, 69,42; H, 5,64; N, 7,59; S, 5,79 Calcd: C, 69.42; H, 5.64; N, 7.59; S, 5.79

Funnet: 69,24; 5,66; 7,53; 6,02 Found: 69.24; 5.66; 7.53; 6.02

Rf-verdi: 0,55 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 50:45:5) Rf value: 0.55 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 7 Example 7

41 -[[2-n-butyl-6-(cykloheksylmetylaminokarbonylamino)-benzimidazol- 1- yl] metyl] bifeny1- 2- karboksylsyre- trifluoracetat 41 -[[2-n-butyl-6-(cyclohexylmethylaminocarbonylamino)-benzimidazol-1- yl] methyl] biphenyl 1- 2- carboxylic acid trifluoroacetate

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

Utbytte: 91,1% av det teoretiske Yield: 91.1% of the theoretical

Smeltepunkt: 149-150°C Melting point: 149-150°C

<C>33<H>38<N>4<0>3 x CF3COOH (652,71) <C>33<H>38<N>4<0>3 x CF3COOH (652.71)

Beregnet: C, 64,41; H, 6,02; N, 8,58 Calculated: C, 64.41; H, 6.02; N, 8.58

Funnet: 64,23; 6,09; 8,7 3 Found: 64.23; 6.09; 8.7 3

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk = 80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 8 Example 8

4'-[[2—n-butyl-6-(N-cykloheksylmetyl)acetamido-benzimidazol-1- yl 1 metyl ] bif eny 1- 2- karboksyl syre 4'-[[2-n-butyl-6-(N-cyclohexylmethyl)acetamido-benzimidazol-1-yl 1 methyl ] biphenyl 1- 2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-6-(N-cykloheksylmetyl)-acetamido-bénzimidazol-1-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-butyl-6-(N-cyclohexylmethyl)-acetamido-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 78,6% av det teoretiske Yield: 78.6% of the theoretical

Smeltepunkt: 185-187°C Melting point: 185-187°C

C34H39N3°3 (537,70) C34H39N3°3 (537.70)

Beregnet: C, 75,95; H, 7,31; N, 7,81 Calculated: C, 75.95; H, 7.31; N, 7.81

Funnet: . 75,75; 7,40; 7,65 Found: . 75.75; 7.40; 7.65

Rf-verdi: 0,45 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk =50:45:5) Rf value: 0.45 (silica gel; eluent: ethyl acetate/ethanol/ammonia =50:45:5)

Eksempel 9 Example 9

4'-[[6-(bicykloheksyl-4-karbonylamino)-2-n-butyl-benzimidazol-1- yllmetyl] bifenyl- 2- karboksylsyre- trifluoracetat 4'-[[6-(bicyclohexyl-4-carbonylamino)-2-n-butyl-benzimidazol-1- ylmethyl] biphenyl- 2- carboxylic acid trifluoroacetate

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

Utbytte: 93,3% av det teoretiske Yield: 93.3% of the theoretical

Smeltepunkt: 104-106°C Melting point: 104-106°C

C38H45N3°3 x CF3COOH (705,82) C38H45N3°3 x CF3COOH (705.82)

Beregnet: C, 68,07; H, 6,57; N, 5,95 Calculated: C, 68.07; H, 6.57; N, 5.95

Funnet: 68,38; 6,64; 5,80 Found: 68.38; 6.64; 5.80

Rf-verdi: 0,30 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk =80:40:2) Rf value: 0.30 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 10 Example 10

41 -[[6-(bicykloheksyl-4-aminokarbonylamino)-2-n-butyl-benzimidazol-l-yl ]metyl]bifenyl-2-karboksylsyre-semitrifluoracetat-monohydrat 41 -[[6-(bicyclohexyl-4-aminocarbonylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid semitrifluoroacetate monohydrate

Fremstillet analogt med Eksempel 1 fra 41 -[[6-(bicykloheksyl-4-aminokarbonylamino)-2-n-butyl-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[6-(bicyclohexyl-4-aminocarbonylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 94,9% av det teoretiske Yield: 94.9% of the theoretical

Smeltepunkt: 119-120°C Melting point: 119-120°C

<C>38<H>46N4°3 x 1/2 CF3COOH x H20 (681,83) <C>38<H>46N4°3 x 1/2 CF3COOH x H2O (681.83)

Beregnet: C, 68,70; H, 7,17; N, 8,22 Calculated: C, 68.70; H, 7.17; N, 8.22

Funnet: 68,32; 6,91; 7,81 Found: 68.32; 6.91; 7.81

Rf-verdi: 0,30 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.30 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 11 Example 11

4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-ftalimino)-benzimidazol-1- vllmetvl1bifenyl- 2- karboksylsyre- dihvdrat 4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-benzimidazole-1- nylmethyl1biphenyl- 2- carboxylic acid dihydrogen

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-ftalimino)-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 14,7% av det teoretiske Yield: 14.7% of the theoretical

Smeltepunkt: 119-122°C Melting point: 119-122°C

C33<H>31<N>3°4 x 2 H2° (53 3, 63) C33<H>31<N>3°4 x 2 H2° (53 3, 63)

Beregnet: C, 69,58; H, 6,19; N, 7,38 Calcd: C, 69.58; H, 6.19; N, 7.38

Funnet: 69,77; 6,34; 7,65 Found: 69.77; 6.34; 7.65

Rf-verdi: 0,45 (kiselgel; élueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.45 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 12 Example 12

41 -[[2-n-butyl-6-(5-dimetylamino-naftalen-l-sulfonamino)benzimidazol- l- yl] metyl1bifenyl- 2- karboksvlsyre- semitrifluoracetat 41 -[[2-n-butyl-6-(5-dimethylamino-naphthalen-1-sulfonamino)benzimidazol-1- yl] methyl 1-biphenyl- 2- carboxylic acid semitrifluoroacetate

Fremstillet analogt med Eksempel 1 fra 4 ' - [. [ 2-n-butyl-6-(5-dimetylamino-naftalen-l-sulfonamino)benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4' - [. [2-n-butyl-6-(5-dimethylamino-naphthalene-1-sulfonamino)benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 92,3% av det teoretiske Yield: 92.3% of the theoretical

Smeltepunkt: 148-150°C Melting point: 148-150°C

C37<H>36<N>404S X 1/2 CF3COOH (689,78) C37<H>36<N>404S X 1/2 CF3COOH (689.78)

Beregnet: C, 66,17; H, 5,33; N, 8,12; S, 4,64 Calculated: C, 66.17; H, 5.33; N, 8.12; S, 4.64

Funnet: 65,40; 5,33; 7,92; 5,19 Found: 65.40; 5.33; 7.92; 5.19

Eksempel 13 Example 13

4'-[[2-n-buty1-6-(2,3-difenyl-maleinsyreimido)benzimidazol-1- yl1metyl1 bifeny1- 2- karboksylsyre 4'-[[2-n-buty1-6-(2,3-diphenyl-maleic imido)benzimidazol-1-yl1methyl1 biphenyl1-2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(2,3-difenyl-maleinsyreimido)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(2,3-diphenyl-maleic acid imido)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 82,6% av det teoretiske Yield: 82.6% of the theoretical

Smeltepunkt: 236-237°C Melting point: 236-237°C

C41H33N3°4 (631,73) C41H33N3°4 (631.73)

Beregnet: C, 77,95; H, 5,27; N, 6,65 Calculated: C, 77.95; H, 5.27; N, 6.65

Funnet: 77,66; 5,24; 6,56 Found: 77.66; 5.24; 6.56

Rf-verdi: 0,65 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 50:45:5) Rf value: 0.65 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 14 Example 14

41 -[[2-n-butyl-6-(N-metansulfonyl-2-fenyletylamino)-benzimidazol-1- vl] metyl1bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(N-methanesulfonyl-2-phenylethylamino)-benzimidazol-1-vl] methyl 1-biphenyl- 2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4 1 -[[2-n-butyl-6-(N-metansulfonyl-2-fenyletylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4 1 -[[2-n-butyl-6-(N-methanesulfonyl-2-phenylethylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride .

Utbytte: 71,4% av det teoretiske Yield: 71.4% of the theoretical

Smeltepunkt: 215-216°C Melting point: 215-216°C

C34H3<5N>3°4 (581,73) C34H3<5N>3°4 (581.73)

Beregnet: C, 70,20; H, 6,06; N, 7,22; S, 5,51 Calculated: C, 70.20; H, 6.06; N, 7.22; S, 5.51

Funnet: 69,99; 6,14; 7,23; 5,55 Found: 69.99; 6.14; 7.23; 5.55

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 15 Example 15

4'-[[2-n-butyl-6-(2,3-dimetyl-maleinsyreimido)-benzimidazol-1- vl " I metyl 1 bif enyl- 2- karboksylsyre 4'-[[2-n-butyl-6-(2,3-dimethyl-maleic imido)-benzimidazol-1-vl" I methyl 1 biphenyl-2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(2,3-dimetyl-maleinsyreimido)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(2,3-dimethyl-maleic acid imido)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 69,6% av det teoretiske Yield: 69.6% of the theoretical

Smeltepunkt: 289-290°C Melting point: 289-290°C

C31H29N3°4 (5 07,59) C31H29N3°4 (5 07.59)

Beregnet: C, 73,35; H, 5,76; N, 8,2 8 Calculated: C, 73.35; H, 5.76; N, 8.2 8

Funnet:" 73,14; 5,90; 8,20 Found:" 73.14; 5.90; 8.20

Rf-verdi: 0,55 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 50:45:5) Rf value: 0.55 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 16 Example 16

4'-[[6-(N-benzensulfonyl-n-pentylamino)-2-n-butyl-benzimidazol-1- yl1 metyl] bifeny1- 2- karboksylsyre 4'-[[6-(N-benzenesulfonyl-n-pentylamino)-2-n-butyl-benzimidazol-1-yl1 methyl] biphenyl1-2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(N-benzensulf onyl-n-pentylamino) -2-n-butyl-benzimidazol-l-yl]metyl]bifeny1-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(N-benzenesulfonyl-n-pentylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 83,9% av det teoretiske Yield: 83.9% of the theoretical

Smeltepunkt: 243-244°C Melting point: 243-244°C

C36<H>39N304S (609,78) C36<H>39N304S (609.78)

Beregnet: C, 70,91; H, 6,45; N, 6,89; S, 5,26 Calculated: C, 70.91; H, 6.45; N, 6.89; S, 5.26

Funnet: 70,92; 6,21; 6,98; 5,19 Found: 70.92; 6.21; 6.98; 5.19

Rf-verdi: 0,45 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk =80:40:2) Rf value: 0.45 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 17 Example 17

4'-[[2-n-butyl-6-(N-4-metoksybenzensulfonyl-n-pentylamino)-benzimidazol- l- yl] metyl1bifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(N-4-methoxybenzenesulfonyl-n-pentylamino)-benzimidazol-1-yl] methyl 1-biphenyl-2- carboxylic acid

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

Utbytte: 84,6% av det teoretiske Yield: 84.6% of the theoretical

Smeltepunkt: 2 07-2 08°C Melting point: 2 07-2 08°C

C37<H>41N305S (639,81) C37<H>41N305S (639.81)

Beregnet: C, 69,46; H, 6,46; N, 6,57; S, 5,01 Calcd: C, 69.46; H, 6.46; N, 6.57; S, 5.01

Funnet: 69,31; 6,50; . 6,77; 5,21 Found: 69.31; 6.50; . 6.77; 5.21

Rf-verdi: 0,50 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk =80:40:2) Rf value: 0.50 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 18 Example 18

4'-[[2-n-butyl-6-(N-4-klorbenzensulfonyl-metylamino)-benzimidazol- l- yl1metyl1 bifeny1- 2- karboksylsyre z 4'-[[2-n-butyl-6-(N-4-chlorobenzenesulfonyl-methylamino)-benzimidazol-1- yl1methyl1 biphenyl1-2- carboxylic acid z

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(N-4-klorbenzensulfonyl-metylamino)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(N-4-chlorobenzenesulfonyl-methylamino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride .

Utbytte: 84,8% av det teoretiske Yield: 84.8% of the theoretical

Smeltepunkt: 24 0-2 41°C Melting point: 24 0-2 41°C

C32H30ClN3O4S (58 8,12) C32H30ClN3O4S (58 8.12)

Beregnet: C, 65,35; H, 5,14; N, 7,14; Cl, 6,0"3 ; S, 5,45 Funnet: 65,02; 5,30; 7,17; 6,21; 5,4 6 Calculated: C, 65.35; H, 5.14; N, 7.14; Cl, 6.0"3 ; S, 5.45 Found: 65.02; 5.30; 7.17; 6.21; 5.4 6

Eksempel 19 Example 19

41 -[[2-n-butyl-6-(N-fenylmetansulfonyl-metylamino)-benzimidazol-1- yl] metyl1bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(N-phenylmethanesulfonyl-methylamino)-benzimidazol-1-yl] methyl 1-biphenyl- 2- carboxylic acid

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

Utbytte: 54,9% av det teoretiske Yield: 54.9% of the theoretical

Smeltepunkt: 208-209°C Melting point: 208-209°C

C33H33<N>3°4S (567,70) C33H33<N>3°4S (567.70)

Beregnet: C, 69,82; H, 5,86; N, 7,40; S, 5,65 Calcd: C, 69.82; H, 5.86; N, 7.40; S, 5.65

Funnet: 69,54; 5,79; 7,47; 5,59 Found: 69.54; 5.79; 7.47; 5.59

Eksempel 20 Example 20

41 -[[2-n-butyl-6-(N-4-metylbenzensulfonyl-metylamino)-benz imidazol- l- ylImetyl1bifenvl- 2- karboksvlsyre 41 -[[2-n-butyl-6-(N-4-methylbenzenesulfonyl-methylamino)-benz imidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

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

Utbytte: 92,5% av det teoretiske Yield: 92.5% of the theoretical

Smeltepunkt: 259-260°C Melting point: 259-260°C

C33H33<N>3°4S (567,70) C33H33<N>3°4S (567.70)

Beregnet: C, 69,82; H, 5,86; N, 7,40; S, 5,65 Calcd: C, 69.82; H, 5.86; N, 7.40; S, 5.65

Funnet: 69,70; 5,90; 7,44; 5,68 Found: 69.70; 5.90; 7.44; 5.68

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk =80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 21 Example 21

4'-[[2-n-butyl-6-(N-n-propylsulfonyl-metylamino)-benzimidazol-1- yllmetvllbifenyl- 2- karboksylsyre 4'-[[2-n-butyl-6-(N-n-propylsulfonyl-methylamino)-benzimidazol-1-ylmethylbiphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(N-n-propylsulfonyl-metylamino)-benzimidazol-l-yl]metyl]bifenyl-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(N-n-propylsulfonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 67,3% av det teoretiske Yield: 67.3% of the theoretical

Smeltepunkt: 222-223°C Melting point: 222-223°C

C29H33<N>3°4S (519,66) C29H33<N>3°4S (519.66)

Beregnet: C, 67,03; H, 6,40; N, 8,09; S, 6,17 Calculated: C, 67.03; H, 6.40; N, 8.09; S, 6,17

Funnet: 67,02; 6,49; 8,04; 6,18 Found: 67.02; 6.49; 8.04; 6.18

Rf-verdi: 0,2 0 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.2 0 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 22 Example 22

4'-[[2-n-butyl-6-(N-4-metoksybenzensulfonyl-n-propylamino)-benzimidazol- l- ylImetyl1bifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(N-4-methoxybenzenesulfonyl-n-propylamino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

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

Utbytte: 86,4% av det teoretiske Yield: 86.4% of the theoretical

Smeltepunkt: 227-228°C Melting point: 227-228°C

C35<H>37<N>305S (611,7 5) C35<H>37<N>305S (611.7 5)

Beregnet: C, 68,72; H, 6,10; N, 6,87; S, 5,24 Calcd: C, 68.72; H, 6.10; N, 6.87; S, 5.24

Funnet: 68,54; 6,20; 6,88; 5,25 Found: 68.54; 6.20; 6.88; 5.25

Rf-verdi: 0,2 5 (kiselgel; elueringsmiddel: etylacetat/ etanol/ammoniakk =80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 23 Example 23

41 -[[2-n-butyl-6-(N-4-metylbenzensulfonyl-n-propylamino)-benzimidazol- l- yl] metyl] bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(N-4-methylbenzenesulfonyl-n-propylamino)-benzimidazol-1-yl] methyl] biphenyl- 2- carboxylic acid

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

Utbytte: 82,8% av det teoretiske Yield: 82.8% of the theoretical

Smeltepunkt: 223-224°C Melting point: 223-224°C

C35<H>37<N>304S (595,76) C35<H>37<N>304S (595.76)

Beregnet: C, 70,56; H, 6,26; N, 7,05; S, 5,38 Calculated: C, 70.56; H, 6.26; N, 7.05; S, 5.38

Funnet: 70,25; 6,20; 7,24; 5,61 Found: 70.25; 6.20; 7.24; 5.61

Rf-verdi: 0,28 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.28 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 24 Example 24

41 -[[2-n-butyl-6-(N-4-klorbenzensulfonyl-isopropylamino)-benzimidazol- l- ylImetyl1bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(N-4-chlorobenzenesulfonyl-isopropylamino)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

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

Utbytte: 82,1% av det teoretiske Yield: 82.1% of the theoretical

Smeltepunkt: 260-261°C Melting point: 260-261°C

C34H34C1N30AS (616,17) C34H34C1N30AS (616.17)

Beregnet: C, 66,28; H, 5,56; N, 6,82; Cl, 5,75; S, 5,20 Funnet: 66,05; 5,77; 7,05; 5,87 5,34 Rf-verdi: 0,30 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Calculated: C, 66.28; H, 5.56; N, 6.82; Cl, 5.75; S, 5.20 Found: 66.05; 5.77; 7.05; 5.87 5.34 Rf value: 0.30 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 2 5 Example 2 5

4'-[[6-(N-benzoyl-isopropylamino)-2-n-butyl-benzimidazol-1- ylImetyl1bifenvl- 2- karboksvlsvre 4'-[[6-(N-benzoyl-isopropylamino)-2-n-butyl-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41-[[6-(N-benzoyl-isopropylamino) -2-n-butyl-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41-[[6-(N-benzoyl-isopropylamino)-2-n-butyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 58,3% av det teoretiske Yield: 58.3% of the theoretical

Smeltepunkt: 209-210°C Melting point: 209-210°C

C35H35N303 (54 5,68) C35H35N303 (54 5.68)

Beregnet: C, 77,04; H, 6,46; N, 7,7 0 Calculated: C, 77.04; H, 6.46; N, 7.7 0

Funnet: 76,66; 6,57; 7,65 Found: 76.66; 6.57; 7.65

Rf-verdi-: 0,2 0 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk =80:40:2) Rf value: 0.20 (silica gel; eluent: ethyl acetate/ethanol/ammonia =80:40:2)

Eksempel 2 6 Example 2 6

4'-[[2-n-butyl-6-(1H,3H-kinazolin-2,4-dion-3-yl)-benzimidazol-1- vl1 metyl] bifenyl- 2- karboksvlsvre- hemihydrat 4'-[[2-n-butyl-6-(1H,3H-quinazolin-2,4-dion-3-yl)-benzimidazol-1-ylmethyl] biphenyl- 2- carboxylic acid hemihydrate

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-6-(1H,3H-kinazolin-2,4-dion-3-yl)-benzimidazol-l-yl]metyl]bifenyl-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid . Prepared analogously to Example 1 from 4'-[[2-n-butyl-6-(1H,3H-quinazolin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid -tert.butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 53,1% av det teoretiske Yield: 53.1% of the theoretical

Smeltepunkt: 3 38-3 4 0°C Melting point: 3 38-3 4 0°C

C33<H>28N404 x 1/2 H20 (553, 61) C33<H>28N404 x 1/2 H2O (553, 61)

Beregnet: C, 71,59; H, 5,28; N, 10,12 Calculated: C, 71.59; H, 5.28; N, 10,12

Funnet: 71,19; 5,33; 10,22 Found: 71.19; 5.33; 10.22

Eksempel 27 Example 27

41 -[[2-n-butyl-6-(N-4-klorbenzensulfonyl-benzylamino)-benzimidazol- l- vlImetyl] bifenyl- 2- karboksvlsvre 41 -[[2-n-butyl-6-(N-4-chlorobenzenesulfonyl-benzylamino)-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid

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

Utbytte: 64,5% av det teoretiske Yield: 64.5% of the theoretical

Smeltepunkt: 212-213°C Melting point: 212-213°C

C38H34C1N304S (664,22) C38H34C1N304S (664.22)

Beregnet: C, 68,72; H, 5,16; N, 6,33; Cl, 5,34; S, 4,83 Funnet: 68,76; 5,27; 6,39; 5,62; 4,81 Rf-verdi: 0,28 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Calcd: C, 68.72; H, 5.16; N, 6.33; Cl, 5.34; S, 4.83 Found: 68.76; 5.27; 6.39; 5.62; 4.81 Rf value: 0.28 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 28 Example 28

4'-[[2-n-butyl-6-(N-n-butansulfonyl-benzylamino)-benzimidazol-1- ylImetyl1bifenyl- 2- karboksylsyre 4'-[[2-n-butyl-6-(N-n-butanesulfonyl-benzylamino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-6-(N-n-butansulf onyl-benzylamino) -benzimidazol-l-yl"] metyl ]bif enyl-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-butyl-6-(N-n-butanesulfonyl-benzylamino)-benzimidazol-1-yl"] methyl ]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 66,4% av det teoretiske Yield: 66.4% of the theoretical

Smeltepunkt: 193-194°C Melting point: 193-194°C

C36<H>3<9N>304S (609,78) C36<H>3<9N>304S (609.78)

Beregnet: C, 70,91; H, 6,45; N, 6,89; S, 5,26 Calculated: C, 70.91; H, 6.45; N, 6.89; S, 5.26

Funnet: 70,76; 6,54; 6,94; 5,40_ Found: 70.76; 6.54; 6.94; 5.40_

Rf-verdi: 0,25 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.25 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 29 Example 29

41 -[[2-n-butyl-6-(N-6,7-dimetoksynaftalen-2-sulfonyl-metylamino)-benzimidazol- l- ylImetyl1bifenyl- 2- karboksvlsyre 41 -[[2-n-butyl-6-(N-6,7-dimethoxynaphthalene-2-sulfonyl-methylamino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(N-6,7-dimetoksynaftalen-2-sulfonyl-metylamino)-benzimidazol-1-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(N-6,7-dimethoxynaphthalene-2-sulfonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-tert. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 87,0% av det teoretiske Yield: 87.0% of the theoretical

Smeltepunkt: 2 61-262°C Melting point: 2 61-262°C

C38H37<N>3°6S (663,79) C38H37<N>3°6S (663.79)

Beregnet: C, 68,76; H, 5,62; N, 6,33; S, 4,8 3 Calcd: C, 68.76; H, 5.62; N, 6.33; S, 4.8 3

Funnet: 69,00; 6,00; 6,15; 5,07 Found: 69.00; 6.00; 6.15; 5.07

Rf-verdi: 0,23 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk = 80:40:2) Rf value: 0.23 (silica gel; eluent: ethyl acetate/ethanol/ammonia = 80:40:2)

Eksempel 3 0 Example 3 0

41 -[[2-n-butyl-6-(2-okso-2,5-dihydro-3,4-tetrametyleri-pyrrol-l-yl)-benzimidazol- l- ylImetyl] bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(2-oxo-2,5-dihydro-3,4-tetramethylery-pyrrol-1-yl)-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4<1->[[2-n-butyl-6-(2-okso-2,5-dihydro-3,4-tetrametylen-pyrrol-l-yl)-benzimidazol-l-yl ]metyl ] bif enyl-2-karboksylsyre-tert . butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4<1->[[2-n-butyl-6-(2-oxo-2,5-dihydro-3,4-tetramethylene-pyrrol-1-yl)-benzimidazol-1-yl ]methyl ]biphenyl-2-carboxylic acid-tert . butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 38,0% av det teoretiske Yield: 38.0% of the theoretical

Smeltepunkt: 146-148°C Melting point: 146-148°C

C33H33<N>3°3 (519,65) C33H33<N>3°3 (519.65)

Rf-verdi: 0,3 0 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.3 0 (silica gel; eluent: methylene chloride/

etanol = 9:1) ethanol = 9:1)

Eksempel 31 Example 31

4'-[[2-n-butyl-5-(2-okso-2,5-dihydro-3,4-tetrametylen-pyrrol-l-yl)-benzimidazol- l- ylImetyl] bifenyl- 2- karboksylsyre 4'-[[2-n-butyl-5-(2-oxo-2,5-dihydro-3,4-tetramethylene-pyrrol-1-yl)-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-5-(2-okso-2,5-dihydro-3,4-tetrametylen-pyrrol-l-yl)-benzimidazol-l-yl] metyl] bif enyl-2-karboksylsyre-tert. butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-butyl-5-(2-oxo-2,5-dihydro-3,4-tetramethylene-pyrrol-1-yl)-benzimidazol-1-yl] methyl ] biphenyl-2-carboxylic acid-tert. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 15,5% av det teoretiske Yield: 15.5% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C33H3<3N>3O3 (519,65) C33H3<3N>3O3 (519.65)

Rf-verdi: 0,20 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.20 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Eksempel 3 2 Example 3 2

4'-[[2-n-butyl-6-(3,3-dimetylpiperidin-l-yl)-benzimidazol-1- ylImetyl1bifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-1-yl]methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(3,3-dimetylpiperidin-l-yl)-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 86% av det teoretiske Yield: 86% of the theoretical

Smeltepunkt: fra 12 0°C (sintring) Melting point: from 12 0°C (sintering)

C32H37N302 (495,70) C32H37N302 (495.70)

Beregnet: C, 77,54; H, 7,52; N, 8,4 8 Calculated: C, 77.54; H, 7.52; N, 8.4 8

Funnet: 77,54; 7,24; 8,19 Found: 77.54; 7.24; 8,19

Rf-verdi: 0,3 5 (kiselgel; elueringsmiddel: metylenklorid/. Rf value: 0.3 5 (silica gel; eluent: methylene chloride/.

etanol =9:1) ethanol =9:1)

Eksempel 3 3 Example 3 3

4'-[[2-n-butyl-6-(heptametylenimino-benzimidazol-l-yl)-metyllbifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(heptamethyleneimino-benzimidazol-1-yl)-methyl-biphenyl-1-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(heptametylenimino-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(heptamethyleneimino-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 71% av det teoretiske Yield: 71% of the theoretical

Smeltepunkt: 195-198°C Melting point: 195-198°C

C32H37N302 (495,60) C32H37N302 (495.60)

Beregnet: C, 7 7,55; H, 7,52; N, 8,48 Calculated: C, 7 7.55; H, 7.52; N, 8.48

Funnet: 77,40; 7,66; 8,2 3 Found: 77.40; 7.66; 8.2 3

Rf-verdi: 0,40 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.40 (silica gel; eluent: methylene chloride/

etanol = 9:1) ethanol = 9:1)

Eksempel 34 Example 34

41 -[[2-n-butyl-6-(piperidin-1-y1)-benzimidazol-l-yl]metyl]-bif eny 1- 2- karboksylsyre 41 -[[2-n-butyl-6-(piperidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(piperidin-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(piperidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 84% av det teoretiske Yield: 84% of the theoretical

Smeltepunkt: 199-200°C Melting point: 199-200°C

C30H3<3N>3°2 (4 67, 60) C30H3<3N>3°2 (4 67, 60)

Beregnet: C, 77,06; H, 7,11; N, 8,99 Calculated: C, 77.06; H, 7.11; N, 8.99

Funnet 76,85; 7,28; 9,02 Found 76.85; 7.28; 9.02

Rf-verdi: 0,40 (kiselgel; elueringsmiddel: metylenklorid/ etanol = 9:1) Rf value: 0.40 (silica gel; eluent: methylene chloride/ ethanol = 9:1)

Eksempel 3 5 Example 3 5

4'-[[2-n-butyl-6-(4-metylpiperidin-l-yl)-benzimidazol-1-vl1 metyl1- bifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(4-methylpiperidin-1-yl)-benzimidazol-1-yl1-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(4-metylpiperidin-l-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(4-methylpiperidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 82% av det teoretiske Yield: 82% of the theoretical

Smeltepunkt: 162-165°C Melting point: 162-165°C

C31H3<5N>3°2 (481, 60) C31H3<5N>3°2 (481, 60)

Beregnet: C, 77,31; H, 7 , 33; N, 8 , 73 Calculated: C, 77.31; H, 7, 33; N, 8 , 73

Funnet 77,20; 7,19; 8,63 Found 77.20; 7.19; 8.63

Rf-verdi: 0,40 (kiselgel; elueringsmiddel: metylenklorid/ etanol =9:1) Rf value: 0.40 (silica gel; eluent: methylene chloride/ ethanol =9:1)

Eksempel 3 6 Example 3 6

4'-[(2-n-butyl-6-(heksametylenimino-benzimidazol-l-yl]metyl]-bifenyl- 2- karboksylsyre 4'-[(2-n-butyl-6-(hexamethyleneimino-benzimidazol-1-yl]methyl]-biphenyl- 2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[J2-n-butyl-6-(heksametylenimino-benzimidazol-l-yl)metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 4'-[N2-n-butyl-6-(hexamethyleneimino-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 3 4% av det teoretiske Yield: 3 4% of the theoretical

Smeltepunkt: 197-199°C Melting point: 197-199°C

C31H3<5N>3°2 (481, 60) C31H3<5N>3°2 (481, 60)

Beregnet: C, 77,31; H, 7,33; N, 8,73 Calculated: C, 77.31; H, 7.33; N, 8.73

Funnet 76,99; 7,35; 8,62 Found 76.99; 7.35; 8.62

Rf-verd.i: 0,40 (kiselgel; elueringsmiddel: metylenklorid/ etanol = 9:1) Rf value in: 0.40 (silica gel; eluent: methylene chloride/ ethanol = 9:1)

Eksempel 37 Example 37

4'-[[2-n-propyl-6-(2-okso-piperidin-l-yl)-benzimidazol-1-vlImetyl1- bifenyl- 2- karboksvlsvre 4'-[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

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

Utbytte: 60% av det teoretiske Yield: 60% of the theoretical

Smeltepunkt: 2 08-210°C Melting point: 2 08-210°C

<C>29<H>29N3°3 (467,60) <C>29<H>29N3°3 (467.60)

Beregnet: C, 74,49; H, 6,25; N, 8,99 Calculated: C, 74.49; H, 6.25; N, 8.99

Funnet 74,00; 6,29; 8,90 Found 74.00; 6.29; 8.90

Rf-verdi: 0,50 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.50 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Eksempel 3 8 Example 3 8

4'-[[2-n-propyl-6-(propansultam-1-yl)-benzimidazol-l-yl]metyl]-bifenvl- 2- karboksylsyre 4'-[[2-n-propyl-6-(propanesultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid

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

Utbytte: 49% av det teoretiske Yield: 49% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C27<H>27<N>304S (489,58) C27<H>27<N>304S (489.58)

Beregnet: C, 66,23; H, 5,56; N, 8,56; S, 6,55 Calculated: C, 66.23; H, 5.56; N, 8.56; S, 6.55

Funnet 66,08; 5,50; 8,37; 6,51 Found 66.08; 5.50; 8.37; 6.51

Rf-verdi: 0,47 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.47 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Massespektrum: (M + H)<+> = 490 Mass spectrum: (M + H)<+> = 490

Eksempel 3 9 Example 3 9

4'-[[2-n-propyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bif envl- 2- karboksyl syre 4'-[[2-n-propyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4<1->[[2-n-propyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 4<1->[[2-n-propyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte-: 57% av det teoretiske Yield: 57% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C28<H>29N30AS (503,63) C28<H>29N30AS (503.63)

Beregnet: C, 66,77; H, 5,80; N, 8,34; S, 6,37 Calculated: C, 66.77; H, 5.80; N, 8.34; S, 6.37

Funnet 66,59; 5,77; 8,18; 6,3 3 Found 66.59; 5.77; 8.18; 6.3 3

Rf-verdi: 0,51 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.51 (silica gel; eluent: methylene chloride/

etanol - 9:1) ethanol - 9:1)

Massespektrum: (M + H)<+> = 504 Mass spectrum: (M + H)<+> = 504

Eksempel 4 0 Example 4 0

4•-[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bifeny1- 2- karboksylsyre 4•-[[2-n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-1-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.

Utbytte: 51% av det teoretiske Yield: 51% of the theoretical

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

C29<H>31N304S (517,63) C29<H>31N304S (517.63)

Beregnet: C, 67,29; H, 6,04; N, 8,12; S, 6,19 Calculated: C, 67.29; H, 6.04; N, 8.12; S, 6,19

Funnet 67,22; 5,97; 7,97; 6,10 Found 67.22; 5.97; 7.97; 6.10

Rf-verdi: 0,52 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.52 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Massespektrum: (M + H)<+> = 518 Mass spectrum: (M + H)<+> = 518

Eksempel 41 Example 41

4'-[[2-n-butyl-6-(benzoksazol-2-yl)-benzimidazol-l-yl]metyl]-2- flH) - tetrazol- 5- vl) - bifenyl 4'-[[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-1-yl]methyl]-2-flH)-tetrazol-5-vl)-biphenyl

a) 2- h- butyl- 5-( benzoksazol- 2- yH benzimidazol a) 2-h-butyl-5-(benzoxazole-2-yH benzimidazole

Til en suspensjon av 2,52 g (10 mmol) 2-n-butyl-benzimidazol-5-karboksylsyre i 15 ml N-metylpyrrolidinon ble det under omrøring ved 10°C dråpevis tilsatt 1,43 g (12 mmol) tionylklorid. Blandingen ble omrørt ved romtemperatur i 15 minutter til, hvorpå 1,31 g To a suspension of 2.52 g (10 mmol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone, 1.43 g (12 mmol) of thionyl chloride was added dropwise while stirring at 10°C. The mixture was stirred at room temperature for another 15 minutes, after which 1.31 g

(11 mmol) 2-aminofenol ble tilsatt og omrøringen fortsatt i 2 timer ved 140°C. Blandingen ble deretter helt over på ca. 50 g is og under omrøring tilsatt 5 ml 3 0% natronlut. Det utfelte råprodukt ble suget av og renset ved søylekromatografi (3 00 g kiselgel; elueringsmiddel: metylenklorid + 3% etanol). (11 mmol) of 2-aminophenol was added and stirring continued for 2 hours at 140°C. The mixture was then poured over in approx. 50 g of ice and, while stirring, added 5 ml of 30% caustic soda. The precipitated crude product was suctioned off and purified by column chromatography (300 g silica gel; eluent: methylene chloride + 3% ethanol).

Utbytte: 1,2 g (41% av det teoretiske) Yield: 1.2 g (41% of theoretical)

Smeltepunkt: 118-120°C Melting point: 118-120°C

C18<H>l7N30 (291,36) C18<H>17N30 (291.36)

Beregnet: C, 74,20; H, 5,88; N, 14,42 Calculated: C, 74.20; H, 5.88; N, 14.42

Funnet: 73,98; 5,97; 14,20 Found: 73.98; 5.97; 14.20

b) Isomerblanding av 4'-[[2-n-buty1-6-(benzoksazol-2-yl)benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyrenitril og b) Isomer mixture of 4'-[[2-n-butyl-6-(benzoxazol-2-yl)benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid nitrile and

41 -[[2-n-buty1-5-(benzoksazol-2-yl)-benzimidazol-1-vlImetyl1 bifeny1- 2- karboksylsyrenitril 41 -[[2-n-Butyl-5-(benzoxazol-2-yl)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid nitrile

En oppløsning av 1 g (3,43 mmol) 2-n-butyl-5-(benzoksazol-2-yl)-benzimidazol og 0,98 g (3,60 mmol) 4'-brommetyl-bifenyl-2-karboksylsyrenitril i 20 ml dimetylsulfoksyd ble tilsatt 0,41 g (3,6 mmol) kalium-tert.butylat og omrørt i 4 8 timer ved romtemperatur. Blandingen ble deretter helt over i 100 ml vann, mettet med natriumklorid og ekstrahert, tre ganger med 3 0 ml etylacetat. Ved søylekromatografi (200 g kiselgel; elueringsmiddel: etylacetat/petroleter (1:1)). ble det oppnådd 1,4 g (85% av det teoretiske) av en blanding av isomerer i forholdet 1:1, som begynte å sintre fra 130°C. A solution of 1 g (3.43 mmol) of 2-n-butyl-5-(benzoxazol-2-yl)-benzimidazole and 0.98 g (3.60 mmol) of 4'-bromomethyl-biphenyl-2-carboxylic acid nitrile in 20 ml of dimethyl sulfoxide was added to 0.41 g (3.6 mmol) of potassium tert.butylate and stirred for 48 hours at room temperature. The mixture was then poured into 100 ml of water, saturated with sodium chloride and extracted three times with 30 ml of ethyl acetate. By column chromatography (200 g silica gel; eluent: ethyl acetate/petroleum ether (1:1)). 1.4 g (85% of theoretical) of a mixture of isomers in the ratio 1:1 was obtained, which began to sinter from 130°C.

C32<H>26N40 (482,59) C32<H>26N40 (482.59)

Beregnet: C, 79,64; H, 5,43; N, 11,61 Calcd: C, 79.64; H, 5.43; N, 11.61

Funnet: 79,64; 5,36; 11,59 Found: 79.64; 5.36; 11.59

c) 4'-[[2-n-butyl-6-(benzoksazol-2-yl)-benzimidazol-l-yl]-metyll- 2-( lH- tetrazol- 5- yl)- bifenyl c) 4'-[[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl

En.oppløsning av (1:1)-isomerblandingen av 4'-[[2-n-butyl-6-(benzoksazol-2-yl)-benzimidazol-1-yl]metyl]bifeny1-2-karboksylsyrenitril og 4'-[[2-n-butyl-5-(benzoksazol-2-yl)-benzimidazol-l-yl] metyl] bif enyl-2-karboksylsyrenitril i 20 ml dimetylformamid ble tilsatt 2 g ammoniumklorid og 2 g natriumazid og oppvarmet i 4 timer til 120-130°C. Etter ny tilsetning av 2 g ammoniumklorid og 2 g natriumazid og ytterligere oppvarming i 18 timer til 120-130°C, ble blandingen helt over i 100 ml vann. Den utfelte produktblandingen ble suget av og separert ved søylekromatografi (300 g kiselge-1, elueringsmiddel: metylenklorid + 3% etanol). A solution of the (1:1) isomeric mixture of 4'-[[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid nitrile and 4'- [[2-n-butyl-5-(benzoxazol-2-yl)-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid nitrile in 20 ml of dimethylformamide was added 2 g of ammonium chloride and 2 g of sodium azide and heated for 4 hours to 120-130°C. After further addition of 2 g of ammonium chloride and 2 g of sodium azide and further heating for 18 hours at 120-130°C, the mixture was poured into 100 ml of water. The precipitated product mixture was sucked off and separated by column chromatography (300 g silica gel-1, eluent: methylene chloride + 3% ethanol).

Utbytte: 100 mg (2 0% av det teoretiske) i amorf form Yield: 100 mg (20% of the theoretical) in amorphous form

C32<H>27N70 (52 5,62) C32<H>27N70 (52 5.62)

Beregnet: C, 7 3,12; H, 5,18; N, 18,66 Calculated: C, 7 3.12; H, 5.18; N, 18.66

Funnet: 73,10; 5,50; 18,42 Found: 73.10; 5.50; 18.42

Rf-verdi: 0,75 (kiselgel; elueringsmiddel: metylenklorid/ Rf value: 0.75 (silica gel; eluent: methylene chloride/

etanol = 9:1) ethanol = 9:1)

Eksempel 42 41 -[[2-n-propyl-5-(1-metylbenzimidazol-2-yl)-benzimidazol-1-yl]metyl]-2-(lH-tetrazol-5-yl)bifenyl og 41 -[[2-n-propyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-1-vl1 metyl1- 2-( lH- tetrazol- 5- vl) bifenyl Example 42 41 -[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl and 41 -[[ 2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-vl1 methyl1- 2-(1H- tetrazol-5-vl)biphenyl

Fremstillet analogt med Eksempel 41 fra en blanding av 4'-[[2-n-propyl-5-(l-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og 41 -[[2-n-propyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from a mixture of 4'-[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and 41 -[ [2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

5- isomer: 5-isomer:

Utbytte: 29% av det teoretiske Yield: 29% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C32H28N8 (524 , 61) C32H28N8 (524 , 61)

Beregnet: C, 73,26; H, 5,38; N, 21,36 Calculated: C, 73.26; H, 5.38; N, 21.36

Funnet 73,03; 5,22; 21,26 Found 73.03; 5.22; 21,26

Massespektrum: (M + H)<+> = 52 5 Mass spectrum: (M + H)<+> = 52 5

6- isomer: 6-isomer:

Utbytte: 3 4% av det teoretiske Yield: 3 4% of the theoretical

Smeltepunkt: 198-200°C Melting point: 198-200°C

C32H28N8 - (524,61) C32H28N8 - (524.61)

Beregnet: C, 73,26; H, 5,38; N, 21,36 Calculated: C, 73.26; H, 5.38; N, 21.36

Funnet: 73,11; 5,27; 21,19 Found: 73.11; 5.27; 21.19

Massespektrum: (M + H)<+> = 525 Mass spectrum: (M + H)<+> = 525

Eksempel 4 3 Example 4 3

41 -[[2-n-butyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-1-yl] metyl1- 2- flH- tetrazol- 5- yl) bifenyl 41 -[[2-n-butyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl] methyl1- 2- flH- tetrazol-5- yl) biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(1-mety-lbenzimidazol-2-yl) -benzimidazol-l-yl ]metyl ] -bifeny 1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(1-methyl-lbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide .

Utbytte: 28% av det teoretiske Yield: 28% of the theoretical

Smeltepunkt: 224-226°C Melting point: 224-226°C

C33H3<0N>8 (53 8,63) C33H3<0N>8 (53 8.63)

Beregnet: C, 73,58; H, 5,61; N, 20,81 Calculated: C, 73.58; H, 5.61; N, 20.81

Funnet: 73,31; 5,73; 19,99 Found: 73.31; 5.73; 19.99

Rf-verdi = 0,76 (kiselgel; elueringsmiddel: metylenklorid/ etanol =9:1) Rf value = 0.76 (silica gel; eluent: methylene chloride/ ethanol =9:1)

Massespektrum: (M + H)<+> = 539 Mass spectrum: (M + H)<+> = 539

Eksempel 44 Example 44

4'-[[2-n-butyl-6-(2-okso-piperidin-l-yl)-benzimidazol-1-vlImetvl1- 2- rlH- tetrazol- 5- vl) bifenvl 4'-[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-vlImetvl1- 2- rlH-tetrazol-5-vl)biphenvl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 2 0% av det teoretiske Yield: 2 0% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C30<H>31N7O (505,63) Beregnet: C, 67,94; H, 6,23; N, 17,3 3 C30<H>31N7O (505.63) Calcd: C, 67.94; H, 6.23; N, 17.3 3

Funnet: 67,67; 6,13; 17,52 Found: 67.67; 6.13; 17.52

Rf-verdi = 0,30 (kiselgel; elueringsmiddel: metylenklorid/ etanol =9:1) Rf value = 0.30 (silica gel; eluent: methylene chloride/ ethanol =9:1)

Eksempel 45 Example 45

41 -[[2-n-butyl-6-(3,3-dimetylpiperidin-l-yl)-benzimidazol-1-yl] metyl1- 2-( lH- tetrazol- 5- yl) bifenyl- hydroklorid 41 -[[2-n-butyl-6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-1-yl] methyl 1- 2-(1H- tetrazol-5-yl) biphenyl hydrochloride

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(3,3-dimetylpiperidin-l-yl)-benzimidazol-l-yl]metyl]-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-1-yl]methyl]-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 8% av det teoretiske Yield: 8% of the theoretical

Smeltepunkt: sintrer fra 148°C Melting point: sinters from 148°C

<C>32H37N7 x HC1 (519,70) <C>32H37N7 x HC1 (519.70)

Massespektrum: (M + H)<+> = 52 0 Mass spectrum: (M + H)<+> = 52 0

Eksempel 4 6 Example 4 6

4'-[[2-n-butyl-6-(4,4-tetrametylenglutarimido)-benzimidazol-1-vlimetyl1- 4- klor- 2- flH- tetrazol- 5- yl) bifenyl 4'-[[2-n-butyl-6-(4,4-tetramethyleneglutarimido)-benzimidazol-1-vlimethyl1- 4- chloro- 2- flH- tetrazol- 5- yl) biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(4,4-tetrametylenglutarimido)-benzimidazol-l-yl]metyl]-4-klorbifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(4,4-tetramethyleneglutarimido)-benzimidazol-1-yl]methyl]-4-chlorobiphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 4 0% av det teoretiske Yield: 40% of the theoretical

Smeltepunkt: sintrer fra 160°C Melting point: sinters from 160°C

C34<H>34<N>702C1 (608,16) C34<H>34<N>702C1 (608.16)

Beregnet: C, 67,15; H, 5,64; N, 16,12 Calculated: C, 67.15; H, 5.64; N, 16,12

Funnet: 66,90; 5,86; 15,86 Found: 66.90; 5.86; 15.86

Rf-verdi = 0,50 (kiselgel; elueringsmiddel: metylenklorid/ Rf value = 0.50 (silica gel; eluent: methylene chloride/

etanol = 9:1) ethanol = 9:1)

Eksempel 4 7 Example 4 7

4'-[[2-n-butyl-6-(propansultam-l-yl)-benzimidazol-l-yl]metyl]-2-( lH- tetrazol- 5- yl) bifenyl 4'-[[2-n-butyl-6-(propanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(propansultam-l-yl)-benzimidazol-l-ylJmetyl]-bifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(propanesultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 46% av det teoretiske Yield: 46% of the theoretical

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

C28<H>2<9N>702S (52 7,70) C28<H>2<9N>702S (52 7.70)

Beregnet: C, 63,73; H, 5,54; N, 18,58; S, 6,08 Calculated: C, 63.73; H, 5.54; N, 18.58; S, 6.08

Funnet: 62,52; 5,56; 18,40; 6,00 Found: 62.52; 5.56; 18.40; 6.00

Rf-verdi = 0,35 (kiselgel; elueringsmiddel: metylenklorid/ Rf value = 0.35 (silica gel; eluent: methylene chloride/

etanol = 9:1) ethanol = 9:1)

Eksempel 4 8 Example 4 8

4<1->[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-2- dH- tetrazol- 5- vl) bifenvl 4<1->[[2-n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-dH-tetrazol-5-vl) biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-1-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 3 0% av det teoretiske Yield: 3 0% of the theoretical

Smeltepunkt: 189-191°C Melting point: 189-191°C

C29<H>31N702S (541,7 0) C29<H>31N702S (541.7 0)

Beregnet: C, 64,30; H, 5,95; N, 18,10: S, 5,92 Calculated: C, 64.30; H, 5.95; N, 18.10: S, 5.92

Funnet: 64,40; 5,75; 17,90; 5,85 Found: 64.40; 5.75; 17.90; 5.85

Rf-verdi = 0,37 (kiselgel; elueringsmiddel: metylenklorid/ etanol = 9:1) Rf value = 0.37 (silica gel; eluent: methylene chloride/ ethanol = 9:1)

Eksempel 49 Example 49

4'-[[2-n-propyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-2-( lH- tetrazol- 5- vHbifenyl 4'-[[2-n-propyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazole-5-vHbiphenyl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-n-propyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-n-propyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 3 7% av det teoretiske Yield: 3 7% of the theoretical

Smeltepunkt: 204-206°C Melting point: 204-206°C

C28<H>29<N>702S (52 7,63) C28<H>29<N>702S (52 7.63)

Beregnet: C, 63,73; H, 5,54; N, 18,58; S, 6,08 Calculated: C, 63.73; H, 5.54; N, 18.58; S, 6.08

Funnet: 63,70; 5,49; 18,37; 6,19 Found: 63.70; 5.49; 18.37; 6.19

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

Massespektrum: m/e = 527 Mass spectrum: m/e = 527

Eksempel 50 Example 50

Blanding av: 4'-[[2-n-butyl-6-(2-hydroksy-cykloheksylaminokarbonyl)-benzimidazol-l-yl ] metyl ] -2- ( lH-tet ra zol -5 -yl ) bif enyl og Mixture of: 4'-[[2-n-butyl-6-(2-hydroxy-cyclohexylaminocarbonyl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl and

4'-[[2-n-butyl-5-(2-hydroksy-cykloheksylaminokarbonyl)-benzimidazol- l- yl] metyl 1 - 2 -( lH- tetrazol- 5- yl) bifenyl 4'-[[2-n-butyl-5-(2-hydroxy-cyclohexylaminocarbonyl)-benzimidazol-1-yl] methyl 1-2-(1H-tetrazol-5-yl)biphenyl

Fremstillet analogt med Eksempel 41 fra en blanding av 4'-[[2-n-butyl-6-(2-hydroksy-cykloheksylaminokarboriyl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og 4'-[[2-n-butyl-5-(2-hydroksy-cykloheksylaminokarbonyl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from a mixture of 4'-[[2-n-butyl-6-(2-hydroxy-cyclohexylaminocarboryyl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and 4'-[[ 2-n-butyl-5-(2-hydroxy-cyclohexylaminocarbonyl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 8% av det teoretiske Yield: 8% of the theoretical

Smeltepunkt: 198-200°C Melting point: 198-200°C

C32H35N702 (549,70) C32H35N702 (549.70)

Rf-verdi = 0,30 (kiselgel; elueringsmiddel: metylenklorid/ etanol =9:1) Rf value = 0.30 (silica gel; eluent: methylene chloride/ ethanol =9:1)

Massespektrum: (M + H)<+> = 550 Mass spectrum: (M + H)<+> = 550

Eksempel 51 Example 51

4'-[[2-n-butyl-6-(2-okso-pyrrolidin-l-yl)-benzimidazol-l-vl Imetyl 1 - 2- f lH- tetrazol- 5- vl ) bif envl 4'-[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-vl Imethyl 1 - 2- f lH- tetrazol-5-vl ) bifenvl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-n-butyl-6-(2-okso-pyrrolidin-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 15% av det teoretiske Yield: 15% of the theoretical

Smeltepunkt: 153-155°C Melting point: 153-155°C

C29<H>29N70 (491,60) C29<H>29N70 (491.60)

Beregnet: C, 70,85; H, 5,95; N, 19,95 Calculated: C, 70.85; H, 5.95; N, 19.95

Funnet: 70,79; 6,17; 19,71 Found: 70.79; 6.17; 19.71

Rf-verdi = 0,45 (kiselgel; elueringsmiddel: metylenklorid/ etanol = 9:1) Rf value = 0.45 (silica gel; eluent: methylene chloride/ ethanol = 9:1)

Massespektrum: (M + H)<+> = 492 Mass spectrum: (M + H)<+> = 492

Eksempel 52 Example 52

Blanding av Mixture of

4 1 - [ [2-n.-butyl-6^ (1, l-dimetyl-2-hydroksy-etylamino-karbonyl) - benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)bifenyl og 4 1 - [[2-n-butyl-6^(1,1-dimethyl-2-hydroxy-ethylamino-carbonyl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl) biphenyl and

4'-[[2-n-butyl-5-(1,l-dimetyl-2-hydroksy-etylamino-karbonyl)-benzimidazol- l- yl] metyl]- 2-( lH- tetrazol- 5- yl) bifenvl 4'-[[2-n-butyl-5-(1,1-dimethyl-2-hydroxy-ethylamino-carbonyl)-benzimidazol-1-yl] methyl]- 2-(1H-tetrazol-5-yl) biphenyl

Fremstillet analogt med Eksempel 41 fra en blanding av 4'-[[2-n-butyl-6-(1,l-dimetyl-2-hydroksy-etylaminokarbonyl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og 4'-[[2-n-butyl-5-(1,l-dimetyl-2-hydroksy-etylaminokarbonyl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from a mixture of 4'-[[2-n-butyl-6-(1,1-dimethyl-2-hydroxy-ethylaminocarbonyl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and 4'-[[2-n-butyl-5-(1,1-dimethyl-2-hydroxyethylaminocarbonyl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 14% av det teoretiske Smeltepunkt: amorft Yield: 14% of the theoretical Melting point: amorphous

C30H3<3N>7°2 (52 3,60) C30H3<3N>7°2 (52 3.60)

Rf-verdi = 0,30 (kiselgel; elueringsmiddel: metylenklorid/ etanol =9:1) Rf value = 0.30 (silica gel; eluent: methylene chloride/ ethanol =9:1)

Massespektrum: (M + H)<+> = 524 Mass spectrum: (M + H)<+> = 524

Eksempel 53 4'-[[2-n-butyl-6-(2-okso-heksametylenimino)-benzimidazol-1-vl Imetvl1- 2- flH- tetrazol- 5- vl) bifenvl Example 53 4'-[[2-n-butyl-6-(2-oxo-hexamethyleneimino)-benzimidazol-1-vl Imetvl1-2-flH-tetrazole-5-vl)biphenvl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-butyl-6- Prepared analogously to Example 41 from 4'-[[2-n-butyl-6-

(2-okso-heksametylenimino)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. (2-oxo-hexamethyleneimino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 34% av det teoretiske Yield: 34% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C31<H>33N70 (519,70) C31<H>33N70 (519.70)

Beregnet: C, 71,65; H, 6,40; N, 18,87 Calculated: C, 71.65; H, 6.40; N, 18.87

Funnet: 70,99; 6,32; 18,75 Found: 70.99; 6.32; 18.75

Rf-verdi = 0,15 (kiselgel; elueringsmiddel: metylenklorid/ Rf value = 0.15 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Eksempel 54 Example 54

4'-[[2-n-propyl-6-(2-okso-piperidin-l-yl)-benzimidazol-1-vllmetyll- 2-( lH- tetrazol- 5- vl) bifenyl 4'-[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-ylmethyl-2-(1H-tetrazol-5-yl)biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-n-propyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 14,5% av det teoretiske Yield: 14.5% of the theoretical

Smeltepunkt: sintrer fra 125°C Melting point: sinters from 125°C

C29<H>29N70 (491,60) C29<H>29N70 (491.60)

Rf-verdi = 0,25 (kiselgel; elueringsmiddel: metylenklorid/ Rf value = 0.25 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Massespektrum: (M + H)<+> = 492 Mass spectrum: (M + H)<+> = 492

Eksempel 55 Example 55

41 -[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-1-vl1metvl1- 2-( lH- tetrazol- 5- vl) bifenvl 41 -[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-vl1methyl1- 2-(1H-tetrazol-5-vl)biphenyl

a) 4'-[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-1-ylImetyl1- 2-( 1- trifenylmetyl- tetrazol- 5- yl) bifenyl a) 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-ylmethyl1-2-(1-triphenylmethyl-tetrazol-5-yl) biphenyl

Til en oppløsning av 1,04 g (3,3 mmol) 2-n-butyl-5-(3,3-dimetylglutarimido)-benzimidazol og 425 mg (3,8 mmol) kalium-tert.butylat i 25 ml dimetylsulfoksyd ble det tilsatt 1,8 g (3,3 mmol) 4<1->brommetyl-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl. Blandingen ble omrørt i 3 timer ved romtemperatur, hvoretter 150 ml vann ble rørt inn, blandingen ekstrahert tre ganger med 3 0 ml porsjoner etylacetat og det organiske ekstrakt tørket og inndampet. Det oppnådde residuum ble renset ved søylekromatografi (300 g kiselgel; elueringsmiddel: etylacetat/petroleter (2:1)). To a solution of 1.04 g (3.3 mmol) of 2-n-butyl-5-(3,3-dimethylglutarimido)-benzimidazole and 425 mg (3.8 mmol) of potassium tert-butylate in 25 ml of dimethylsulfoxide was 1.8 g (3.3 mmol) of 4<1->bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl were added. The mixture was stirred for 3 hours at room temperature, after which 150 ml of water was stirred in, the mixture was extracted three times with 30 ml portions of ethyl acetate and the organic extract was dried and evaporated. The residue obtained was purified by column chromatography (300 g silica gel; eluent: ethyl acetate/petroleum ether (2:1)).

Utbytte: 400 mg (15% av det teoretiske) Yield: 400 mg (15% of the theoretical)

Rf-verdi = 0,38 (etylacetat/petroleter = 6:1) Rf value = 0.38 (ethyl acetate/petroleum ether = 6:1)

b) 41 -[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-1- vlImetvl1-2-f lH- tetrazol- 5- vl)- bifenyl b) 41 -[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-vlImetvl1-2-f1H-tetrazol-5-vl)- biphenyl

En oppløsning av 400 mg (0,5 mmol) 41 -[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-l-yl)metyl]-2-(1-trifenylmetyl-tetrazol-S-yl) -bif enyl i 10 ml metanol ble tilsatt 1,5 ml metanolisk saltsyre og omrørt i 2 timer ved romtemperatur og deretter inndampet, hvorpå residuet ble tilsatt 15 ml vann og gjort alkalisk med konsentrert ammoniakk, hvorved produktet gikk i oppløsning. Ved surgjøring med iseddik utfeltes råproduktet som så ble renset ved søylekromatografi (150 g kiselgel; elueringsmiddel: metylenklorid + 5% etanol). A solution of 400 mg (0.5 mmol) 41 -[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-yl)methyl]-2-(1-triphenylmethyl-tetrazole-S -yl)-biphenyl in 10 ml of methanol was added to 1.5 ml of methanolic hydrochloric acid and stirred for 2 hours at room temperature and then evaporated, whereupon the residue was added to 15 ml of water and made alkaline with concentrated ammonia, whereby the product dissolved. Upon acidification with glacial acetic acid, the crude product is precipitated, which was then purified by column chromatography (150 g silica gel; eluent: methylene chloride + 5% ethanol).

Utbytte: 150 mg (55% av det teoretiske) Yield: 150 mg (55% of the theoretical)

Smeltepunkt: 184-186°C Melting point: 184-186°C

C32H33N7°2 (54 7,70) C32H33N7°2 (54 7.70)

Beregnet: C, 70,18; H, 6,07; N, 17,90 Calculated: C, 70.18; H, 6.07; N, 17.90

Funnet: 69,98; 6,20 17,67 Found: 69.98; 6.20 17.67

Eksempel 56 Example 56

4'-[[2-n-butyl-6-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol- l- yllmetyl ] - 2- ( lH- tetrazol- 5- yl) bif enyl 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-ylmethyl]-2-(1H-tetrazol-5-yl)biphenyl

Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-butyl-6-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og saltsyre i etanol. Prepared analogously to Example 55 from 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl )-biphenyl and hydrochloric acid in ethanol.

Utbytte: 53,8% av det teoretiske Yield: 53.8% of the theoretical

Smeltepunkt: 124-126°C Melting point: 124-126°C

C33<H>38N80 (550,71) C33<H>38N80 (550.71)

Rf-verdi = 0,25 (kiselgel; elueringsmiddel: metylenklorid/ Rf value = 0.25 (silica gel; eluent: methylene chloride/

etanol =9:1) ethanol =9:1)

Beregnet: C, 69,79; H, 6,95; N, 20,35 Calcd: C, 69.79; H, 6.95; N, 20.35

Funnet.:- 69,78 ; 7,05; 2 0,31 Found.:- 69.78 ; 7.05; 2 0.31

Massespektrum: (M + H)<+> = 492 Mass spectrum: (M + H)<+> = 492

Eksempel 57 Example 57

4'-[[2-n-butyl-5-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol- l- yllmetvll- 2-( lH- tetrazol- 5- vl) bifenvl- dihvdrat 4'-[[2-n-butyl-5-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-ylmethyl-2-(1H-tetrazol-5-yl) biphenyl dihydrogen

Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-butyl-5-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl]metyl]-2-(1-trifénylmetyl-tetrazol-5-yl)-bifenyl og saltsyre i etanol. Prepared analogously to Example 55 from 4'-[[2-n-butyl-5-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl )-biphenyl and hydrochloric acid in ethanol.

Utbytte: 7 6,2% av det teoretiske Yield: 7 6.2% of the theoretical

Smeltepunkt: 201-203°C Melting point: 201-203°C

<C>32<H>38N80 x 2 H20 (586,74) <C>32<H>38N80 x 2 H20 (586.74)

Beregnet: C, 65,50; H, 7,21; N, 19,09 Calculated: C, 65.50; H, 7.21; N, 19.09

Funnet: 65,43; 7,07; 19,12 Found: 65.43; 7.07; 19,12

Eksempel 58 Example 58

4'~[[2-n-butyl-6-(N-cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol- l- vl] metyl]- 2-( lH- tetrazol- 5- vl) bifenyl- hydrat 4'~[[2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-vl] methyl]- 2-(1H- tetrazole-5-vl) biphenyl- hydrate

Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-butyl-6-(N-cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol-1-' yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og saltsyre i etanol. Prepared analogously to Example 55 from 4'-[[2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-'yl]methyl]-2-(1-triphenylmethyl-tetrazol-5- yl)-biphenyl and hydrochloric acid in ethanol.

Utbytte: 95,2% av det teoretiske Yield: 95.2% of the theoretical

Smeltepunkt: 128-132°C Melting point: 128-132°C

C37<H>46N80 x H20 (63 6,84) C37<H>46N80 x H20 (63 6.84)

Beregnet: C, 69,78 ; H, 7,59 ; N, 17,59 Calculated: C, 69.78 ; H, 7.59; N, 17.59

Funnet: 69,61; 7,71; 17,41 Found: 69.61; 7.71; 17.41

Rf-verdi = 0,45 (kiselgel; elueringsmiddel: Rf value = 0.45 (silica gel; eluent:

etanol/ammoniakk =80/40/2) ethanol/ammonia =80/40/2)

Eksempel 59 Example 59

41 -[[2-n-butyl-5-(N-cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol- l- vl] metyl1- 2-( lH- tetrazol- 5- vl) bifenvl- hydrat 41 -[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-vl] methyl 1- 2-(1H-tetrazol-5-vl)biphenyl- hydrate

Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-butyl-5-(N-cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol-1-yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og saltsyre i etanol. Prepared analogously to Example 55 from 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl )-biphenyl and hydrochloric acid in ethanol.

Utbytte: 88,6% av det teoretiske Yield: 88.6% of the theoretical

Smeltepunkt: 117-12 0°C Melting point: 117-12 0°C

C37<H>46N80 x H20 (636,84) C37<H>46N80 x H20 (636.84)

Beregnet: C, 69,78; H, 7,59; N, 17,59 Calcd: C, 69.78; H, 7.59; N, 17.59

Funnet: 7 0,06; 7,58; 17,56 Found: 7 0.06; 7.58; 17.56

Rf-verdi = 0,45 (kiselgel; elueringsmiddel: Rf value = 0.45 (silica gel; eluent:

etanol/ammoniakk = 80:40/2) ethanol/ammonia = 80:40/2)

Eksempel 60 Example 60

4'-[[2-n-butyl-6-(5-dimetylaminonaftalen-l-sulfonamino)-benzimidazol- l- ylJmetyl1- 2-( lH- tetrazol- 5- yl) bifenyl- hydrat 4'-[[2-n-butyl-6-(5-dimethylaminonaphthalene-1-sulfonamino)-benzimidazol-1-yl]methyl1- 2-(1H-tetrazol-5-yl) biphenyl- hydrate

Fremstillet analogt med Eksempel 55 fra 41 -[[2-n-butyl-6-(5-dimetylaminonaftalen-l-sulfonamino)-benzimidazol-l-yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og saltsyre i etanol. Prepared analogously to Example 55 from 41 -[[2-n-butyl-6-(5-dimethylaminonaphthalen-1-sulfonamino)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl) -biphenyl and hydrochloric acid in ethanol.

Utbytte: 44,7% av det teoretiske Yield: 44.7% of the theoretical

C37<H>36<N>802S X H20 (67 4,81) C37<H>36<N>802S X H20 (67 4.81)

Beregnet: C, 65,85; H, 5,67; N, 16,60; S, 4,75 Calculated: C, 65.85; H, 5.67; N, 16.60; S, 4.75

Funnet: 65,80; 5,46; 16,42; 4,90 Found: 65.80; 5.46; 16.42; 4.90

Eksempel 61 Example 61

41 -[[2-n-butyl-6-(2-okso-3,4-tetrametylen-pyrrolidin-l-yl)-benzimidazol- l- ylImetyl1- bifenvl- 2- karboksylsyre 41 -[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-yl)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

420 mg (0,81 mmol) 4'-[[2-n-butyl-6-(2-okso-l,2-dihydro-3,4-tetrametylen-pyrrol-l-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre ble oppløst i 60 ml metanol og 60 ml etylacetat og under tilsetning av 200 mg palladium på kull (10%) og hydrert ved 4 0°C under 5 bar hydrogentrykk. Katalysatoren ble suget av, oppløsningsmidlet fordampet og råproduktet renset ved søyle-kromatograf i (200 g kiselgel; oppløsningsmiddel: metylenklorid + 3% etanol). 420 mg (0.81 mmol) 4'-[[2-n-butyl-6-(2-oxo-1,2-dihydro-3,4-tetramethylene-pyrrol-1-yl)-benzimidazol-1-yl ]methyl]-biphenyl-2-carboxylic acid was dissolved in 60 ml of methanol and 60 ml of ethyl acetate and with the addition of 200 mg of palladium on charcoal (10%) and hydrogenated at 40°C under 5 bar hydrogen pressure. The catalyst was sucked off, the solvent evaporated and the crude product purified by column chromatography (200 g silica gel; solvent: methylene chloride + 3% ethanol).

Utbytte': 260 mg (62% av det teoretiske) Yield': 260 mg (62% of the theoretical)

Smeltepunkt: amorft Melting point: amorphous

C33<H>35N303 (521, 67) C33<H>35N303 (521, 67)

Beregnet: C, 75,98; H, 6,76; N, 8,06 Calculated: C, 75.98; H, 6.76; N, 8.06

Funnet: 75,75; 6,62; 8,24 Found: 75.75; 6.62; 8.24

Eksempel 62 Example 62

Blanding av Mixture of

4'-[[2-n-butyl-6-(5,5-pentametylen-oksazolin-2-yl)-benzimidazol-l-yl ) -metyl ] -2- ( lH-tetrazol-5-yl ) -bif enyl 4'-[[2-n-butyl-6-(5,5-pentamethylene-oxazolin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-bif enyl

og and

4'-[[2-n-buty1-5-(5,5-pentametylen-oksazolin-2-yl)-benzimidazol-l- vl) - metvll- 2- flH- tetrazol- 5- vl)- bifenyl 4'-[[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl)-benzimidazol-1-vl)-methyl-2-flH-tetrazol-5-vl)-biphenyl

En oppløsning av 93 0 mg (2 mmol) av en isomerblanding av 4<1->[[2-n-buty1-6-karboksy-benzimidazol-1-yl)-metyl]-2-(lH-tetrazol-S-yl) -bif enyl og 4'-[[2-n-butyl-5-karboksy-benzimidazol-l-yl)-metyl]-2-(lH-tetrazol-5-yl)-bifenyl og 356 mg (2,2 mmol) karbonyldiimidazol i 30 ml tetrahydrofuran ble omrørt i 30 minutter ved romtemperatur. Deretter ble det tilsatt 3 32 mg (2 mmol) l-(aminometyl)-cykloheksanol-dihydroklorid under videre omrøring i 15 minutter ved romtemperatur. Deretter ble blandingen inndampet, langsomt og dråpevis tilsatt 2 ml tionylklorid, omrørt i 1 time, hvoretter tionylkloridet ble avdestillert og residuet tilsatt 5 ml isvann. Det uoppløselige råprodukt ble renset ved søylekromatografi (150 g kiselgel; elueringsmiddel: metylenklorid + 5% etanol). Det ble derved oppnådd 25 mg (2% av det teoretiske) av en blanding av 4'-[[2-n-buty1-6-(5,5-pentametylen-oksazolin-2-yl)-benzimidazol-l-yl )-metyl]-2-(lH-tetrazol-5-yl)-bifenyl og 4'-[[2-n-butyl-5-(5,5-pentametylen-oksazolin-2-yl)-benzimidazol-l-yl)-metyl]-2-(1H-tetrazol-5-yl)-bifenyl A solution of 930 mg (2 mmol) of an isomeric mixture of 4<1->[[2-n-buty1-6-carboxy-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-S- yl)-biphenyl and 4'-[[2-n-butyl-5-carboxy-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and 356 mg (2, 2 mmol) of carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred for 30 minutes at room temperature. 32 mg (2 mmol) of 1-(aminomethyl)-cyclohexanol dihydrochloride were then added with further stirring for 15 minutes at room temperature. The mixture was then evaporated, slowly and dropwise added 2 ml of thionyl chloride, stirred for 1 hour, after which the thionyl chloride was distilled off and the residue added to 5 ml of ice water. The insoluble crude product was purified by column chromatography (150 g silica gel; eluent: methylene chloride + 5% ethanol). 25 mg (2% of the theoretical) of a mixture of 4'-[[2-n-buty1-6-(5,5-pentamethylene-oxazolin-2-yl)-benzimidazol-1-yl) were thereby obtained -methyl]-2-(1H-tetrazol-5-yl)-biphenyl and 4'-[[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl)-benzimidazol-1-yl )-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Smeltepunkt: fra 215°C (dekomp.) Melting point: from 215°C (decomp.)

C33H35N70 (54 5,67) C33H35N70 (54 5.67)

Massespektrum: (M + H)<+> = 54 6 Mass spectrum: (M + H)<+> = 54 6

Eksempel 63 Example 63

41 -[[2-n-butyl-6-(N-metyl-fenylaminokarbonylamino)-benzimidazol-l- yl) - metyl ] - bif enyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(N-methyl-phenylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

En-oppløsning av 0,8 g (2,00 mmol) 4'-[[2-n-butyl-6-amino-benzimidazol-l-yl)-metyl]bifenyl-2-karboksylsyré' og 0,9 g N-metyl-isatinsyre-anhydrid i 3 ml pyridin ble kokt i 48 timer under tilbakeløpskjøling og deretter inndampet til tørrhet, hvorpå residuet ble oppslemmet i 5 ml metylenklorid, suget av og vasket med ytterligere med 5 ml metylenklorid og tørket. A solution of 0.8 g (2.00 mmol) 4'-[[2-n-butyl-6-amino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid' and 0.9 g N -methyl isatinic anhydride in 3 ml of pyridine was boiled for 48 hours under reflux and then evaporated to dryness, whereupon the residue was slurried in 5 ml of methylene chloride, suctioned off and washed with a further 5 ml of methylene chloride and dried.

Utbytte: 0,66 g (62% av det teoretiske) Yield: 0.66 g (62% of theoretical)

Smeltepunkt: 274-276°C Melting point: 274-276°C

<C>33<H>32N403 (53 2,60) <C>33<H>32N403 (53 2.60)

Beregnet: C, 74,41; H, 6,06; N, 10,57 Calculated: C, 74.41; H, 6.06; N, 10.57

Funnet: 74,23; 5,94; 10,66 Found: 74.23; 5.94; 10.66

Eksempel 64 Example 64

4'-[[2-n-butyl-5-(3-karboksy-propionyl)-benzimidazol-l-yl)-metyl1- bifenyl- 2- karboksylsyre 4'-[[2-n-butyl-5-(3-carboxy-propionyl)-benzimidazol-1-yl)-methyl-1-biphenyl-2-carboxylic acid

En oppløsning av 200 mg (0,39 mmol) 4'-[[2-n-butyl-5-(3-metoksykarbonyl-propionyl)-benzimidazol-l-yl)-metyl]-bifeny1-2-karboksylsyre-metylester og 0,75 ml natronlut i 4 ml etanol ble omrørt i 2 timer ved 75°C og deretter tilsatt 40 ml vann og surgjort med iseddik. Alkoholen ble deretter avdestillert, den oppnådde blanding omrørt i 1 time ved romtemperatur og det utfelte produkt suget av og vasket med 10 ml vann og tørket. A solution of 200 mg (0.39 mmol) of 4'-[[2-n-butyl-5-(3-methoxycarbonyl-propionyl)-benzimidazol-1-yl)-methyl]-biphenyl 1-2-carboxylic acid methyl ester and 0.75 ml of caustic soda in 4 ml of ethanol was stirred for 2 hours at 75°C and then 40 ml of water was added and acidified with glacial acetic acid. The alcohol was then distilled off, the resulting mixture was stirred for 1 hour at room temperature and the precipitated product was suctioned off and washed with 10 ml of water and dried.

Utbytte: 12 0 mg (64% av det teoretiske) Yield: 120 mg (64% of theoretical)

Smeltepunkt: 200-202°C Melting point: 200-202°C

C29H28N204 (484,60) C29H28N204 (484.60)

Beregnet: C, 71,88; H, 5,83; N, 5,78 Calculated: C, 71.88; H, 5.83; N, 5.78

Funnet: 71,66; 5,86; 5,63 Found: 71.66; 5.86; 5.63

Eksempel 65 Example 65

4<1->[[2-n-butyl-6-(3-karboksy-2-metyl-propionyl)-benzimidazol-1- yll- metyl1- bifenyl- 2- karboksylsyre x 0, 25 H20 4<1->[[2-n-butyl-6-(3-carboxy-2-methyl-propionyl)-benzimidazol-1-yl-methyl-1-biphenyl-2-carboxylic acid x 0.25 H20

Fremstillet analogt med Eksempel 64 fra 41 -[[2-n-butyl-6-(3-metoksykarbpnyl-2-metyl-propionyl)-benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyre-metylester og natronlut i etanol. Prepared analogously to Example 64 from 41 -[[2-n-butyl-6-(3-methoxycarbonyl-2-methyl-propionyl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid methyl ester and caustic soda in ethanol .

Utbytte: 18% av det teoretiske Yield: 18% of the theoretical

Smeltepunkt: 193-194°C Melting point: 193-194°C

<C>30<H>30<N>2°5 x V4 H2° (498,60) <C>30<H>30<N>2°5 x V4 H2° (498.60)

Beregnet: C, 71,62; H, 6,11; N, 5,56 Calculated: C, 71.62; H, 6.11; N, 5.56

Funnet: 71,72; 6,09; 5,68 Found: 71.72; 6.09; 5.68

Rf-verdi: 0,37 (kiselgel; elueringsmiddel: metylenklorid/ etanol/iseddik = 18/1/0,05) Rf value: 0.37 (silica gel; eluent: methylene chloride/ ethanol/ glacial acetic acid = 18/1/0.05)

Eksempel 66 Example 66

41 -[[2-n-butyl-6-(3-karboksy-propionyl)-benzimidazol-l-yl]-metyl1- bifenyl- 2- karboksylsyre 41 -[[2-n-butyl-6-(3-carboxy-propionyl)-benzimidazol-1-yl]-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 64 fra 4'-[[2-n-butyl-6-(3-metoksykarbonyl-propionyl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre-metylester og natronlut i etanol. Prepared analogously to Example 64 from 4'-[[2-n-butyl-6-(3-methoxycarbonyl-propionyl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid methyl ester and caustic soda in ethanol.

Utbytte: 97% av det teoretiske Yield: 97% of the theoretical

Smeltepunkt: 240-242°C Melting point: 240-242°C

C29H28N205 (484,60) C29H28N2O5 (484.60)

Beregnet: C, 71,88; H, 5,83; N, 5,78 Calculated: C, 71.88; H, 5.83; N, 5.78

Funnet: 71,74; 6,07; 5,93 Found: 71.74; 6.07; 5.93

Eksempel 67 Example 67

4'-[[2-n-butyl-6-(2,3-dimetylmaleinsyreimino)-benzimidazol-1- yl1- metyll- bifenvl- 2- karboksvlsvre 4'-[[2-n-butyl-6-(2,3-dimethylmaleic imino)-benzimidazol-1-yl1-methyl-biphenyl-2-carboxylic acid

52,5 mg (0,1 mmol) 4'-[[2-n-butyl-6-(2,3-dimetylmaleinsyre- . amino]benzimidazol-l-yl)-metyl]bifeny1-2-karboksylsyre ble oppvarmet til koking i 2 ml bis-(2-metoksy-etyl)-eter i 1 time. Oppløsningsmidlet ble avdestillert, residuet fordelt mellom etylacetat og vann. Den organiske fase ble vasket to ganger til med vann, tørket med magnesiumsulfat og inndampet på rotasjonsfordamper. Residuet ble utgnidd med 1 ml aceton, suget av, vasket med eter og tørket i vakuum ved 65°C. 52.5 mg (0.1 mmol) of 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid-.amino]benzimidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid was heated to boiling in 2 ml of bis-(2-methoxyethyl) ether for 1 hour. The solvent was distilled off, the residue partitioned between ethyl acetate and water. The organic phase was washed twice more with water, dried with magnesium sulfate and evaporated on a rotary evaporator. The residue was triturated with 1 ml of acetone, sucked off, washed with ether and dried in vacuo at 65°C.

Utbytte: 29,0 mg (57,2% av det teoretiske) Yield: 29.0 mg (57.2% of theoretical)

Smeltepunkt: 289-291°C Melting point: 289-291°C

C31H29N3°4 (507,59) C31H29N3°4 (507.59)

Beregnet: C, 73,35; H, 5,76; N, 8,29 Calculated: C, 73.35; H, 5.76; N, 8.29

Funnet: 73,50; 5,64; 8,10 Found: 73.50; 5.64; 8,10

Eksempel 68 Example 68

41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-ftalimino)-benzimidazol-1-ylImetyl1bifenyl- 2- karboksylsyre- hydrat 41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid hydrate

0,275 g (0,5 mmol) 4•-[[2-n-butyl-6-(2-karboksy-3,4,5,6-tetrahydrobenzamino)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre i 5 ml pyridin, ble kokt under tilbakeløpskjøling i 4 timer. Blandingen ble deretter inndampet til tørrhet i vakuum i 0.275 g (0.5 mmol) 4•-[[2-n-butyl-6-(2-carboxy-3,4,5,6-tetrahydrobenzamino)-benzimidazol-1-yl]methyl]-biphenyl-2- carboxylic acid in 5 ml of pyridine, was boiled under reflux for 4 hours. The mixture was then evaporated to dryness in vacuo

rotasjonsfordamper og råproduktet omkrystallisert fra aceton. Det ble suget av, vasket med aceton og tørket i vakuum ved 7 0°C. rotary evaporator and the crude product recrystallized from acetone. It was sucked off, washed with acetone and dried in vacuum at 70°C.

Utbytte: 0,2 g (72,4% av det teoretiske) Yield: 0.2 g (72.4% of theoretical)

Smeltepunkt: 22 6-2 2 8°C Melting point: 22 6-2 2 8°C

C30<H>31<N>3°4 x H2° (551,64) C30<H>31<N>3°4 x H2° (551.64)

Beregnet: C, 71,85; H, 6,03; N, 7,62 Calcd: C, 71.85; H, 6.03; N, 7.62

Funnet: 71,83; 5,90; 7,61 Found: 71.83; 5.90; 7.61

Eksempel 69 Example 69

4 1 - [ [ 2-n-butyl-6- (pyrrolidinokarbonylami.no) -benzimidazol-l-yl ] - metyl1- bifenyl- 2- karboksvlsvre- tert- butylester 4 1 - [ [ 2-n-butyl-6-(pyrrolidinocarbonylami.no)-benzimidazol-1-yl]- methyl 1- biphenyl- 2- carboxyl- tert-butyl ester

2,0 g (15 mmol) pyrrolidinkarbonylklorid i 50 ml tørr kloroform ble dråpevis tilsatt 2,3 g (6 mmol) 4'-[(6-amino-2-n-butyl-benzimidazol-l-yl)-metyl]-bifenyl-2-karboksylsyre-tert-butylester oppløst i 50 ml tørr pyridin, i løpet av 1 time. Reaksjonsoppløsningen ble omrørt i 24 timer og deretter inndampet. Det oljeaktige residuet ble fordelt mellom etylacetat og 10% natriumhydrogenkarbonatoppløsning, den organiske fase fraskilt og inndampet på rotasjonsfordamper etter tørking med magnesiumsulfat. Rensingen ble foretatt over en kiselgelsøyle (kornstørrelse: 0,063 -0,2 mm) under eluering med petroleter/etylacetat = 3:7. De respektive søylefraksjoner ble inndampet på rotasjonsfordamper og tørket i vakuum ved 50°C. 2.0 g (15 mmol) of pyrrolidine carbonyl chloride in 50 ml of dry chloroform was added dropwise to 2.3 g (6 mmol) of 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]- biphenyl-2-carboxylic acid tert-butyl ester dissolved in 50 ml of dry pyridine, during 1 hour. The reaction solution was stirred for 24 hours and then evaporated. The oily residue was partitioned between ethyl acetate and 10% sodium bicarbonate solution, the organic phase separated and evaporated on a rotary evaporator after drying with magnesium sulfate. The purification was carried out over a silica gel column (grain size: 0.063-0.2 mm) eluting with petroleum ether/ethyl acetate = 3:7. The respective column fractions were evaporated on a rotary evaporator and dried in vacuum at 50°C.

Utbytte: 1,7 g (61,8% av det teoretiske) Yield: 1.7 g (61.8% of the theoretical)

Smeltepunkt: 68-70°C (amorft) Melting point: 68-70°C (amorphous)

C34<H>40N4°3 (552,72) C34<H>40N4°3 (552.72)

Rf-verdi: 0,35 (kiselgel; elueringsmiddel: etylacetat/ Rf value: 0.35 (silica gel; eluent: ethyl acetate/

etanol =19:1) ethanol =19:1)

Eksempel 7 0 Example 7 0

41 -[[2-n-butyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]-metyl] bifenvl- 2- karboksylsyre- trifluoracetat- monohvdrat 41 -[[2-n-butyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl] biphenyl- 2- carboxylic acid- trifluoroacetate- monohydrate

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre/metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid/methylene chloride.

Utbytte: 91,7% av det teoretiske Yield: 91.7% of the theoretical

Smeltepunkt: 2 3 3-2 34°C Melting point: 2 3 3-2 34°C

C30<H>32<N>4°3 x CF3COOH x H20 (628,25) C30<H>32<N>4°3 x CF3COOH x H2O (628.25)

Beregnet: C, 61,14; H, 5,61; N, 8,91 Calculated: C, 61.14; H, 5.61; N, 8.91

Funnet: 61,25; 5,62; 9,09 Found: 61.25; 5.62; 9.09

Rf-verdi: 0,48 (kiselgel; elueringsmiddel: etylacetat/etanol/ ammoniakk =50:45:5) Rf value: 0.48 (silica gel; eluent: ethyl acetate/ethanol/ammonia =50:45:5)

Eksempel 71 Example 71

41 -[[2-n-butyl-6-(2,3-dimetylmaleinsyreimino)-benzimidazol-1- yl1 metyl1bifenvl- 2- karboksylsyre 41 -[[2-n-butyl-6-(2,3-dimethylmaleic imino)-benzimidazol-1-yl1 methyl1biphenyl-2-carboxylic acid

314 mg (0,5 mmol) 41 -[(6-amino-2-n-butyl-benzimidazol-l-yl)metyl]bifenyl-2-karboksylsyre-trifluoracetat ble kokt under tilbakeløpskjøling sammen med 7 6 mg (0,6 mmol) 2,3-dimetylmalein-syreanhydrid i 10 ml pyridin i 18 timer. Deretter ble oppløsnings-midlet fordampet på rotasjonsfordamper og den oljeaktige substans fordelt mellom etylacetat og 10% natriumhydrogenkarbonat-oppløsning. Den organiske fase ble fraskilt, tørket med magnesiumsulfat og etter frafiltrering av dette, inndampet på rotasjonsfordamper. Ved utgnidning med aceton og eter ble det oppnådd et hvitt krystallinsk produkt som etter avsugning ble tørket i vakuum ved 50°C. 314 mg (0.5 mmol) of 41 -[(6-amino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid trifluoroacetate was refluxed together with 7 6 mg (0.6 mmol) of 2,3-dimethylmaleic anhydride in 10 ml of pyridine for 18 hours. The solvent was then evaporated on a rotary evaporator and the oily substance distributed between ethyl acetate and 10% sodium bicarbonate solution. The organic phase was separated, dried with magnesium sulphate and, after filtering it off, evaporated on a rotary evaporator. By rubbing with acetone and ether, a white crystalline product was obtained which, after suction, was dried in vacuum at 50°C.

Utbytte: 165 mg (65,0% av det teoretiske) Yield: 165 mg (65.0% of the theoretical)

Smeltepunkt: 288-290°C Melting point: 288-290°C

<C>31<H>29N304 (507,59) <C>31<H>29N304 (507.59)

Beregnet: C, 73,35; H, 5,76; N, 8,29 Calculated: C, 73.35; H, 5.76; N, 8.29

Funnet: 73,14; 5,94; 8,32 Found: 73.14; 5.94; 8.32

Eksempel 72 Example 72

41 -[(2-n-butyl-6-heksahydrohomoftalimino-benzimidazol-l-yl)-metyl] bifenyl- 2- karboksylsyre 41 -[(2-n-butyl-6-hexahydrohomophthalimino-benzimidazol-1-yl)-methyl] biphenyl- 2- carboxylic acid

Fremstillet analogt med Eksempel 71 fra 4'-[(6-amino-2-n-butyl-benzimidazol-l-yl)-metyl]bifenyl-2-karboksylsyre og heksahydrohomoftalsyre-anhydrid i pyridin. Prepared analogously to Example 71 from 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and hexahydrohomophthalic anhydride in pyridine.

Utbytte: 15,3% av det teoretiske Yield: 15.3% of the theoretical

Smeltepunkt: 183-185°C Melting point: 183-185°C

<C>34<H>35N304 (54 9,67) <C>34<H>35N304 (54 9.67)

Beregnet: C, 74,29; H, 6,49; N, 7,64 Calculated: C, 74.29; H, 6.49; N, 7.64

Funnet: 74,09; 6,47; 7,80 Found: 74.09; 6.47; 7.80

Eksempel 73 Example 73

4'-[[2-n-butyl-6-(benzofuran-2-karbonylamino)-benzimidazol-1- vllmetvl1- bifenyl- 2- karboksylsyre 4'-[[2-n-butyl-6-(benzofuran-2-carbonylamino)-benzimidazole-1- β-methylmethyl-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 71 fra 41 -[(6-amino-2-n-butyi-benzimidazol-l-yl)metyl]-bifenyl-2-karboksylsyre og benzofuran-2-karboksylsyre-anhydrid i pyridin. Prepared analogously to Example 71 from 41 -[(6-amino-2-n-butyl-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylic acid and benzofuran-2-carboxylic acid anhydride in pyridine.

Utbytte: 8 0,7% av det teoretiske Yield: 8 0.7% of the theoretical

Smeltepunkt: 321-323°C Melting point: 321-323°C

<C>34<H>39N30A (543, 62) <C>34<H>39N30A (543, 62)

Beregnet: C, 75,12; H, 5,38; N, 7,73 Calculated: C, 75.12; H, 5.38; N, 7.73

Funnet: 74,92; 5,45; 7,87 Found: 74.92; 5.45; 7.87

Eksempel 74 Example 74

4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1- yl)- benzimidazol- 1- vllmetyl] bifeny1- 2- karboksylsyre- hydrat 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-ylmethyl] biphenyl-2- carboxylic acid hydrate

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1- yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 42,2% av det teoretiske Yield: 42.2% of the theoretical

Smeltepunkt: 119-122°C Melting point: 119-122°C

C36<H>36N4°3 X H20 (590,72) C36<H>36N4°3 X H2O (590.72)

Beregnet: C, 73,20; . H, 6,48; N, 9,48 Calculated: C, 73.20; . H, 6.48; N, 9.48

Funnet: 73,11;. 6,50; 9,67 Found: 73.11;. 6.50; 9.67

Eksempel 75 Example 75

4'-[[2-n-butyl-6-(2-karboksy-cykloheksylmetylkarbonylamino)-benzimidazol- l- ylImetyl1bifeny1- 2- karboksylsyre- hydrat 4'-[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid hydrate

a) 4'-[[2-n-butyl-6-(2-karboksy-cykloheksylmetylkarbonylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert-butylester a) 4'-[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester

1,3 g (2,86 mmol) 4'-[(6-amino-2-n-butyl-benzimidazol-l-yl)-metyl]bifenyl-2-karboksylsyre-tert-butylester, 0,6 g (5,35 mmol) heksahydrohomoftalsyre-anhydrid og 5 ml pyridin ble kokt under tilbakeløpskjøling under omrøring i 3 timer. Deretter ble pyridinet inndampet i vakuum på rotasjonsfordamper, residuet utkrystallisert fra aceton, vasket med aceton og tørket i vakuum ved 7 0°C. 1.3 g (2.86 mmol) 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid tert-butyl ester, 0.6 g (5 .35 mmol) of hexahydrohomophthalic anhydride and 5 ml of pyridine were refluxed with stirring for 3 hours. The pyridine was then evaporated in vacuum on a rotary evaporator, the residue crystallized from acetone, washed with acetone and dried in vacuum at 70°C.

Utbytte: 0,67 g (37,6% av det teoretiske) Yield: 0.67 g (37.6% of the theoretical)

Smeltepunkt: 227-229°C Melting point: 227-229°C

C38H4<5N>3°5 (62 3 , 79) C38H4<5N>3°5 (62 3 , 79)

Beregnet: C, 73,17; H, 7,27; N, 6,74 Calculated: C, 73.17; H, 7.27; N, 6.74

Funnet: 72,93; 7,15; 6,94 Found: 72.93; 7.15; 6.94

b) 4<1> -[[2-n-butyl-6-(2-karboksy-cykloheksylmetylkarbonylamino)-benzimidazol- l- y11metyl1bifenvl- 2- karboksylsyre b) 4<1>-[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazole-1-y11methyl1biphenyl-2-carboxylic acid

0,6 g (0,06 mmol) 41 -[[2-n-butyl-6-(2-karboksy-cykloheksylmetylkarbonylamino)-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester, 30 ml metylenklorid og 10 ml trifluoreddiksyre ble omrørt ved romtemperatur i 3 timer. Blandingen ble fortynnet med 2 0 ml metylenklorid og utristet med vann, hvoretter den organiske fase ble tørket over natriumsulfat og inndampet til tørrhet. Residuet ble oppløst i etanol og gjort alkalisk ved tilsetning av ammoniakk. Oppløsningsmidlet ble avdestillert i vakuum. Den gjenværende vandige oppløsning ble surgjort med etylacetat, det utkrystalliserte produkt suget av, vasket med vann og tørket i vakuum ved 7 0°C. 0.6 g (0.06 mmol) 41 -[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester, 30 ml methylene chloride and 10 ml of trifluoroacetic acid were stirred at room temperature for 3 hours. The mixture was diluted with 20 ml of methylene chloride and shaken out with water, after which the organic phase was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in ethanol and made alkaline by the addition of ammonia. The solvent was distilled off in vacuo. The remaining aqueous solution was acidified with ethyl acetate, the crystallized product was sucked off, washed with water and dried in vacuo at 70°C.

Utbytte: 0,55 g (98,2% av det teoretiske) Yield: 0.55 g (98.2% of theoretical)

Smeltepunkt: 160-162°C Melting point: 160-162°C

C3A<H>37<N>305 x H20 (58 5,68) C3A<H>37<N>305 x H20 (58 5.68)

Beregnet: C, 69,72; H,.6,71; N, 7,17 Calcd: C, 69.72; H,.6.71; N, 7.17

Funnet: 69,63; 6,64; 7,33 Found: 69.63; 6.64; 7.33

Eksempel 7 6 Example 7 6

41 -[[2-n-butyl-6-(2-karboksy-3,4,5,6-tetrahydrobenzamino)-benzimidazol- 1- vl1mety11bifeny1- 2- karboksylsyre 41 -[[2-n-butyl-6-(2-carboxy-3,4,5,6-tetrahydrobenzamino)-benzimidazol-1- ylmethylbiphenyl-2-carboxylic acid

0,4 g (1 mmol) 41 -[(6-amino-2-n-butyl-benzimidazol-l-yl)-metyl]bifenyl-2-karboksylsyre oppløst i 7 ml pyridin, ble tilsatt 0,34 g (1,1 mmol) 1-cykloheksen-l,2-dikarboksylsyre-anhydrid og omrørt i 2 1/2 time ved romtemperatur. Blandingen ble deretter avkjølt med is og det utkrystalliserte produkt suget av, vasket med avkjølt aceton og tørket i vakuum ved 7 0°C 0.4 g (1 mmol) of 41 -[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid dissolved in 7 ml of pyridine, was added 0.34 g (1 .1 mmol) 1-cyclohexene-1,2-dicarboxylic anhydride and stirred for 2 1/2 hours at room temperature. The mixture was then cooled with ice and the crystallized product was suctioned off, washed with cooled acetone and dried in vacuum at 70°C

Utbytte: 0,37 g (67,2% av det teoretiske) Yield: 0.37 g (67.2% of theoretical)

Smeltepunkt: 250-252°C Melting point: 250-252°C

C33H33N305 (551,64) C33H33N305 (551.64)

Beregnet: C, 71,85; H, 6,03; N, 7,62 Calcd: C, 71.85; H, 6.03; N, 7.62

Funnet:- 71,70; 5,99; 7,60 Found:- 71.70; 5.99; 7.60

Eksempel 77 Example 77

41 -[[2-n-propyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-1-ylImetyl1bifeny1- 2- karboksylsyre 41 -[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl1-biphenyl-2-carboxylic acid

604 mg (1,0 mmol) 4'-[[2-nitro-5-(l-metylbenzimidazol-2-yl)-N-n-butyryl-anilino]metyl]bifeny1-2-karboksylsyre-tert-butylester ble omrørt i 50 ml metylenklorid under tilsetning av 10 ml trifluoreddiksyre i 3 timer ved romtemperatur. Oppløsningsmidlet ble deretter avdestillert, residuet oppløst i 25 ml iseddik og hydrert ved 80°C under tilsetning av 500 mg palladium/kull (10%). For opparbeidning ble oppløsningsmidlet avdestillert i vakuum, residuet oppløst i 30 ml 2N natronlut og oppløsningen vasket med 20 ml dietyleter. Råproduktet, som ved surgjøring utfeltes fra den vandige fase, ble renset ved påfølgende søylekromatografi (80 g kiselgel, elueringsmiddel: metylenklorid/metanol = 15:1) Utbytte: 90 mg (18% av det teoretiske) 604 mg (1.0 mmol) of 4'-[[2-nitro-5-(1-methylbenzimidazol-2-yl)-N-n-butyryl-anilino]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester was stirred for 50 ml of methylene chloride while adding 10 ml of trifluoroacetic acid for 3 hours at room temperature. The solvent was then distilled off, the residue dissolved in 25 ml of glacial acetic acid and hydrated at 80°C with the addition of 500 mg of palladium/charcoal (10%). For work-up, the solvent was distilled off in vacuo, the residue dissolved in 30 ml of 2N caustic soda and the solution washed with 20 ml of diethyl ether. The crude product, which is precipitated from the aqueous phase upon acidification, was purified by subsequent column chromatography (80 g silica gel, eluent: methylene chloride/methanol = 15:1) Yield: 90 mg (18% of the theoretical)

Smeltepunkt: 214-216°C Melting point: 214-216°C

C32H28N4°2 (500,60) C32H28N4°2 (500.60)

Beregnet: C, 76,78; H, 5,64; N, 11,19 Calculated: C, 76.78; H, 5.64; N, 11,19

Funnet: 76,58; 5,49; 11,30 Found: 76.58; 5.49; 11.30

Eksempel 7 8 Example 7 8

4'-[[2-n-propyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-1-y11metyl] bifeny1- 2- karboksylsyre 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid

En suspensjon av 940 mg (2,0 mmol) 4'-[(2-n-propyl-6-karboksy-benzimidazol-l-yl)metyl]bifenyl-2-karboksylsyre-tert-butylester og 320 mg (2,0 mmol) karbonyldiimidazol i en oppløsning av 1,0 ml trietylamin i 30 ml tetrahydrofuran ble omrørt ved romtemperatur i 30 minutter og deretter tilsatt 250 mg (2,0 mmol) 2-metylamino-anilin og omrørt videre i 16 timer." Deretter ble blandingen inndampet til tørrhet og residuet i 20 ml fosforoksyklorid kokt under tilbakeløpskjøling i 1 time under omrøring. Den største delen av fosforoksykloridet ble deretter avdestillert, det mørke klebrige residuet tilsatt 30 ml vann og den således oppnådde sterkt sure suspensjon kokt under tilbakeløpskjøling i ca. 1 time og etter avkjøling justert til pH 6 og inndampet. Det oppnådde råprodukt ble deretter renset ved søylekromatografi (120 g kiselgel, elueringsmiddel: metylenklorid/metanol = 15:1) A suspension of 940 mg (2.0 mmol) 4'-[(2-n-propyl-6-carboxy-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid tert-butyl ester and 320 mg (2.0 mmol) of carbonyldiimidazole in a solution of 1.0 ml of triethylamine in 30 ml of tetrahydrofuran was stirred at room temperature for 30 minutes and then 250 mg (2.0 mmol) of 2-methylaminoaniline was added and stirred further for 16 hours." Then the mixture was evaporated to dryness and the residue in 20 ml of phosphorus oxychloride boiled under reflux for 1 hour with stirring. The greater part of the phosphorus oxychloride was then distilled off, the dark sticky residue added to 30 ml of water and the thus obtained strongly acidic suspension boiled under reflux for about 1 hour and after cooling adjusted to pH 6 and evaporated.The obtained crude product was then purified by column chromatography (120 g silica gel, eluent: methylene chloride/methanol = 15:1)

Utbytte: 73 mg (7,3% av det teoretiske) Yield: 73 mg (7.3% of the theoretical)

Smeltepunkt: 213-215°C Melting point: 213-215°C

C32H2<8N>4°2 (500,60) C32H2<8N>4°2 (500.60)

Beregrtet: C, 7 6,78; H, 5,64; N, 11,19 Calculated: C, 7 6.78; H, 5.64; N, 11,19

Funnet: 76,61; 5,64; 10,94 Found: 76.61; 5.64; 10.94

Eksempel 79 Example 79

4 1 -[[2-n-propyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]-metvl1- 2-( lH- tetrazol- 5- vl)- bifenyl 4 1 -[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl

Til en oppløsning av 650 mg (1,0 mmol) 41 -[(2-n-propyl-6-amino-benzimidazol-l-yl)-metyl]-2-(lH-trifenylmetyl-tetrazol-5-yl)-bifenyl i 30 ml tetrahydrofuran ble det i løpet av 10 minutter dråpevis tilsatt 155 mg (1,0 mmol) 5-klor-valeriansyreklorid opp-løst i 5 ml tetrahydrofuran, og blandingen omrørt i ytterligere 1 time ved romtemperatur og deretter inndampet til tørrhet. Residuet ble utrørt i 20 ml etanol, deretter tilsatt en.oppløsning av 2,0 mmol natriumetylat i 2 0.ml etanol og kokt under tilbakeløps-kjøling i 1 time. Etter avkjøling ble 10 ml metanolisk saltsyre dråpevis tilsatt, blandingen omrørt i 1 time til ved romtemperatur og deretter inndampet. Residuet ble tilsatt 10 ml vann og gjort alkalisk med konsentrert ammoniakk, hvorved produktet gikk i opp-løsning. Surgjøring med iseddik førte til utfelling av råproduktet som deretter ble renset ved søylekromatografi (70 g kiselgel, elueringsmiddel: metylenklorid ■+ 5% etanol). To a solution of 650 mg (1.0 mmol) 41 -[(2-n-propyl-6-amino-benzimidazol-1-yl)-methyl]-2-(1H-triphenylmethyl-tetrazol-5-yl)- biphenyl in 30 ml of tetrahydrofuran, 155 mg (1.0 mmol) of 5-chlorovaleric acid chloride dissolved in 5 ml of tetrahydrofuran was added dropwise over the course of 10 minutes, and the mixture was stirred for a further 1 hour at room temperature and then evaporated to dryness. The residue was stirred in 20 ml of ethanol, then a solution of 2.0 mmol of sodium ethylate in 20 ml of ethanol was added and boiled under reflux for 1 hour. After cooling, 10 ml of methanolic hydrochloric acid was added dropwise, the mixture was stirred for a further 1 hour at room temperature and then evaporated. The residue was added to 10 ml of water and made alkaline with concentrated ammonia, whereby the product dissolved. Acidification with glacial acetic acid led to precipitation of the crude product which was then purified by column chromatography (70 g silica gel, eluent: methylene chloride + 5% ethanol).

Utbytte: 54 mg (11% av det teoretiske) Yield: 54 mg (11% of the theoretical)

Smeltepunkt: sintrer fra 117°C Melting point: sinters from 117°C

C29<H>29N70 (491,60) C29<H>29N70 (491.60)

Beregnet: C, 70,85; H, 5,95; N, 19,95 Calculated: C, 70.85; H, 5.95; N, 19.95

Funnet:' 70,69; 5,94; 19,99 Found:' 70.69; 5.94; 19.99

Analogt ble følgende forbindelser oppnådd: 41 -[[2-n-butyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]-metyl]- 2-( lH- tetrazol- 5- yl)- bifenyl Analogously, the following compounds were obtained: 41 -[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]- 2-(1H-tetrazol-5-yl )- biphenyl

Utbytte: 16% av det teoretiske Yield: 16% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C30H31N7O (505,63) C30H31N7O (505.63)

Beregnet: C, 67,94; H, 6,23; N, 17,3 3 Calcd: C, 67.94; H, 6.23; N, 17.3 3

Funnet: 67,81; 6,29; 17,18 4'-[[2-n-butyl-6-(2-okso-pyrrolidin-l-yl)-benzimidazol-l-yl]-metyl]- 2-( lH- tetrazol- 5- yl)- bifenyl Found: 67.81; 6.29; 17,18 4'-[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-yl]-methyl]- 2-(1H-tetrazol-5-yl)- biphenyl

Utbytte: 9% av det teoretiske Yield: 9% of the theoretical

Smeltepunkt: 150-151°C Melting point: 150-151°C

C29<H>29N7° (491,60) C29<H>29N7° (491.60)

Beregnet: C, 70,85; H, 5,95; N, 19,95 Calculated: C, 70.85; H, 5.95; N, 19.95

Funnet: 70,61; 6,08; 19,80 Found: 70.61; 6.08; 19.80

Eksempel 80 Example 80

4'-[[2-n-butyl-6-(propansultam-l-yl)-benzimidazol-l-yl]-metyl]-2- ClH- tetrazol- 5- vl)- bifenyl 4'-[[2-n-butyl-6-(propanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-ClH-tetrazol-5-vl)-biphenyl

Til en oppløsning av 665 mg (1,0 mmol) 4'-[(2-n-butyl-6-amino-benzimidazol-l-yl)-metyl]-2-(1-trifenylmetyl-tetrazol-5-yl) - bifenyl og 1 ml trietylamin i 30 ml tetrahydrofuran ble det i løpet av 10 minutter dråpevis tilsatt en oppløsning av 265 mg (1,5 mmol) 3-klor-propansulfonsyreklorid i 5 ml tetrahydrofuran under omrøring i 1,5 timer ved romtemperatur. Blandingen ble deretter inndampet til tørrhet, residuet tatt opp i 20 ml etanol, tilsatt en oppløsning av 3,0 mmol natriumetylat i 20 ml etanol og kokt i 2 timer under tilbakeløpskjøling. Etter avkjøling ble 10 ml metanolisk saltsyre dråpevis tilsatt og omrøringen fortsatt i 2 timer til ved romtemperatur, hvorpå blandingen ble inndampet. Residuet ble tilsatt 10 ml vann og bragt i oppløsning konsentrert ammoniakk. Ved surgjøring med iseddik ble råproduktet utfelt og deretter renset ved søylekromatografi (70 g kiselgel, elueringsmiddel: metylenklorid + 5% etanol). To a solution of 665 mg (1.0 mmol) 4'-[(2-n-butyl-6-amino-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl) - biphenyl and 1 ml of triethylamine in 30 ml of tetrahydrofuran, a solution of 265 mg (1.5 mmol) of 3-chloropropanesulfonic acid chloride in 5 ml of tetrahydrofuran was added dropwise over the course of 10 minutes with stirring for 1.5 hours at room temperature. The mixture was then evaporated to dryness, the residue taken up in 20 ml of ethanol, a solution of 3.0 mmol of sodium ethylate in 20 ml of ethanol was added and boiled for 2 hours under reflux. After cooling, 10 ml of methanolic hydrochloric acid was added dropwise and stirring was continued for a further 2 hours at room temperature, after which the mixture was evaporated. The residue was added to 10 ml of water and dissolved in concentrated ammonia. By acidifying with glacial acetic acid, the crude product was precipitated and then purified by column chromatography (70 g silica gel, eluent: methylene chloride + 5% ethanol).

Utbytte: 68,5 mg (13% av det teoretiske) Yield: 68.5 mg (13% of the theoretical)

Smeltepunkt: 202-205°C Melting point: 202-205°C

C28H29<N>7<0>2S (527,70) C28H29<N>7<0>2S (527.70)

Beregnet: C, 63,73; H, 5,54; N, 18,58 Calculated: C, 63.73; H, 5.54; N, 18.58

Funnet: 63,70; 5,61; 18,35 Found: 63.70; 5.61; 18.35

Analogt ble følgende forbindelser oppnådd: 4'-[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-l-yl]-metvl1- 2-( lH- tetrazol- 5- vl)- bifenvl Analogously, the following compounds were obtained: 4'-[[2-n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl

Utbytte: 10% av det teoretiske Yield: 10% of the theoretical

Smeltepunkt: 185-187°C Melting point: 185-187°C

C29<H>31<N>702S (541,70) C29<H>31<N>702S (541.70)

Beregnet: C, 64,30; H, 5,95; N, 18,10 Calculated: C, 64.30; H, 5.95; N, 18,10

Funnet: 64,19; 5,91; 17,92 Found: 64.19; 5.91; 17.92

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

Utbytte: 17% av det teoretiske Yield: 17% of the theoretical

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

C28<H>29N702S (527,63) C28<H>29N702S (527.63)

Beregnet: C, 63,73; H, 5,54; N, 18,58 Calculated: C, 63.73; H, 5.54; N, 18.58

Funnet: 63,63; 5,54; 18,39 Found: 63.63; 5.54; 18.39

Eksempel 81 Example 81

41 -[[2-n-butyl-6-(1-benzyl-imidazolidin-2,4-dion-3-yl)-benzimidazol- l- yl "[ metyl 1 bif enyl- 2- karboksylsyre- trif luoracetat 41 -[[2-n-butyl-6-(1-benzyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1- yl "[ methyl 1 biphenyl- 2- carboxylic acid trifluoroacetate

Fremstillet analogt med Eksempel 1 fra 4 ' - [.[ 2-n-butyl-6-(1-benzyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[.[2-n-butyl-6-(1-benzyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]-biphenyl-2 -carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 58% av det teoretiske Yield: 58% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C35<H>32NA04 x CF3COOH (68 6,71) C35<H>32NA04 x CF3COOH (68 6.71)

Beregnet: C, 64,72; H, 4,84; N, 8,16 Calculated: C, 64.72; H, 4.84; N, 8.16

Funnet: 64,48; 4,68; 8,09 Found: 64.48; 4.68; 8.09

Eksempel 82 Example 82

4'-[[2-n-propyl-6-(5,5-pentametylen-imidazolidin-2,4-dion-3-yl)- benzimidazol- l- yl1- metyl1bifeny1- 2- karboksylsyre 4'-[[2-n-propyl-6-(5,5-pentamethylene-imidazolidin-2,4-dion-3-yl)- benzimidazol-1-yl1-methyl1-biphenyl1-2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4 1 -[ [2-n-propyl-6-(5,5-pentametylen-imidazolidin-2,4-dion-3-yl)-benzimidazol-l-yl ]metyl]bifenyl-2-karboksylsyre-tert-butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4 1 -[ [2-n-propyl-6-(5,5-pentamethylene-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2 -carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 27% av det teoretiske Yield: 27% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C33H34N4°4 (550,63) C33H34N4°4 (550.63)

Beregnet: C, 71,98; H, 6,22; N, 10,18 Calculated: C, 71.98; H, 6.22; N, 10,18

Funnet: 71,93; 6,16; 10,09 Found: 71.93; 6.16; 10.09

Rf-verdi: 0,60 (kiselgel; elueringsmiddel: metylenklorid/- etanol = 9:1) Rf value: 0.60 (silica gel; eluent: methylene chloride/ethanol = 9:1)

Eksempel 83 Example 83

4'-[[2-etyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]-metvll- 2- flH- tetrazol- 5- vl)- bifenvl 4'-[[2-ethyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl-2-flH-tetrazol-5-vl)- biphenyl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-etyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-ethyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 33% av det teoretiske Yield: 33% of the theoretical

Smeltepunkt: sintrer fra 150°C Melting point: sinters from 150°C

C28<H>27N70 (477,58) C28<H>27N70 (477.58)

Beregnet: C, 70,42; H, 5,70; N, 20,53 Calculated: C, 70.42; H, 5.70; N, 20.53

Funnet: 70,48; 5,72; 19,88 Found: 70.48; 5.72; 19.88

Eksempel 84 Example 84

4'-[[2-etyl-6-(butansultam-l-yl)-benzimidazol-l-yl]-metvll- 2-( lH- tetrazol- 5- vl)- bifenvl 4'-[[2-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl

Fremstillet analogt med Eksempel 41 fra 4<1->[[2-etyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyrenitril og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4<1->[[2-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.

Utbytte: 3 6% av det teoretiske Yield: 3 6% of the theoretical

Smeltepunkt: fra 240°C (dekomp.) Melting point: from 240°C (decomp.)

C27<H>2<7N>702S (513,64) C27<H>2<7N>702S (513.64)

Beregnet: C, 63,14; H, 5,30; N, 19,09 Calculated: C, 63.14; H, 5.30; N, 19.09

Funnet: 63,06; 5,19; 19,08 Found: 63.06; 5.19; 19.08

Eksempel 8 5 Example 8 5

4'-[[2-n-propyl-6-(3-n-heksyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol- l- yl1- metyl1- bifeny1- 2- karboksylsyre 4'-[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl1-methyl1-biphenyl1-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-propyl-6-(3-n-heksyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl]methyl]-biphenyl -2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 57% av det teoretiske Yield: 57% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

<C>36<H>37N502 (571,74) <C>36<H>37N502 (571.74)

Beregnet: C, 75,63; H, 6,52; N, 12,2 5 Calculated: C, 75.63; H, 6.52; N, 12.2 5

Funnet: 7 5,58; 6,48; 12,08 Found: 7 5.58; 6.48; 12.08

Eksempel 8 6 Example 8 6

41 -[[2-n-propyl-6-(3-metyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol- l- yll- metyl1bifenyl- 2- karboksylsvre 41 -[[2-n-propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-propyl-6-(3-metyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl]methyl]-biphenyl- 2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 4 0% av det teoretiske Yield: 40% of the theoretical

Smeltepunkt: 2 08-210°C Melting point: 2 08-210°C

C31H2<7N>5<0>2 (501,60) C31H2<7N>5<0>2 (501.60)

Beregnet: C, 74,23; H, 5,43; N, 13,96 Calculated: C, 74.23; H, 5.43; N, 13.96

Funnet: 74,19; 5,32; 13,94 Found: 74.19; 5.32; 13.94

Eksempel 87 Example 87

41 -[[2-n-propyl-6-(1-metyl-imidazolin-2-yl)-benzimidazol-l-yl]-metyl 1 - bif enyl- 2- karboksylsvre 41 -[[2-n-propyl-6-(1-methyl-imidazolin-2-yl)-benzimidazol-1-yl]-methyl 1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-propyl-6-(1-metyl-imidazolin-2-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-propyl-6-(1-methyl-imidazolin-2-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

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

Smeltepunkt: amorft Melting point: amorphous

<C>28<H>28N402 (4 52,57) <C>28<H>28N402 (4 52.57)

Beregnet: C, 74,31; H, 6,24; N, 12,38 Calculated: C, 74.31; H, 6.24; N, 12.38

Funnet: 74,31; 6,11; 12,27 Found: 74.31; 6.11; 12.27

Eksempel 88 Example 88

4'-[[2-h-propyl-6-(1,5-dimetyl-benzimidazol-2-yl)-benzimidazol-1- vllmetyl1bifenvl- 2- karboksylsyre 4'-[[2-h-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)-benzimidazol-1-β-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-propyl-6-(1,5-dimetyl-benzimidazol-2-yl)-benzimidazol-l-yl]metyl]bifenyl-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 48% av det teoretiske Yield: 48% of the theoretical

Smeltepunkt: 256-258°C Melting point: 256-258°C

C33H3<0N>4°2 (514,63) C33H3<0N>4°2 (514.63)

Beregnet: C, 77,02; H, 5,88; N, 10,89 Calculated: C, 77.02; H, 5.88; N, 10.89

Funnet: 76,91; 5,83; 10,72 Found: 76.91; 5.83; 10.72

Eksempel 89 Example 89

4 '-[ [2-n-propyl-6-(l-metyl-5-tr.ifluormetyl-benzimidazol-2-yl) - benzimidazol- l- vlImetyl1 bifeny1- 2- karboksylsyre 4'-[[2-n-propyl-6-(1-methyl-5-trifluoromethyl-benzimidazol-2-yl)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-propyl-6-(l-metyl-5-trifluormetyl-benzimidazol-2-yl) -benzimidazol-1-yl]metyl.]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-propyl-6-(1-methyl-5-trifluoromethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl.]biphenyl-2-carboxylic acid-tert .butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 56% av det teoretiske Yield: 56% of the theoretical

Smeltepunkt: 183-186°C Melting point: 183-186°C

C33H27<F3N>A02 (568,61) C33H27<F3N>A02 (568.61)

Beregnet: C, 69,71; H, 4,79; N, 9,85 Calcd: C, 69.71; H, 4.79; N, 9.85

Funnet: 69,58; 4,72; 9,80 Found: 69.58; 4.72; 9.80

Eksempel 90 Example 90

4'-[[2-n-propyl-6-(5-metyl-imidazolidin-2 , 4-dion-3-yl)-benzimidazol- l- ylImetyl1bifenyl- 2- karboksylsyre 4'-[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-propyl-6-(5-metyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid- tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 29% av det teoretiske Yield: 29% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C28H26N404 (4 82,55) C28H26N404 (4 82.55)

Beregnet: C, 69,69; H, 5,43; N, 11,61 Calcd: C, 69.69; H, 5.43; N, 11.61

Funnet: 69,67; 5,40; 11,55 Found: 69.67; 5.40; 11.55

Eksempel 91 Example 91

41 -[[2-h-propyl-6-(1-metyl-imidazolidin-2,4-dion-3-yl)-benz imidazol- 1- yl 1 metyl 1 bif eny 1- 2- karboksylsyre "" 41 -[[2-h-propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl)-benz imidazol-1- yl 1 methyl 1 bipheny 1- 2- carboxylic acid ""

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-propyl-6-(1-metyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-l-yl]metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid -tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 32% av det teoretiske Yield: 32% of the theoretical

Smeltepunkt: amorft Melting point: amorphous

C28H26N4°4 (482,55) C28H26N4°4 (482.55)

Beregnet: C, 69,69; H, 5,43; N, 11,61 Calcd: C, 69.69; H, 5.43; N, 11.61

Funnet: 69,61; 5,38; 11,49 Found: 69.61; 5.38; 11.49

Eksempel 92 Example 92

4 ' - [(2-n-propyl-6-(l-butyl-benzimidazol-2-yl)-benzimidazol-1-yl) metyl1bifenvl- 2- karboksylsyre 4'-[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-1-yl)methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 59% av det teoretiske Yield: 59% of the theoretical

Smeltepunkt: sintrer fra 14 9°C Melting point: sinters from 14 9°C

<C>35<H>34N402 (542,69) <C>35<H>34N402 (542.69)

Beregnet: C, 77,46; H, 6,32; N, 10,32 Calculated: C, 77.46; H, 6.32; N, 10.32

Funnet: 77,37; 6,31; 10,35 Found: 77.37; 6.31; 10.35

Eksempel 9 3 Example 9 3

4!-[(2-n-butyl-6-(lH-benzimidazol-2-yl)-benzimidazol-l-yl)-metyl 1 bi f eny 1- 2- karboksylsyre 4!-[(2-n-butyl-6-(1H-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl 1-biphenyl 1-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[(2-n-butyl-6-(lH-benzimidazol-2-yl)-benzimidazol-l-yl)metyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[(2-n-butyl-6-(1H-benzimidazol-2-yl)-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 62% av det teoretiske Yield: 62% of the theoretical

Smeltepunkt: 200-202°C Melting point: 200-202°C

C32H28N402 (500,61) C32H28N402 (500.61)

Beregnet: C, 7 6,78; H, 5,64; N, 11,19 Calculated: C, 7 6.78; H, 5.64; N, 11,19

Funnet: 76,54; 5,60; 11,16 Found: 76.54; 5.60; 11,16

Eksempel 94 Example 94

41 -[(2-ri-butyl-6-heksahydrohomoftalimino-benzimidazol-l-yl) metyllbifenyl- 2- karboksylsyre 41 -[(2-ri-butyl-6-hexahydrohomophthalimino-benzimidazol-1-yl) methylbiphenyl- 2- carboxylic acid

0,4 g (0,64 mmol) 4<1->[(2-n-butyl-6-(2-karboksy-cykloheksylmetylkarbonylamino)-benzimidazol-l-yl)-metyl]bifeny1-2-karboksylsyre-tert-butylester ble under omrøring i 5 ml fosforoksyklorid kokt under tilbakeløpskjøling i 1 1/2 time. Etter avkjøling ble blandingen helt over i isvann og det utfelte råprodukt suget av. Dette ble oppløst i etanol/vann gjort alkalisk med ammoniakk og inndampet under vakuum inntil utkrystallisering. Produktet ble deretter suget av, vasket med vann og tørket i vakuum ved 120°C. Utbytte: 0,15 g (42,8% av det teoretiske) 0.4 g (0.64 mmol) 4<1->[(2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid-tert- butyl ester was boiled with stirring in 5 ml of phosphorus oxychloride under reflux for 1 1/2 hours. After cooling, the mixture was poured into ice water and the precipitated crude product was sucked off. This was dissolved in ethanol/water made alkaline with ammonia and evaporated under vacuum until crystallization. The product was then sucked off, washed with water and dried in vacuum at 120°C. Yield: 0.15 g (42.8% of theoretical)

Smeltepunkt: 241-243°C Melting point: 241-243°C

C34H3<5N>3°4 (549,66) C34H3<5N>3°4 (549.66)

Beregnet: C, 74,29; H, 6,49; N, 7,64 Calculated: C, 74.29; H, 6.49; N, 7.64

Funnet: 74,14; 6,64; 7,81 Found: 74.14; 6.64; 7.81

Eksempel 95 Example 95

41 -[(2-n-butyl-6-(7-nitro-benzofurazan-4-ylamino)-benzimidazol-l- vl ) metyl 1bifenyl- 2- karboksylsyre 41 -[(2-n-butyl-6-(7-nitro-benzofurazan-4-ylamino)-benzimidazol-l-vl) methyl 1-biphenyl-2- carboxylic acid

Fremstillet fra 41 -[(6-amino-2-n-butyl-benzimidazol-l-yl)-metyl]bifenyl-2-karboksylsyre og 4-klor-7-nitro-benzofurazan i pyridin ved romtemperatur. Prepared from 41 -[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and 4-chloro-7-nitro-benzofurazan in pyridine at room temperature.

Utbytte: 13,1% av det teoretiske Yield: 13.1% of the theoretical

Rf-verdi: 0,75 (kiselgel; metylenklorid/etanol = 9:1) Rf value: 0.75 (silica gel; methylene chloride/ethanol = 9:1)

C31H2<6N>6°5 (562,58) C31H2<6N>6°5 (562.58)

Beregnet: C, 66,18; H, 4,66; N, 14,93 Calculated: C, 66.18; H, 4.66; N, 14.93

Funnet: 66,35; 4,76; 15,13 Found: 66.35; 4.76; 15.13

Eksempel 9 6 Example 9 6

41 -[[2-etyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]-metyl1bifenvl- 2- karboksvlsyre- trifluoracetat- semihydrat 41 -[[2-ethyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl-1-biphenyl-2-carboxylic acid-trifluoroacetate- hemihydrate

Fremstillet analogt med Eksempel 1 fra 41 -[[2-etyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluroeddiksyre i metylenklorid . Prepared analogously to Example 1 from 41-[[2-ethyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 8 0,9% av det teoretiske Yield: 8 0.9% of the theoretical

Smeltepunkt: 178-179°C Melting point: 178-179°C

<C>28<H>28<N>4°3 x CF3COOH x 0,5 H20 (591,59) <C>28<H>28<N>4°3 x CF3COOH x 0.5 H2O (591.59)

Beregnet: C, 60,90; H, 5,11; N, 9,47 Calculated: C, 60.90; H, 5.11; N, 9.47

Funnet: 61,10; 5,22; 9,26 Found: 61.10; 5.22; 9.26

Rf-verdi: 0,48 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.48 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 97 Example 97

41 -[[2-metyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]-metyl1bifenyl- 2- karboksylsyre- trifluoracetat 41 -[[2-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl-1-biphenyl- 2- carboxylic acid- trifluoroacetate

Fremstillet analogt med Eksempel 1 fra 4'-[[2-metyl-6-(pyrrolidinokarbonylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 82,1% av det teoretiske Yield: 82.1% of the theoretical

Smeltepunkt: 181-182°C Melting point: 181-182°C

C27<H>26<N>4°3 x CF3COOH (568,55) C27<H>26<N>4°3 x CF3COOH (568.55)

Beregnet: C, 61,26; H, 4,79; N, 9,85 Calculated: C, 61.26; H, 4.79; N, 9.85

Funnet:-. 60,99; 5,09; 9,89 Found:-. 60.99; 5.09; 9.89

Rf-verdi: 0,38 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 98 Example 98

4'-[[2-n-propyl-6-(pyrrolidinokarbonylamino)-benzimidazol-1- v11metyl] bifenyl- 2- karboksylsyre- trifluoracetat 4'-[[2-n-propyl-6-(pyrrolidinocarbonylamino)-benzimidazole-1-β11methyl] biphenyl- 2- carboxylic acid trifluoroacetate

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-propyl-6-(pyrroolidinokarbonylamino)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-propyl-6-(pyrroolidinocarbonylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 79,7% av det teoretiske Yield: 79.7% of the theoretical

Smeltepunkt: 207-208°C. Melting point: 207-208°C.

C29<H>30<N>4°3 x CF3COOH (596,61) C29<H>30<N>4°3 x CF3COOH (596.61)

Beregnet: C, 62,41; H, 5,24; N, 9,39 Calculated: C, 62.41; H, 5.24; N, 9.39

Funnet: 62,38; 5,36; 9,4 2 Found: 62.38; 5.36; 9.4 2

Rf-verdi: 0,55 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.55 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 99 Example 99

4'-[[2-metylmerkapto-6-(pyrrolidinokarbonylamino)-benzimidazol-1- vlImetyl1bifenyl- 2- karboksylsyre- trifluoracetat 4'-[[2-Methylmercapto-6-(pyrrolidinocarbonylamino)-benzimidazole-1-methyl-1-biphenyl-2-carboxylic acid- trifluoroacetate

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

Utbytte: 96,1% av det teoretiske Yield: 96.1% of the theoretical

-Smeltepunkt: 177-178°C -Melting point: 177-178°C

C27<H>26<N>4°3S x CF3COOH (600,61) C27<H>26<N>4°3S x CF3COOH (600.61)

Beregnet: C, 57,99; H, 4,53; N, 9,33 Calculated: C, 57.99; H, 4.53; N, 9.33

Funnet: 57,68; 4,75; 9,3 0 Found: 57.68; 4.75; 9.3 0

Rf-verdi: 0,52 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.52 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 100 Example 100

41 -[[6-(2,3-dimetylmaleinsyreimido)-2-metylmerkapto-benzimidazol-1- yll metyl1bifenvl- 2- karboksylsyre 41 -[[6-(2,3-Dimethylmaleic imido)-2-methylmercapto-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(2,3-dimetyl-maleinsyreimido) -2-metylmerkapto-benz imidazol-l-yl]metyl]bifeny1-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(2,3-dimethyl-maleic imido)-2-methylmercapto-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 91,7% av det teoretiske Yield: 91.7% of the theoretical

Smeltepunkt: 276-277°C Melting point: 276-277°C

C28H23<N>304S (4 97,57) C28H23<N>304S (4 97.57)

Beregnet: C, 67,59; H, 4,66; N, 8,45; S, 6,44 Calculated: C, 67.59; H, 4.66; N, 8.45; S, 6.44

Funnet: 67,57; 4,94; 8,40; 6,37 Found: 67.57; 4.94; 8.40; 6.37

Rf-verdi: 0,47 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.47 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 101 Example 101

4'-[[2-n-butyl-6-[3-(7-nitrobenzofurazan-4-ylamino)-propionyl-amino] benzimidazol- 1- yl] metyl1- 2 flH- tetrazol- 5- vl) bifenvl- hydrat 4'-[[2-n-butyl-6-[3-(7-nitrobenzofurazan-4-ylamino)-propionyl-amino] benzimidazol-1- yl] methyl 1-2flH- tetrazol-5-vl) biphenyl- hydrate

Fremstillet analogt med Eksempel 55. fra 41 -[[2-n-butyl-6-[3-(7-nitrobenzofuranzan-4-ylamino)-propionylamino]benzimidazol-1-yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)bifenyl og 2N saltsyre i etanol Prepared analogously to Example 55. from 41 -[[2-n-butyl-6-[3-(7-nitrobenzofuranzan-4-ylamino)-propionylamino]benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl- tetrazol-5-yl)biphenyl and 2N hydrochloric acid in ethanol

Utbytte: 3 3,3% av det teoretiske Yield: 3 3.3% of the theoretical

Smeltepunkt: 179-181°C Melting point: 179-181°C

C34<H>31<N>1l<0>4 x H20 (675,70) C34<H>31<N>1l<0>4 x H2O (675.70)

Beregnet: C, 60,43; H, 4,92; N, 22,80 Calculated: C, 60.43; H, 4.92; N, 22.80

Funnet:" 60,24; 5,09; 22,69 Found:" 60.24; 5.09; 22.69

Eksempel 102 Example 102

4 ' -[[2-n-butyl-6-[3-(7-nitrobenzofurazan-4-ylamino)-propionyl-amino] benzimidazol-l-yl ] metyl ]-bifeny1-2-karboksylsyre-trifluoracetat- hydrat 4'-[[2-n-butyl-6-[3-(7-nitrobenzofurazan-4-ylamino)-propionyl-amino] benzimidazol-1-yl] methyl ]-biphenyl 1-2-carboxylic acid trifluoroacetate hydrate

Fremstillet analogt med Eksempel 1 fra 4'-[[2-n-butyl-6-[3-(7-nitrobenzofuranzan-4-ylamino)-propionylamino]benzimidazol-l-yl ]metyl ] -bif enyl-2-karboksylsyre-tert . butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[2-n-butyl-6-[3-(7-nitrobenzofuranzan-4-ylamino)-propionylamino]benzimidazol-1-yl]methyl ]-biphenyl-2-carboxylic acid- tart. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 87,5% av det teoretiske Yield: 87.5% of the theoretical

Smeltepunkt: 127°C (dekomp.) Melting point: 127°C (decomp.)

C34<H>31<N>7°6 x CF3COOH x H20 (7 65,69) C34<H>31<N>7°6 x CF3COOH x H2O (7 65.69)

Beregnet: C, 56,47; H, 4,47; N, 12,80 Calculated: C, 56.47; H, 4.47; N, 12.80

Funnet: 56,68; 4,27; 12,67 Found: 56.68; 4.27; 12.67

Eksempel 103 Example 103

4'-[[6-(2,3-dimetylmaleinsyreimido)-2-metyl-benzimidazol-l-yl]-metyl]- bifenyl- 2- karboksylsyre 4'-[[6-(2,3-Dimethylmaleic imido)-2-methyl-benzimidazol-1-yl]-methyl]- biphenyl- 2- carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(2,3-dimetyl-maleinsyreimido) -2-metyl-benzimidazol-l-yljmetyl]bifenyl-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(2,3-dimethyl-maleic imido)-2-methyl-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 9 4,4% av det teoretiske Yield: 9 4.4% of the theoretical

Smeltepunkt: 3 27-3 28°C Melting point: 3 27-3 28°C

<C>28<H>23N3°4 (465,51) <C>28<H>23N3°4 (465.51)

Beregnet: C, 72,25 ; H, 4,98; N, 9,03 Calculated: C, 72.25 ; H, 4.98; N, 9.03

Funnet: 72,00; 5,08; 9,06 Found: 72.00; 5.08; 9.06

Rf-verdi: 0,33 (kiselgel; etylacetat/etanol/ammoniakk =50:45:5) Rf value: 0.33 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5)

Eksempel 104 Example 104

4'-[[6-(2,3-dimetylmaleinsyreimido)-benzimidazol-l-yl]metyl]-bif enyl- 2- karboksyl syre- semihvdrat 4'-[[6-(2,3-Dimethylmaleic imido)-benzimidazol-1-yl]methyl]-biphenyl- 2- carboxylic acid hemihydrate

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(2,3-dimetyl-maleinsyreimido)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(2,3-dimethyl-maleic imido)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 95,5% av det teoretiske Yield: 95.5% of the theoretical

Smeltepunkt: 223-224°C Melting point: 223-224°C

C27<H>21<N>3°4 x 0,5 H20 (460,49) C27<H>21<N>3°4 x 0.5 H2O (460.49)

Beregnet: C, 70,42; H, 4,82; N, 9,13 Calculated: C, 70.42; H, 4.82; N, 9,13

Funnet: 70,30; 4,88; 8,81 Found: 70.30; 4.88; 8.81

Rf-verdi: 0,34 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.34 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 105 Example 105

4'-[[6-(2,3-dimetylmaleinsyreimido)-2-n-propyl-benzimidazol-1- ylImetyl] bifenyl- 2- karboksylsyre- monohydrat 4'-[[6-(2,3-Dimethylmaleic imido)-2-n-propyl-benzimidazol-1-ylmethyl] biphenyl- 2- carboxylic acid monohydrate

Fremstillet analogt med Eksempel 1 fra 4<1->[[6-(2,3-dimetyl-maleinsyreimido) -2-n-propyl-benzimidazol-1-yl]metyl]bifeny1-2-karboksy.l syre-tert. butylester og trif luoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4<1->[[6-(2,3-dimethyl-maleic acid imido)-2-n-propyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid tert. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 92,5% av det teoretiske Yield: 92.5% of the theoretical

Smeltepunkt: 3 09-310°C Melting point: 3 09-310°C

C30<H>27N3O4 x H20 (511,58) C30<H>27N3O4 x H20 (511.58)

Beregnet: C, 70,44; H, 5,71; N, 8,21 Calculated: C, 70.44; H, 5.71; N, 8.21

Funnet: 70,44; 5,64; 8,19 Found: 70.44; 5.64; 8,19

Rf-verdi: 0,47 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.47 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 106 Example 106

4<1->[[6-(2,3-dimetylmaleinsyreimido)-2-etyl-benzimidazol-l-yl]-metyl1bifenvl- 2- karboksylsyre 4<1->[[6-(2,3-Dimethylmaleic imido)-2-ethyl-benzimidazol-1-yl]-methyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 4'-[[6-(2,3-dimetyl-maleinsyreimido)-2-etyl-benzimidazol-l-yl]metyl]bifeny1-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4'-[[6-(2,3-dimethyl-maleic imido)-2-ethyl-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 87,5%.av det teoretisk Yield: 87.5% of that theoretically

Smeltepunkt: 307-308°C Melting point: 307-308°C

C29H25N3°4 (479,53) C29H25N3°4 (479.53)

Beregnet: C, 72,64; H, 5,25; N, 8,76 Calculated: C, 72.64; H, 5.25; N, 8.76

Funnet: 72,41; 5,37; 8,94 Found: 72.41; 5.37; 8.94

Rf-verdi: 0,40 (kiselgel; etylacetat/etanol/ammoniakk = 50:45:5) Rf value: 0.40 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5)

Eksempel 107 Example 107

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

Fremstillet analogt med Eksempel 1 fra 4<1->[[2-etyl-6-(1-metyl-benz imidazol -2 -yl ) -benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre-tert. butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 4<1->[[2-ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-tert. butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 31% av det teoretiske Yield: 31% of the theoretical

Smeltepunkt: 183-185°C Melting point: 183-185°C

C31H26N4°2 (486, 60) C31H26N4°2 (486, 60)

Beregnet: C, 76,52; H, 5,39; N, 11,52 Calculated: C, 76.52; H, 5.39; N, 11.52

Funnet: 76,73; 5,49; 11,70 Found: 76.73; 5.49; 11.70

Eksempel 108 Example 108

4 '-[[2-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-2- flH- tetrazol- 5- vl)- bifenvl 4'-[[2-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-flH-tetrazol-5-vl)-biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-metyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-2-cyano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 27% av det teoretiske Yield: 27% of the theoretical

Smeltepunkt: 173-175°C Melting point: 173-175°C

C26H25N702S (499,60) C26H25N702S (499.60)

Beregnet: C, 62,51; H, 5,04; N, 19,63; S, 6,42 Calculated: C, 62.51; H, 5.04; N, 19.63; S, 6.42

Funnet: 62,39; 5,05; 19,44; 6,33 Massespektrum: m/e = 499 Found: 62.39; 5.05; 19.44; 6.33 Mass spectrum: m/e = 499

Eksempel 109 Example 109

41 -[[2-metyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]-metvll- 2-( lH- tetrazol- 5- yl)- bifenvl 41 -[[2-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)- biphenyl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-metyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]-2-cyano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 26,5% av det teoretiske Yield: 26.5% of the theoretical

Smeltepunkt: 214-217°C Melting point: 214-217°C

C30H24N8 (496,80) C30H24N8 (496.80)

Beregnet: C, 72,56; H, 4,87; N, 22,56 Calculated: C, 72.56; H, 4.87; N, 22.56

Funnet: 72,32; 5,01; 22,23 Found: 72.32; 5.01; 22,23

Eksempel 110 Example 110

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

Fremstillet analogt med Eksempel 41 fra 4<1->[[6-(butansultam-l-yl )-benzimidazol-l-ylJmetyl]-2-cyano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4<1->[[6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 60,0% av det teoretiske Yield: 60.0% of the theoretical

Smeltepunkt: 24 6-24 9°C Melting point: 24 6-24 9°C

C25<H>2<3N>702S (48 5,60) C25<H>2<3N>702S (48 5.60)

Beregnet: C, 61,84; H, 4,77; N, 20,19 Calculated: C, 61.84; H, 4.77; N, 20,19

Funnet: 61,75; 4,92; 20,28 Found: 61.75; 4.92; 20,28

Eksempel 111 Example 111

4'-[[2-etyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-l-yl]-metyl1- 2-( lH- tetrazol- 5- yl)- bifenvl 4'-[[2-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl-1- 2-(1H-tetrazol-5-yl)- biphenyl

Fremstillet analogt med Eksempel 41 fra 4'-[[2-etyl-6-(1-metylbenzimidazol-2-yl)-benzimidazol-l-yl]metyl]-2-cyano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 4'-[[2-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 41,0% av det teoretiske Yield: 41.0% of the theoretical

Smeltepunkt: fra 178°C (sintring) Melting point: from 178°C (sintering)

C31H26N8 (510,60) C31H26N8 (510.60)

Beregnet: C, 72,92; H, 5,13; N, 21,95 Calculated: C, 72.92; H, 5.13; N, 21.95

Funnet: 72,94; 5,25; 21,71 Found: 72.94; 5.25; 21.71

Massespektrum: m/e = 510 Mass spectrum: m/e = 510

Eksempel 112 Example 112

4 1 - [' [ 2-etyl-6- (N-benzensulf onyl-metylamino) -benzimidazol-1- yllmetvl1- 2-( lH- tetrazol- 5- yl)- bifenvl 4 1 - [' [ 2-ethyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-ylmethyl-2-(1H-tetrazol-5-yl)-biphenyl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-etyl-6-(N-bénzensulfonyl-metylamino) -benzimidazol-l-yl ]metyl ] -2-cy.ano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-ethyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 66,0% av det teoretiske Yield: 66.0% of the theoretical

Smeltepunkt: 226-228°C Melting point: 226-228°C

C30<H>27N7O2S (549,70) C30<H>27N7O2S (549.70)

Beregnet: C, 65,55; H, 4,95; N, 17,84; S, 5,83 Calculated: C, 65.55; H, 4.95; N, 17.84; S, 5.83

Funnet: 65,38; 4,95; 17,59; 5,79 Found: 65.38; 4.95; 17.59; 5.79

Eksempel 113 Example 113

4'-[[2-n-propyl-6-(N-benzensulfonyl-metylamino)-benzimidazol-1- vllmetvl]- 2-( lH- tetrazol- 5- vl)- bifenvl 4'-[[2-n-propyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-ylmethyl]- 2-(1H-tetrazole-5-yl)- biphenyl

Fremstillet analogt med Eksempel 41 fra 41 -[[2-n-propyl-6-(N-benzensulfonyl-metylamino)-benzimidazol-l-yl]metyl]-2-cyano-bifenyl og natriumazid i dimetylformamid. Prepared analogously to Example 41 from 41 -[[2-n-propyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Utbytte: 83,4% av det teoretiske Yield: 83.4% of the theoretical

Smeltepunkt: 177-179°C Melting point: 177-179°C

C31<H>29N702S (56 3,70) C31<H>29N702S (56 3.70)

Beregnet: C, 66,05; H, 5,18; N, 17,40; S, 5,69 Calculated: C, 66.05; H, 5.18; N, 17.40; S, 5.69

Funnet: 65,89; 5,14; 17,21; 5,73 Found: 65.89; 5.14; 17.21; 5.73

Eksempel 114 Example 114

4'-[(2-n-butyl-6-benzensulfonyloksy-benzimidazol-1-yl)metyl]-bifenvl- 2- karboksylsyre 4'-[(2-n-butyl-6-benzenesulfonyloxy-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[(2-n-butyl-6-benzensulfonyloksy-benzimidazol-1-yl)-metyl]bifeny1-2-karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[(2-n-butyl-6-benzenesulfonyloxy-benzimidazol-1-yl)-methyl]biphenyl 1-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 8,2% av det teoretiske Yield: 8.2% of the theoretical

Smeltepunkt: 193-195°C Melting point: 193-195°C

C31<H>28N205S (540,60) C31<H>28N205S (540.60)

Beregnet: C, 68,92; H, 5,22; N, 5,18 Calcd: C, 68.92; H, 5.22; N, 5.18

Funnet: 68,94; 5,08; 5,08 Found: 68.94; 5.08; 5.08

Eksempel 115 Example 115

4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l- yl) - benzimidazol- l- yllmetyll- 2-( 1H)- tetrazol- 5- vl)- bifenyl Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-butyl-6-(3-benzyl-3 ,4,5, 6-tetrahydro-2 (l.H) -pyrimidinon-l-yl) -benzimidazol-1-yl]metyl]-2-(l-trifenylmetyl-tetrazol-5-yl)-bifenyl og metanol i metanolisk saltsyre. 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-ylmethyl-2-(1H )-tetrazole-5-vl)-biphenyl Prepared analogously to Example 55 from 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1.H)-pyrimidinone -1-yl)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.

Utbytte: 28,0% av det teoretiske Yield: 28.0% of the theoretical

Smeltepunkt: fra 125°C (sintring) Melting point: from 125°C (sintering)

C36H36N8° (596,80) C36H36N8° (596.80)

Beregnet: C, 7 2,46; H, 6,08; N, 18,7 8 Calculated: C, 7 2.46; H, 6.08; N, 18.7 8

Funnet: 72,26; 5,94; 18,85 Found: 72.26; 5.94; 18.85

Eksempel 116 Example 116

4'-[[2-h-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1- vl)- benzimidazol- 1- yllmetyl1- 2 f1H)- tetrazol- 5- yl)- bifenyl 4'-[[2-h-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-vl)-benzimidazol-1-ylmethyl1-2f1H)- tetrazol-5-yl)-biphenyl

Fremstillet analogt med Eksempel 55 fra 41 -[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-benzimidazol-1-yl]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og metanol i metanolisk saltsyre. Prepared analogously to Example 55 from 41 -[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl ]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.

Utbytte: 31,0% av det teoretiske Yield: 31.0% of the theoretical

Smeltepunkt: fra 125°C (dekomp.) Melting point: from 125°C (decomp.)

C36H36N8° (596,80) C36H36N8° (596.80)

Beregnet: C, 72,46; H, 6,08; N, 18,78 Calculated: C, 72.46; H, 6.08; N, 18.78

Funnet: 72,27; 6,03; 18,61 Found: 72.27; 6.03; 18.61

Eksempel 117 Example 117

4<1->[[2-n-propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1- yl)- benzimidazol- l- yllmetyll- 2( 1H)- tetrazol- 5- yl)- bifenvl 4<1->[[2-n-propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-ylmethyl-2( 1H)-tetrazol-5-yl)-biphenyl

Fremstillet analogt med Eksempel 55 fra 4'-[[2-n-propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-benzimidazol-1-yl]metyl]-2-(l-trifenylmetyl-tetrazol-5-yl)-bifenyl og metanol i metanolisk saltsyre. Prepared analogously to Example 55 from 4'-[[2-n-propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1- yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.

Utbytte: 3 5,0% av det teoretiske Yield: 3 5.0% of the theoretical

Smeltepunkt: fra 132°C (dekomp.) Melting point: from 132°C (decomp.)

C35<H>34N80 (582,71) C35<H>34N80 (582.71)

Beregnet: C, 72,14; H, 5,88; N, 19,23 Calculated: C, 72.14; H, 5.88; N, 19,23

Funnet: 71,98; 6,02; 19,11 Found: 71.98; 6.02; 19.11

Eksempel 118 Example 118

4'-[[2-etyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl) - benzimidazol- l- yl1 metyl1- 2( 1H)- tetrazol- 5- yl)- bifenyl 4'-[[2-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl1-methyl1-2(1H)- tetrazol-5-yl)-biphenyl

Fremstillet analogt med Eksempel 55 fra 4'-[[2-etyl-6-(3-benzyl-3,4,5,6-tetrahydr6-2(1H)-pyrimidinon-l-yl)-benzimidazol-l-yl ]metyl]-2-(1-trifenylmetyl-tetrazol-5-yl)-bifenyl og metanol i metanolisk saltsyre. Prepared analogously to Example 55 from 4'-[[2-ethyl-6-(3-benzyl-3,4,5,6-tetrahydr6-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl] methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.

Utbytte: 22,0% av det teoretiske Yield: 22.0% of the theoretical

Smeltepunkt: fra 106°C (dekomp.) Melting point: from 106°C (decomp.)

C34<H>32N80 (568,68) C34<H>32N80 (568.68)

Beregnet: C, 71,81; H, 5,67; N, 19,70 Calculated: C, 71.81; H, 5.67; N, 19.70

Funnet: 71,73; 5,54; 19,92 Found: 71.73; 5.54; 19.92

Eksempel 119 Example 119

4 ' - [ [ 2-h-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol- l- ylImetyl1- bifenyl- 2- karboksylsyre 4'-[[ 2-h-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 64 fra 4'-[[2-n-butyl-6-(4 , 5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-l-ylJmetyl]-bifenyl-2-karboksylsyre-metylester og natronlut i etanol. Prepared analogously to Example 64 from 4'-[[2-n-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]-biphenyl-2- carboxylic acid methyl ester and caustic soda in ethanol.

Utbytte: 80,0% av det teoretiske Yield: 80.0% of the theoretical

Smeltepunkt: 276-283°C Melting point: 276-283°C

<C>29<H>28N403 (4 80,60) <C>29<H>28N403 (4 80.60)

Beregnet: C, 72,48; H, 5,87; N, 11,66 Calculated: C, 72.48; H, 5.87; N, 11.66

Funnet: 72,20; 6,13; 11,53 Found: 72.20; 6.13; 11.53

Massespektrum: m/e = 480 Mass spectrum: m/e = 480

Analogt med Eksempel 119 ble følgende forbindelser oppnådd: 4'-[[2-etyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-l-yl]metyl]-bifeny1-2-karboksylsyre 41 -[[2-n-propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-l-yl ]metyl]bifenyl-2-karboksylsyre 4'-[[2-n-butyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-l-yl ] metyl ] bif eny 1-2 -karboksylsyre 41 -[[2-n-propyl-6-(2-metyl-4,5-dihydro-pyridazin-3-on-6-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre 41 -[[2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazin-3-on-6-yl)-benzimidazol-l-yl]metyl]bifeny1-2-karboksylsyre Analogous to Example 119, the following compounds were obtained: 4'-[[2-ethyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]-biphenyl 1-2-carboxylic acid 41 - [[2-n-propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-6- (2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]bipheny 1-2-carboxylic acid 41 -[[2-n-propyl-6-(2-methyl-4,5- dihydro-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid 41 -[[2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazine -3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid

Eksempel 12 0 Example 12 0

4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol- l- ylImetyl1 bifeny1- 2- karboksylsyre 4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 64 fra 4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-l-yl]metyl]-bifenyl-2-karboksylsyre-metylester og natronlut i etanol. Prepared analogously to Example 64 from 4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]-biphenyl- 2-carboxylic acid methyl ester and caustic soda in ethanol.

Utbytte: 66,0% av det teoretiske Yield: 66.0% of the theoretical

Smeltepunkt: 236-241°C ' Melting point: 236-241°C '

C28H26N4°3 (4 66,54) C28H26N4°3 (4 66.54)

Beregnet: C, 7 2,09; H, 5,62; N, 12,01 Calculated: C, 7 2.09; H, 5.62; N, 12.01

Funnet: 71,88; 5,61; 11,95 Found: 71.88; 5.61; 11.95

Eksempel 121 Example 121

4'-[[2-etyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1- ylImetyl1bifeny1- 2- karboksylsyre 4'-[[2-ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-ylmethyl1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 64 fra 4'-[[2-etyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-l-ylJmetyl]bifenyl-2- karboksylsyre-metylester og natronlut i etanol. Prepared analogously to Example 64 from 4'-[[2-ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid methyl ester and caustic soda in ethanol.

Utbytte: 71,0% av det teoretiske Yield: 71.0% of the theoretical

Smeltepunkt: 255-257°C Melting point: 255-257°C

C27H24N403 (452,51) C27H24N403 (452.51)

Beregnet: C, 71,67; H, 5,35; N, 12,38 Calculated: C, 71.67; H, 5.35; N, 12.38

Funnet: 71,41; 5,51; 12,12 Found: 71.41; 5.51; 12,12

Eksempel 122 Example 122

4'-[[2-n-butyl-6-(3-cykloheksyl-propylamino)-benzimidazol-1- ylImetyl1bifeny1- 2- karboksylsyre 4'-[[2-n-butyl-6-(3-cyclohexyl-propylamino)-benzimidazol-1-ylmethyl-1-biphenyl-2-carboxylic acid

Fremstillet analogt med Eksempel 1 fra 41 -[[2-n-butyl-6-(3-cykloheksyl-propylamino)-benzimidazol-l-yl]metyl]-bifenyl-2- karboksylsyre-tert.butylester og trifluoreddiksyre i metylenklorid. Prepared analogously to Example 1 from 41 -[[2-n-butyl-6-(3-cyclohexyl-propylamino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Utbytte: 85,7% av det teoretiske Yield: 85.7% of the theoretical

Smeltepunkt: 152-153°C Melting point: 152-153°C

C34<H>11<N>302 x 0,75 CF3COOH (609,24) C34<H>11<N>302 x 0.75 CF3COOH (609.24)

Beregnet: C, 69,99; H, 6,91; N, 6,90 Calculated: C, 69.99; H, 6.91; N, 6.90

Funnet: 70,02; 6,93; 6,84 Found: 70.02; 6.93; 6.84

Rf-verdi: 0,24 (kiselgel; etylacetat/etanol/ammoniakk = 80:40:2) Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia = 80:40:2)

Claims (2)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive benzimidazoler med den generelle formel hvor R1 er en tetrahydrobenzimidazolyl- eller imidazopyridinyl gruppe eller en benzimidazolyl- eller benzoksazolylgruppe som i fenylkjernen eventuelt er substituert med et fluor-, klor-eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, hvor NH-gruppen i den nevnte imidazolring dessuten kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en aminogruppe som er substituert med en bicykloheksyl karbonyl- eller bifenylkarbonylgruppe, eller en hydroksycykloalkylaminokarbonylgruppe med 5 til 7 karbonatomer i cykloalkyldelen, som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en bicykloheksyl- eller bifenyl-substituert aminokarbonylaminogruppe som dessuten på N-atomet kan være substituert med én eller to alkylgrupper som hver har 1 til 3 karbonatomer, dessuten, med unntak av 2-okso-3,4-tetrametylen-pyrrolidin-l- yl-gruppen, en 5-, 6- eller 7-leddet alkylenimino- eller alkenyleniminogruppe, hvor en metylengruppe kan være erstattet med en karbonyl- eller sulfonylgruppe, og som eventuelt er substituert med én eller to alkylgrupper med 1 til 3 karbonatomer eller med en tetrametylen- eller pentametylengruppe, en 3,4,5,6-tetrahydro-2(1H)-pyrimidinongruppe som eventuelt kan være substituert med en alkyl- eller fenylalkylgruppe med 1 til 3 karbonatomer i hver alkyldel, en rettkjedet eller forgrenet hydroksyalkylaminokarbonylgruppe med 4 til 6 karbonatomer i alkyldelen, en maleinsyreamido- eller maleinsyreimidogruppe som eventuelt kan være mono- eller disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med en fenylgruppe, hvor substituentene kan være like eller forskjellige, en imidazolin- eller imidazolgruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en imidazolidindiongruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, med en fenylalkylgruppe med 1 til 3 karbonatomer i alkyldelen, med en tetrametylen-, pentametylen- eller heksametylengruppe, en a-lkylsulfonyloksygruppe med 1 til 6 karbonatomer, en benzensulfonyloksygruppe som eventuelt kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en alkylamino- eller fenylalkylaminogruppe som er substituert med en alkylsulfonylgruppe med 4 til 6 karbonatomer eller med en fenylalkylsulfonylgruppe, hvori hver alkyldel kan inneholde 1 til 3 karbonatomer, en amino- eller alkylaminogruppe som er substituert med en naftalensulfonylgruppe, som i naftalenringen kan være substituert med en dialkylaminogruppe eller med én eller to alkoksygrupper, hvor hver alkyldel kan inneholde 1 til 3 karbonatomer, en alkoksygruppe med 3 til 5 karbonatomer som i 3-, 4- eller 5-stillingen er substituert med en imidazolylgruppe, en alkoksygruppe med 2 til 5 karbonatomer som i 2-, 3-, 4- eller 5-stilling er substituert med en benzimidazolyl- eller tetrahydrobenzimidazolylgruppe, en pyridazin-3-on- eller dihydro-pyridazin-3-on-gruppe, som 1 2-stillingen kan være substituert med en eventuelt fenyl-substituert alkylgruppe med 1 til 3 karbonatomer, og som i karbonskjelettet ytterligere kan være substituert med 1 eller 2 alkylgrupper med 1 til 3 karbonatomer, en pyrrolidino-, piperidino- eller heksametyleniminogruppe som er substituert med 2 alkylgrupper som hver har 1 til 3 karbonatomer, en 7-nitro-benzofurazan-4-yl-aminoalkanoylaminogruppe, hvor alkanoyldelen kan inneholde 2 eller 3 karbonatomer, en heptametylenimino-, 1H,3H-kinazolin-2,4-dion-3-yl-, pentametylen-oksazolin-2-yl-, benzofurankarbonylamino- eller 7-nitro-benzofurazan-4-yl-aminogruppe, eller når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, betyr R1 i 6-stilling dessuten en aminogruppe som er substituert med en fenylsulfonyl-, cykloheksylmetylaminokarbonyl-, 2- karboksycykloheksyImetylkarbonyl-, 2-tert.butoksykarbonyl-cykloheksylmetylkarbonyl-, 2-karboksy-3,4,5,6-tetrahydrobenzoyl-, N-metyl-fenylaminokarbonyl- eller 3-cykloheksylpropylgruppe; en metylaminogruppe som er substituert med en propylsulfonyl-, fenylsulfonyl-, metylfenylsulfonyl- eller klorfenylsulfonylgruppe; en n-pentylaminogruppe som er substituert med en fenylsulfonyl-eller metoksyfenylsulfonylgruppe; en n-propylaminogruppe som er substituert med en metylfenylsulfonyl- eller metoksyfenylsulfonylgruppe; en isopropylaminogruppe som er substituert med en benzoyl-eller klorfenylsulfonylgruppe; en N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydrohomoftalimido-, N-metan-sulfonyl-2-fenyletylamino-, N-klorfenylsulfonyl-benzylamino-, piperidino-, 4-metyl-piperidino- eller heksametyleniminogruppe, eller, når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, betyr R1 i 5- eller 6-stilling en 2-okso-l,2-dihydro-3,4-tetrametylen-pyrrolidin-l-yl-, 3-karboksypropionyl- eller 3- karboksy-2-metyl-propionylgruppe, eller, når R3 utgjør en karboksygruppe og R2 utgjør en metyl-, etyl-, n-propyl-, n-butyl- eller metylmerkaptogruppe, betyr R1 i 6-stilling en pyrrolidinokarbonylaminogruppe, eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en n-butylgruppe, betyr R1 i 5- eller 6-stilling en n-pentylaminogruppe som er substituert med en metylaminokarbonyl- eller cykloheksylaminokarbonylgruppe, eller i 6-stilling en 3,3-dimetylglutarsyreimido- eller 4,4-tetrametylen-glutarsyreimidogruppe, eller når R3 utgjør en tetrazolylgruppe og R2 utgjør en etyl-eller n-propylgruppe, betyr R1 i 6-stilling dessuten en N-benzensulf onyl -metylaminogruppe, eller når R3 utgjør en tert-butoksykarbonylgruppe og R2 utgjør en N-butylgruppe, betyr R1 i 6-stilling også en 2-karboksycyklo-heksylmetylkarbonylamino- eller pyrrolidinokarbonylaminogruppe, R2 er et hydrogenatom eller en rettkjedet eller forgrenet alkylgruppe med 1 til 5 karbonatomer, hvori en metylengruppe kan være erstattet med et svovelatom, R3 er en karboksy- eller lH-tetrazolylgruppe, eller en alkoksykarbonylgruppe med tilsammen 2 til 5 karbonatomer, og R4 er et hydrogen-, fluor-, klor- eller bromatom, deres 1-, 3-isomerblandinger og deres farmasøytisk akseptable salter med uorganiske eller organiske syrer eller baser, karakterisert, ved a) cyklisering av en forbindelse med den generelle formel hvor R1 er som tidligere definert, en av restene X1 eller Y1 utgjør en gruppe med den generelle formel og den andre av restene X1 eller Y1 utgjør en gruppe med den generelle formel hvor R2 til R4 er som tidligere definert, R5 er et hydrogenatom eller en R2CO-gruppe, hvor R2 er som tidligere definert, Zy og Z2, som kan være like eller forskjellige, eventuelt er substituerte aminogrupper eller hydroksy- eller merkaptogrupper som eventuelt er substituert med lavere alkylgrupper, eller Z1 og Z2 sammen utgjør 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, hvor imidlertid en av restene X., eller Y1 må utgjøre en gruppe med den generelle formel hvorpå det således oppnådde N-oksyd reduseres, eller b) omsetning av et benzimidazol med den generelle formel hvor R1 og R2 er som tidligere definert, med en bifenyl-forbindelse med den generelle formel hvor R3 og R4 er som tidligere definert, og Z3 utgjør en nukleofil utgående gruppe, så som et halogenatom eller en substituert sulfonyloksygruppe, eller c) for fremstilling av en forbindelse med den generelle formel I, hvor R3 utgjør en karboksygruppe, overføring av en forbindelse med den generelle formel hvor R2 og R4 er som tidligere definert, r/ har de betydninger som tidligere er definert for R1 og utgjør en 3-alkoksykarbonylpropionyl- eller 3-alkoksykarbonyl-2-metylpropionylgruppe, hvor alkoksydelen kan inneholde 1 til 3 karbonatomer, og R3' utgjør en gruppe som ved hydrolyse, termolyse eller hydrogenolyse kan overføres i en karboksygruppe, i en tilsvarende karboksyforbindelse, eller d) for fremstilling av en forbindelse med den generelle formel I, hvor R3 utgjør en lH-tetrazolylgruppe, avspaltning av en beskyttelsesrest fra en forbindelse med den generelle formel hvor R.,, R2 og R4 er som tidligere definert, og R3" utgjør en lH-tetrazolylgruppe som i 1- eller 3-stilling er beskyttet med en beskyttelsesrest, eller e) for'fremstilling av en forbindelse med den generelle formel I, hvor R3 utgjør en lH-tetrazplylgruppe, omsetning av en forbindelse med den generelle formel hvor R1, R2 og R4 er som tidligere definert, med hydrogenazidsyre eller salter derav, eller f) for fremstilling av forbindelser med den generelle formel I, hvor R1 utgjør en pentametyleri-oksazolin-2-yl-gruppe, omsetning av en forbindelse med den generelle formel hvor R2 til R4 er som tidligere definert, med 1-aminometyl-cykloheksanol i nærvær av et middel som aktiverer syren, eller g) for fremstilling av en forbindelse med den generelle formel I, hvor R, utgjør en 2-okso-3,4-tetrametylen-pyrrolidin-l-yl-gruppe, hydrering av en forbindelse med den generelle formel hvor R2, R3 og R4 er som tidligere definert, eller h) for fremstilling av forbindelser med den generelle formel I hvor, R1 betyr en aminogruppe som er substituert med en bicykloheksylkarbonyl- eller bifenylkarbonylgruppe som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 kabonatomer, en aminokarbonylaminogruppe som er substituert med en bicykloheksyl- eller bif enylgruppe,' som dessuten kan være substituert på N-atomet med én eller to alkylgrupper som hver har 1 til 3 karbonatomer, en maleinsyreamido- eller maleinsyreimidogruppe som eventuelt kan være mono- eller disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med en fenylgruppe, hvor substituentene kan være like eller forskjellige, en alkylamino- eller fenylalkylaminogruppe som er substituert med en alkylsulfonylgruppe med 4 til 6 karbonatomer eller med en fenylalkylsulfonylgruppe, hvori hver alkyldel kan inneholde 1 til 3 karbonatomer, en amino- eller alkylaminogruppe som er substituert med naftalensulfonylgruppe, som på naftalenringen kan være substituert med en dialkylaminogruppe eller med én eller to alkoksygrupper, hvor hver alkyldel kan inneholde 1 til 3 karbonatomer, en 7-nitro-benzofurazan-4-ylaminoalkanoyl-aminogruppe hvor alkanoyldelen kan inneholde 2 eller 3 karbonatomer, en benzofuran-karbonylamino- eller 7-nitro-benzo-furazan-4-ylaminogruppe, eller også, når R3 utgjør en karboksygruppe og R2 utgjør en n-butylgruppe, R1 i 6-stilling, betyr en aminogruppe som er substituert med en fenylsulfonyl-, cykloheksylmetylaminokarbonyl-, 2-karboksycykloheksylmetylkarbonyl-, 2-tert.butoksykarbonyl-cykloheksylmetylkarbonyl-, 2-karboksy-3,4,5,6-tetrahydrobenzoyl-, N-metyl-fenylaminokarbonyl- eller 3-cykloheksylpropylgruppe, en metylaminogruppe som er substituert med en propylsulfonyl-, fenylsulfonyl-, metylfenylsulfonyl- eller klorfenylsulfonylgruppe, en n-pentylaminogruppe som er substituert med en fenylsulfonyl-eller metoksyfenylsulfonylgruppe, en n-propylaminogruppe som er substituert med en metylfenylsulfonyl- eller metoksyfenyl-sulf onylgruppe, en isbpropylaminogruppe som er substituert med en benzoyl- eller klorfenylsulfonylgruppe, en N-acetyl-cykloheksylmetylamino-, 3,4,5,6-tetrahydroftalimido-, heksahydrohomoftalimido-, N-metansulfonyl-2-fenyletylamino- eller N-klorfenylsulfonyl-benzylaminogruppe, eller, når R3 utgjør en karboksygruppe og R2 utgjør en n- butylgruppe, R1 i 5- eller 6-stilling, betyr en 2-okso-l,2-dihydro-3,4-tetrametylen-pyrrolidin-l-yl-gruppe, eller, når R3 utgjør en karboksygruppe og R2 en metyl-, etyl-, n-propyl-, n-butyl eller metylmerkaptogruppe,.R., i 6-stilling, betyr en pyrrolidinokarbonylaminogruppe, eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en n-butylgruppe, R, i 5- eller 6-stilling, betyr en n-pentylaminogruppe som er substituert med en metylaminokarbonyl-eller cykloheksylaminokarbonylgruppe, eller i 6-stilling, betyr en 3,3-dimetylglutarsyreimido- eller 4,4-tetrametylen-glutarsyreimidogruppe, - eller også, når R3 utgjør en tetrazolylgruppe og R2 utgjør en etyl- eller n-propylgruppe, R1 i 6-stilling, betyr en N-benzensulfonyl-metylaminogruppe, eller også, når R3 utgjør en tert-butoksykarbonylgruppe og R2 utgjør en N-butylgruppe, R., i 6-stilling, betyr en 2-karboksy-cykloheksylmetylkarbonylamino- eller pyrrolidinokarbonylaminogruppe, omsetning av en forbindelse med den generelle formel hvor R2, R3 og R4 er som tidligere definert, og R6 er et hydrogenatom, en n-pentyl-, cykloheksyImetyl-, alkyl-eller fenylalkylgruppe som hver har 1 til 3 karbonatomer i alkyldelen, med en forbindelse med den generelle formel hvor Z4 er en nukleofil utgående gruppe, W er en -CO- eller -S02-gruppe og R7 er en 2-hydroksykarbonyl-etenylgruppe, hvor etényldelen er mono- eller disubstituert med en alkylgruppe med 1 til 3 karbonatomer eller med en fenylgruppe, og hvor substituentene kan være like eller forskjellige, en alkylgruppe med 3 til 6 karbonatomer, en fenylalkylgruppe med 1 til 3 karbonatomer i alkyldelen, en naftalengruppe som eventuelt kan være substituert med en dialkylaminogruppe eller med én eller to alkoksygrupper, hvor hver alkyldel kan inneholde 1 til 3 karbonatomer, en metyl-, fenyl-, metylfenyl-, metoksyfenyl-, klorfenyl-, bifenyl-, bicykloheksyl-, 2-karboksy-cykloheksyl-metyl-, 2-karboksy-3,4,5,6-tetrahydrofenyl-, 3-karboksy-l,1-dimetylpropyl-, 3-karboksy-2,2-tetrametylen-propyl-, 7-nitrobenzofurazan-4-ylaminometyl- eller 7-nitro-benzofurazan-4-ylaminoetylgruppe, eller også, når W utgjør en -CO-gruppe, en R8NR9-gruppe, hvor R8 utgjør et hydrogenatom eller en alkylgruppe med 1 til 3 karbonatomer, R, utgjør en metyl-, cykloheksyl-, cykloheksyImetyl-, fenyl-, bifenyl- eller bicykloheksylgruppe eller R8 og Kg sammen med det mellomliggende nitrogenatom utgjør en pyrrolidinogruppe, eller også, Z4 sammen med Rg utgjør en ytterligere karbon- nitrogen-binding, eller også, R7 sammen med W, betyr en 7-nitro-benzofurazan-4- yl-aminogruppe, eller i) for fremstilling av forbindelser med den generelle formel I, hvor R1 betyr en tetrahydrobenzimidazolyl- eller imidazopyridinylgruppe eller en benzimidazolylgruppe, som i fenylkjernen eventuelt er substituert med et fluor-, klor- eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, hvor NH-gruppen i ovennevnte.imidazolringer dessuten kan være substituert med en alkylgruppe med 1 til 6 karbonatomer eller med en cykloalkylgruppe med 3 til 7 karbonatomer, en hydroksycykloalkylaminokarbonylgruppe med 5 til 7 karbonatomer i cykloalkyldelen og som på N-atomet dessuten kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, eller en rettkjedet eller forgrenet hydroksyalkylaminokarbonylgruppe med 4 til 6 karbonatomer i alkyldelen, omsetning av en forbindelse med den generelle formel hvor R2 til R4 er som tidligere definert, eller deres reaktive derivater, med et amin med den generelle formel hvor - R10 er et hydrogenatom, en cykloalkylgruppe eller en alkylgruppe med 1 til 6 karbonatomer og betyr en hydroksyalkylgruppe med 4 til 6 karbonatomer, en hydroksycykloalkylgruppe med 5 til 7 karbonatomer eller en 2-aminofenylgruppe som i fenylkjernen kan være substituert med et fluor-, klor- eller bromatom, med en alkylgruppe med 1 til 3 karbonatomer, med en alkoksygruppe med 1 til 3 karbonatomer eller med en trifluormetylgruppe, eller betyr en 2-aminocyklo-heksyl- eller 2-aminopyridylgruppe, eventuelt under samtidig dekarboksylering, og om nødvendig, beskyttelsesrester benyttet under omsetningene a) til i) for å beskytte reaktive grupper, avspaltes og/eller om ønskes, en således oppnådd 1-, 3-isomerblanding av en forbindelse med den generelle formel I adskilles deretter ved isomer-spaltning i sine 1- og 3-isomerer, eller en således oppnådd forbindelse med den generelle formel I overføres i sitt salt, spesielt for farmasøytisk anvendelse, i sitt fysiologisk akseptable salt, med en uorganisk eller organisk syre eller base. 1. Analogous process for the preparation of therapeutically active benzimidazoles with the general formula where R1 is a tetrahydrobenzimidazolyl or imidazopyridinyl group or a benzimidazolyl or benzoxazolyl group which in the phenyl nucleus is optionally substituted with a fluorine, chlorine or bromine atom, with an alkyl group with 1 to 3 carbon atoms, with an alkoxy group of 1 to 3 carbon atoms or with a trifluoromethyl group, where the NH group in the mentioned imidazole ring can also be substituted with an alkyl group of 1 to 6 carbon atoms or with a cycloalkyl group of 3 to 7 carbon atoms, an amino group which is substituted with a bicyclohexyl carbonyl or biphenylcarbonyl group, or a hydroxycycloalkylaminocarbonyl group with 5 to 7 carbon atoms in the cycloalkyl part, which on the N atom may also be substituted with an alkyl group with 1 to 3 carbon atoms, a bicyclohexyl or biphenyl-substituted aminocarbonylamino group which also on the N -atom may be substituted by one e or two alkyl groups each having 1 to 3 carbon atoms, in addition, with the exception of the 2-oxo-3,4-tetramethylene-pyrrolidin-l-yl group, a 5-, 6- or 7-membered alkylenimino or alkenylenimino group, where a methylene group may be replaced by a carbonyl or sulfonyl group, and which is optionally substituted with one or two alkyl groups with 1 to 3 carbon atoms or with a tetramethylene or pentamethylene group, a 3,4,5,6-tetrahydro-2(1H) -pyrimidinone group which may optionally be substituted with an alkyl or phenylalkyl group with 1 to 3 carbon atoms in each alkyl part, a straight-chain or branched hydroxyalkylaminocarbonyl group with 4 to 6 carbon atoms in the alkyl part, a maleic acid amido or maleic acid imido group which may optionally be mono- or disubstituted with a alkyl group with 1 to 3 carbon atoms or with a phenyl group, where the substituents may be the same or different, an imidazoline or imidazole group which may optionally be substituted with an alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group of 3 to 7 carbon atoms, an imidazolidinedione group which may optionally be substituted with an alkyl group of 1 to 3 carbon atoms, with a phenylalkyl group of 1 to 3 carbon atoms in the alkyl part, with a tetramethylene, pentamethylene or hexamethylene group, a -alkylsulfonyloxy group with 1 to 6 carbon atoms, a benzenesulfonyloxy group which may optionally be substituted with an alkyl group with 1 to 3 carbon atoms, an alkylamino or phenylalkylamino group which is substituted with an alkylsulfonyl group with 4 to 6 carbon atoms or with a phenylalkylsulfonyl group, in which each alkyl part may contain 1 to 3 carbon atoms, an amino or alkylamino group which is substituted with a naphthalenesulfonyl group, which in the naphthalene ring may be substituted with a dialkylamino group or with one or two alkoxy groups, where each alkyl part may contain 1 to 3 carbon atoms, an alkoxy group with 3 to 5 carbon atoms which in the 3-, 4- or 5-position is substit unsubstituted with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in the 2-, 3-, 4- or 5-position with a benzimidazolyl or tetrahydrobenzimidazolyl group, a pyridazin-3-one or dihydro-pyridazin-3-one -group, as the 1 2-position can be substituted with an optionally phenyl-substituted alkyl group with 1 to 3 carbon atoms, and which in the carbon skeleton can further be substituted with 1 or 2 alkyl groups with 1 to 3 carbon atoms, a pyrrolidino-, piperidino- or hexamethyleneimino group which is substituted with 2 alkyl groups each having 1 to 3 carbon atoms, a 7-nitro-benzofurazan-4-yl-aminoalkanoylamino group, where the alkanoyl part may contain 2 or 3 carbon atoms, a heptamethyleneimino-, 1H,3H-quinazoline-2,4 -dion-3-yl-, pentamethylene-oxazolin-2-yl-, benzofurancarbonylamino- or 7-nitro-benzofurazan-4-yl-amino group, or when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in 6 means -position also an amino group which is substituted with a phenylsulfonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.butoxycarbonylcyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3-cyclohexylpropyl group; a methylamino group substituted with a propylsulfonyl, phenylsulfonyl, methylphenylsulfonyl or chlorophenylsulfonyl group; an n-pentylamino group substituted with a phenylsulfonyl or methoxyphenylsulfonyl group; an n-propylamino group substituted with a methylphenylsulfonyl or methoxyphenylsulfonyl group; an isopropylamino group substituted with a benzoyl or chlorophenylsulfonyl group; an N-acetyl-cyclohexylmethylamino-, 3,4,5,6-tetrahydrophthalimido-, hexahydrohomophthalimido-, N-methanesulfonyl-2-phenylethylamino-, N-chlorophenylsulfonyl-benzylamino-, piperidino-, 4-methyl-piperidino- or hexamethyleneimino group, or, when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in the 5- or 6-position means a 2-oxo-1,2-dihydro-3,4-tetramethylene-pyrrolidin-1-yl-, 3-carboxypropionyl or 3-carboxy-2-methyl-propionyl group, or, when R3 is a carboxy group and R2 is a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R1 means in the 6-position a pyrrolidinocarbonylamino group, or also, when R3 constitutes a tetrazolyl group and R2 constitutes an n-butyl group, R1 in the 5- or 6-position means an n-pentylamino group which is substituted with a methylaminocarbonyl or cyclohexylaminocarbonyl group, or in the 6-position a 3, 3-dimethylglutaric acid imido or 4,4-tetramethyleneglutaric acid imido group, or when R3 forms a tetrazolyl group and R2 forms an ethyl or n-propyl group, R1 in the 6-position also means an N-benzenesulfonyl-methylamino group, or when R3 forms a tert-butoxycarbonyl group and R2 forms an N-butyl group, R1 in the 6-position also means a 2-carboxycyclohexylmethylcarbonylamino- or pyrrolidinocarbonylamino group, R2 is a hydrogen atom or a straight-chain or branched alkyl group with 1 to 5 carbon atoms, in which a methylene group may be replaced by a sulfur atom, R3 is a carboxy or 1H-tetrazolyl group, or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, and R4 is a hydrogen, fluorine, chlorine or bromine atom, their 1-, 3-isomer mixtures and their pharmaceutically acceptable salts with inorganic or organic acids or bases, characterized, by a) cyclization of a compound of the general formula where R 1 is as previously defined, one of the residues X1 or Y1 constitutes a group of the general formula and the other of the residues X1 or Y1 constitutes a group of the general formula wherein R2 to R4 are as previously defined, R5 is a hydrogen atom or an R2CO group, where R2 is as previously defined, Zy and Z2, which may be the same or different, are optionally substituted amino groups or hydroxy or mercapto groups which are optionally substituted with lower alkyl groups, or Z1 and Z2 together constitute an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, where however one of the residues X., or Y1 must constitute a group of the general formula upon which the N-oxide thus obtained is reduced, or b) reaction of a benzimidazole of the general formula where R1 and R2 are as previously defined, with a biphenyl compound of the general formula where R3 and R4 are as previously defined, and Z3 constitutes a nucleophilic leaving group, such as a halogen atom or a substituted sulfonyloxy group, or c) for the preparation of a compound with that gene eral formula I, where R 3 constitutes a carboxy group, transfer of a compound of the general formula where R 2 and R 4 are as previously defined, r/ has the meanings previously defined for R 1 and constitutes a 3-Alkoxycarbonylpropionyl- or 3-Alkoxycarbonyl- 2-methylpropionyl group, where the alkoxy part can contain 1 to 3 carbon atoms, and R3' constitutes a group which, by hydrolysis, thermolysis or hydrogenolysis, can be transferred into a carboxy group, in a corresponding carboxy compound, or d) for the preparation of a compound of the general formula I , where R 3 constitutes a 1H-tetrazolyl group, removal of a protecting residue from a compound of the general formula where R. protected with a protective residue, or e) for the preparation of a compound of the general formula I, where R3 constitutes a 1H-tetrazplyl group, reacting a compound of the general formula where R1, R2 and R4 are, as previously defined, with hydrogen azide acid or salts thereof, or f) for the preparation of compounds of the general formula I, where R1 constitutes a pentamethyleryoxazolin-2-yl group, reaction of a compound of the general formula where R2 to R4 are as previously defined, with 1-aminomethyl-cyclohexanol in the presence of an agent which activates the acid, or g) for the preparation of a compound of the general formula I, where R, constitutes a 2-oxo-3,4- tetramethylene-pyrrolidin-1-yl group, hydrogenation of a compound of the general formula where R 2 , R 3 and R 4 are as previously defined, or h) for the preparation of compounds of the general formula I where, R 1 means an amino group which is substituted with a bicyclohexylcarbonyl or biphenylcarbonyl group which may also be substituted on the N atom by an alkyl group with 1 to 3 carbon atoms, an aminocarbonylamino group which is substituted with a bicyclohexyl or biphenyl group,' which may also be substituted on the N atom with one or two alkyl groups each having 1 to 3 carbon atoms, a maleic amido or maleic imido group which may optionally be mono- or disubstituted with an alkyl group with 1 to 3 carbon atoms or with a phenyl group, where the substituents may be the same or different . a dialkylamino group or with one or two alkoxy groups, where each alkyl part may contain 1 to 3 carbon atoms, a 7-nitro-benzofurazan-4-ylaminoalkanoyl-amino group where the alkanoyl part may contain 2 or 3 carbon atoms, a benzofuran-carbonylamino- or 7-nitro- benzo-furazan-4-ylamino group, or also, when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in the 6-position, means an amino group which is substituted with a phenylsulfonyl-, cyclohexylmethylaminocarbonyl-, 2-carboxycyclohexylmethylcarbonyl-, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl-, 2-carboxy-3,4,5,6-tetrahydrobenzoyl- . substituted with a methylphenylsulfonyl or methoxyphenylsulfonyl group, an isopropylamino group substituted with a benzoyl or chlorophenylsulfonyl group, an N-acetyl-cyclohexylmethylamino-, 3,4,5,6-tetrahydrophthalimido-, hexahydrohomophthalimido-, N-methanesulfonyl-2 -phenylethylamino- or N-chlorophenylsulfonyl-benzylamino group, or, when R3 constitutes a carboxy group and R2 constitutes an n-butyl group, R1 in the 5- or 6-position, bet yr a 2-oxo-1,2-dihydro-3,4-tetramethylene-pyrrolidin-1-yl group, or, when R 3 constitutes a carboxy group and R 2 a methyl-, ethyl-, n-propyl-, n-butyl or methyl mercapto group,. R., in the 6-position, means a pyrrolidinocarbonylamino group, or also, when R 3 constitutes a tetrazolyl group and R 2 constitutes an n-butyl group, R, in the 5- or 6-position, means an n-pentylamino group which is substituted with a methylaminocarbonyl- or cyclohexylaminocarbonyl group, or in the 6-position, means a 3,3-dimethylglutaric acid imido group or 4,4-tetramethyleneglutaric acid imido group, - or also, when R3 forms a tetrazolyl group and R2 forms an ethyl or n-propyl group, R1 in the 6- position, means an N-benzenesulfonyl-methylamino group, or also, when R3 constitutes a tert-butoxycarbonyl group and R2 constitutes an N-butyl group, R., in the 6-position, means a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group, reaction of a compound of the general formula wherein R 2 , R 3 and R 4 are as previously defined, and R 6 is a hydrogen atom, an n-pentyl, cyclohexylmethyl, alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl moiety, with a compound having the general form l where Z4 is a nucleophilic leaving group, W is a -CO- or -SO2 group and R7 is a 2-hydroxycarbonyl-ethenyl group, where the ethenyl part is mono- or disubstituted with an alkyl group of 1 to 3 carbon atoms or with a phenyl group, and where the substituents may be the same or different, an alkyl group with 3 to 6 carbon atoms, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, a naphthalene group which may optionally be substituted with a dialkylamino group or with one or two alkoxy groups, where each alkyl part may contain 1 to 3 carbon atoms, a methyl-, phenyl-, methylphenyl-, methoxyphenyl-, chlorophenyl-, biphenyl-, bicyclohexyl-, 2-carboxy-cyclohexyl-methyl-, 2-carboxy-3,4,5,6-tetrahydrophenyl-, 3-carboxy-1,1-dimethylpropyl-, 3-carboxy-2,2-tetramethylene-propyl-, 7-nitrobenzofurazan-4-ylaminomethyl- or 7-nitro-benzofurazan-4-ylaminoethyl group, or also, when W constitutes a -CO group, an R8NR9 group, where R8 is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms is, R constitutes a methyl, cyclohexyl, cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl group or R8 and Kg together with the intervening nitrogen atom form a pyrrolidino group, or alternatively, Z4 together with Rg constitutes an additional carbon-nitrogen bond , or also, R7 together with W, means a 7-nitro-benzofurazan-4-yl-amino group, or i) for the preparation of compounds of the general formula I, where R1 means a tetrahydrobenzimidazolyl or imidazopyridinyl group or a benzimidazolyl group, as in the phenyl nucleus is optionally substituted with a fluorine, chlorine or bromine atom, with an alkyl group with 1 to 3 carbon atoms, with an alkoxy group with 1 to 3 carbon atoms or with a trifluoromethyl group, where the NH group in the above-mentioned imidazole rings can also be substituted with a alkyl group with 1 to 6 carbon atoms or with a cycloalkyl group with 3 to 7 carbon atoms, a hydroxycycloalkylaminocarbonyl group with 5 to 7 carbon atoms in the cycloalkyl part and as on the N atom d essuten may be substituted with an alkyl group with 1 to 3 carbon atoms, or a straight-chain or branched hydroxyalkylaminocarbonyl group with 4 to 6 carbon atoms in the alkyl part, reaction of a compound of the general formula where R 2 to R 4 are as previously defined, or their reactive derivatives, with an amine with the general formula where - R10 is a hydrogen atom, a cycloalkyl group or an alkyl group with 1 to 6 carbon atoms and means a hydroxyalkyl group with 4 to 6 carbon atoms, a hydroxycycloalkyl group with 5 to 7 carbon atoms or a 2-aminophenyl group which in the phenyl nucleus can be substituted with a fluorine, chlorine or bromine atom, with an alkyl group of 1 to 3 carbon atoms, with an alkoxy group of 1 to 3 carbon atoms or with a trifluoromethyl group, or means a 2-aminocyclohexyl or 2-aminopyridyl group, optionally under simultaneous decarboxylation, and if necessary, protective residues used during reactions a) to i) to protect reactive groups, of is cleaved and/or if desired, a thus obtained 1-, 3-isomer mixture of a compound of the general formula I is then separated by isomer cleavage into its 1- and 3-isomers, or a thus obtained compound of the general formula I is transferred in its salt, especially for pharmaceutical use, in its physiologically acceptable salt, with an inorganic or organic acid or base. 2. Fremgangsmåte ifølge krav 1 for fremstilling av benzimidazoler med den generelle formel I:. 4'-[[2-n-propyl-6-(l-metylbenzimidazol-2-yl)-benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyre,2. Process according to claim 1 for the production of benzimidazoles with the general formula I:. 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid, 41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-ftalimino)-benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyre, 4'-[[2-n-butyl-6-(2,3-difenyl-maleinsyreimido)-benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyre,41 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid, 4'-[[2-n-butyl-6-(2,3-diphenyl-maleic imido)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid, 41 -[[2-n-butyl-6-(2,3-dimetyl-maleinsyreimido)-benzimidazol-l-yl]-metyl]bifenyl-2-karboksylsyre,41 -[[2-n-butyl-6-(2,3-dimethyl-maleic imido)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid, 41 -[[2-n-butyl-6-(N-fenylmetansulfonyl-metylamino)-benzimidazol-l-yl ]metyl]bifeny1-2-karboksylsyre, 4'-[[2-n-butyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[[2-n-butyl-6-(2-okso-pyrrolidin-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 41 -[[2-n-butyl-6-(2-okso-heksametylenimino)-benzimidazol-l-yl]-metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4<1->[[2-n-butyl-6-(3,3-dimetylglutarimido)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[[2-n-butyl-6-(N-metylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl ] metyl ] -2- (lH-tetrazo.l-5-yl) -bif enyl , 4'-[[2-n-butyl-6-(cykloheksylaminokarbonyl-n-pentylamino)-benzimidazol-l-yl ]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[[2-n-butyl-6-(2-okso-3,4-tetrametylen-pyrrolidin-l-yl)benzimidazol-l-yl ]metyl]bifeny1-2-karboksylsyre, 41 -[[2-n-butyl-6-(propansultam-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 4'-[[2-n-propyl-6-(butånsultam-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl, 41 -[[2-n-butyl-6-(butansultam-l-yl)-benzimidazol-l-yl]metyl]-2-(1H-tetrazol-5-yl)-bifenyl, 4<1->[[2-n-propyl-6-(l-metyl-benzimidazol-2-yl)-benzimidazol-1-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl og 4<1->[[2-n-propyl-6-(2-okso-piperidin-l-yl)-benzimidazol-l-yl]metyl]-2-(lH-tetrazol-5-yl)-bifenyl og deres salter med uorganiske eller organiske syrer eller baser, karakterisert ved at tilsvarende utgangsforbindelser benyttes.41 -[[2-n-butyl-6-(N-phenylmethanesulfonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl 1-2-carboxylic acid, 4'-[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4'-[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 41 - [[2-n-butyl-6-(2-oxo-hexamethyleneimino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4<1->[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazo.1-5-yl)-biphenyl, 4'-[[2-n-butyl-6-(cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4'-[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-yl)benzimidazol-1-yl]methyl]biphenyl1-2-carboxylic acid, 41 -[[2- n-butyl-6-(propanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4'-[[2-n-propyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 41 -[[2- n-butyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl, 4<1->[[2-n-propyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl and 4<1->[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl and their salts with inorganic or organic acids or bases, characterized in that corresponding starting compounds are used.
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Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8904174D0 (en) * 1989-02-23 1989-04-05 British Bio Technology Compounds
NZ232785A (en) * 1989-03-15 1991-03-26 Janssen Pharmaceutica Nv 5-(1,2 benzisoxazol-, benzimidazol and benzisothiazol-3- yl)-1h-benzimadazol-2-yl carbamic acid ester derivatives preparatory processes, intermediates and anthelmintic compositions
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
US5594003A (en) * 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
SI9210098B (en) * 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation
DE4224133A1 (en) * 1992-07-22 1994-01-27 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
US5614519A (en) * 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
DE4225756A1 (en) * 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4224752A1 (en) * 1992-04-11 1994-02-03 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
US5602127A (en) * 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5798364A (en) * 1992-03-26 1998-08-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Imidazopyridines
CA2077419C (en) * 1991-09-10 1998-08-25 Yasushi Honma Imidazopyridine derivatives and process for preparation thereof
EP0543263A3 (en) * 1991-11-16 1993-08-25 Dr. Karl Thomae Gmbh Benziimidazoles, pharmaceuticals containing them and process for their preparation
DE4219534A1 (en) * 1992-02-19 1993-12-16 Thomae Gmbh Dr K Substituted biphenylyl derivatives, pharmaceutical compositions containing them and methods for their preparation
DE4207904A1 (en) * 1992-03-12 1993-09-16 Thomae Gmbh Dr K SUBSTITUTED BENZIMIDAZOLYL DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US5612360A (en) * 1992-06-03 1997-03-18 Eli Lilly And Company Angiotensin II antagonists
DE4237656A1 (en) * 1992-06-13 1993-12-16 Merck Patent Gmbh benzimidazole derivatives
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
DE4304455A1 (en) * 1993-02-15 1994-08-18 Bayer Ag Heterocyclic substituted phenyl-cyclohexane-carboxylic acid derivatives
DE4408497A1 (en) * 1994-03-14 1995-09-21 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
US5753672A (en) * 1994-04-19 1998-05-19 Tanabe Seiyaku Co., Ltd. Imidazopyridine derivatives and process for preparing the same
PL318199A1 (en) * 1994-06-29 1997-05-26 Smithkline Beecham Corp Antagonists of vitronectin receptors
JP3063162B2 (en) * 1995-12-28 2000-07-12 藤沢薬品工業株式会社 Benzimidazole derivatives
TW453999B (en) 1997-06-27 2001-09-11 Fujisawa Pharmaceutical Co Benzimidazole derivatives
SE9903028D0 (en) 1999-08-27 1999-08-27 Astra Ab New use
DE10314702A1 (en) * 2003-03-31 2004-10-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for the preparation of telmisartan
CA2542499A1 (en) * 2003-10-16 2005-04-28 Teva Pharmaceutical Industries Ltd. Preparation of candesartan cilexetil
MX2007004426A (en) * 2004-10-15 2007-06-14 Teva Pharma Process for preparing telmisartan.
US20100120694A1 (en) 2008-06-04 2010-05-13 Synergy Pharmaceuticals, Inc. Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders
US7879802B2 (en) 2007-06-04 2011-02-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
ES2624828T3 (en) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others
US8829035B2 (en) 2009-05-29 2014-09-09 Sumitomo Chemical Company, Limited Agent for treatment or prevention of diseases associated with activity of neurotrophic factors
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CA2905438A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
AU2014235209B2 (en) 2013-03-15 2018-06-14 Bausch Health Ireland Limited Guanylate cyclase receptor agonists combined with other drugs
EP3004138B1 (en) 2013-06-05 2024-03-13 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase c, method of making and using same
ES2806135T3 (en) 2013-06-21 2021-02-16 Zenith Epigenetics Ltd New bicyclic bromodomain inhibitors
ES2661437T3 (en) 2013-06-21 2018-04-02 Zenith Epigenetics Corp. New substituted bicyclic compounds as bromodomain inhibitors
EP3027604B1 (en) 2013-07-31 2019-02-20 Zenith Epigenetics Ltd. Novel quinazolinones as bromodomain inhibitors
CN107108552A (en) * 2014-08-05 2017-08-29 百时美施贵宝公司 Heterocyclic kinase inhibitors
EP3227281A4 (en) 2014-12-01 2018-05-30 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
CA2966449A1 (en) 2014-12-11 2016-06-16 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
CN107406438B (en) 2014-12-17 2021-05-14 恒翼生物医药科技(上海)有限公司 Inhibitors of bromodomains

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820843A (en) * 1987-05-22 1989-04-11 E. I. Du Pont De Nemours And Company Tetrazole intermediates to antihypertensive compounds
US4880804A (en) * 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
CA2016710A1 (en) * 1989-05-15 1990-11-15 Prasun K. Chakravarty Substituted benzimidazoles as angiotensin ii antagonists
EP0479892A1 (en) * 1989-06-30 1992-04-15 E.I. Du Pont De Nemours And Company Fused-ring aryl substituted imidazoles
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
IL95975A (en) * 1989-10-24 1997-06-10 Takeda Chemical Industries Ltd N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them
IL96019A0 (en) * 1989-10-31 1991-07-18 Fujisawa Pharmaceutical Co Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same

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