NO314183B1 - Benzimidazole derivatives, their use and pharmaceutical preparations containing them - Google Patents

Benzimidazole derivatives, their use and pharmaceutical preparations containing them Download PDF

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NO314183B1
NO314183B1 NO19994858A NO994858A NO314183B1 NO 314183 B1 NO314183 B1 NO 314183B1 NO 19994858 A NO19994858 A NO 19994858A NO 994858 A NO994858 A NO 994858A NO 314183 B1 NO314183 B1 NO 314183B1
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benzoimidazol
ethyl
compound
methyl
carboxamide
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NO19994858A
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NO994858L (en
NO994858D0 (en
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Timothy J Church
Neil Scott Cutshall
Anthony R Gangloff
Thomas E Jenkins
Martin S Linsell
Joane Litvak
Kenneth D Rice
Jeffrey R Spencer
Vivian Rueywen Wang
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Axys Pharm Corp
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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Description

Oppfinnelsens område: Field of the invention:

Foreliggende oppfinnelse vedrører bezimidazolderivater, anvendelse derav og farmasøytiske preparater inneholdende dem The present invention relates to bezimidazole derivatives, their use and pharmaceutical preparations containing them

Beskrivelse av kjent teknikk: Description of prior art:

Tryptase, den dominerende protease som utskilles fra humane mastceller, er antatt å være involvert i nevropeptid-prosessering og vevinflammasjon. Tryptase-konsentrasjoner er forhøyet i blodstrømmen i flere timer etter anafylaksi (Schwartz et al. (1987) N. Eng. J. Med. 316:1622-1626), er øket i nasal- og lunge-vaskevæske fra atopiske pasienter etter spesifikk antigen-påvirkning (Castells et al. (1988) J. Allerg. Clin. Immunol. 141:563-568) og er forhøyet i lunge-vaskevæske fra atopiske astmatikere etter endobronkial allergen-påvirkning. Røykere har ofte påfallende forhøyelse av bronkoalveolar-vaskevæske tryptasenivåer, et funn som gir noe støtte for hypotesen at frigjøring av proteinase fra aktiverte mastceller kan bidra til lunge-destruksjon ved røyker-emfysem. (Celenteron etat. (1988) Chest94:119-123). I tillegg er tryptase vist å være et kraftig mitogen for fibroblaster, hvilket indikerer at det er involvert ved pulmonal fibrose og interstitiell lungesykdom (Ross et al. (1991) J. Clin. Invest. 88:493-499). Tryptase, the predominant protease secreted by human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours after anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316:1622-1626), are increased in nasal and lung lavage fluid from atopic patients by specific antigen exposure (Castells et al. (1988) J. Allerg. Clin. Immunol. 141:563-568) and is elevated in lung lavage fluid from atopic asthmatics after endobronchial allergen exposure. Smokers often have markedly elevated bronchoalveolar lavage tryptase levels, a finding that lends some support to the hypothesis that release of proteinase from activated mast cells may contribute to lung destruction in smoker's emphysema. (Celenteron etat. (1988) Chest94:119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, indicating its involvement in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Clin. Invest. 88:493-499).

Astma er ansett som en inflammatorisk lidelse (Hood et al. (1984} I: Benjamin-Cummings, ed. Immunology 2. utg..) og er ofte karakterisert ved progressiv utvikling av hyper-responsivitet i luftrøret og bronkiene både for immunospesifikke allergener og generaliserte kjemiske eller fysiske stimuli. Sykdommen involverer multiple biokjemiske mediatorer både i akutte og kroniske stadier. Hyper-responsivitet i astmatisk bronkievev er antatt å være resultat av kroniske inflammatoriske reaksjoner som irriterer og skader epitelet som bekler luftveisveggen og medfører patologisk fortykning av det underliggende vev. Bronkial-biopsier fra pasienter med bare mild astma har trekk av inflammasjon i luftveisveggen. Asthma is considered an inflammatory disorder (Hood et al. (1984} In: Benjamin-Cummings, ed. Immunology 2. ed..) and is often characterized by the progressive development of hyper-responsiveness in the trachea and bronchi both to immunospecific allergens and generalized chemical or physical stimuli. The disease involves multiple biochemical mediators in both acute and chronic stages. Hyper-responsiveness in asthmatic bronchial tissue is believed to be the result of chronic inflammatory reactions that irritate and damage the epithelium lining the airway wall and cause pathological thickening of the underlying tissue. Bronchial biopsies from patients with only mild asthma have features of inflammation in the airway wall.

Allergiske responser mot inhalerte allergener kan initiere en inflammatorisk sekvens. For eksempel kan allergener aktivere mastceller og basofiler som er til stede i epitelet og underliggende glattmuskelvev, ved å binde IgE lokalisert på celleoverflaten. Aktiverte mastceller frigjør en rekke fordannede eller primære kjemiske mediatorer (f.eks. histamin) av den inflammatoriske respons og danner en rekke andre sekundære mediatorer av inflammasjon (f.eks. superoksyd, lipid-avledede mediatorer, etc.) in situ. I tillegg blir flere store molekyler (f.eks. proteoglykaner, tryptase, chymase, etc.) frigjort ved degranulering av mastceller. Allergic responses to inhaled allergens can initiate an inflammatory sequence. For example, allergens can activate mast cells and basophils present in the epithelium and underlying smooth muscle tissue, by binding IgE located on the cell surface. Activated mast cells release a variety of endogenous or primary chemical mediators (eg, histamine) of the inflammatory response and form a variety of other secondary mediators of inflammation (eg, superoxide, lipid-derived mediators, etc.) in situ. In addition, several large molecules (e.g. proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.

Frigjøringen av disse fordannede mediatorer fra mastceller er sannsynligvis grunnen til den tidlige bronkie-konstriksjon ved astmatisk reaksjon på luftbårne allergener. Den tidlige fase av den astmatiske reaksjon toppes omtrent femten minutter etter utsettelse for allergenet og blir generelt fulgt av bedring i løpet av de påfølgende én til to timer. Tjuefem til trettifem prosent av pasientene opplever en ytterligere nedsettelse i respiratorisk funksjon som maksimaliseres seks til tolv timer etter utsettelsen. Denne sene reaksjonsfase blir ledsaget av en markert økning i antallet inflammatoriske celler (f.eks. eosinofiler, nøytrofiler, lymfocytter, etc.) som infiltrerer bronkievevet. De infiltrerende celler blir trukket til stedet ved frigjøring av mastcelle-avledede kjemotaktiske midler og blir deretter aktivert under den sene reaksjonsfasen. Den sene astmatiske respons er antatt å være en sekundær inflammatorisk reaksjon delvis mediert av den sekretoriske aktivitet til granulocytter. The release of these formed mediators from mast cells is probably the reason for the early bronchial constriction in asthmatic reaction to airborne allergens. The early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to the allergen and is generally followed by recovery over the next one to two hours. Twenty-five to thirty-five percent of patients experience a further reduction in respiratory function that is maximized six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchial tissue. The infiltrating cells are attracted to the site by the release of mast cell-derived chemotactic agents and are then activated during the late reaction phase. The late asthmatic response is thought to be a secondary inflammatory reaction partly mediated by the secretory activity of granulocytes.

Tryptase er implisert i nedbrytning av vasodilaterende og bronkorelakserende nevropeptider (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248:947-951; og Tam et al. (1990) Am. J. Respir. Celt Mol. Biol. 3:27-32) og modulering av bronkial respons på histamin (Sekizawa et al. (1989) J. Clin. Invest. 83:175-179). Disse funn indikerer at tryptase kan øke bronkokonstriksjon ved astma ved å ødelegge bronkodilaterende peptider. Tryptase spalter fibrinogen a-kjeder og kinninogen med høy molekylvekt, hvilket indikerer at tryptase spiller en rolle med heparin som en lokal antikoagulant. Tryptase aktiverer prostromelysin (pro-MMP-3) og prokollagenase (pro-MMP-1) via MMP-3, hvilket indikerer at tryptase er involvert i vevinflammasjon og remodellering og ledd-destruksjon ved revmatoid artritt. Videre beskytter administrering av tryptase-inhibitor mot utvikling av de sene og luftveis-hyper-responsive faser hos allergen-påvirkede sauer (Clark et al. (1995) Am. J. Respir. Crit. Care Med, 152: 2076-2083) og hemmer umiddelbar hud-respons på intradermal injeksjon av allergen i allergiske sauer (Molinari et al. (1995) Amer. Physiol. Soc. 79(6): 1966-1970). Alle de ovenfor beskrevne funn indikerer klart anvendeligheten av tryptase-inhibitorer som terapeutiske midler ved behandling av astma og andre lidelser forbundet med inflammasjon av luftveiene. Tryptase is implicated in the degradation of vasodilator and bronchorelaxant neuropeptides (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248:947 -951; and Tam et al. (1990) Am. J. Respir. Celt Mol. Biol. 3:27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al. (1989) J. Clin. Invest. 83 :175-179). These findings indicate that tryptase can increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase cleaves fibrinogen α-chains and high molecular weight kininogen, indicating that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, indicating that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Furthermore, administration of tryptase inhibitor protects against the development of the late and airway hyper-responsive phases in allergen-affected sheep (Clark et al. (1995) Am. J. Respir. Crit. Care Med, 152: 2076-2083) and inhibits immediate skin response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6): 1966-1970). All the findings described above clearly indicate the utility of tryptase inhibitors as therapeutic agents in the treatment of asthma and other disorders associated with inflammation of the airways.

Angivelsene i disse og andre dokumenter, omfattende patenter og patent-søknader, referert til i denne søknaden inntas her ved referanse. The statements in these and other documents, including patents and patent applications, referred to in this application are incorporated herein by reference.

OPPSUMMERING AV OPPFINNELSEN SUMMARY OF THE INVENTION

Denne søknaden angår en forbindelse med formel I: This application concerns a compound of formula I:

hvor: where:

n1 er 0 eller 1, n2 erO, 1,2, 3 eller 4; n1 is 0 or 1, n2 is 0, 1, 2, 3 or 4;

A sammen med B er 1 H-benzoimidazol-2-yl eller 4,5,6,7-tetrahydro-IH-benzimidazol-2-yl; A together with B is 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl;

X<1> og X<2> er nabostilte ringelementer i en aromatisk ring,og X<1> and X<2> are adjacent ring elements in an aromatic ring, and

X<1> er en heteroatom-gruppe valgt fra -N=, -NR<5->, hvor X<1> is a heteroatom group selected from -N=, -NR<5->, where

R<5> har samme betydning som R<6>; R<5> has the same meaning as R<6>;

C er 1 H-benzoimidazol-2-yl eller 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yi. C is 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl.

X4 og X<5> er nabostilte ringelementer i en aromatisk ring, X4 and X<5> are adjacent ring elements in an aromatic ring,

X<5> er en heteroatom-gruppe valgt fra -N=, og -NR<6->, hvor X<5> is a heteroatom group selected from -N=, and -NR<6->, where

R<6> er hydrogen, en gruppe valgt fra eventuelt med én eller flere hydroksy substituert (C^alkyl, benzoyl, Ci-Ce-alkoksy-Ci-Ce-alkyl, (d.6)alkanoyloksy, (Ci.6)alkylkarbamoyl, di(Ci-6)alkylkarbamoyl, (Ci-6)alkyloksykarbonyl eller (Ci.6)alkyloksysulfonyl; R<6> is hydrogen, a group selected from optionally with one or more hydroxy substituted (C 1-6 alkyl, benzoyl, C 1-C 6-alkyl, C 1-6 )alkanoyloxy, (C 1-6 )alkylcarbamoyl , di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxycarbonyl or (C 1-6 )alkyloxysulfonyl;

X<3> er -CR<7>R8-, hvor X<3> is -CR<7>R8-, where

R7 er hydrogen eller (Ci-e)alkyl; og R 7 is hydrogen or (C 1-6 )alkyl; and

R<8> er hydrogen eller (Ci^Jalkyl, R<8> is hydrogen or (Ci-J alkyl,

R<1> er R<1> is

imidazolyl, imidazolyl,

-(CH2)xNHC(NR<9>)R<9>, -(CH2)xNHC(NR<9>)R<9>,

-(CH2)XNHC(NH)NR<9>R<9>, -(CH2)XNHC(NH)NR<9>R<9>,

-C(NR<9>)R<9>, -C(NR<9>)R<9>,

-C(NH)NHR<10>, -C(NH)NHR<10>,

-C(NH)NR<10>R<10> eller -C(NH)NR<10>R<10> or

-(CR<11>R<11>)yNH2. -(CR<11>R<11>)yNH2.

og er bundet til hvilket som helst ringatom med en tilgjengelig valens i B, hvor and is bonded to any ring atom with an available valence in B, where

x er 0 eller 1, x is 0 or 1,

yer 0, 1, 2 eller 3, yer 0, 1, 2 or 3,

hver R<9> uavhengig er hydrogen eller (C^Jalkyl, each R<9> independently is hydrogen or (C₁₋₄alkyl,

hver R<10> uavhengig er (C^Jalkyl, og each R<10> independently is (C₁₋Jalkyl, and

hver R<11> uavhengig er hydrogen, {Ci.3)alkyl eller sammen med en annen R<11> og et karbonatom til hvilket begge er tilknyttet, danner cyklopropyl, each R<11> independently is hydrogen, {Ci.3)alkyl or together with another R<11> and a carbon atom to which both are attached form cyclopropyl,

hver R<2> uavhengig er: each R<2> independently is:

(C^)alkyl, (C 1 )alkyl,

(Ci^)alkyloksykarbonyl, (C 1-4 )alkyloxycarbonyl,

(Ci^)alkanoyloksy, (C 1-4 )alkanoyloxy,

halogen eller halogen or

hydroksy, hydroxy,

og er bundet til hvilket som helst ringatom med en tilgjengelig valens i B, and is bonded to any ring atom with an available valence in B,

eller R<1> og R<2> sammen med to naboliggende karbonatomer i ring B danner en fenylring; or R<1> and R<2> together with two neighboring carbon atoms in ring B form a phenyl ring;

og and

R<4> er: R<4> is:

(CH2)Y-NH2, (CH2)Y-NH2,

eller or

-C(0)N(R<13>)R<12>, -C(0)N(R<13>)R<12>,

og er bundet til hvilket som helst ringkarbonatom med en tilgjengelig valens i C, hvor: and is bonded to any ring carbon atom with an available valence at C, where:

R<12> er -R15 eller -X<6->(R<15>)ni5, hvor R<12> is -R15 or -X<6->(R<15>)ni5, where

n15er 1 eller 2, n15 is 1 or 2,

X<6> er (Ci.io)alkylen, oksy(C2-io)alkylen, og X<6> is (C1-10)alkylene, oxy(C2-10)alkylene, and

hver R<15> er hydrogen, Ci-Ce-alkoksy, amino. OH, karboksy C1-C6-alkoksykarbonyl, fenyl-Ci-C4-alkoksykarbonyl, tetrazolyl, eventuelt med OH substituert kinolyl, eventuelt med okso og/eller CrC6-alkyl subsituert kinazolinyl, eventuelt med OH elter Ci-C6-alkoksy substituert indolyl, benzoksazolinyl, pyridyl, C3-C7-cykloalkyl, eventuelt med Ci-C6-alkoksykarbonyl substituert C3-C7-cykloalkoksy, tetrahydronaftyl, eventuelt med OH substituert naftyl, fenyl eventuelt substituert med én eller flere substituenter valgt blant halogen, C^ Cq-karbonyl, amino-Ci-C6-alkyl, karboksy, Ci-Ce-alkoksy eller CrCs-alkylendioksy, fenoksy eventuelt substituert med én eller flere substituenter valgt blant Ci-C6-alkoksy, Ci-C6-alkoksykarbonyl, karboksy, Ci-Cs-alkoksy-Ci-Ce-alkoksy-Ci-Ce-alkyl, Ci-Cs-alkoksy-Ci-Ce-alkyl, eventuelt med Ci-Ce-alkyl substituert oksadiazolyl, morfolinyl, halogen, tetrazolyl, C3-C7-cykloalkoksykarbonyl, Ci-Ce-alkoksy-Ci-Ce-alkoksykarbonyl, CN eller karbamoyl, each R<15> is hydrogen, C1-C6 alkoxy, amino. OH, carboxy C1-C6-Alkoxycarbonyl, phenyl-Ci-C4-Alkoxycarbonyl, tetrazolyl, optionally with OH substituted quinolyl, optionally with oxo and/or CrC6-alkyl substituted quinazolinyl, optionally with OH or Ci-C6-Alkoxy substituted indolyl, benzoxazolinyl . -Ci-C6-alkyl, carboxy, C1-C6-alkoxy or CrCs-alkylenedioxy, phenoxy optionally substituted with one or more substituents selected from C1-C6-alkyl, C1-C6-alkoxycarbonyl, carboxy, C1-C6-alkoxy-Ci -Ce-Alkoxy-Ci-Ce-Alkyl, Ci-Cs-Alkoxy-Ci-Ce-Alkyl, optionally with Ci-Ce-Alkyl substituted oxadiazolyl, morpholinyl, halogen, tetrazolyl, C3-C7-Ci-Ce-Alkoxycarbonyl, Ci-Ce-Alkoxy -Ci-Ce-Alkoxycarbonyl, CN or Carbamoyl,

R<13> er hydrogen eller (d-ejalkyl; R<13> is hydrogen or (di-nonalkyl;

eller et W-oksyd-derivat, blanding av isomer og farmasøytisk godtagbart salt derav. or a W-oxide derivative, mixture of isomer and pharmaceutically acceptable salt thereof.

Foreliggende oppfinnelse tilveiebringer også farmasøytiske preparater på basis av forbindelsene ifølge foreliggende oppfinnelse. Disse farmasøytiske preparatene kan være i en rekke former omfattende orale doseformer, inhalerbare former, så vel som injiserbare og infuserbare løsninger. Når de anvendes i inhalerings- eller aerosol-form, blir forbindelsene ifølge foreliggende oppfinnelse anvendt i kombinasjon med en farmasøytisk godtagbar bærer-løsning eller tørt pulver som kan omdannes til aerosol-form. Tilsvarende, når de anvendes ved oral administrering blir forbindelsene ifølge foreliggende oppfinnelse anvendt i kombinasjon med en farmasøytisk godtagbar bærer egnet for slik oral administrering. Når de anvendes for behandling av immunomedierte inflammatoriske hud-lidelser, blir forbindelsene ifølge foreliggende oppfinnelse anvendt i kombinasjon med en ikke-toksisk, farmasøytisk godtagbar topisk bærer. Forbindelsene ifølge foreliggende oppfinnelse kan anvendes i kombinasjon med antiinflammatoriske midler eller andre astma-terapier, så som B-adrenerge agonister, antiinflammatoriske kortikosteroider, anticholinerge midler, bronkodilatatorer så som metylxantener og lignende. The present invention also provides pharmaceutical preparations based on the compounds according to the present invention. These pharmaceutical preparations may be in a variety of forms including oral dosage forms, inhalable forms, as well as injectable and infusible solutions. When used in inhalation or aerosol form, the compounds according to the present invention are used in combination with a pharmaceutically acceptable carrier solution or dry powder that can be converted into aerosol form. Similarly, when used by oral administration, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used for the treatment of immune-mediated inflammatory skin disorders, the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical carrier. The compounds according to the present invention can be used in combination with anti-inflammatory agents or other asthma therapies, such as B-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergic agents, bronchodilators such as methylxanthenes and the like.

Forbindelsene beskrevet her er nyttige for forebygging og behandling av immunomedierte inflammatoriske lidelser og spesielt de forbundet med luftveiene, omfattende astma og spesielt den hyper-responsive fase forbundet med kronisk astma og allergisk rhinitt. Således kan de anvendes til fremstilling av et farmasøytisk preparat for behandling av immunomedierte inflammatoriske lidelser. En immunomediert inflammatorisk tilstand kan behandles med en terapeutisk effektiv dose eller mengde av en forbindelse ifølge foreliggende oppfinnelse. Videre er forbindelsene beskrevet her nyttige for behandling av syncytiale virale infeksjoner. The compounds described herein are useful for the prevention and treatment of immune-mediated inflammatory disorders and particularly those associated with the respiratory tract, including asthma and particularly the hyper-responsive phase associated with chronic asthma and allergic rhinitis. Thus, they can be used for the production of a pharmaceutical preparation for the treatment of immune-mediated inflammatory disorders. An immunomediated inflammatory condition can be treated with a therapeutically effective dose or amount of a compound of the present invention. Furthermore, the compounds described herein are useful for the treatment of syncytial viral infections.

KORT BESKRIVELSE AV TEGNINGENE BRIEF DESCRIPTION OF THE DRAWINGS

Figur 1 sammenligner den spesifikke lungeresistens hos en kontroll (åpne kvadrater) med 2-{5-aminometyl-1 H-benzoimidazol-2-ylmetyl)-A/-(3-fenylpropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 4; fylte kvadrater) over tid målt i timer. Figure 1 compares the specific lung resistance of a control (open squares) to 2-{5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(3-phenylpropyl)-1H-benzoimidazole-5-carboxamide (Compound 4 ; filled squares) over time measured in hours.

Figur 2 er et stolpediagram som viser luftveis-hyperresponsivitet (målt som PC400) antigen-utfordrede hos sauer behandlet med Forbindelse 4 ved aerosol-administrering av tre 1 mg doser mot sauer behandlet med en kontroll. Figure 2 is a bar graph showing airway hyperresponsiveness (measured as PC400) in antigen-challenged sheep treated with Compound 4 by aerosol administration of three 1 mg doses versus sheep treated with a control.

DETALJERT BESKRIVELSE AV OPPFINNELSEN DETAILED DESCRIPTION OF THE INVENTION

Definisjoner: Definitions:

Hvis ikke annet er angitt er de følgende betegnelser anvendt i beskrivelsen og kravene definert for formålene i denne søknaden og har betydningene gitt nedenfor: (Ci-e)alkanoyl omfatter restene formyl, acetyl, propionyl, butyryl, isobutyryl, krotonoyl, isokrotonyl, etc. Unless otherwise stated, the following designations used in the description and claims are defined for the purposes of this application and have the meanings given below: (Ci-e)alkanoyl includes the residues formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.

(Ci-B)alkyl omfatter metyl, etyl, propyl, isopropyl, butyl, se/c-butyl, isobutyl, ferf-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-metylallyl, etynyl, 1-propynyl, 2-propynyl, 3-oksopentyl, 3-tioksopentyl, 3-iminopentyl, etc. (Ci-B)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec/c-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl , 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, 3-oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.

(Ci.io)alkylen omfatter metylen (-CH2-), etylen (-CH2CH2-), metyletylen, vinylen, etynylen, trimetylen (-CH2CH2CH2-), 2-oksotrimetylen (-CH2C(0)CH2-), 2- tiatrimetylen (-CH2C(S)CH2-), 2-iminotrimetylen (-CH2C(NH)CH2-), propenylen (-CH2CH=CH- eller-CH=CHCH2-), propanylyliden (=CHCH2CH2-), propendiylen (=CHCH=CH-), 1-aminotetrametylen, pentametylen, etc. (Ci.io)alkylene includes methylene (-CH2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethynylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C(0)CH2-), 2-thiatrimethylene (-CH2C(S)CH2-), 2-iminotrimethylene (-CH2C(NH)CH2-), propenylene (-CH2CH=CH- or -CH=CHCH2-), propanilylidene (=CHCH2CH2-), propendylylene (=CHCH= CH-), 1-aminotetramethylene, pentamethylene, etc.

(Ci-ejalkyloksy omfatter restene metoksy, etoksy, propoksy, isopropoksy, butoksy, se/c-butoksy, isobutoksy, ferf-butoksy, vinyloksy, allyloksy, 1-propenyloksy, isopropenyloksy, 1-butenyloksy, 2-butenyloksy, 3- butenyloksy, 2-metylallyloksy, etynyloksy, 1-propynyloksy, 2-propynyloksy, etc. (Ci-ejalkyloxy includes the residues methoxy, ethoxy, propoxy, isopropoxy, butoxy, se/c-butoxy, isobutoxy, terf-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.

"Amino" betyr resten -NH2. "Amino" means the residue -NH2.

"Dyr" omfatter mennesker, ikke-humane pattedyr (f.eks. hunder, katter, kaniner, kveg, hester, sauer, geiter, griser, hjortedyr, etc.) og ikke-pattedyr (f.eks. fugler etc). "Animals" includes humans, non-human mammals (eg dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg birds, etc.).

"Karbamoyl" betyr resten -C(0)NH2. "Carbamoyl" means the residue -C(O)NH2.

"Karboksy" betyr resten -C(0)OH. "Carboxy" means the residue -C(0)OH.

"Cyano" betyr resten -CN. "Cyano" means the residue -CN.

(C3-i4)cykloalkyl omfatter cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheksenyl, 2,5-cykloheksadienyl, bicyklo[2,2,2]oktyl, oksocykloheksyl, dioksocykloheksyl, tiocykloheksyl, etc. (C3-14)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2,2,2]octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.

"Avbeskyttelse av" angir fjerning av eventuelle beskyttende grupper til stede etter at den sefektive reaksjon er utført. "Deprotection of" refers to the removal of any protecting groups present after the effective reaction has been performed.

"Sykdom" omfatter spesifikt en hvilken som helst sykelig tilstand hos et dyr eller i en del av det og omfatter en sykelig tilstand som kan være forårsaket av eller forbundet med, medisinsk eller veterinær terapi anvendt på dyr, "Disease" specifically includes any morbid condition in an animal or part thereof and includes a morbid condition which may be caused by, or associated with, medical or veterinary therapy applied to animals,

dvs. "bivirkninger" av slik terapi. i.e. "side effects" of such therapy.

"Kondensert heteropolycyklisk rest" omfatter "kondensert heterobicyklisk rest" og betyr en heterocyklisk rest inneholdende to til tre kondenserte ringer som har antallet ringelementer angitt, hvor minst to ringelementer av én ring er felles med en andre ring (f.eks. omfatter en heteropolycyklisk rest inneholdende fra 8 til 18 ringatomer og karbocykliske keton- og tioketon-derivater derav, 1 H-benzimidazol-2-yl, 1 H-nafto[2,3-cf]imidazol-2-yl, 1 H-imidazo[4,5-f]kinolin-2-yl, 1 H-imidazo[4,5-b]pyrid in-2-yl, 1 H-fenantro[9,10-cqimidazol-2-yl, 1 H-imidazo[4,5-g]kinoksalin-2-yl, 2,6-diokso-2,3,6,7-tetrahydro-1H-purin-8-ylt 2,6-ditiokso-2,3,6I9-tetrahydro-1H-purin-8-yl, 7f7-purin-8-yl, 1,6-dihydrocyklopentaimidazol-2-yl, 4-kinolin-2-yl, etc). "Fused heteropolycyclic residue" includes "fused heterobicyclic residue" and means a heterocyclic residue containing two to three fused rings having the number of ring elements indicated, where at least two ring elements of one ring are shared with a second ring (e.g., a heteropolycyclic residue comprises containing from 8 to 18 ring atoms and carbocyclic ketone and thioketone derivatives thereof, 1 H-benzimidazol-2-yl, 1 H-naphtho[2,3-cf]imidazol-2-yl, 1 H-imidazo[4,5 -f]quinolin-2-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-phenanthro[9,10-cqimidazol-2-yl, 1H-imidazo[4,5 -g]quinoxalin-2-yl, 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl 2,6-dithioxo-2,3,619-tetrahydro-1H-purin- 8-yl, 7β-purin-8-yl, 1,6-dihydrocyclopentamidazol-2-yl, 4-quinolin-2-yl, etc).

"Guanidino" betyr resten -NHC(NH)NH2. "Guanidino" means the residue -NHC(NH)NH2.

"Halogen" betyr fluor, klor, brom eller jod. "Halogen" means fluorine, chlorine, bromine or iodine.

"Hydroksy" betyr resten -OH. "Hydroxy" means the residue -OH.

"Immunomediert inflammatorisk lidelse" betyr sykdommer som er "Immune-mediated inflammatory disorder" means diseases which are

forbundet med mastcelle-mediator-frigjøring og mottagelige for behandling med en tryptase-inhibitor (f.eks. immediat-type hypersensitivitetssykdommer så som astma, allergisk rhinitt, urtikaria og angioødem, eksematøs anafylaksi, dermatitt så som atopisk dermatitt, hyperproliferativ hudsykdom, peptiske ulcere, inflammatorisk tarmlidelse, okulær og vernal konjunktivitt, revmatoid artritt, inflammatoriske hud-lidelser og lignende). associated with mast cell mediator release and amenable to treatment with a tryptase inhibitor (e.g. immediate-type hypersensitivity diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczematous anaphylaxis, dermatitis such as atopic dermatitis, hyperproliferative skin disease, peptic ulcers , inflammatory bowel disease, ocular and vernal conjunctivitis, rheumatoid arthritis, inflammatory skin disorders and the like).

"Hyper-responsivitet" betyr senfase bronkokonstriksjon og luftveis-hyperreaktivitet forbundet med kronisk astma. Hyper-responsivitet i astmatisk bronkiolart vev er antatt å være et resultat av kroniske "Hyper-responsiveness" means the late-phase bronchoconstriction and airway hyper-reactivity associated with chronic asthma. Hyper-responsiveness in asthmatic bronchiolar tissue is thought to be the result of chronic

inflammasjonsreaksjoner, som irriterer og skader epitelet som kler luftveiene og medfører patologisk fortykning av det underliggende vev. inflammatory reactions, which irritate and damage the epithelium lining the airways and cause pathological thickening of the underlying tissue.

"Syncytial viral infeksjon" betyr en infeksjon med et virus, så som respiratorisk syncytial virus, som forårsaker dannelse av en cellulær protoplasmatisk masse, dvs. syncytia, via infeksjon. "Syncytial viral infection" means an infection with a virus, such as respiratory syncytial virus, which causes the formation of a cellular protoplasmic mass, i.e. syncytia, via infection.

"Imino" betyr resten =NH. "Imino" means the residue =NH.

"Isomerer" betyr forbindelser med formel I som har identiske molekylformler, men adskiller seg i type eller sekvens av binding av deres atomer eller plassering av deres atomer i rommet. Isomerer som adskiller seg ved deres plassering av atomer i rommet er betegnet "stereoisomerer". Stereoisomerer som ikke er speilbilder av hverandre er betegnet "diastereomerer" og stereoisomerer som er ikke-superponerbare speilbilder er betegnet "enantiomerer" eller noen ganger "optiske isomerer". Et karbonatom bundet til fire ikke-identiske substituenter er betegnet et "chiralt senter". En forbindelse med ett chiralt senter har to enantiomere former med motsatt chiralitet og er betegnet en "racemisk blanding". En forbindelse som har mer enn ett chiralt senter har 2""<1> enantiomere par, hvor n er antallet chirale sentere. Forbindelser med mer enn ett chiralt senter kan eksistere som enten en individuell diastereomer eller som en blanding av diastereomerer, betegnet en "diastereomer blanding". Når ett chiralt senter er til stede kan en stereoisomer karakteriseres ved den absolutte konfigurasjon av det chirale senter. Absolutt konfigurasjon angir plasseringen i rommet av substituentene bundet til det chirale senter. Substituentene bundet til det aktuelle chirale senter er rangert i henhold til the Sequence Rule of Cahn, Ingold and Prelog og den absolutte deskriptor R eller S er angitt i parentes fulgt av en bindestrek og det kjemiske navnet til forbindelsen. Forbindelser med formel I som inneholder et chiralt senter kan eksistere som individuelle stereosiomerer eller blandinger av steroisomerer. For formålene med foreliggende søknad skal det forstås at når det henvises til en forbindelse med formel I med navn eller formel og konfigurasjonen ikke er angitt omfattes alle mulige konfigurasjoner av forbindelsen. "Isomers" means compounds of formula I which have identical molecular formulas but differ in the type or sequence of bonding of their atoms or the position of their atoms in space. Isomers that differ by their position of atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of each other are termed "diastereomers" and stereoisomers that are non-superimposable mirror images are termed "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four non-identical substituents is termed a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality and is termed a "racemic mixture". A compound having more than one chiral center has 2""<1> enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomer mixture". When one chiral center is present, a stereoisomer can be characterized by the absolute configuration of the chiral center. Absolute configuration indicates the position in space of the substituents bound to the chiral center. The substituents attached to the relevant chiral center are ranked according to the Sequence Rule of Cahn, Ingold and Prelog and the absolute descriptor R or S is indicated in parentheses followed by a hyphen and the chemical name of the compound. Compounds of formula I containing a chiral center may exist as individual stereoisomers or mixtures of stereoisomers. For the purposes of the present application, it should be understood that when reference is made to a compound of formula I by name or formula and the configuration is not specified, all possible configurations of the compound are included.

"Eventuell" eller "eventuelt" betyr at den deretter beskrevne hendelse eller omstendighet kan eller kan ikke forekomme og at beskrivelsen omfatter tilfeller hvor hendelsen eller omstendigheten forekommer og tilfeller hvor den "Contingent" or "eventually" means that the event or circumstance described below may or may not occur and that the description includes cases where the event or circumstance occurs and cases where the

ikke forekommer. For eksempel betyr uttrykket "eventuelt substituert med én til tre rester" at gruppen referert til kan eller kan ikke være susbtituert for å falle innenfor omfanget av foreliggende oppfinnelse. does not occur. For example, the phrase "optionally substituted with one to three residues" means that the group referred to may or may not be substituted to fall within the scope of the present invention.

"N-oksyd-derivater" betyr derivater av en forbindelse med formel I hvor nitrogener er i en oksydert tilstand (dvs. O-N), som har den ønskede farmakologiske aktivitet. A/-oksyd-derivater av forbindelser med formel I kan fremstilles ved metoder kjent til fagfolk på området. "N-oxide derivatives" means derivatives of a compound of formula I wherein the nitrogens are in an oxidized state (ie, O-N), which have the desired pharmacological activity. N-oxide derivatives of compounds of formula I can be prepared by methods known to those skilled in the art.

"Patologi" for en sykdom betyr den vesentlige natur, årsak og utvikling av sykdommen så vel som de strukturelle og funksjonelle endringer som er et resultat av sykdomsprosessene. "Pathology" for a disease means the essential nature, cause and development of the disease as well as the structural and functional changes resulting from the disease processes.

"Farmasøytisk godtagbar" betyr det som er nyttig for fremstilling av et farmasøytisk preparat som generelt er sikkert, ikke-toksisk og ikke hverken biologisk eller på annen måte er uønsket og omfatter det som er godtagbart for veterinær anvendelse så vel som for human-farmasøytisk anvendelse. "Pharmaceutically acceptable" means that which is useful for the manufacture of a pharmaceutical preparation which is generally safe, non-toxic and not biologically or otherwise undesirable and includes that which is acceptable for veterinary use as well as for human pharmaceutical use .

"Farmasøytisk godtagbare salter" betyr salter av forbindelser med formel I som er farmasøytisk godtagbare, som definert ovenfor og som har den ønskede farmakologiske aktivitet. Slike salter omfatter syreaddisjonssalter dannet med uorganiske syrer så som saltsyre, bromhydrogensyre, svovelsyre, salpetersyre, fosforsyre og lignende; eller med organiske syrer så som eddiksyre, propionsyre, heksansyre, heptansyre, cyklopentanpropionsyre, glykolsyre, pyrodruesyre, melkesyre, malonsyre, ravsyre, eplesyre, maleinsyre, fumarsyre, vinsyre, sitronsyre, benzosyre, o-(4-hydroksybenzoyl)benzosyre, kanelsyre, mandelsyre, metansulfonsyre, etansulfonsyre, 1,2-etandisulfonsyre, 2-hydroksyetansulfonsyre, benzensulfonsyre, p-klorbenzensulfonsyre, 2-naftalensulfonsyre, p-toluensulfonsyre, kamfersulfonsyre, 4-metylbicyklo[2,2,2]okt-2-en-1 -karboksylsyre, glukoheptonsyre, 4,4'-metylenbis(3-hydroksy-2-en-1-karboksylsyre), 3-fenylpropionsyre, trimetyleddiksyre, tertiær butyleddiksyre, laurylsvovelsyre, glukonsyre, glutaminsyre, hydroksynaftoesyre, salicylsyre, stearinsyre, muconsyre og lignende. "Pharmaceutically acceptable salts" means salts of compounds of formula I which are pharmaceutically acceptable, as defined above, and which have the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]oct-2-ene-1-carboxylic acid , glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulphuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Farmasøytisk godtagbare salter omfatter også baseaddisjonssalter som kan dannes når sure protoner som er til stede kan reagere med uorganiske eller organiske baser. Godtagbare uorganiske baser omfatter natriumhydroksyd, natriumkarbonat, kaliumhydroksyd, aluminiumhydroksyd og kalsiumhydoksyd. Godtagbare organiske baser omfatter etanolamin, dietanolamin, trietanolamin, trometamin, W-metylglukamin og lignende. Pharmaceutically acceptable salts also include base addition salts which can be formed when acidic protons present can react with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Beskyttende gruppe" har betydningen som konvensjonelt er forbundet med dette innen syntetisk organisk kjemi, dvs. en gruppe som selektivt blokkerer et reaktivt element i en multifunksjonell forbindelse slik at en kjemisk reaksjon kan utføres selektivt med et annet ubeskyttet reaktivt element og som lett kan fjernes etter at den selektive reaksjon er fullført. "Protecting group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e. a group which selectively blocks a reactive element in a multifunctional compound so that a chemical reaction can be carried out selectively with another unprotected reactive element and which can be easily removed after the selective reaction is complete.

"Beskyttede derivater" betyr derivater av forbindelser med formel I hvor et reaktivt element eller elementer er blokkert med beskyttende grupper. Beskyttede derivater av forbindelser med formel I er nyttige for fremstilling av forbindelser med formel I. Egnede beskyttelsesgrupper for reaktive nitrogenatomer omfatter fert-butoksykarbonyl, benzyloksykarbonyl og hvilke som helst andre egnede amino-beskyttende grupper (se f.eks. T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981). Spesielt er et egnet beskyttet derivat med formel I eksemplifisert ved forbindelsen 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1 H-benzoimidazol-2-ylmetylJ-4,5,6,7-tetrahydro-1 W-benzoimidazol-5-karboksylsyre. "Protected derivatives" means derivatives of compounds of formula I in which a reactive element or elements are blocked with protecting groups. Protected derivatives of compounds of formula I are useful for the preparation of compounds of formula I. Suitable protecting groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino-protecting groups (see, e.g., T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981). In particular, a suitable protected derivative of formula I is exemplified by the compound 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethylJ-4,5,6, 7-tetrahydro-1N-benzoimidazole-5-carboxylic acid.

'Terapeutisk effektiv mengde" betyr den mengde som når den blir administrert til et dyr, er effektiv for behandling av en sykdom. "Therapeutically effective amount" means that amount which, when administered to an animal, is effective in the treatment of a disease.

"Behandling" eller "behandling av" angir hvilken som helst administrering av en forbindelse ifølge foreliggende oppfinnelse og omfatter: "Treatment" or "treatment of" refers to any administration of a compound of the present invention and includes:

(1) forhindring av at sykdommen skal forekomme hos et dyr som kan være predisponert for sykdommen, men som enda ikke merker eller viser patologien eller symptomer ved sykdommen, (2) hemning av sykdommen, dvs. stansing av utviklingen av dens patologi og/eller symptomer, eller (3) forbedring av sykdommen, dvs. reversering av dens patologi og/eller symptomer. (1) preventing the disease from occurring in an animal that may be predisposed to the disease, but which does not yet notice or show the pathology or symptoms of the disease, (2) inhibition of the disease, i.e. halting the development of its pathology and/or symptoms, or (3) amelioration of the disease, i.e., reversal of its pathology and/or symptoms.

Forbindelsene med formel I og mellomproduktene og utgangsmaterialene anvendt for deres fremstilling er betegnet i henhold til IUPAC nomenklatur-reglene. For eksempel er en forbindelse med formel I hvor: The compounds of formula I and the intermediates and starting materials used for their preparation are designated according to the IUPAC nomenclature rules. For example, a compound of formula I is where:

A sammen med B omfatter 5-guanidino-1H-benzoimidazol-2-yl, A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl,

C omfatter 5-(2-naft-1 -yletylkarbamoyl)-1 H-benzoimidazol-2-yl og X<3> er -CH2-, C comprises 5-(2-naphth-1-ylethylcarbamoyl)-1H-benzoimidazol-2-yl and X<3> is -CH2-,

betegnet 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-A/-(2-naft-1-yletyl- designated 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl-

1 H-benzoimidazol-5-karboksamid; 1 H-benzoimidazole-5-carboxamide;

A sammen med B omfatter 5-guanidino-1H-benzoimidazol-2-yl, A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl,

C omfatter 6-(2-naft-1-yletylkarbamoyl)-1-metyl-1H-benzoimidazol-2-yl og X<3> er -CH2- er betegnet 2-(5-guanidino-1 W-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1-yletyl-3H-benzoimidazol-5-karboksamid; C comprises 6-(2-naphth-1-ylethylcarbamoyl)-1-methyl-1H-benzoimidazol-2-yl and X<3> is -CH2- is designated 2-(5-guanidino-1N-benzoimidazol-2- ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl-3H-benzoimidazole-5-carboxamide;

A sammen med B omfatter 5-guanidino-1H-benzoimidazol-2-yl, A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl,

C omfatter 6-[2-(2-karboksyfenyl)etylkarbamoyl]-1-(3-sulfopropy(-1H-benzoimidazol-2-yl og X<3> er -CH2- er betegnet 2-{2-[2-{5-guanidino-1W-benzoimidazol-2-ylmetyl)-3-(3-sulfopropyl)-3H-benzoimidazol-5-ylkarbonylamino]etyl}benzosyre; og C comprises 6-[2-(2-carboxyphenyl)ethylcarbamoyl]-1-(3-sulfopropyl(-1H-benzoimidazol-2-yl) and X<3> is -CH2- is designated 2-{2-[2-{ 5-guanidino-1N-benzoimidazol-2-ylmethyl)-3-(3-sulfopropyl)-3H-benzoimidazol-5-ylcarbonylamino]ethyl}benzoic acid; and

A sammen med B omfatter 5-guanidino-1H-benzoimidazol-2-yl, A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl,

C omfatter 6-[2-(2-metoksyfenyl)etylkarbamoyl]-1-(3-sulfopropyl-1H-benzoimidazot-2-yl og X<3> er -CH2- er betegnet 3-{2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-6-[2-(2-metoksyfenyl)etylkarbamoyl]-benzoimidazol-1 -yl}propan-1 -sulfonsyre. C comprises 6-[2-(2-methoxyphenyl)ethylcarbamoyl]-1-(3-sulfopropyl-1H-benzoimidazot-2-yl and X<3> is -CH2- is designated 3-{2-(5-guanidino- 1H-benzoimidazol-2-ylmethyl)-6-[2-(2-methoxyphenyl)ethylcarbamoyl]-benzoimidazol-1-yl}propane-1-sulfonic acid.

Visse forbindelser med formel I eksisterer i tautomer likevekt. For eksempel eksisterer forbindelser med formel I hvor C omfatter 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl i likevekt mellom tautomerer med de følgende formler: Certain compounds of formula I exist in tautomeric equilibrium. For example, compounds of formula I where C comprises 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl exist in equilibrium between tautomers of the following formulas:

og det skal således forstås at mens forbindelsene ifølge foreliggende oppfinnelse kan være betegnet, illustrert eller på annen måte beskrevet i denne søknaden som én mulig tautomer, skal alle mulige tautomerer omfattes av slike navn, illustrasjoner og beskrivelser. Således skal etyl-2-(4-{2-[1-(5-guanidino-1W-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-4-oksobutyl)benzoat omfatte dens tautomerer etyl-2-(4-{2-[1-(5-guanidino-3W-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-4-oksobutyl)benzoat, etyl 2-(4-{2-[1 -(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oksobutyl)benzoat og etyl 2-(4-{2-[1-(5-guanidino-3H-benzoimidazol-2-yl)-etylj-S^.ej-tetrahydroimidazo^.S-clpyridin-S-ylM-oksobutylJbenzoat. and it is thus to be understood that while the compounds according to the present invention may be designated, illustrated or otherwise described in this application as one possible tautomer, all possible tautomers shall be encompassed by such names, illustrations and descriptions. Thus, ethyl-2-(4-{2-[1-(5-guanidino-1W-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine -5-yl}-4-oxobutyl)benzoate including its tautomers ethyl-2-(4-{2-[1-(5-guanidino-3W-benzoimidazol-2-yl)ethyl]-1,4,6,7 -tetrahydro-imidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate, ethyl 2-(4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl ]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate and ethyl 2-(4-{2-[1-(5-guanidino-3H- benzoimidazol-2-yl)-ethyl (S) -tetrahydroimidazo (S) -pyridin-S-yl (N)-oxobutyl (S)benzoate.

Foretrukne utførelsesformer: Preferred embodiments:

Mens den bredeste definisjon av foreliggende oppfinnelse er angitt under Oppsummering av oppfinnelsen er visse aspekter ved foreliggende oppfinnelse foretrukket. Et foretrukket aspekt ved foreliggende oppfinnelse er en forbindelse med formel I hvor A sammen med B omfatter en kondensert heterobicyklisk rest hvor A inneholder 5 ringelementer og B inneholder 6 ringelementer og X<4> og X<5> er nabostilte elementer i en oksazol-2-yl, 1/-/-imidazol-2-yl eller tiazol-2-ylring. While the broadest definition of the present invention is set forth under Summary of the Invention, certain aspects of the present invention are preferred. A preferred aspect of the present invention is a compound of formula I where A together with B comprises a condensed heterobicyclic residue where A contains 5 ring elements and B contains 6 ring elements and X<4> and X<5> are adjacent elements in an oxazole-2 -yl, 1 H -imidazol-2-yl or thiazol-2-yl ring.

Et foretrukket aspekt ved foreliggende oppfinnelse er forbindelser med formel II: A preferred aspect of the present invention are compounds of formula II:

hvor: where:

de stiplede linjer uavhengig representerer eventuelle bindinger; the dashed lines independently represent any bonds;

hver R<2> uavhengig er: each R<2> independently is:

(Ci.6)alkyl, (Ci-6)alkyl,

halogen eller halogen or

hydroksy; hver hydroxy; each

X<3> er -CR<7>R<8->; hvor R7 og R<8> uavhengig er hydrogen eller (Ci-C6)alkyl; X<3> is -CR<7>R<8->; where R7 and R<8> are independently hydrogen or (C1-C6)alkyl;

X<8> er -CHtRV- eller -C(R<1>)ni= , hvor R1 er: X<8> is -CHtRV- or -C(R<1>)ni= , where R1 is:

imidazolyl, imidazolyl,

-NHC(NH)NR<9>R<9>, -NHC(NH)NR<9>R<9>,

-C(NR<9>)R<9>, -C(NR<9>)R<9>,

-C{NH)NHR<10>, -C{NH)NHR<10>,

-C(NH)NR<1>0R10 eller -C(NH)NR<1>0R10 or

-{CR11R1<1>)yNH2, hvor hver R<9> uavhengig er hydrogen eller (C-i_6)alkyl og hver R<10> uavhengig er (Ci-6)alkyl; og X<9> er -CH(R<4>)- eller -C(R4)= hvor -{CR11R1<1>)yNH2, where each R<9> is independently hydrogen or (C1-6)alkyl and each R<10> is independently (C1-6)alkyl; and X<9> is -CH(R<4>)- or -C(R4)= where

R<4> er: R<4> is:

(CH2)Y-NH2; (CH2)Y-NH2;

eller -C(0)N(R13)R1<2>, or -C(0)N(R13)R1<2>,

hvori y er 0,1, 2 eller 3. where y is 0.1, 2 or 3.

Fortrinnsvis er Preferably is

R5 hydrogen eller (Cn)alkyl, R5 hydrogen or (Cn)alkyl,

R<6> er hydrogen eller (Ci^)alkyl, hvilken alkylgruppe eventuelt er substituert med én til to hydroksy, R<6> is hydrogen or (Ci^)alkyl, which alkyl group is optionally substituted with one to two hydroxy,

R7 er hydrogen eller metyl, og R 7 is hydrogen or methyl, and

R<8> er hydrogen eller metyl; R<8> is hydrogen or methyl;

X8er-C(R1)ni= , hvor X8 is-C(R1)ni= , where

R<1> er: R<1> is:

aminometyl, aminomethyl,

2-amino-1,1-dimetyletyl, 2-amino-1,1-dimethylethyl,

imidazolyl, imidazolyl,

-C(NR<9>)R<9>, hvor -C(NR<9>)R<9>, where

hver R<9> uavhengig er hydrogen eller metyl; each R<9> is independently hydrogen or methyl;

X9 er-C(R4)= X9 is -C(R4)=

hvor R<4> er: where R<4> is:

-C(0)N(R<13>)R<12>, -C(0)N(R<13>)R<12>,

hvor where

R<13> er hydrogen eller (Ci^)alkyl; R<13> is hydrogen or (C1-4)alkyl;

R<12> er -R<15> eller -X<6->(R<15>)ni5, hvor R<12> is -R<15> or -X<6->(R<15>)ni5, where

X<6> er {C-i-io)aikylen eller hetero(CMo)alkylen, og X<6> is {C-1-io)alkylene or hetero(CMo)alkylene, and

hver R<15> uavhengig er som forut definert, each R<15> independently is as previously defined,

eller et /V-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbare salter derav. or a /V-oxide derivative, mixture of isomers or pharmaceutically acceptable salts thereof.

Et foretrukket aspekt ved foreliggende oppfinnelse er forbindelser med formel I hvor: A sammen med B danner 1 H-benzoimidazol-2-yl eller 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl, hvor A preferred aspect of the present invention are compounds of formula I where: A together with B forms 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl, where

R<1> er aminometyl, og R<1> is aminomethyl, and

hver R<2> uavhengig er halogen eller hydroksy; each R<2> independently is halogen or hydroxy;

C er 1H-benzoimidazol-2-yl, hvor C is 1H-benzoimidazol-2-yl, where

R<4>, X6 og R<15> er som forut definert; R<4>, X6 and R<15> are defined as before;

eller et /V-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbare salter derav. or a /V-oxide derivative, mixture of isomers or pharmaceutically acceptable salts thereof.

Videre foretrukket er forbindelser hvor Further preferred are compounds where

A sammen med B danner 1H-benzoimidazol-2-yl og hver A together with B form 1H-benzoimidazol-2-yl and each

R2 uavhengig er halogen eller hydroksy; R 2 independently is halogen or hydroxy;

eller et A/-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav. or an A/-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof.

Spesielt foretrukket bland disse er forbindelser hvor Particularly preferred among these are compounds where

n1 er 0; eller et A/-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav. n1 is 0; or an A/-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof.

Et foretrukket aspekt ved foreliggende oppfinnelse er forbindelser valgt fra A preferred aspect of the present invention is compounds selected from

(a) 2-(2-{2-[1 -{4,6,7-trifluor-l H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre; (forb. 80) (b) 2-(2-{2-[1-(5,6-difluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre; (forb. 81) (c) butyl-2-(2-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 37) (d) propyl-2-(2-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-y!)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 42), og (e) isobutyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 43), A/-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav. (a) 2-(2-{2-[1-{4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid ; (comp. 80) (b) 2-(2-{2-[1-(5,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3N-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoic acid; (comp. 81) (c) butyl-2-(2-{2-[1 -(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoate; (comp. 37) (d) propyl-2-(2-{2-[1 -(5-hydroxy-1H-benzoimidazol-2-yl!)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino }ethoxy)benzoate; (comp. 42), and (e) isobutyl-2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino }ethoxy)benzoate; (comp. 43), A/-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof.

Et foretrukket aspekt ved foreliggende oppfinnelse er forbindelser med formel I hvor R<1> er aminometyl eller et N-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav, spesielt: (a) 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 28); (b) 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)propyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 132); (c) 2-(5-guanidino-1/-/-benzoimidazol-2-ylkarbonyl)-3-(2,3-dihydroksy)propyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 134); (d) 2-(5-guanidino-1/-/-benzoimidazol-2-ylmetyl)-3-(3-hydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 138); (e) 2-(5-guanidino-1H-benzoimidazol-2-ylmety1)-3-(2-hydroksy)etyl-W-(2-naft-1-yletyl)-3/-/-benzoimidazol-5-karboksamid; (forb. 152); (f) 2-[1-(5-guanidino-1H-benzoimidazol-2-y!)etyl]-W-[2-(2-karbamoyl-fenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid; (forb. 249); (g) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-N-[2-(2-karbamoyl-4-klorfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid; (forb. 250); (h) 4-klor-2-[2-{{2-[1-(5-guanidino-1H-benzoimidazot-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonyl}amino)etoksy]benzosyre; (forb. 251); (i) 5-klor-2-[2-({2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonyl}amino)etoksy]benzosyre; (forb. 2 52); A preferred aspect of the present invention are compounds of formula I where R<1> is aminomethyl or an N-oxide derivative, mixture of isomers or a pharmaceutically acceptable salt thereof, in particular: (a) 2-(5-guanidino-1H-benzoimidazole) -2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide; (prob. 28); (b) 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ; (prob. 132); (c) 2-(5-guanidino-1/-/-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol- 5-carboxamide; (prob. 134); (d) 2-(5-guanidino-1/-/-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ; (prob. 138); (e) 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl-N-(2-naphth-1-ylethyl)-3 H -benzoimidazol-5-carboxamide ; (prob. 152); (f) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl!)ethyl]-W-[2-(2-carbamoyl-phenoxy)ethyl]-3-methyl-3H-benzoimidazol-5- carboxamide; (prob. 249); (g) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-N-[2-(2-carbamoyl-4-chlorophenoxy)ethyl]-3-methyl-3H-benzoimidazol-5 -carboxamide; (prob. 250); (h) 4-chloro-2-[2-{{2-[1-(5-guanidino-1H-benzoimidazot-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonyl}amino)ethoxy ]benzoic acid; (prob. 251); (i) 5-Chloro-2-[2-({2-[1 -(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonyl}amino) ethoxy]benzoic acid; (prob. 2 52);

(j) 2-(5-aminometyl-1 H-benzoirnidazol-2-ylmetyl)-3-rnetyl-W-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 102); og (j) 2-(5-aminomethyl-1H-benzonidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide; (prob. 102); and

(k) 2-(5-aminometyl-4)5l6,7-tetrahydro-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (forb. 112); (k) 2-(5-aminomethyl-4)5l6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5- carboxamide (comp. 112);

eller et W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav. or a W-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof.

Farmakologi og anvendelighet: Pharmacology and applicability:

Forbindelsene ifølge foreliggende oppfinnelse er serinprotease-inhibitorer og er som sådanne nyttige for behandling av sykdommer forbundet med øket serinprotease-aktivitet. Spesielt er forbindelsene ifølge foreliggende oppfinnelse tryptase-inhibitorer og er nyttige for behandling av sykdommer forbundet med øket tryptase-aktivitet. In v/f/u-protokoller for screening av potensielle inhibitorer for deres evne til å hemme tryptase er kjent på området. Se f. eks. Sturzebecher et al. (1992) Biol. Chem. Hoppe- Seyler 373:1025-1030. Typisk måler disse forsøk enzym-fremkalt hydrolyse av peptid-baserte kromogene substanser. Detaljer ved en eksempelvis fremgangsmåte for å måle tryptase-hemmende aktivitet er beskrevet nedenfor. The compounds according to the present invention are serine protease inhibitors and as such are useful for the treatment of diseases associated with increased serine protease activity. In particular, the compounds according to the present invention are tryptase inhibitors and are useful for the treatment of diseases associated with increased tryptase activity. In v/f/u protocols for screening potential inhibitors for their ability to inhibit tryptase are known in the art. See e.g. Sturzebecher et al. (1992) Biol. Chem. Hoppe- Seyler 373:1025-1030. Typically, these experiments measure enzyme-induced hydrolysis of peptide-based chromogenic substances. Details of an exemplary method for measuring tryptase inhibitory activity are described below.

I tillegg kan aktiviteten av forbindelsene ifølge foreliggende oppfinnelse evalueres in vivo i én av en rekke dyre-modeller med astma. Se Larson, "Experimental Models of Reversible Airway Obstruction", i The Lun<g>: Scientific Foundations, Crystal, West et al., ed., Raven Press, New york, 1991; Warner et al. (1990) Am. Rev. Respir. Dis. 141:253-257. En ideell dyremodell vil duplisere de viktigste kliniske og fysiologiske trekk ved human astma, omfattende: luftveis-hyperresponsivitet for kjemiske mediatorer og fysiske stimuli; reversering av luftveisobstruksjon med medikamenter nyttige ved human astma (B-adrenerge midler, metylxantiner, kortikosteroider og lignende); luftveisinflammasjon med infiltrering av aktiverte leukocytter; og kroniske inflammatoriske degenerative endringer, så som basalmembran-fortykning, glattmuskel-hypertrofi og epitel-skade. Arter anvendt som dyremodeller omfatter mus, rotter, marsvin, kaniner, hunder og sauer. Alle har noen begrensninger og det riktige valg av dyremodell avhenger av det aktuelle problem. In addition, the activity of the compounds according to the present invention can be evaluated in vivo in one of a number of animal models with asthma. See Larson, "Experimental Models of Reversible Airway Obstruction", in The Lun<g>: Scientific Foundations, Crystal, West et al., ed., Raven Press, New York, 1991; Warner et al. (1990) Am. Fox. Breathe. Haze. 141:253-257. An ideal animal model would duplicate the key clinical and physiological features of human asthma, including: airway hyperresponsiveness to chemical mediators and physical stimuli; reversal of airway obstruction with drugs useful in human asthma (B-adrenergic agents, methylxanthines, corticosteroids and the like); airway inflammation with infiltration of activated leukocytes; and chronic inflammatory degenerative changes, such as basement membrane thickening, smooth muscle hypertrophy and epithelial damage. Species used as animal models include mice, rats, guinea pigs, rabbits, dogs and sheep. All have some limitations and the right choice of animal model depends on the problem in question.

Den initielle astmatiske respons kan evalueres i marsvin og hunder og spesielt, med en basenji-mynde kryss-stamme som utvikler ikke-spesifikk luftveis-hyper-responsivitet for en rekke ikke-allergene substanser, så som metacholin og sitronsyre. Visse utvalgte sauer viser dobbel respons etter antigen-utfordring med Ascaris- proteiner. Hos dobbel-responsive dyr blir den initielle astmatiske respons (IAR) fulgt av en senere astmatisk respons (LAR) 6-8 timer etter påvirkning. Hypersensitivitet for den cholinerge agonist karbachol øker 24 timer etter antigen-utfordring hos de dyr som oppviser LAR. The initial asthmatic response can be evaluated in guinea pigs and dogs and, in particular, with a basenji-like cross-strain that develops non-specific airway hyper-responsiveness to a number of non-allergenic substances, such as methacholine and citric acid. Certain selected sheep show a double response after antigen challenge with Ascaris proteins. In dual-responsive animals, the initial asthmatic response (IAR) is followed by a later asthmatic response (LAR) 6-8 hours after exposure. Hypersensitivity to the cholinergic agonist carbachol increases 24 hours after antigen challenge in the animals exhibiting LAR.

Den allergiske sauemodell (se nedenfor) ble anvendt for å bedømme de potensielle antiastmatiske effekter av forbindelsene ifølge foreliggende oppfinnelse. Administrering av preparater omfattende forbindelsene ifølge foreliggende oppfinnelse til allergiske sauer i både orale og inhalerings- eller aerosol-preparater, før eller etter påvirkning av de spesifikke allergener demonstrerer at slike preparater vesentlig reduserer eller opphever den sene astmatiske respons og resulterende hyper-responsivitet. The allergic sheep model (see below) was used to assess the potential antiasthmatic effects of the compounds of the present invention. Administration of preparations comprising the compounds according to the present invention to allergic sheep in both oral and inhalation or aerosol preparations, before or after exposure to the specific allergens, demonstrates that such preparations significantly reduce or abolish the late asthmatic response and resulting hyper-responsiveness.

Forbindelsene ifølge foreliggende oppfinnelse er også nyttige for behandling av andre immunomedierte inflammatoriske lidelser hvor tryptase-aktivitet bidrar til den patologiske tilstanden. Slike sykdommer omfatter inflammatoriske sykdommer forbundet med mastceller, så som revmatoid artritt, konjunktivitt, revmatoid spondylitt, osteoartritt, gikt-artritt og andre artritiske tilstander, inflammatorisk tarmsykdom, peptiske ulcere og forskjellige hud-lidelser. Videre kan forbindelsene ifølge foreliggende oppfinnelse anvendes for å behandle syncytiale virale infeksjoner. The compounds according to the present invention are also useful for the treatment of other immune-mediated inflammatory disorders where tryptase activity contributes to the pathological condition. Such diseases include inflammatory diseases associated with mast cells, such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcers and various skin disorders. Furthermore, the compounds according to the present invention can be used to treat syncytial viral infections.

Effektiviteten av forbindelsene ifølge foreliggende oppfinnelse for behandling av den store delen av immunomedierte inflammatoriske lidelser kan bedømmes ved enten in vitro eller in vivo prosedyrer. Således kan den antiinflammatoriske effektivitet av forbindelsene ifølge foreliggende oppfinnelse demonstreres ved forsøk velkjent på området, for eksempel the Reversed Passive Arthus Reaction (RPAR)-PAW teknikk (se f. eks. Gangly et al. (1992) U.S. patent nr. 5,126,352). Forsøk for å bestemme den terapeutiske verdi av forbindelser ved behandling av forskjellige hudlidelser, så som hyperproliferativ hudsykdom, er velkjent på området, for eksempel the Arachidonsyre Mouse Ear Test ( Id.). Forbindelsene ifølge foreliggende oppfinnelse kan evalueres for deres antiulcer aktivitet i henhold til metodene beskrevet i Chiu et al. (1984) Archives Intemationales de Pharmacodynamie et de Therapie 270:128-140. The effectiveness of the compounds according to the present invention for treating the majority of immune-mediated inflammatory disorders can be assessed by either in vitro or in vivo procedures. Thus, the anti-inflammatory effectiveness of the compounds according to the present invention can be demonstrated by experiments well known in the field, for example the Reversed Passive Arthus Reaction (RPAR)-PAW technique (see e.g. Gangly et al. (1992) U.S. patent no. 5,126,352). Tests to determine the therapeutic value of compounds in the treatment of various skin disorders, such as hyperproliferative skin disease, are well known in the art, for example the Arachidonic Acid Mouse Ear Test (Id.). The compounds of the present invention can be evaluated for their antiulcer activity according to the methods described in Chiu et al. (1984) Archives Intemationales de Pharmacodynamie et de Therapie 270:128-140.

Effektiviteten av forbindelsene ifølge foreliggende oppfinnelse for blokkering av cellefusjon forårsaket av en syncytial virusinfeksjon kan evalueres ved metodene generelt angitt i Tidwell, et al., J. Med. Chem. 26:294-298 (1983). The effectiveness of the compounds of the present invention in blocking cell fusion caused by a syncytial virus infection can be evaluated by the methods generally set forth in Tidwell, et al., J. Med. Chem. 26:294-298 (1983).

Preparater og admininstrering: Preparations and administration:

En terapeutisk eller farmasøytisk effektiv mengde av en forbindelse ifølge foreliggende oppfinnelse kan administreres til en pasient som lider av en immunomediert inflammatorisk lidelse. I henhold til én utførelsesform er preparatene ifølge foreliggende oppfinnelse nyttige for forebygging av eller lindring av astma. Ved anvendelse av preparatene ifølge foreliggende oppfinnelse for behandling av astma kan forbindelsene administreres . profylaktisk før påvirkning av allergen eller annen utløsende faktor eller etter slik påvirkning. Forbindelsene ifølge foreliggende oppfinnelse er spesielt nyttige for lindring av sen-fase vev-destruksjon som sees både ved sesongbestemt og helårs rhinitt. Foreliggende oppfinnelse muliggjør forebygging og behandling av andre immunomedierte inflammatoriske lidelser forbundet med mastceller så som urtikaria og angioødem og eksematøs dermatitt (atopisk dermatitt) og anafylaksi, så vel som hyperproliferativ hud-sykdom, peptiske ulcere og lignende. De kan videre anvendes for å behandle syncytiale virale infeksjoner, spesielt infeksjoner med respiratorisk syncytial virus. A therapeutically or pharmaceutically effective amount of a compound of the present invention can be administered to a patient suffering from an immune-mediated inflammatory disorder. According to one embodiment, the preparations according to the present invention are useful for preventing or alleviating asthma. When using the preparations according to the present invention for the treatment of asthma, the compounds can be administered. prophylactically before exposure to an allergen or other triggering factor or after such exposure. The compounds of the present invention are particularly useful for alleviating late-phase tissue destruction seen in both seasonal and year-round rhinitis. The present invention enables the prevention and treatment of other immunomediated inflammatory disorders associated with mast cells such as urticaria and angioedema and eczematous dermatitis (atopic dermatitis) and anaphylaxis, as well as hyperproliferative skin disease, peptic ulcers and the like. They can further be used to treat syncytial viral infections, especially infections with respiratory syncytial virus.

Preparatene inneholdende forbindelsene kan administreres for terapeutisk og/eller profylaktisk behandling. Ved terapeutiske anvendelser blir preparater administrert til en pasient som allerede lider av en sykdom, som beskrevet ovenfor, i en mengde tilstrekkelig til å kurere eller i det minste delvis stanse symptomene av sykdommen og komplikasjoner. En mengde tilstrekkelig til å oppnå dette er definert som "terapeutisk effektiv mengde eller dose." Mengder som er effektive for denne anvendelse vil avhenge av alvorlighetsgraden og sykdomsforløpet, tidligere terapi, pasientens helsetilstand og respons på medikamentene og vurderingen til den behandlende lege. The preparations containing the compounds can be administered for therapeutic and/or prophylactic treatment. In therapeutic applications, compositions are administered to a patient already suffering from a disease, as described above, in an amount sufficient to cure or at least partially stop the symptoms of the disease and complications. An amount sufficient to achieve this is defined as "therapeutically effective amount or dose." Amounts effective for this application will depend on the severity and course of the disease, previous therapy, the patient's state of health and response to the drugs, and the judgment of the attending physician.

For profylaktiske anvendelser blir preparater inneholdende forbindelsene ifølge foreliggende oppfinnelse administrert til en pasient som er mottagelig for eller på annen måte har risiko for en spesiell sykdom i en mengde tilstrekkelig til å forhindre eller forbedre begynnelse av symptomer. En slik mengde er definert å være en "profylaktisk effektiv mengde eller dose." Denne kan administreres oralt eller ved inhalering. Ved denne anvendelse avhenger de nøyaktige mengder igjen av pasientens helsetilstand, vekt og lignende. For prophylactic applications, compositions containing the compounds of the present invention are administered to a patient susceptible to or otherwise at risk of a particular disease in an amount sufficient to prevent or ameliorate the onset of symptoms. Such an amount is defined to be a "prophylactically effective amount or dose." This can be administered orally or by inhalation. In this application, the exact amounts again depend on the patient's state of health, weight and the like.

Når det har skjedd en forbedring av pasientens tilstand, blir en vedlikeholdsdose administrert hvis nødvendig. Deretter kan dosen eller administreringshyppigheten eller begge, reduseres, som en funksjon av symptomene, til et nivå ved hvilket den forbedrede tilstanden blir beholdt. Når symptomene er lindret til det ønskede nivå kan behandlingen opphøre. Pasienter kan imidlertid trenge periodisk påfølgende behandling på langtids basis etter eventuell tilbakevending av sykdomssymptomene. When there has been an improvement in the patient's condition, a maintenance dose is administered if necessary. Thereafter, the dose or frequency of administration or both may be reduced, as a function of the symptoms, to a level at which the improved condition is maintained. When the symptoms have been alleviated to the desired level, the treatment can cease. However, patients may need periodic follow-up treatment on a long-term basis after a possible return of the disease symptoms.

Generelt vil en egnet effektiv dose av forbindelsene ifølge foreliggende oppfinnelse være i området 0,05 til 1000 milligram (mg) pr. mottager pr. dag, fortrinnsvis i området 0,1 til 100 mg pr. dag. Den ønskede dose blir fortrinnsvis presentert i én, to, tre, fire eller flere underdoser administrert med passende mellomrom i løpet av dagen. Disse underdosene kan administreres som enhetsdoseformer, foreksempel inneholdende 0,01 til 1000 mg, fortrinnsvis 0,01 til 100 mg av aktiv bestanddel pr. enhetsdoseform. In general, a suitable effective dose of the compounds according to the present invention will be in the range of 0.05 to 1000 milligrams (mg) per recipient per day, preferably in the range of 0.1 to 100 mg per day. The desired dose is preferably presented in one, two, three, four or more sub-doses administered at suitable intervals during the day. These sub-doses can be administered as unit dosage forms, for example containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of active ingredient per unit dosage form.

Preparatet anvendt ved disse terapier kan foreligge i en rekke former. Disse omfatter for eksempel faste, halvfaste og flytende doseformer, så som The preparation used in these therapies can be available in a number of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as

tabletter, enterisk belagte tabletter, piller, pulvere, væske-løsninger eller suspensjoner, liposomer og injiserbare og infuserbare løsninger. Inhalasjonspreparater, så som aerosol-preparater, er også omfattet. Foretrukne preparater er de for orale, intranasale, topiske og parenterale anvendelser, men det vil forstås at den foretrukne form vil avhenge av den spesielle terapeutiske anvendelse. Spesielt foretrukne preparater er orale eller aerosol-preparater. Metodene for formulering og fremstilling av terapeutiske preparater omfattende forbindelsene ifølge foreliggende oppfinnelse er velkjent på området og er beskrevet i for eksempel Remin<g>ton's Pharmaceutical Sciences og The Merck Index 11. Ed., (Merck & Co. 1989). tablets, enteric coated tablets, pills, powders, liquid solutions or suspensions, liposomes and injectable and infusible solutions. Inhalation preparations, such as aerosol preparations, are also covered. Preferred formulations are those for oral, intranasal, topical and parenteral applications, but it will be understood that the preferred form will depend on the particular therapeutic application. Particularly preferred preparations are oral or aerosol preparations. The methods for formulating and producing therapeutic preparations comprising the compounds according to the present invention are well known in the field and are described in, for example, Remin<g>ton's Pharmaceutical Sciences and The Merck Index 11th Ed., (Merck & Co. 1989).

Mens den aktive bestanddel ifølge foreliggende oppfinnelse kan administreres alene, er det foretrukket å presentere den som del av et farmasøytisk preparat. Preparatene ifølge foreliggende oppfinnelse omfatter minst én forbindelse beskrevet her i en terapeutisk eller farmasøytisk effektiv dose sammen med en farmakologisk godtagbar bærer. De farmasøytiske preparater vil således inneholde forbindelsene ifølge foreliggende oppfinnelse i konsentrasjoner tilstrekkelige til å levere en passende dose. Når for eksempel den passende dose er 0,05 mg pr. dag, vil konsentrasjonen av forbindelsen ifølge foreliggende oppfinnelse i det farmasøytiske preparatet være 0,05 mg pr. dose, når én dose pr. dag blir anvendt. For inhalerings- eller aerosol-preparater, vil konsentrasjonen av forbindelsene ifølge foreliggende oppfinnelse i preparatet generelt avhenge av mengden av dosen. Typiske konsentrasjoner av forbindelsene ifølge foreliggende oppfinnelse i inhalerings- eller aerosol-preparater vil være fra ca. 0,01 til ca. 30 mg/ml. Preparatet kan omfatte andre klinisk nyttige forbindelser, så som B-adrenergika ( f. eks. albuterol, terbutalin, formoterol, fenoterol og prenalin) og kortikosteroider ( f. eks. beclometasom, triamcinolon, flunisolid og dexametason). While the active ingredient according to the present invention can be administered alone, it is preferred to present it as part of a pharmaceutical preparation. The preparations according to the present invention comprise at least one compound described here in a therapeutically or pharmaceutically effective dose together with a pharmacologically acceptable carrier. The pharmaceutical preparations will thus contain the compounds according to the present invention in concentrations sufficient to deliver an appropriate dose. When, for example, the appropriate dose is 0.05 mg per day, the concentration of the compound according to the present invention in the pharmaceutical preparation will be 0.05 mg per dose, when one dose per day is used. For inhalation or aerosol preparations, the concentration of the compounds according to the present invention in the preparation will generally depend on the amount of the dose. Typical concentrations of the compounds according to the present invention in inhalation or aerosol preparations will be from approx. 0.01 to approx. 30 mg/ml. The preparation may include other clinically useful compounds, such as B-adrenergics (e.g. albuterol, terbutaline, formoterol, fenoterol and prenaline) and corticosteroids (e.g. beclometasom, triamcinolone, flunisolide and dexamethasone).

Kjemi: Chemistry:

Generelt blir forbindelsene ifølge foreliggende oppfinnelse syntetisert ved anvendelse av standard teknikker og reagenser kjent for og anvendt av fagfolk på området. Det vil sees at bindingene mellom de forskjellige funksjonelle grupper generelt omfatter karbon knyttet til nitrogenet i et amid eller karbamat, oksygenet i karbamat eller karbonet i karbonyl. Fagfolk på området vil forstå at metoder og reagenser for dannelse av disse bindinger er velkjente og lett tilgjengelige. Se f. eks. March, Advanced organic chemistr<y>, 4th Ed. (Wiley 1992), Larock, Comprehensive Organic Transformations (VCH 1989); og Furniss, et al., Vogel's Textbook of Practical Organic Chemistry 5th ed. In general, the compounds according to the present invention are synthesized using standard techniques and reagents known to and used by those skilled in the art. It will be seen that the bonds between the different functional groups generally comprise carbon linked to the nitrogen in an amide or carbamate, the oxygen in carbamate or the carbon in carbonyl. Those skilled in the art will appreciate that methods and reagents for forming these bonds are well known and readily available. See e.g. March, Advanced organic chemistry, 4th Ed. (Wiley 1992), Larock, Comprehensive Organic Transformations (VCH 1989); and Furniss, et al., Vogel's Textbook of Practical Organic Chemistry 5th ed.

(Longman 1989), som alle inntas herved referanse. (Longman 1989), all of which are hereby incorporated by reference.

Forbindelser med formel I hvor X<4> og X<5> er nabostilte elementer i en oksazol-2-yl-, 1H-imidazol-2-yl- eller tiazol-2-yl-ring kan fremstilles ved metodene vist i det følgende reaksjonsskjema: Compounds of formula I where X<4> and X<5> are adjacent elements in an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods shown in the following reaction scheme:

hvor L er en utgående gruppe, D sammen med vinylengruppen til hvilken den er kondensert, omfatter en monocyklisk eller kondensert bicyklisk divalent rest inneholdende fra 5 til 15 ringatomer, hvor hver ring inneholder 5 til 7 ringatomer og hvert ringatom eventuelt er et heteroatom, R<29> er -OH, -NHR<6> eller -SH, X<8> er -O-, -NR<6>- eller -S- og n2, n3, n4, A, B, X<1>, X<2>, X<3>, X<5>, R<1>, R<2>, R<3>, R4 og R<6> er som definert under Oppsummering av oppfinnelsen. where L is a leaving group, D together with the vinylene group to which it is condensed, comprises a monocyclic or fused bicyclic divalent residue containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring atom optionally being a heteroatom, R< 29> is -OH, -NHR<6> or -SH, X<8> is -O-, -NR<6>- or -S- and n2, n3, n4, A, B, X<1>, X<2>, X<3>, X<5>, R<1>, R<2>, R<3>, R4 and R<6> are as defined under Summary of the Invention.

Forbindelser med formel I hvor X<4> og X<5> er nabostilte elementer i en oksazol-2-yl-, 1H-imidazol-2-yl- eller tiazol-2-yl-ring (Formel l(a)) kan fremstilles ved omsetning av en forbindelse med formel 1 eller et beskyttet derivat derav, med en forbindelse med formel 2 eller et beskyttet derivat derav og deretter avbeskyttelse hvis nødvendig. Reaksjonen mellom forbindelsene med formlene 1 og 2 kan utføres i ren form, men blir fortrinnsvis utført i nærvær av 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon (DMPU) eller polyfosforsyre, ved 160 til 200°C, fortrinnsvis 180-190°C og krever 1 til 5 timer for å bli fullstendig (se f.eks. Eksempler 4(d), 6(h), 8(k), 9(d) og 10(d), nedenfor). Avbeskyttelse kan utføres ved hvilke som helst metoder som fjerner den beskyttende gruppen og gir det ønskede produkt i rimelig utbytte (se f.eks. Eksempel 2(g), nedenfor). Compounds of formula I where X<4> and X<5> are adjacent elements in an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring (Formula 1(a)) can is produced by reacting a compound of formula 1 or a protected derivative thereof, with a compound of formula 2 or a protected derivative thereof and then deprotection if necessary. The reaction between the compounds of formulas 1 and 2 can be carried out in pure form, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or polyphosphoric acid, by 160 to 200°C, preferably 180-190°C and requires 1 to 5 hours to complete (see, e.g., Examples 4(d), 6(h), 8(k), 9(d) and 10 (d), below). Deprotection can be accomplished by any method which removes the protecting group and provides the desired product in reasonable yield (see, e.g., Example 2(g), below).

På lignende måte kan forbindelser med formel I i hvilke X<1> og X<2> er nabostilte elementer i en oksazol-2-yl-, 1H-imidazol-2-yl- eller tiazol-2-yl-ring fremstilles ved metodene vist i det følgende reaksjonsskjema: In a similar way, compounds of formula I in which X<1> and X<2> are neighboring elements in an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods shown in the following reaction scheme:

hvor L er én utgående gruppe, R30 er -OH, -NHR<5> eller -SH, X<8> er -O-, -NR<6->eller -S- og n2, n3, n4, B, C, X<1>, X<3>, X4, X<5>, R<1>, R<2>, R3, R4 og R6 er som definert under Oppsummering av oppfinnelsen (se f.eks. Eksempler 2(e) og 7{h), nedenfor). where L is one leaving group, R30 is -OH, -NHR<5> or -SH, X<8> is -O-, -NR<6->or -S- and n2, n3, n4, B, C , X<1>, X<3>, X4, X<5>, R<1>, R<2>, R3, R4 and R6 are as defined under Summary of the invention (see e.g. Examples 2(e ) and 7{h), below).

Isolering og rensning av forbindelsene og mellomproduktene beskrevet her kan om ønsket utføres ved en hvilken som helst egnet separerings- eller rensnings-metode så som for eksempel filtrering, ekstraksjon, krystallisering, kolonnekromatografi, tynnskiktskromatografi eller tykkskiktskromatografi, høytrykks væskekromatografi (HPLC) eller en kombinasjon av disse metoder. Spesifikke illustrasjoner av egnede separerings- og isolerings-metoder kan sees i eksemplene nedenfor. Imidlertid kan selvfølgelig andre ekvivalente separerings- eller isolerings-metoder anvendes. Kjernemagnetiske resonans-(NMR) spektra ble registrert på et General Electric "QE Plus" spektrometer (300 MHz). Infrarøde (IR) spektra ble registrert på Perkin-Elmer 1600 Fourier Transform IR (FTIR). Analytisk HPLC ble utført på en Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. utstyrt med en PLRP-kolonne, 1 mm x 150 mm. Preparativ HPLC ble utført på en Gilson LC ved anvendelse av en VYDAC 1 x 25 cm Cis revers fase (RP) kolonne eller et Waters Prep LC2000 system ved anvendelse av en Vydac 5 x 25 cm Cis RP kolonne. Massespektra (MS) ble oppnådd på Finnigan SSQ 710 med en ESI-kilde ved direkte infusjon eller ved HPLC MS (Ultrafast Microprotein Analyzer, Cia kolonne 2 mm X 150 mm). Hvis ikke på annen måte angitt ble alle reagenser og utstyr enten fremstilt i henhold til publiserte metoder eller ble anskaffet fra kommersielle kilder, så som Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (St Louis, MO) og ICN Chemical Co. (Irvin, CA). Teknikkene anvendt for å utføre syntesene beskrevet nedenfor vil kjennes av fagfolk på området som rutinemessige (se f. eks. March, Larock eller Furniss, ovenfor). Isolation and purification of the compounds and intermediates described herein may, if desired, be accomplished by any suitable separation or purification method such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, high pressure liquid chromatography (HPLC) or a combination of these methods. Specific illustrations of suitable separation and isolation methods can be seen in the examples below. However, other equivalent separation or isolation methods can of course be used. Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric "QE Plus" spectrometer (300 MHz). Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR). Analytical HPLC was performed on an Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. equipped with a PLRP column, 1 mm x 150 mm. Preparative HPLC was performed on a Gilson LC using a VYDAC 1 x 25 cm Cis reverse phase (RP) column or a Waters Prep LC2000 system using a Vydac 5 x 25 cm Cis RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 with an ESI source by direct infusion or by HPLC MS (Ultrafast Microprotein Analyzer, Cia column 2 mm X 150 mm). Unless otherwise stated, all reagents and equipment were either prepared according to published methods or were obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (St Louis, MO) and ICN Chemical Co. (Irvine, CA). The techniques used to perform the syntheses described below will be known to those skilled in the art as routine (see, e.g., March, Larock or Furniss, supra).

Ytterligere fremgangsmåter for fremstilling av forbindelser med formel I: Forbindelser med formel I kan fremstilles som farmasøytisk godtagbare syreaddisjonssalter ved omsetning av den frie baseformen av en forbindelse med formel I med en farmasøytisk godtagbar uorganisk eller organisk syre. Alternativt kan de farmasøytisk godtagbare baseaddisjonssalter av forbindelsene med formel I fremstilles ved omsetning av de frie syreformer av forbindelsene med formel I med farmasøytisk godtagbare uorganiske eller organiske baser. Uorganiske og organiske syrer og baser egnet for fremstilling av de farmasøytisk godtagbare salter av forbindelsene med formel I er angitt i definisjonsavsnittene i denne søknaden. Alternativt kan saitformene av forbindelsene med formel I fremstilles ved anvendelse av salter av utgangsmaterialene eller mellomproduktene. Additional methods for preparing compounds of formula I: Compounds of formula I can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of a compound of formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salts of the compounds of formula I can be prepared by reacting the free acid forms of the compounds of formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of the compounds of formula I are indicated in the definition sections of this application. Alternatively, the salt forms of the compounds of formula I can be prepared using salts of the starting materials or intermediates.

De frie syre- eller frie base-formene av forbindelsene med formel I kan fremstilles fra den tilsvarende baseaddisjonssalt- eller syreaddisjonssalt-formen. For eksempel kan forbindelser med formel I i syreaddisjonssalt-form omdannes til den tilsvarende frie base ved behandling med en egnet base (f.eks. ammoniumhydroksyd-løsning, natriumhydroksyd, etc). Forbindelser med formel I i en baseaddisjonssalt-form kan omdannes til den tilsvarende frie syre ved behandling med en egnet syre (f.eks. saltsyre, etc). The free acid or free base forms of the compounds of formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compounds of formula I in acid addition salt form can be converted into the corresponding free base by treatment with a suitable base (eg ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of formula I in a base addition salt form can be converted to the corresponding free acid by treatment with a suitable acid (e.g. hydrochloric acid, etc).

W-oksydene av forbindelsene med formel I kan fremstilles ved metoder kjent for fagfolk på området. For eksempel kan W-oksyder fremstilles ved behandling av en uoksydert form av forbindelsen med formel l med et oksydasjonsmiddel (f.eks. trifluorpereddiksyre, permaleinsyre, perbenzosyre, pereddiksyre, mefa-klorperoksybenzosyre, etc.) i et egnet inert organisk oppløsningsmiddel (f.eks. et halogenert hydrokarbon så som metylenklorid) ved omtrent 0°C. Alternativt kan A/-oksydene av forbindelsene med formel I fremstilles fra A/-oksydet av et passende utgangsmateriale. The W-oxides of the compounds of formula I can be prepared by methods known to those skilled in the art. For example, W-oxides can be prepared by treating an unoxidized form of the compound of formula I with an oxidizing agent (e.g. trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, mepha-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g. eg a halogenated hydrocarbon such as methylene chloride) at about 0°C. Alternatively, the A/-oxides of the compounds of formula I can be prepared from the A/-oxide of a suitable starting material.

Forbindelser med formel I i uoksydert form kan fremstilles fra W-oksyder av forbindelser med formel I ved behandling med et reduksjonsmiddel (f.eks. svovel, svoveldioksyd, trifenylfosfin, litiumborhydrid, natriumborhydrid, fosfortriklorid, tribromid, etc.) i et egnet inert organisk oppløsningsmiddel (f.eks. acetonitril, etanol, vandig dioksan, etc.) ved 0 til 80°C. Compounds of formula I in unoxidized form can be prepared from W-oxides of compounds of formula I by treatment with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.

Prodrug-derivater av forbindelsene med formel I kan fremstilles ved metoder kjent for fagfolk på området (se f.eks. Eksempel 12 nedenfor.). For ytterligere detaljer om prodrug og deres fremstilling se Saulnier ef a/.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985).. Prodrug derivatives of the compounds of formula I can be prepared by methods known to those skilled in the art (see, e.g., Example 12 below.). For further details on prodrugs and their preparation see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. 4:1985)..

Beskyttede derivater av forbindelsene med formel I kan fremstilles ved metoder kjent for fagfolk på området. En detaljert beskrivelse av teknikkene som kan anvendes for dannelse av beskyttende grupper og fjerning av dem kan finnes i T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc 1981. Protected derivatives of the compounds of formula I can be prepared by methods known to those skilled in the art. A detailed description of the techniques that can be used for the formation of protecting groups and their removal can be found in T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc 1981.

Forbindelser med formel I kan fremstilles som deres individuelle stereoisomerer ved omsetning av en racemisk blanding av forbindelsen med et optisk aktivt spaltnings-middel for å danne et par av diastereoisomere forbindelser, separering av diastereomerene og gjenvinning av den optisk rene enantiomer. Mens spaltning av enantiomerer kan utføres ved anvendelse av kovalente diastereomere derivater av forbindelser med formel I, er dissosierbare komplekser foretrukket (f.eks. krystallinske diastereoisomere salter). Diastereomerene har distinkte fysiske egenskaper (f.eks. smeltepunkter, kokepunkter, oppløselig heter, reaktivitet, etc.) og kan lett separeres ved å utnytte disse ulikhetene. Diastereomerene kan separeres ved kromatografi eller, fortrinnsvis, ved separerings/spaltnings-teknikker basert på forskjeller i oppløselighet. Den optisk rene enantiomer blir deretter gjenvunnet sammen med oppløsningsmidlet, ved hvilken som helst praktisk metode som ikke resulterer i racemisering. En mer detaljert beskrivelse av teknikker som kan anvendes for spaltningen av stereoisomerer av forbindelser fra deres racemiske blanding kan finnes i Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981). Compounds of formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds of formula I, dissociable complexes are preferred (eg crystalline diastereoisomeric salts). The diastereomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by exploiting these differences. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered along with the solvent by any convenient method which does not result in racemization. A more detailed description of techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Hon Wiley & Sons, Inc. (1981).

Som oppsummering vises en fremgangsmåte for fremstilling av en forbindelse med formel I, hvilken fremgangsmåte omfatter: In summary, a method for the preparation of a compound of formula I is shown, which method comprises:

(a) omsetning av en forbindelse med formel 1: (a) reaction of a compound of formula 1:

eller et beskyttet derivat derav, med en forbindelse med formel 2: or a protected derivative thereof, with a compound of formula 2:

eller et beskyttet derivat derav, hvor L er en utgående gruppe, D sammen med vinylen- gruppen til hvilken den er kondensert, omfatter en monocyklisk eller kondensert bicyklisk divalent rest som inneholder fra 5 tii 15 ringatomer, hvor hver ring inneholder 5 til 7 ringatomer og hvert ringatom eventuelt er et or a protected derivative thereof, where L is a leaving group, D together with the vinylene group to which it is fused, comprises a monocyclic or fused bicyclic divalent residue containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring atom optionally is a

heteroatom, R29 er -OH, -NHR<6> eller -SH og n1, n2, n3, A, B, X1, X2, X3, R1, R<2>, R<3>, R4 og R<6> er som definert under Oppsummering av oppfinnelsen, og deretter avbeskyttelse hvis nødvendig, hvilket gir en forbindelse med formel I hvor X<4> og X<5> er nabostilte elementer i en oksazol-2-yl-, 1 W-imidazol-2-yl- eller tiazol-2-yl-ring; eller heteroatom, R29 is -OH, -NHR<6> or -SH and n1, n2, n3, A, B, X1, X2, X3, R1, R<2>, R<3>, R4 and R<6> is as defined under Summary of the invention, and then deprotection if necessary, which gives a compound of formula I where X<4> and X<5> are adjacent elements in an oxazol-2-yl-, 1 W-imidazol-2- yl or thiazol-2-yl ring; or

(b) omsetning av en forbindelse med formel 3: (b) reacting a compound of formula 3:

eller et beskyttet derivat derav, med en forbindelse med formel 4: eller et beskyttet derivat derav, hvor L er en utgående gruppe, R<30> er -OH, - NHR<5> eller -SH og n1, n2, n3, B, C, X3, X4, X5, R1, R2, R<3>, R4 og R<5> er som definert under Oppsummering av oppfinnelsen og deretter avbeskyttelse hvis nødvendig, hvilket gir en forbindelse med formel I hvor X<1> og X<2> er nabostilte elementer i en oksazol-2-yl-, 1H-imidazol-2-yl- eller tiazol-2-yl-ring; (c) eventuelt videre omdannelse av en forbindelse med formel I til et farmasøytisk godtagbart salt; (d) eventuelt videre omdannelse av en saltform av en forbindelse med formel I til ikke-saltform; (e) eventuelt videre omdannelse av en uoksydert form av en forbindelse med formel I til et farmasøytisk godtagbart W-oksyd; (f) eventuelt videre omdannelse av en A/-oksyd-form av en forbindelse med formel I til dens uoksyderte form; (g) eventuelt videre omdannelse av en ikke-derivatisert forbindelse med formel I til et farmasøytisk prodrug-derivat; og (h) eventuelt videre omdannelse av et prodrug-derivat av en forbindelse med formel I til dens ikke-derivatiserte form. or a protected derivative thereof, with a compound of formula 4: or a protected derivative thereof, where L is a leaving group, R<30> is -OH, - NHR<5> or -SH and n1, n2, n3, B , C, X3, X4, X5, R1, R2, R<3>, R4 and R<5> are as defined under Summary of the Invention and then deprotection if necessary, giving a compound of formula I wherein X<1> and X<2> are adjacent elements in an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring; (c) optionally further converting a compound of formula I into a pharmaceutically acceptable salt; (d) optionally further converting a salt form of a compound of formula I into non-salt form; (e) optionally further converting an unoxidized form of a compound of formula I into a pharmaceutically acceptable W-oxide; (f) optionally further converting an A/-oxide form of a compound of formula I into its unoxidized form; (g) optionally further converting a non-derivatized compound of formula I into a pharmaceutical prodrug derivative; and (h) optionally further converting a prodrug derivative of a compound of formula I into its non-derivatized form.

Eksempler: Examples:

De følgende eksempler er bare gitt som en illustrasjon og skal ikke på noen måte betraktes som en begrensning av omfanget av foreliggende oppfinnelse. Fagfolk på området vil forstå at visse variasjoner og modifikasjoner kan gjøres innenfor omfanget av foreliggende oppfinnelse. The following examples are given by way of illustration only and are not to be considered in any way as a limitation of the scope of the present invention. Those skilled in the art will understand that certain variations and modifications can be made within the scope of the present invention.

EKSEMPEL 1 EXAMPLE 1

2-naft-2-yletylamin 2-Naphth-2-ylethylamine

En løsning omfattende 2-naft-2-yletanol (0,5 g, 2,9 mmol) i tørr DMF (5 ml) ble under nitrogen blandet med difenylfosforylazid (0,74 ml, 3,42 mmol) og 1,8-diazaabicyklo[5,4,0]undec-7-en (0,47 ml. 3,14 mmol). Blandingen ble oppvarmet ved 65°C i 3 timer og deretter fordelt mellom vann og dietyleter. Det vandige laget ble separert og ekstrahert med dietyleter. De samlede organiske lag ble vasket med 3N saltsyre og deretter mettet natriumbikarbonat, tørket A solution comprising 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) was mixed under nitrogen with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and 1,8- diazaabicyclo[5,4,0]undec-7-ene (0.47 mL, 3.14 mmol). The mixture was heated at 65°C for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3N hydrochloric acid and then saturated sodium bicarbonate, dried

(MgS04), filtrert og konsentrert ved rotasjonsinndamping. Residuet ble oppløst i THF (5 ml) og løsningen ble blandet med trifenylfosfin (1 g, 3,81 mmol), omrørt i 2 timer ved romtemperatur, fortynnet med vann (0,100 ml), omrørt i 3 timer og fortynnet med konsentrert saltsyre (0,33 ml), hvilket ga et presipitat, behandlet med etanol (5 ml) for å oppløse fellingen og behandlet med dietyleter, tilsatt langsomt, hvilket ga et hvitt presipitat. Presipitatet ble isolert ved filtrering, vasket med dietyleter og tørket under vakuum, hvilket ga 2-naft-2-yletylamin-hydroklorid (0,447 g, 75% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 8.18 (br s, 3H), 7,82-7,88 (m, 3H), 7,74 (s, 1H), 7,38-7,48 (rn, 3H), 3,07 (m, 4H). (MgSO 4 ), filtered and concentrated by rotary evaporation. The residue was dissolved in THF (5 mL) and the solution was mixed with triphenylphosphine (1 g, 3.81 mmol), stirred for 2 h at room temperature, diluted with water (0.100 mL), stirred for 3 h and diluted with concentrated hydrochloric acid ( 0.33 ml), which gave a precipitate, treated with ethanol (5 ml) to dissolve the precipitate and treated with diethyl ether, added slowly, which gave a white precipitate. The precipitate was isolated by filtration, washed with diethyl ether and dried under vacuum to give 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield); <1>H-NMR (300 MHz, DMSO-d6): 8.18 (br s, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-7 .48 (rn, 3H), 3.07 (m, 4H).

Ved å følge metoden i Eksempel 1 ble de følgende mellomprodukt-aminer fremstilt: 2- naft-1-yletylamin, utbytte=56%, <1>H-NMR (300 MHz, DMSO-d6): 8,26 (br s, 3H), 8,16 (d, 1H, J = 8,1 Hz), 7,92 (dd, 1H, J=1,5, 7,8 Hz), 7,81 (dd, 1H, J=1,2, 7,5 Hz), 7,40-7,56 (m, 4H), 3,37 (m, 2H), 3,05 (t, 2H, J=7,4 Hz); By following the method in Example 1, the following intermediate amines were prepared: 2-naphth-1-ylethylamine, yield=56%, <1>H-NMR (300 MHz, DMSO-d6): 8.26 (br s, 3H), 8.16 (d, 1H, J = 8.1 Hz), 7.92 (dd, 1H, J=1.5, 7.8 Hz), 7.81 (dd, 1H, J=1 .2, 7.5 Hz), 7.40-7.56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, J=7.4 Hz);

3- cykloheksylpropylamin, utbytte=40%, <1>H-NMR (300 MHz, CDCI3): 2,68 (t, 2H, J=7,2 Hz), 2,17 (br s, 2H), 1,64-1,71 (m, 5H), 1,46 (m, 2H), 1,18 (m,6H) 0,87 (m, 2H); 3- cyclohexylpropylamine, yield=40%, <1>H-NMR (300 MHz, CDCl3): 2.68 (t, 2H, J=7.2 Hz), 2.17 (br s, 2H), 1, 64-1.71 (m, 5H), 1.46 (m, 2H), 1.18 (m, 6H) 0.87 (m, 2H);

3-fenyl-2-propenylamin, utbytte=53%, <1>H-NMR (300 MHz, DMSO-d6): 8,39 (br s, 3H), 7,26-7,41 (m, 5H), 6,72 (d, 1H, J = 16,2 Hz), 6,29 (dt, 1H, J=16,2, 6,6 Hz), 3,56 (d, 2H, J = 6,6 Hz); 3-phenyl-2-propenylamine, yield=53%, <1>H-NMR (300 MHz, DMSO-d6): 8.39 (br s, 3H), 7.26-7.41 (m, 5H) , 6.72 (d, 1H, J = 16.2 Hz), 6.29 (dt, 1H, J=16.2, 6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz);

3-fenyl-2-propynylamin, utbytte=62%, <1>H-NMR (300 MHz, DMSO-d6): 8,67 (br s, 2H), 7,38-7,42 (m, 5H), 3,91 (m, 2H); og 3-phenyl-2-propynylamine, yield=62%, <1>H-NMR (300 MHz, DMSO-d6): 8.67 (br s, 2H), 7.38-7.42 (m, 5H) , 3.91 (m, 2H); and

3,3-difenylpropylamin, utbytte=50%, <1>H-NMR (300 MHz, DMSO-d6): 8,10 (br s, 3H), 7,30 (m, 8H), 7,19 (m, 2H), 4,11 (t, 1H, J=7,9 Hz), 2,62 (m, 2H) 2,33 (m, 2H). 3,3-diphenylpropylamine, yield=50%, <1>H-NMR (300 MHz, DMSO-d6): 8.10 (br s, 3H), 7.30 (m, 8H), 7.19 (m , 2H), 4.11 (t, 1H, J=7.9 Hz), 2.62 (m, 2H) 2.33 (m, 2H).

EKSEMPEL 2 EXAMPLE 2

2- (5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-Ay-(4-fenylbutyl)- 2-(5-aminomethyl-1/-/-benzoimidazol-2-ylmethyl)-α-(4-phenylbutyl)-

1 H-benzoimidazol-5-karboksamid trifluoracetat (Forbindelse 1) 1 H-benzoimidazole-5-carboxamide trifluoroacetate (Compound 1)

(a) Etylcyanoacetat (8 ml, 75 mmol) i vannfri benzen (100 ml) ble blandet under nitrogen med vannfri etanol (6 ml, 105 mmol). Blandingen ble avkjølt til 10°C (is/aceton) og boblet 20 minutter med tørr hydrogenklorid-gass. Blandingen ble langsomt oppvarmet til romtemperatur, lukket og omrørt i omtrent 18 timer. Blandingen ble fortynnet med dietyleter (400 ml) og fikk stå i 5 timer ved romtemperatur, hvilket ga et krystallinsk, fast stoff. Det faste stoffet ble isolert ved filtrering, vasket mange ganger med vannfri dietyleter og tørket, hvilket ga etyl 3-etoksy-3-iminopropionat (13,2 g, 90% utbytte) som et farveløst, krystallinsk, fast stoff; <1>H-NMR (300 MHz, CDCI3): 7,84 (d, 1H, J = 10,0 Hz), 7,19-7,36 (m, 5H), 7,00-7,06 (m, 2H), 4,10 (t, 2H, J=5,7 Hz), 2,73 (t, 2H, (a) Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was mixed under nitrogen with anhydrous ethanol (6 mL, 105 mmol). The mixture was cooled to 10°C (ice/acetone) and bubbled for 20 minutes with dry hydrogen chloride gas. The mixture was slowly warmed to room temperature, sealed and stirred for about 18 hours. The mixture was diluted with diethyl ether (400 mL) and allowed to stand for 5 h at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to give ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; <1>H-NMR (300 MHz, CDCl3): 7.84 (d, 1H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 ( m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H,

J = 6,5 Hz), 1,89 (m, 4H). J = 6.5 Hz), 1.89 (m, 4H).

(b) En blanding av 3,4-diaminobenzosyre (9,4 g, 62 mmol), etyl 3-etoksy-3- iminopropionat og iseddik (15 ml) ble omrørt 30 minutter ved 110°C under (b) A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial acetic acid (15 mL) was stirred for 30 min at 110°C under

nitrogen. Blandingen ble hellet over knust is (50 ml) og omrørt 30 minutter, hvilket ga en mørk gul olje. Blandingen ble omrørt mens dietyleter (25 ml) ble tilsatt, hvilket ga et grått presipitat. Fellingen ble isolert ved filtrering, vasket mange ganger med dietyleter og tørket under vakuum, hvilket ga 2-etoksykarbonylmetyl-1H-benzoimidazol-5-karboksylsyre (12,6 g, nitrogen. The mixture was poured over crushed ice (50 mL) and stirred for 30 minutes, yielding a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added, giving a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried under vacuum to give 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g,

83% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 12,77 (bred s, 1H), 8,10 (s, 1H), 7,79 (d, 1H, J=8,4 Hz), 7,57 (d, 1H, J=8,4 Hz), 4,11 (q, 2H, J = 7,1 Hz), 4,02 (s, 2H), 1,17 (t, 3H, J=7,1 Hz). (c) En blanding av dinitrofenylmetanol (22 g, 111 mmol), trifenylfosfin (34,5 g, 131 mmol) og ftalimid (17,6 g, 119 mmol) i THF (450 ml) ble omrørt ved - 10°C (is/aceton) under nitrogen mens dietyl-azodikarboksylat (20,7 ml, 131 mmol) ble tilsatt dråpevis. Blandingen ble omrørt 2 timer ved -10°C og deretter fortynnet med dietyleter (900 ml) og lagret ved -20°C i omtrent 18 timer, hvilket ga et krystallinsk, fast stoff. Det faste stoffet ble isolert ved filtrering og vasket, hvilket ga 2-(3,4-dinitrobenzyl)isoindol-1,3-dion (24,6 g, 67% utbytte) som et gråhvitt, krystallinsk, fast stoff; <1>H-NMR (300 MHz, DMSO-d6): 7,87-7,94 (m, 5H), 7,74-7,82 (m, 2H), 4,96 (s, 2H). (d) En blanding av 2-(3,4-dinitrobenzyl)isoindol-1,3-dion (8 g, 24,4 mmol), fremstilt som i Eksempel 1 og 10% palladium på karbon (300 mg) ble blandet med vannfri etanol (200 ml, vannfri THF (100 ml) og iseddik (30 ml) under en kontinuerlig strøm av nitrogen. Blandingen ble deretter omrørt kraftig 15 timer ved romtemperatur under hydrogen, filtrert og konsentrert til et volum på omtrent 30 ml ved rotasjonsinndampning. Blandingen ble fortynnet med vann (100 ml) og ammoniumhydroksyd ble tilsatt, hvilket ga et oransje presipitat. Fellingen ble isolert ved filtrering og vasket mange ganger med vann for å gi 2-(3,4-diaminobenzyl)-isoindol-1,3-dion (6 g, 91% utbytte); <1>H-NMR (300 MHz, DMSO-de): 7,76-7,85 (m, 4H), 6,31-6,43 (m, 3H), 4,51 (bred s, 4H), 4,47 (s, 2H). 83% yield); <1>H-NMR (300 MHz, DMSO-d6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J = 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J =7.1 Hz). (c) A mixture of dinitrophenylmethanol (22 g, 111 mmol), triphenylphosphine (34.5 g, 131 mmol) and phthalimide (17.6 g, 119 mmol) in THF (450 mL) was stirred at -10°C ( ice/acetone) under nitrogen while diethyl azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred for 2 h at -10°C and then diluted with diethyl ether (900 mL) and stored at -20°C for about 18 h to give a crystalline solid. The solid was isolated by filtration and washed to give 2-(3,4-dinitrobenzyl)isoindole-1,3-dione (24.6 g, 67% yield) as an off-white crystalline solid; <1>H-NMR (300 MHz, DMSO-d6): 7.87-7.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H). (d) A mixture of 2-(3,4-dinitrobenzyl)isoindole-1,3-dione (8 g, 24.4 mmol), prepared as in Example 1 and 10% palladium on carbon (300 mg) was mixed with anhydrous ethanol (200 mL), anhydrous THF (100 mL) and glacial acetic acid (30 mL) under a continuous stream of nitrogen. The mixture was then stirred vigorously for 15 h at room temperature under hydrogen, filtered and concentrated to a volume of about 30 mL by rotary evaporation. The mixture was diluted with water (100 mL) and ammonium hydroxide was added to give an orange precipitate.The precipitate was isolated by filtration and washed several times with water to give 2-(3,4-diaminobenzyl)-isoindole-1,3- dione (6 g, 91% yield); <1>H-NMR (300 MHz, DMSO-de): 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H) , 4.51 (broad s, 4H), 4.47 (s, 2H).

(e) En finmalt blanding av 2-(3,4-diaminobenzyl)isoindol-1,3-dion (2,0 g, (e) A finely ground mixture of 2-(3,4-diaminobenzyl)isoindole-1,3-dione (2.0 g,

7,5 mmol) og 2-etoksykarbonylmetyl-1H-benzimidazol-5-karboksylsyre (0,93 g, 3,75 mmol) ble oppvarmet 1 time ved 185<6>C under nitrogen. Blandingen ble suspendert i 1:1 metylenklorid/etanol (20 ml) og omrørt kraftig i 1 time. De faste stoffene ble oppsamlet ved filtrering, vasket med 1:1 metylenklorid/etanol (3 x 20 ml) og tørket, hvilket ga 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)- 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) were heated for 1 hour at 185<6>C under nitrogen. The mixture was suspended in 1:1 methylene chloride/ethanol (20 mL) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with 1:1 methylene chloride/ethanol (3 x 20 mL) and dried to give 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-

1H-benzoimidazol-2-ylmetyl]-1H-benzoimidazol-5-karboksylsyre (0,98 g, 29% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 12,45 (bred s, 1H), 8,07 (s, 1H), 7,80-7,83 (m, 6H), 7,51 (d, 1H, J=7,5 Hz), 7,43 (s, 1H), 7,11 (d, 1H, J=7,2 Hz), 4,82 (s, 2H), 4,48 (s, 2H). (f) 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylmetyl]-1H-benzoimidazol-5-karboksylsyre (0,05 g, 0,111 mmol) ble oppløst i vannfri dimetylformamid (0,5 ml_) og løsningen ble blandet med 1-hydroksybenzotriazol-hydrat (0,017 g, 0,126 mmol), benzotriazol-1-yloksytrispyrrolidinofosfoniumheksafluor-fosfat (0,063 g, 0,121 mmol) og W-metylmorfolin (0,013 ml_, 0,118 mmol) ved romtemperatur under en atmosfære av tørr N2. Etter 2 minutter ble 4-fenylbutylamin (0,02 ml_, 0,127 mmol) tilsatt og blandingen ble omrørt ved romtemperatur i 2 timer. Blandingen ble overført til en separasjonstrakt inneholdende en 20% etanol/etylacetat-løsning (7 mL), 0,2 N HCI (3,5 ml_) og mettet vandig NaCI (3,5 ml_). Den vandige fasen ble ekstrahert én gang med 20% etanol/etylacetat-løsning (7 mL) og de samlede organiske faser ble vasket med en løsning inneholdende 0,2 N HCI (3,5 mL) i mettet vandig NaCI.(3,5 ml) fulgt av en endelig vasking med mettet vandig natriumbikarbonat-løsning (7 mL). Den organiske fasen ble deretter tørket over vannfritt natriumsulfat, filtrert og konsentrert til tørrhet på en rotasjonsinndamper, hvilket ga 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylmetyl]-A/-(3-fenylpropyl)-1H-benzoimidazol-5-karboksamid som råmateriale (0,14g). 1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazol-5-carboxylic acid (0.98 g, 29% yield); <1>H-NMR (300 MHz, DMSO-d6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J=7.2 Hz), 4.82 (s, 2H), 4.48 (p, 2H). (f) 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazol-5-carboxylic acid (0.05 g, 0.111 mmol ) was dissolved in anhydrous dimethylformamide (0.5 ml_) and the solution was mixed with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) and W-methylmorpholine (0.013 ml_, 0.118 mmol) at room temperature under an atmosphere of dry N 2 . After 2 minutes, 4-phenylbutylamine (0.02 mL, 0.127 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing a 20% ethanol/ethyl acetate solution (7 mL), 0.2 N HCl (3.5 mL), and saturated aqueous NaCl (3.5 mL). The aqueous phase was extracted once with 20% ethanol/ethyl acetate solution (7 mL) and the combined organic phases were washed with a solution containing 0.2 N HCl (3.5 mL) in saturated aqueous NaCl (3.5 ml) followed by a final wash with saturated aqueous sodium bicarbonate solution (7 ml). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness on a rotary evaporator to give 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-A /-(3-phenylpropyl)-1H-benzoimidazole-5-carboxamide as raw material (0.14g).

(9) (9)

2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylmet yl]-/V-(3-fenylpropyl)-1H-benzoimidazol-5-karboksamid (0,14 g, råmateriale) ble oppløst i vannfri etanol (0,5 mL) og løsningen ble blandet med vannfri hydrazin (0,15 mL, 0,48 mmol). Blandingen ble oppvarmet ved tilbakeløp under N2 i 1 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-/N-(3-phenylpropyl)-1H-benzoimidazol-5-carboxamide ( 0.14 g, crude material) was dissolved in anhydrous ethanol (0.5 mL) and the solution was mixed with anhydrous hydrazine (0.15 mL, 0.48 mmol). The mixture was heated at reflux under N2 for 1

time og deretter konsentrert på en rotasjonsinndamper. Residuet ble plassert under vakuum (0,15 Torr) i 2 timer for å fjerne overskudd av hydrazin. Residuet ble fortynnet med 3M HCI (0,5 mL) og blandingen ble oppvarmet ved 50°C i 20 minutter. Reaksjonsblandingen ble avkjølt til romtemperatur og omrørt i ytterligere 20 minutter, hvilket ga et fast presipitat. Fellingen ble isolert ved filtrering og vasket med vann (4x1,5 mL). Filtratene ble samlet og vasket med en 20% etanol/etylacetat-løsning (2x7 mL). De samlede vandige faser ble hour and then concentrated on a rotary evaporator. The residue was placed under vacuum (0.15 Torr) for 2 hours to remove excess hydrazine. The residue was diluted with 3M HCl (0.5 mL) and the mixture was heated at 50°C for 20 minutes. The reaction mixture was cooled to room temperature and stirred for an additional 20 minutes, yielding a solid precipitate. The precipitate was isolated by filtration and washed with water (4x1.5 mL). The filtrates were collected and washed with a 20% ethanol/ethyl acetate solution (2x7 mL). The combined aqueous phases were

lyofilisert, hvilket ga råproduktet som et hydroklorid-salt. Råmaterialet ble renset ved preparativ revers fase HPLC, hvilket ga 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylmetyl]-A/-(3-fenylpropyl)-1A7-benzoimidazol-5-karboksamid (0,04 g, 0,07 mmol) som et hvitt, fast stoff; <1>H-NMR (300 MHz, CD3OD): 8,14 (s, 1H), 7,84-7,89 (m, 2H), 7,77 (d, 1H, J=8,1 Hz), 7,71 (d, 1H, J=8,1 Hz), 7,56 (d, 1H, J=8,1 Hz), 7,12-7,27 (m, 5H), lyophilized to give the crude product as a hydrochloride salt. The crude material was purified by preparative reverse phase HPLC to give 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-N-(3-phenylpropyl )-1A7-benzoimidazole-5-carboxamide (0.04 g, 0.07 mmol) as a white solid; <1>H-NMR (300 MHz, CD3OD): 8.14 (s, 1H), 7.84-7.89 (m, 2H), 7.77 (d, 1H, J=8.1 Hz) , 7.71 (d, 1H, J=8.1 Hz), 7.56 (d, 1H, J=8.1 Hz), 7.12-7.27 (m, 5H),

4,29 (s, 2H), 3,43 (t, 2H, J=7,2 Hz), 2,66 (t, 2H, J=7,2 Hz), 1,69 (m, 4H). 4.29 (s, 2H), 3.43 (t, 2H, J=7.2 Hz), 2.66 (t, 2H, J=7.2 Hz), 1.69 (m, 4H).

Ved en metode tilsvarende den i Eksempel 2 ble de følgende forbindelser ifølge foreliggende oppfinnelse fremstilt: 2-(5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-A/-naft-1-ylmetyl-1H-benzoimidazol-5-karboksamid (Forbindelse 2), 'H-NMR (300 MHz, CD3OD): 8.13 (m, 2H), 7,88 (m, 2H), 7,80 (m, 2H), 7,73 (d, 1H, J=7,9 Hz), 7,67 (d, 1H, J=7,9 Hz), 7,38-7,54 (m, 5H), 5,01 (s, 2H), 4,26 (s, 2H); By a method corresponding to that in Example 2, the following compounds according to the present invention were prepared: 2-(5-aminomethyl-1/-/-benzoimidazol-2-ylmethyl)-N-naphth-1-ylmethyl-1H-benzoimidazol-5 -carboxamide (Compound 2), 1H-NMR (300 MHz, CD3OD): 8.13 (m, 2H), 7.88 (m, 2H), 7.80 (m, 2H), 7.73 (d, 1H , J=7.9 Hz), 7.67 (d, 1H, J=7.9 Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-benzyl-1H-benzoimidazol-5-karboksamid (Forbindelse 3), 'H-NMR (300 MHz, CD3OD): 8,18 (s, 1h), 7,91 (d, 1H, J=7,9 Hz). 7,82 (s. 1H), 7,76 (d, 1H, J=7,9), 7,72 (d, 1H, J=7,9 Hz), 7,54 (d, 1H, J=7,9 Hz), 7,23-7,38 (m, 5H), 4,60 (s, 2H), 4,28 (s, 2H); 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-benzyl-1H-benzoimidazol-5-carboxamide (Compound 3), 1H-NMR (300 MHz, CD3OD): 8.18 (s, 1h), 7.91 (d, 1H, J=7.9 Hz). 7.82 (p. 1H), 7.76 (d, 1H, J=7.9), 7.72 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J= 7.9 Hz), 7.23-7.38 (m, 5H), 4.60 (s, 2H), 4.28 (s, 2H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(3-fenylpropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 4), <1>H-NMR (300 MHz, CD3OD): 8.14 (s, 1H), 7,87 (d, 1H, J=8,6 Hz), 7,8 (s, 1H), 7,76 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6 Hz), 7,54 (d, 1H, J=8,6 Hz), 7,24 (m, 4H), 7,16 (m, 1H), 4,28 (s, 2H), 3,46 (t, 2H, J=7,9 Hz), 2,95 (t, 2H, J=7,9 Hz), 1,62 (kintet, 2H, 7,9 Hz); 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-A/-(3-phenylpropyl)-1H-benzoimidazole-5-carboxamide (Compound 4), <1>H-NMR (300 MHz, CD3OD): 8.14 (s, 1H), 7.87 (d, 1H, J=8.6 Hz), 7.8 (s, 1H), 7.76 (d, 1H, J=8.6 Hz), 7, 71 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, J=8.6 Hz), 7.24 (m, 4H), 7.16 (m, 1H), 4, 28 (s, 2H), 3.46 (t, 2H, J=7.9 Hz), 2.95 (t, 2H, J=7.9 Hz), 1.62 (kinted, 2H, 7.9 Hz);

2-(5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-A/-(2-fenyletyl)- 2-(5-aminomethyl-1/-/-benzoimidazol-2-ylmethyl)-N-(2-phenylethyl)-

1 H-benzoimidazol-5-karboksamid (Forbindelse 5), ^-NMR (300 1 H -benzoimidazole-5-carboxamide (Compound 5), 3-NMR (300

MHz, DMSO-de): 8,12 (s, 1H), 7,83 (m, 2H), 7,78 (d, 1H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J = 9,3 Hz), 7,29 (m, 4H), 7,22 (m, 1H), 4,29 (s, 2H), 3,65 (t, 2H, J=7,9 Hz), 2,95 (t, 2H, J=7,9 Hz); MHz, DMSO-de): 8.12 (s, 1H), 7.83 (m, 2H), 7.78 (d, 1H, J=9.3 Hz), 7.71 (d, 1H, J =9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.29 (m, 4H), 7.22 (m, 1H), 4.29 (s, 2H), 3.65 (t, 2H, J=7.9 Hz), 2.95 (t, 2H, J=7.9 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(3-aminometyl)benzyl-1H-benzoimidazol-5-karboksamid (Forbindelse 6), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-A/-(3-aminomethyl)benzyl-1H-benzoimidazole-5-carboxamide (Compound 6), <1>H-NMR (300

MHz, DMSO-de): 9,31 (t, 1H, J=5,7 Hz), 8,58 (br s, 3H), 8,41 (br s, 3H), 8,28 (s, 1H), 7,97 (m, 2H), 7,79 (d, 1H, J=9,3 Hz), 7,75 (d, 1H, J=9,3 Hz), 7,59 (d, 1H, J=9,3 Hz), 7,43 (s, 1H), 7,35 (s, 3H), 5,07 (s, 2H), 4,50 (m, 2H), 4,18 (m, 2H), 3,97 (m, 2H); MHz, DMSO-de): 9.31 (t, 1H, J=5.7 Hz), 8.58 (br s, 3H), 8.41 (br s, 3H), 8.28 (s, 1H ), 7.97 (m, 2H), 7.79 (d, 1H, J=9.3 Hz), 7.75 (d, 1H, J=9.3 Hz), 7.59 (d, 1H , J=9.3 Hz), 7.43 (s, 1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m, 2H), 4.18 (m , 2H), 3.97 (m, 2H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(2-aminoetyl)-1-mety 1H-benzoimidazol-5-karboksamid (Forbindelse 7), <1>H-NMR (300 MHz, DMSO-d6): 8,86 (br, 1H), 8,50 (br s, 3H), 8,24 (s, 1H), 8,08 (br s, 3H), 7,93 (m, 2H), 7,77 (d, 1H, J = 8,7 Hz), 7,55 (d, 1H, J=9,2 Hz), 5,02 (br, s, 2H), 4,16 (m, 2H), 3,94 (s, 2H), 3,50 (m, 2H), 2,96 (m, 2H); 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(2-aminoethyl)-1-methyl 1H-benzoimidazole-5-carboxamide (Compound 7), <1>H-NMR (300 MHz, DMSO-d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m, 2H ), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (d, 1H, J=9.2 Hz), 5.02 (br, s, 2H), 4.16 (m , 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-W-(2-aminoetyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 8), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(2-aminoethyl)-1H-benzoimidazole-5-carboxamide (Compound 8), <1>H-NMR (300

MHz, DMSO-de): 8,97 (t, 1H, J=4,3 Hz), 8,58 (br s, 3H), 8,31 (s, 1H), 8,16 (brs, 3H), 7,97 (m, 2H), 7,79 (d, 1H, J=10 Hz), 7,73 (d, 1H, J=10 Hz), 7,59 (d, 1H, J=10 Hz), 5,09 (s, 1H), 4,19 (m, 2H), 3,54 (m, 2H), 2,99 (m, 2H); MHz, DMSO-de): 8.97 (t, 1H, J=4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (brs, 3H) , 7.97 (m, 2H), 7.79 (d, 1H, J=10 Hz), 7.73 (d, 1H, J=10 Hz), 7.59 (d, 1H, J=10 Hz ), 5.09 (s, 1H), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);

2-(5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-W-(4-aminobutyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 9), <1>H-NMR (300 2-(5-aminomethyl-1/-/-benzoimidazol-2-ylmethyl)-N-(4-aminobutyl)-1H-benzoimidazole-5-carboxamide (Compound 9), <1>H-NMR (300

MHz, DMSO-de): 8,77 (t, 1H, J=5,7 Hz), 8,61 (brs, 3H), 8,24 (s, 1H), 7,90-8,02 (m, 5H), 7,78 (d, 1H, J=9,3 Hz), 7,74 (d, 1H, J=9,3 Hz), 7,60 (d, 1H, J=9,3 Hz), 5,09 (s, 1H), 4,18, (m, 2H), 3,28 (m, 2H), 2,78 (m, 2H), 1,12 (m, 4H); MHz, DMSO-de): 8.77 (t, 1H, J=5.7 Hz), 8.61 (brs, 3H), 8.24 (s, 1H), 7.90-8.02 (m , 5H), 7.78 (d, 1H, J=9.3 Hz), 7.74 (d, 1H, J=9.3 Hz), 7.60 (d, 1H, J=9.3 Hz ), 5.09 (s, 1H), 4.18, (m, 2H), 3.28 (m, 2H), 2.78 (m, 2H), 1.12 (m, 4H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(3-aminopropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 10), <1>H-NMR (300 MHz, DMSO-ds): 8,9 (t, 1H, J=5,0 Hz), 8,53 (br s, 3H), 8,23 (s, 1H), 7,97 (br s, 3H), 7,94 (s, 1H), 7,89 (d, 1Ht J=8,6 Hz), 7,78 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6), 7,57 (d, 1H, J=8,6 Hz), 5,03 (s, 2H(, 4,40 (m, 2H), 3,34 (m, 2H), 2,81 (m, 2H), 1,81 (m, 2H); og 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(3-aminopropyl)-1H-benzoimidazole-5-carboxamide (Compound 10), <1>H-NMR (300 MHz, DMSO-ds ): 8.9 (t, 1H, J=5.0 Hz), 8.53 (br s, 3H), 8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1Ht J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.71 (d, 1H, J=8.6 ), 7.57 (d, 1H, J=8.6 Hz), 5.03 (s, 2H(, 4.40 (m, 2H), 3.34 (m, 2H), 2.81 (m , 2H), 1.81 (m, 2H); and

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-W-cykloheksylmetyl-1H-benzimidazol-5-karboksamid (Forbindelse 11), 'H-NMR (300 MHz, CD3OD): 8,15 (s, 1H), 7,88 (d, 1H, J=7,6 Hz), 7,84 (s, 1H), 7,76 (d, 1H, J=7,6 hz), 7,72 (d, 1H, J=7,6 Hz), 7,54 (d, 1H, J=7,6 Hz), 4,29 (s, 2H), 3,26 (d, 2H, J=7,2 Hz), 1,64-1,86 (m, 6H), 1,20-1,37 (m, 3H), 0,95-1,09 (m, 2H). 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-cyclohexylmethyl-1H-benzimidazol-5-carboxamide (Compound 11), 1H-NMR (300 MHz, CD3OD): 8.15 (s, 1H ), 7.88 (d, 1H, J=7.6 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=7.6 hz), 7.72 (d, 1H , J=7.6 Hz), 7.54 (d, 1H, J=7.6 Hz), 4.29 (s, 2H), 3.26 (d, 2H, J=7.2 Hz), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).

EKSEMPEL 3 EXAMPLE 3

2-(5-arninometyl-1H-benzoimidazol-2-ylmetyi)-A/-(3-aminopropyl)-1-metyl-1H-benzoimidazol-5-karboksamid (Forbindelse 12) (a) En blanding omfattende 3-nitro-4-klorbenzosyre (1,3 g, 6,45 mmol), 10% metylamin og vann (10 ml) i et forseglet rør ble oppvarmet ved 100°C i 11 timer, konsentrert til 1 ml og deretter fortynnet med konsentrert saltsyre, hvilket 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(3-aminopropyl)-1-methyl-1H-benzoimidazole-5-carboxamide (Compound 12) (a) A mixture comprising 3-nitro- 4-Chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 mL) in a sealed tube was heated at 100 °C for 11 h, concentrated to 1 mL and then diluted with concentrated hydrochloric acid, which

ga et gult presipitat. Fellingen ble isolert ved filtrering, vasket med vann og deretter dietyleter og tørket for å gi 3-nitro-4-metylaminobenzosyre (2,1 g, gave a yellow precipitate. The precipitate was isolated by filtration, washed with water and then diethyl ether and dried to give 3-nitro-4-methylaminobenzoic acid (2.1 g,

86% utbytte); 'H-NMR (300 MHz, CDCfe): 8,56 (d, 1H, J = 2,1 Hz), 8,52 (q, 1H, J=8,6 Hz), 7,94 (dd, 1H, 9,3, 2,1 Hz), 7,00 (d, 1H, J=9,3 Hz), 2,97 (d, 3H, 86% dividend); 1H-NMR (300 MHz, CDCfe): 8.56 (d, 1H, J = 2.1 Hz), 8.52 (q, 1H, J=8.6 Hz), 7.94 (dd, 1H , 9.3, 2.1 Hz), 7.00 (d, 1H, J=9.3 Hz), 2.97 (d, 3H,

J = 8,6 Hz). J = 8.6 Hz).

(b) Etylalkohol (100 mL) ble satt til en kolbe inneholdende 3-nitro-4-metylaminobenzosyre (2,09 g, 10,7 mmol) og 10% Pd/C (30 mg) under en stabil strøm av N2. Blandingen ble omrørt under hydrogen i 16 timer, filtrert gjennom en millipore 0,22 mm type GV filterskive og konsentrert på en rotasjonsinndamper. Residuet ble tørket under vakuum, hvilket ga 3-amino-4-metylaminobenzosyre (1,1 g, 61% utbytte). (c) Etyl-3-etoksy-3-iminopropionat, fremstilt som i Eksempel 2(a), ble omsatt med 3-amino-4-metylaminobenzosyre under betingelser lignende de angitt i Eksempel 2(b), hvilket ga 2-etoksykarbonylmetyl-1-metyl-1 H-benzoimdazol-5-karboksylsyre (71% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 7,18 (dd, 1H, J=8,1 Hz), 7,11 (d, 1H, J=1,2 Hz), 6,33 (d, 1H, J=8,1 Hz), 5,28 (brs, 1H),4,67 (br s, 1H), 3,34 (br s, 2H), 2,72 (s, 3H). (d) 2-(3,4-diaminobenzyl)isoindol-1,3-dion, fremstilt som i Eksempel 2(d), ble omsatt med 2-etoksykarbonylmetyM -metyl-1 H-benzoimidazol-5-karboksylsyre under betingelser lignende de angitt i Eksempel 2(e), hvilket ga 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1 H-benzoimidazol-2-ylmetyl]-1 -metyl-1 H-benzoimidazol-5-karboksylsyre (48% utbytte); <1>H-NMR (300 (b) Ethyl alcohol (100 mL) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd/C (30 mg) under a steady stream of N 2 . The mixture was stirred under hydrogen for 16 hours, filtered through a millipore 0.22 mm type GV filter disc and concentrated on a rotary evaporator. The residue was dried under vacuum to give 3-amino-4-methylaminobenzoic acid (1.1 g, 61% yield). (c) Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 3-amino-4-methylaminobenzoic acid under conditions similar to those given in Example 2(b), giving 2-ethoxycarbonylmethyl- 1-methyl-1H-benzoimdazole-5-carboxylic acid (71% yield); <1>H-NMR (300 MHz, DMSO-d6): 7.18 (dd, 1H, J=8.1 Hz), 7.11 (d, 1H, J=1.2 Hz), 6.33 (d, 1H, J=8.1 Hz), 5.28 (brs, 1H), 4.67 (br s, 1H), 3.34 (br s, 2H), 2.72 (s, 3H) . (d) 2-(3,4-diaminobenzyl)isoindole-1,3-dione, prepared as in Example 2(d), was reacted with 2-ethoxycarbonylmethyl-methyl-1H-benzoimidazole-5-carboxylic acid under conditions similar to those stated in Example 2(e), giving 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-1H- benzoimidazole-5-carboxylic acid (48% yield); <1>H-NMR (300

MHz, DMSO-d6): 8,10 (s, 1H), 7,80-7,84 (m, 5H), 7,57 (d, 1H, J=10,0 Hz), 7,40 (br s, 2H), 7,10 (br s, 1H), 4,80 (s, 2H), 4,56 (s, 2H), 3,79 (s, 3H). MHz, DMSO-d6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H).

(e) 2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)- (e) 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-

1 tf-benzoimidazol-2-ylmetyl]-1 -metyl-1 H-benzoimidazol-5-karboksylsyre (0,05 g, 0,108 mmol), 1-hydroksybenzotriazol (0,016 g, 0,118 mmol), 1-(3-dimetylaminopropyl)-3-etylkarbodiimid-hydroklorid (0,023 g, 0,12 mmol) og det mono-BOC beskyttede derivat av 1,3-diaminopropan ble oppløst ved 0°C i metylenklorid (1 mL) og DM F (minimal mengde tilstrekkelig til å bevirke en løsning). Løsningen ble regulert til pH-8 med /V-metylmorfolin og blandingen fikk langsomt oppvarmes til romtemperatur og ble deretter omrørt i 20 timer. Blandingen ble overført til en separasjonstrakt, fortynnet med metylenklorid, vasket med 0,1 N HCI-løsning og deretter mettet NaHCOvløsning, tørket over natriumsutfat, filtrert og konsentrert. Residuet ble renset ved preparativ TLC (10% metanol/etylacetat), hvilket ga 2-[6-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1 H-benzoimidazol-2-ylmetyl]-1 -metyl-W-(3-aminopropyl)-1 H-benzoimidazol-5-karboksamid (0,02 g, 28% utbytte); 'H-NMR (300 1 t -benzoimidazol-2-ylmethyl]-1 -methyl-1 H -benzoimidazol-5-carboxylic acid (0.05 g, 0.108 mmol), 1-hydroxybenzotriazole (0.016 g, 0.118 mmol), 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and the mono-BOC protected derivative of 1,3-diaminopropane were dissolved at 0°C in methylene chloride (1 mL) and DM F (minimum amount sufficient to effect a solution). The solution was adjusted to pH-8 with /V-methylmorpholine and the mixture was allowed to slowly warm to room temperature and was then stirred for 20 hours. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with 0.1 N HCl solution and then saturated NaHCO solution, dried over sodium hydroxide solution, filtered and concentrated. The residue was purified by preparative TLC (10% methanol/ethyl acetate) to give 2-[6-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1 -methyl-N-(3-aminopropyl)-1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield); 'H-NMR (300

MHz, CDCI3): 7,75-7,81 (m, 4H), 7,61-7,68 (m, 3H), 7,33 (brs, 1H), 7,27 (d, 1H, J=8,6 Hz), 7,15 (d, 1H, J=9,3 Hz), 5,10 (brt, 1H), 4,90 (brs, 2H), 4,57 (s, 2H), 3,71 (s, 3H), 3,49 (q, 2H, J=7,2 Hz), 3,24 (q, 2H, J=7,2 Hz), 1,72 (m, 2H), 1,41 (s, 9H); MHz, CDCl3): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (brs, 1H), 7.27 (d, 1H, J= 8.6 Hz), 7.15 (d, 1H, J=9.3 Hz), 5.10 (brt, 1H), 4.90 (brs, 2H), 4.57 (s, 2H), 3 .71 (s, 3H), 3.49 (q, 2H, J=7.2 Hz), 3.24 (q, 2H, J=7.2 Hz), 1.72 (m, 2H), 1 .41 (p, 9H);

(f) 2-[6-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)- (f) 2-[6-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-

1 /-/-benzoimidazol-2-ylmetyl]-1 -metyl-A/-(3-aminopropyl)-1/-/-benzoimidazol-5-karboksamid ble avbeskyttet under betingelser lignende de angitt i Eksempel 2(g), hvilket ga 2-(5-aminometyl-1 H-benzoimidazol-2-ylmetyl)-A/-(3-aminopropyl)-1 -metyl-1 H-benzoimidazol-5-karboksamid (20% utbytte); 'H-NMR (300 MHz, DMSO-d6): 8,85 (t, 1H, J=5,7 Hz), 8,55 (br s, 3H), 8,20 (s, 1H), 8,01 (br s, 3H), 7,74 (m, 2H), 7,80 (d, 1H, 1 /-/-benzoimidazol-2-ylmethyl]-1-methyl-A/-(3-aminopropyl)-1/-/-benzoimidazol-5-carboxamide was deprotected under conditions similar to those stated in Example 2(g), which gave 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(3-aminopropyl)-1-methyl-1H-benzoimidazol-5-carboxamide (20% yield); 1H-NMR (300 MHz, DMSO-d6): 8.85 (t, 1H, J=5.7 Hz), 8.55 (br s, 3H), 8.20 (s, 1H), 8, 01 (br s, 3H), 7.74 (m, 2H), 7.80 (d, 1H,

J = 6,6 Hz), 5,07 (s, 2H), 4,16 (m, 2H), 3,96 (s, 3H), 3,32 (m, 2H), 2,79 (m, 2H), 1,80 (m, 2H). J = 6.6 Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1.80 (m, 2H).

Ved å følge fremgangsmåten i Eksempel 3 ble de følgende forbindelser ifølge foreliggende oppfinnelse fremstilt: 3-[2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(2-naft-1-yletyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 13), <1>H-NMR (300 By following the procedure in Example 3, the following compounds according to the present invention were prepared: 3-[2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-A/-(2-naphth-1-ylethyl)-1H- benzoimidazole-5-carboxamide (Compound 13), <1>H-NMR (300

MHz, CD3OD): 8,25 (d, 1H, J= 8,1 Hz), 8,09 (s, 1H), 7,67-7,86 (m, 6H), 7,37-7,54 (m, 5H), 4,27 (s, 2H), 3,73 (t, 2H, J = 7,4 Hz), 3,41 (t, 2H, J=7,4 Hz); MHz, CD3OD): 8.25 (d, 1H, J= 8.1 Hz), 8.09 (s, 1H), 7.67-7.86 (m, 6H), 7.37-7.54 (m, 5H), 4.27 (s, 2H), 3.73 (t, 2H, J = 7.4 Hz), 3.41 (t, 2H, J = 7.4 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(3,3-difenylpropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 14), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(3,3-diphenylpropyl)-1H-benzoimidazole-5-carboxamide (Compound 14), <1>H-NMR (300

MHz, CD3OD): 8,11 (s, 1H), 7,77-7,86 (m, 3H), 7,70 (d, 1H, J=9,3), 7,56 (d, 1H, J=9,3 Hz), 7,23-7,39 (m, 8H), 7,13-7,19 (m, 2H), 4,30 (s, 2H), 4,07 (t, 1H, J=7,2 Hz), 3,40 (t, 2H, J=7,2 Hz), 2,44 (q, 2H, J=7,2 Hz); MHz, CD3OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J=9.3), 7.56 (d, 1H, J=9.3 Hz), 7.23-7.39 (m, 8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H , J=7.2 Hz), 3.40 (t, 2H, J=7.2 Hz), 2.44 (q, 2H, J=7.2 Hz);

2-(5-amtnometyl-1H-benzoimidazol-2-ylmetyl)-W-(2-naft-2-yletyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 15), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(2-naphth-2-ylethyl)-1H-benzoimidazol-5-carboxamide (Compound 15), <1>H-NMR (300

MHz, CD3OD): 8,10 (s, 1H), 7,67-7,86 (rn, 8H), 7,55 (d, 1H, J=10,0 Hz), 7,38-7,44 (m, 3H), 4,28 (s, 2H), 3,72 (t, 2H, J=7,2 Hz), 3,10 (t, 2H, J=7,2 Hz); MHz, CD3OD): 8.10 (s, 1H), 7.67-7.86 (rn, 8H), 7.55 (d, 1H, J=10.0 Hz), 7.38-7.44 (m, 3H), 4.28 (s, 2H), 3.72 (t, 2H, J=7.2 Hz), 3.10 (t, 2H, J=7.2 Hz);

2-(1H-benzoimidazol-2-ylmetyl)-W-[2-(1H-indol-3-yl)etyl]-1H-benzoimidazol-5-karboksamid (Forbindelse 16), 'H-NMR (300 2-(1H-benzoimidazol-2-ylmethyl)-N-[2-(1H-indol-3-yl)ethyl]-1H-benzoimidazol-5-carboxamide (Compound 16), 1H-NMR (300

MHz, CD3OD): 8,09 (s, 1H), 7,81-7,84 (m, 2H), 7,74 (d, 1H, J=8,6 Hz), 7,67 (d, 1H, J=8,6 Hz), 7,52-7,58 (m, 2H), 7,30 (d, 1H, J=7,9), 7,01-7,08 (m, 2H), 6,94 (t, 1H, J=7,9 Hz), 4,26 (s, 2H), 3,68 (t, 2H, J=6,8 Hz), 3,06 (t, 2H, J=6,8 Hz); MHz, CD3OD): 8.09 (s, 1H), 7.81-7.84 (m, 2H), 7.74 (d, 1H, J=8.6 Hz), 7.67 (d, 1H , J=8.6 Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H, J=7.9), 7.01-7.08 (m, 2H), 6.94 (t, 1H, J=7.9 Hz), 4.26 (s, 2H), 3.68 (t, 2H, J=6.8 Hz), 3.06 (t, 2H, J =6.8Hz);

2-(5-aminome1yl-1H-benzoimidazol-2-ylmetyl)-/v"-[2-(5-metoksy)indol-3-yl]-1H-benzoimidazol-5-karboksamid (Forbindelse 17), 'H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-[2-(5-methoxy)indol-3-yl]-1H-benzoimidazol-5-carboxamide (Compound 17), 'H- NMR (300

MHz, CD3OD): 8,10 (s, 1H), 7,81-7,85 (m, 2H), 7,76 (d, 1H, J=8,2 Hz), 7,69 (d, 1H, J=8,2 Hz), 7,54 (d, 1H, J=8,2 Hz), 7,20 (d, 1H, J=8,2 Hz), 7,07 (m, 2H), 6,70 (dd, 1H, J=10,0, 2,2 Hz), 4,27 (s, 2H), 3,65-3,71 (m, 5H), 3,04 (t, 2H, J=7,2 Hz); MHz, CD3OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H), 7.76 (d, 1H, J=8.2 Hz), 7.69 (d, 1H , J=8.2 Hz), 7.54 (d, 1H, J=8.2 Hz), 7.20 (d, 1H, J=8.2 Hz), 7.07 (m, 2H), 6.70 (dd, 1H, J=10.0, 2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3.04 (t, 2H, J=7.2 Hz);

2-(5-aminomety 1-1 H-benzoimidazol-2-ylmetyl)-A/-(2,3,4,5,6-pentahydroksyheksyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 18), 2-(5-aminomethyl 1-1H-benzoimidazol-2-ylmethyl)-A/-(2,3,4,5,6-pentahydroxyhexyl)-1H-benzoimidazole-5-carboxamide (Compound 18),

'H-NMR (300 MHz, CD3OD/D20 (1/1)): 8,15 (s, 1H), 7,86-7,90 (m, 2H), 7,83 (d, 1H, J=9,6 Hz), 7,77 (d, 1H, J=9,6 Hz), 7,61 (d, 1H, J=9,6 Hz), 4,32 (s, 2H), 4,01 (m, 1H), 3,62-3,86 (m, 6H), 3,47-3,55 (m, 1H); 1H-NMR (300 MHz, CD 3 OD/D 2 O (1/1)): 8.15 (s, 1H), 7.86-7.90 (m, 2H), 7.83 (d, 1H, J= 9.6 Hz), 7.77 (d, 1H, J=9.6 Hz), 7.61 (d, 1H, J=9.6 Hz), 4.32 (s, 2H), 4.01 (m, 1H), 3.62-3.86 (m, 6H), 3.47-3.55 (m, 1H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(2-fenoksyetyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 19), <1>H-NMR (300 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(2-phenoxyethyl)-1H-benzoimidazole-5-carboxamide (Compound 19), <1>H-NMR (300

MHz, CD3OD): 8,16 (s, 1H), 7,88 (d, 1H, J=9,3 Hz), 7,84 (s, 1H), 7,76 (d,.1H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,23 (2H, J=7,9 Hz), 6,85-6,96 (m, 3H), 4,27 (s, 2H), 4,16 (t, 2H, J=6,1 Hz), 3,78 (t, 2H, J=6,1 Hz); MHz, CD3OD): 8.16 (s, 1H), 7.88 (d, 1H, J=9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J= 9.3 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.55 (d, 1H, J=9.3 Hz), 7.23 (2H, J=7.9 Hz ), 6.85-6.96 (m, 3H), 4.27 (s, 2H), 4.16 (t, 2H, J=6.1 Hz), 3.78 (t, 2H, J= 6.1Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-W-(3-fenylprop-2-ynyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 20), 1 H-N MR (300 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-W-(3-phenylprop-2-ynyl)-1H-benzoimidazol-5-carboxamide (Compound 20), 1 H-N MR (300

MHz, CD3OD): 8,18 (s, 1H), 7,91 (d, 1H, J=9,3 Hz), 7,84 (s, 1H), 7,76 (d, 1H, J=9,3), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,38-7,43 (m, 2H), 7,28-7,32 (m, 3H), 4,40 (s, 2H). 4,27 (s, 2H); MHz, CD3OD): 8.18 (s, 1H), 7.91 (d, 1H, J=9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=9 ,3), 7.71 (d, 1H, J=9.3 Hz), 7.55 (d, 1H, J=9.3 Hz), 7.38-7.43 (m, 2H), 7 .28-7.32 (m, 3H), 4.40 (s, 2H). 4.27 (s, 2H);

2-(5-aminometyl-1H-benzimidazol-2-ylmetyl)-A/-(E-3-fenylallyl)-1tf-benzimidazol-5-karboksamid (Forbindelse 21), 1H-NMR (300 2-(5-Aminomethyl-1H-benzimidazol-2-ylmethyl)-N-(E-3-phenylallyl)-1tf-benzimidazol-5-carboxamide (Compound 21), 1H-NMR (300

MHz, CD3OD): 8,19 (s, 1H), 7,92 (d, 1H, J=9,3 Hz), 7,86 (s, 1H), 7,76 (d, 1H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,33-7,39 (m, 2H), 7,18-7,30 (m, 3H), 6,60 (d, 1H, J=15,8 Hz), 6,34 (dt, 1H, J=15,8, 6,1 Hz), 4,27 (s, 2H), 4,17 (d, 2H, J=6,1 Hz); MHz, CD3OD): 8.19 (s, 1H), 7.92 (d, 1H, J=9.3 Hz), 7.86 (s, 1H), 7.76 (d, 1H, J=9 .3 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.55 (d, 1H, J=9.3 Hz), 7.33-7.39 (m, 2H), 7.18-7.30 (m, 3H), 6.60 (d, 1H, J=15.8 Hz), 6.34 (dt, 1H, J=15.8, 6.1 Hz), 4 .27 (s, 2H), 4.17 (d, 2H, J=6.1 Hz);

2-(5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-/V-(3-cykloheksylpropyl)-1tf-benzoimidazol-5-karboksamid (Forbindelse 22), 'H-NMR (300 2-(5-aminomethyl-1 H -benzoimidazol-2-ylmethyl)- N -(3-cyclohexylpropyl)-1 t -benzoimidazole-5-carboxamide (Compound 22), 1 H-NMR (300

MHz, CD3OD): 8,13 (s, 1H), 7,86 (d, 1H, J=9,3 Hz), 7,81 (s, 1H), 7,74 (d, 1H, MHz, CD3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.3 Hz), 7.81 (s, 1H), 7.74 (d, 1H,

J=9,3 Hz), 7,69 (d, 1H, J=9,3 Hz), 7,53 (d, 1H, J=9,3 Hz), 4,27 (s, 2H), 3,36 (t, 2H, J=7,2 Hz), 1,61-1,78 (m, 7H), 1,19-1,32 (m, 6H). 0,90 (m, 2H); J=9.3 Hz), 7.69 (d, 1H, J=9.3 Hz), 7.53 (d, 1H, J=9.3 Hz), 4.27 (s, 2H), 3 .36 (t, 2H, J=7.2 Hz), 1.61-1.78 (m, 7H), 1.19-1.32 (m, 6H). 0.90 (m, 2H);

3-[2-(5-aminometyl-1 H-benzoimidazol-2-ylmetyl)-N-okt-1 -yl-1H-benzimidazol-5-karboksamid (Forbindelse 23), <1>H-NMR (300 MHz, CD3OD): 8,13 (s, 1H), 7,86 (d, 1H, J=9,7 Hz), 7,82 (s, 1H), 7,74 (d, 1H, J=9,7 Hz), 7,69 (d, 1H, J=9,7), 7,49 (d, 1H, J=9,7 Hz), 4,27 (s, 2H), 3,39 (t, 2H, J=7,2 Hz), 1,64 (m, 2H), 1,26-1,43 (m, 11 H), 0,88 (m, 2H); 3-[2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-oct-1-yl-1H-benzimidazol-5-carboxamide (Compound 23), <1>H-NMR (300 MHz, CD3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.7 Hz), 7.82 (s, 1H), 7.74 (d, 1H, J=9.7 Hz), 7.69 (d, 1H, J=9.7), 7.49 (d, 1H, J=9.7 Hz), 4.27 (s, 2H), 3.39 (t, 2H , J=7.2 Hz), 1.64 (m, 2H), 1.26-1.43 (m, 11H), 0.88 (m, 2H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-W-metyl-A/-(2-fenyletyl)-1H-benzimidazol-5-karboksamid (Forbindelse 24), 'H-NMR (300 MHz, CD3OD): 7,76 (s), 7,69 (d), 7,63 (d), 7,44-7,55 (m), 7,20-7,28 (m), 7,09-7,14 (m), 6,97 (d), 6,85 (br s), 4,19 (s), 3,72 (t), 3,47 (t), 3,22 (s), 3,08 (s), 2,87 (t), 2,76 (t); og 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-methyl-N-(2-phenylethyl)-1H-benzimidazole-5-carboxamide (Compound 24), 1H-NMR (300 MHz, CD3OD ): 7.76 (s), 7.69 (d), 7.63 (d), 7.44-7.55 (m), 7.20-7.28 (m), 7.09-7 .14 (m), 6.97 (d), 6.85 (br s), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3 .08 (s), 2.87 (h), 2.76 (h); and

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-A/-(1-metyl-3-fenylpropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 25), <1>H-NMR (300 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-N-(1-methyl-3-phenylpropyl)-1H-benzoimidazole-5-carboxamide (Compound 25), <1>H-NMR (300

MHz, CD3OD): 8,05 (s, 1H), 7,79 (d, 1H, J=9,3 Hz), 7,75 (s, 1H), 7,68 (d, 1H, J=9,3 Hz), 7,63 (d, 1H, J=9,3 Hz), 7,46 (d, 1H, J=9,3 Hz), 7,09-7,17 (m, 4H), 7,03 (m, 1H), 4,43 (s, 2H), 4,08 (m, 1H), 2,61 (t, 2H, J=7,9 Hz), 1,17-1,93 (m, 2H), 1,18 (d,3H, J=7,2 Hz). MHz, CD3OD): 8.05 (s, 1H), 7.79 (d, 1H, J=9.3 Hz), 7.75 (s, 1H), 7.68 (d, 1H, J=9 ,3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.46 (d, 1H, J=9.3 Hz), 7.09-7.17 (m, 4H), 7.03 (m, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 2.61 (t, 2H, J=7.9 Hz), 1.17-1.93 (m, 2H), 1.18 (d, 3H, J=7.2 Hz).

EKSEMPEL 4 EXAMPLE 4

C-{2-[5-(4-fenylbutoksy)-1H-benzoimidazol-2-ylmetyl]-1H-benzoimidazol-5-yl}metylamin (Forbindelse 26) C-{2-[5-(4-phenylbutoxy)-1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazol-5-yl}methylamine (Compound 26)

(a) 4-fenyl-1-butanol (1 mL, 6,49 mmol) i THF (3 mL) ble blandet under tørr nitrogen med natriumhydrid (0,26 g, 6,5 mmol) i en 60% mineralolje-dispersjon. Blandingen ble omrørt kraftig i 5 minutter, blandet med 3,4-dinitroklorbenzen (1,3 g, 6,42 mmol) og deretter omrørt 10 timer ved romtemperatur. Blandingen ble fordelt mellom dietyleter og 3N saltsyre. Det vandige laget ble separert og ekstrahert mange ganger med dietyleter. De samlede organiske lag ble tørket (MgS04), filtrert og konsentrert ved rotasjonsinndampning. Residuet ble renset ved "flash" kromatograft (9:1 heksanr/dietyleter), hvilket ga 4-(4-fenylbutoksy)-1,2-dinitrobenzen (1,16 g, 72% utbytte); <1>H-NMR (300 (a) 4-Phenyl-1-butanol (1 mL, 6.49 mmol) in THF (3 mL) was mixed under dry nitrogen with sodium hydride (0.26 g, 6.5 mmol) in a 60% mineral oil dispersion . The mixture was stirred vigorously for 5 min, mixed with 3,4-dinitrochlorobenzene (1.3 g, 6.42 mmol) and then stirred for 10 h at room temperature. The mixture was partitioned between diethyl ether and 3N hydrochloric acid. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO 4 ), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatograph (9:1 hexane/diethyl ether) to give 4-(4-phenylbutoxy)-1,2-dinitrobenzene (1.16 g, 72% yield); <1>H-NMR (300

MHz, CDCI3): 7,84 (d, 1H, J = 10.0 Hz), 7,19-7,36 (m, 5H), 7,00-7,06 (m, 2H), 4,10 (t, 2H, J=5,7 Hz), 2,73 (t, 2H, J = 6,5 Hz), 1,89 (m, 4H). (b) Etyl-3-etoksy-3-iminopropionat, fremstilt som i Eksempel 2(a), ble omsatt med 2-(3,4-diaminobenzyl)isoindol-1,3-dion under betingelser lignende de angitt i Eksempel 2(b), hvilket ga etyl-5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylacetat (71% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 7,78-7,9 (m, 4H), 7,43-7,47 (m, 2H), 7,12 (d, 1H, J=9,43 Hz), 4,82 (s, 2H), 4,07 (q, 2H, J = 7,2 Hz), 3,44 (s, 2H), 1,38 (t, 3H, J=7,2 Hz). (c) 4-(4-fenylbutoksy)-1,2-dinitrobenzen ble redusert under betingelser lignende de angitt i Eksempel 3(b), hvilket ga MHz, CDCl3): 7.84 (d, 1H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t , 2H, J=5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H). (b) Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 2-(3,4-diaminobenzyl)isoindole-1,3-dione under conditions similar to those stated in Example 2( b), giving ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-yl acetate (71% yield); <1>H-NMR (300 MHz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J =9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J =7.2 Hz). (c) 4-(4-phenylbutoxy)-1,2-dinitrobenzene was reduced under conditions similar to those given in Example 3(b) to give

4- (4-fenylbutoksy)benzen-1,2-diamin (86% urenset utbytte). 4-(4-phenylbutoxy)benzene-1,2-diamine (86% crude yield).

(d) En blanding av 5-(4-fenylbutoksy)benzen-1,2-diamin (0,06 g, 0,234 mmol) og etyl-5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1H-benzoimidazol-2-ylacetat (0,1 g, 0,234 mmol) ble oppvarmet 1 time ved 185°C under nitrogen. Blandingen ble suspendert i dietyleter og omrørt kraftig i 1 time . De faste stoffene ble oppsamlet ved filtrering, vasket med dietyleter og tørket, hvilket ga 2-{2-[5-(4-fenylbutoksy)-1H-benzoimidazol-2-ylmetyl]-3W-benzoimidazol-5-ylmetyl}isoindol-1,3-dion (0,1 g, 0,18 mmol). (e) 2-{2-[5-(4-fenylbutoksy)-1H-benzoimidazpl-2-ylmetyl]-3H-benzoimidazol-5-ylmetyl}isoindol-1,3-dionet ble avbeskyttet under betingelser lignende de angitt i Eksempel 2(g), hvilket ga C-{2-[5-(4-fenylbutoksy)-1H-benzoimidazol-2-ylmetyl]-1W-benzoimidazol-5-yl}metylamin (0,05 g, 55% utbytte); 'H-NMR (300 MHz, CD3OD): 7,83 (d, 1H, J = 8,6 Hz), 7,76 (s, 1H), 7,69 (d, 1H, J = 10,0 Hz), 7,48 (d, 1H, J=8,6 Hz), (d) A mixture of 5-(4-phenylbutoxy)benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) )-1H-benzoimidazol-2-yl acetate (0.1 g, 0.234 mmol) was heated for 1 hour at 185°C under nitrogen. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solids were collected by filtration, washed with diethyl ether and dried to give 2-{2-[5-(4-phenylbutoxy)-1H-benzoimidazol-2-ylmethyl]-3W-benzoimidazol-5-ylmethyl}isoindole-1 ,3-dione (0.1 g, 0.18 mmol). (e) The 2-{2-[5-(4-phenylbutoxy)-1H-benzoimidazpl-2-ylmethyl]-3H-benzoimidazol-5-ylmethyl}isoindole-1,3-dione was deprotected under conditions similar to those stated in Example 2(g), which gave C-{2-[5-(4-phenylbutoxy)-1H-benzoimidazol-2-ylmethyl]-1W-benzoimidazol-5-yl}methylamine (0.05 g, 55% yield); 1H-NMR (300 MHz, CD3OD): 7.83 (d, 1H, J = 8.6 Hz), 7.76 (s, 1H), 7.69 (d, 1H, J = 10.0 Hz ), 7.48 (d, 1H, J=8.6 Hz),

6,99-7,16 (m, 5H), 6,92 (d, 1H, J = 10,0 Hz), 6,80 (t, 1H, J=7,2 Hz), 4,44 (s, 2H), 3,93 (t, 2H, J=6.5 Hz), 2,56 (t, 2H, J = 7,2 Hz), 1,72 (m, 2H). 6.99-7.16 (m, 5H), 6.92 (d, 1H, J = 10.0 Hz), 6.80 (t, 1H, J=7.2 Hz), 4.44 (s , 2H), 3.93 (t, 2H, J=6.5 Hz), 2.56 (t, 2H, J = 7.2 Hz), 1.72 (m, 2H).

EKSEMPEL 5 EXAMPLE 5

2-fenyletyl-2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-1H-benzoimidazol-5- karbamat-trifluoracetat (Forbindelse 27) 2-Phenylethyl-2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-1H-benzoimidazol-5-carbamate-trifluoroacetate (Compound 27)

2-[5-(1,3-diokso-1,3-dihydroisoindol-2-ylmetyl)-1/-/-benzoimidazol-2-ylmetyl]-1H-benzoimidazol-5-karboksylsyre (0,060 g, 0,133 mmol) i fenetanol (0,160 mL, 1,34 mmol) ble blandet med difenylfosforyl-azid (0,034 mL, 0,158 mmol) og trietylamin (0,022 mL, 0,158 mmol) ved 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1/-/-benzoimidazol-2-ylmethyl]-1H-benzoimidazol-5-carboxylic acid (0.060 g, 0.133 mmol) in phenethanol (0.160 mL, 1.34 mmol) was mixed with diphenylphosphoryl azide (0.034 mL, 0.158 mmol) and triethylamine (0.022 mL, 0.158 mmol) at

romtemperatur under nitrogen. Blandingen ble omrørt i 1 time ved 120°C, avkjølt til romtemperatur og blandet med etanol (0,5 ml) og hydrazin (0,020 ml, 0,637 mmol). Blandingen ble omrørt i 45 minutter ved 95°C, avkjølt til romtemperatur og fortynnet med 3N saltsyre (0,5 ml). Blandingen ble omrørt 20 minutter ved 55°C og deretter filtrert. De filtrerte faste stoffer ble vasket med 3N saltsyre og de samlede filtrater ble vasket med etylacetat (15 ml) og lyofilisert. Residuet ble renset ved preparativ revers fase HPLC, hvilket ga det ønskede produkt (0,008 g, 11% utbytte); 'H-NMR (300 MHz, CD3OD): 8,10 (s, 1H), 7,75 (s, 1H), 7,68 (d, 1H, J = 9,3 Hz), 7,63 (d, 1H, J=9,3 . Hz), 7,38-7,44 (m, 2H), 7,19-7,32 (m, 5H), 4,36 (t, 2H, J = 6,8 Hz), 4,23 (s, 2H), 1,98 (t, 2H, J=6,8 Hz). room temperature under nitrogen. The mixture was stirred for 1 hour at 120°C, cooled to room temperature and mixed with ethanol (0.5 mL) and hydrazine (0.020 mL, 0.637 mmol). The mixture was stirred for 45 min at 95°C, cooled to room temperature and diluted with 3N hydrochloric acid (0.5 mL). The mixture was stirred for 20 minutes at 55°C and then filtered. The filtered solids were washed with 3N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 mL) and lyophilized. The residue was purified by preparative reverse phase HPLC to give the desired product (0.008 g, 11% yield); 1H-NMR (300 MHz, CD3OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d , 1H, J=9.3 . Hz), 7.38-7.44 (m, 2H), 7.19-7.32 (m, 5H), 4.36 (t, 2H, J = 6, 8 Hz), 4.23 (s, 2H), 1.98 (t, 2H, J=6.8 Hz).

EKSEMPEL 6 EXAMPLE 6

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-W-(2-naftalen-1-yletyl)-3-metyl-3H-benzoimidazol-5-karboksyamid (Forbindelse 28) (a) En løsning omfattende 2-nitro-1,4-fenylendiamin (21,0 g, 137 mmol) i etanol (350 mL) og 4,0 M hydrogenklorid i dioksan (30,8 mL, 123 mmol) ble omrørt ved romtemperatur i 15 minutter og deretter ble dietyleter (1 L) tilsatt, hvilket ga et presipitat. Fellingen ble oppsamlet ved filtrering, vasket med ytterligere dietyleter og tørket/' vakuum, hvilket ga 2-nitro-1,4-fenylenediamin-hydroklorid (23,3 g, 100% utbytte). (b) En blanding omfattende 2-nitro-1,4-fenylendiamin-hydroklorid (15,0 g, 79,1 mmol), cyanamid (25,0 g, 595 mmol) og vann (5 mL) ble oppvarmet ved 60°C og omrørt i 1,5 timer, fikk avkjøles til romtemperatur og deretter ble overskudd av dietyleter langsomt tilsatt, hvilket ga et presipitat. Fellingen ble oppsamlet ved filtrering, vasket med ytterligere dietyleter og tørket / vakuum, hvilket ga W-(4-amino-3-nitrofenyl)guanidin-hydroklorid (18,0 g, 98% utbytte); 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-N-(2-naphthalen-1-ylethyl)-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 28) (a) A solution comprising 2 -nitro-1,4-phenylenediamine (21.0 g, 137 mmol) in ethanol (350 mL) and 4.0 M hydrogen chloride in dioxane (30.8 mL, 123 mmol) were stirred at room temperature for 15 min and then diethyl ether (1 L) was added, giving a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried under vacuum to give 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield). (b) A mixture comprising 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 mL) was heated at 60° C and stirred for 1.5 hours, allowed to cool to room temperature and then excess diethyl ether was slowly added, giving a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried/vacuum to give N-(4-amino-3-nitrophenyl)guanidine hydrochloride (18.0 g, 98% yield);

'H-NMR (300 MHz, DMSO-d6): 9,7 (s), 7,8 (s), 7,6 (s), 7,5 (s), 7,3 (d), 7,1 (d). 1H-NMR (300 MHz, DMSO-d6): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7, 1 (d).

(c) En blanding omfattende A/-(4-amino-3-nitrofenyl)guanidin-hydroklorid (12,0 g, 51,8 mmol), 10% palladium på karbon (1,0 g), tetrahydrofuran (100 mL) og metanol (100 mL) ble hydrogenert ved én atmosfære, filtrert og konsentrert / vakuum, hvilket ga W-(3,4-diaminofenyl)guanidin-hydroklorid (10,3 g, 98% (c) A mixture comprising N-(4-amino-3-nitrophenyl)guanidine hydrochloride (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL) was hydrogenated at one atmosphere, filtered and concentrated/vacuum to give N-(3,4-diaminophenyl)guanidine hydrochloride (10.3 g, 98%

utbytte) som et mørkt, fast stoff; 'H-NMR (300 MHz, DMSO-d6): 9,4 (s), 7,2 (s), 6,5 (d), 6,3 (s), 6,2 (d), 4,7 (s). (d) En blanding omfattende W-(3,4-diaminofenyl)guanidin-hydroklorid (9,9 g, 49 mmol), etoksykarbonimidoyleddiksyre-etylester-hydroklorid (12,4 g, 59 mmol) og eddiksyre (20 mL) ble oppvarmet i et oljebad ved 110°C og omrørt i 1,5 timer, avkjølt til romtemperatur og konsentrert / vakuum. Residuet ble oppløst i etanol (15 mL) og deretter ble etylacetat (10 mL) satt til løsningen, hvilket ga et presipitat i suspensjon. Suspensjonen ble filtrert og et overskudd av etyleter ble satt til filtratet, hvilket ga et andre presipitat. Fellingen ble oppsamlet ved filtrering, vasket med ytterligere etyleter og tørket / vakuum, hvilket ga etyl-5-guanidino-1H-benzoimidazol-2-ylacetat-hydroklorid (14,1 g, 94% utbytte) som et gråhvitt, fast stoff; <1>H-NMR (300 MHz, DMSO-d6): 10,2 (s), 7,8 (d), 7,7 (m), 7,3 (d), 4,5 (s), 4,2 (q), 1,2 (t). (e) En blanding omfattende 4-nitro-3-metoksybenzosyre (5,0 g, 25,4 mmol) og vandig metylamin (40%, 15 mL) i et forseglet rør ble oppvarmet i et oljebad ved 100°C i 12 timer, fikk avkjøles til romtemperatur og ble deretter hellet i en omrørt oppslemning av 1M vandig saltsyre og is, hvilket ga et oransje presipitat. Fellingen ble oppsamlet ved filtrering, skyllet med vann og omkrystallisert fra varm etanol, hvilket ga 3-metylamino-4-nitrobenzosyre som et klart rødt, krystallinsk fast stoff (3,6 g, 73% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 13,5 (s), 8,3 (q), 8,2 (d), 7,4 (s), 7,1 (d), 3,0 (d). (f) En blanding omfattende 3-metylamino-4-nitrobenzosyre (13,0 g, 66,3 mmol), PyBOP (38,0 g, 73,0 mmol), hydroksybenztriazol-hydrat (9,9 g, 73,0 mmol), dimetylformamid (100 mL) og N-metylmorfolin (18,3 mL) ble omrørt ved romtemperatur i 15 minutter og deretter ble 2-naftylen-1-yletylamin (13,8 g, 66,3 mmol) tilsatt. Blandingen ble omrørt i ytterligere 30 minutter og konsentrert / vakuum. Residuet ble fordelt mellom vann og etylacetat og det organiske laget ble vasket med vann, 0,1M vandig saltsyre, mettet vandig natriumhydrogenkarbonat og deretter mettet vandig natriumklorid, tørket (magnesiumsulfat), filtrert og konsentrert /' vakuum. Residuet ble renset ved omkrystallisering fra varm etanol, hvilket ga 3-metylamino-A/-(2-naftalen-1-yl-etyl)-4-nitrobenzamid som et klart rødt, krystallinsk fast stoff (21,3 g, 92% utbytte); <1>H-NMR (300 MHz, DMSO-d6): 8,8 (t), 8,3 (d), 8,2 (q), 8,1 (d), 7,9 (d), 7,8 (d), 7,6-7,3 (m), 7,2 (s), 7,0 (d), 3,6 (q), 3,3 (t), 3,0 (d). (g) En blanding omfattende 3-metylamino-W-(2-naft-1-yletyl)-4-nitrobenzamid (21,3 g, 61 mmol), 10% palladium på karbon (1,0 g), tetrahydrofuran (100 ml) og metanol (100 ml) ble hydrogenert ved én atmosfære, filtrert og konsentrert / vakuum, hvilket ga 4-amino-3-metylamino-A/-(2-naft-1-yletyl)-4-benzamid (18,4 g, 95% utbytte) som et bleket, amorft fast stoff; <1>H-NMR (300 MHz, DMSO-d6): 8,3 (d), 8,2 (t), 7,9 (d), 7,8 (d), 7,6-7,4 (m), 7,1 (d), 6,9 (s), 6,5 (d), 5,0 (s), 3,5 (q), 3,2 (t), 2,7 (s). (h) En blanding omfattende etyl-5-guanidino-1H-benzoimidazol-2-ylacetat-hydroklorid (0,5 g, 1,7 mmol), 4-amino-3-metylamino-A/-(2-naft-1-yletyl)-4-benzamid (0,5 g, 1,7 mmol) og dimetylformamid (2 mL) ble oppvarmet i et oljebad ved 185°C og omrørt under en nitrogen-atmosfære i 3,5 timer, avkjølt til romtemperatur og hellet i omrørt acetonitril (150 mL), hvilket ga et presipitat. Fellingen ble vasket med ytterligere acetonitril og dietyleter (150 mL), oppsamlet ved filtrering og tørket /' vakuum, hvilket ga et gråhvitt, fast stoff. Det faste stoffet ble renset ved preparativ revers fase HPLC, hvilket ga 2-(5-guanidino-1W-benzoimidazol-2-ylmetyl)-W-(2-naft-1-yletyl)-3-metyl-3H-benzoimidazol-5-karboksamid som et hvitt, fast stoff (0,5 g, 57 %); LRMS(ESI): Beregnet for C30H28N6O: 516,6; Funnet (MH<+>): 517,2. yield) as a dark solid; 1H NMR (300 MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4, 7 (s). (d) A mixture comprising N-(3,4-diaminophenyl)guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) was heated in an oil bath at 110°C and stirred for 1.5 hours, cooled to room temperature and concentrated / vacuum. The residue was dissolved in ethanol (15 mL) and then ethyl acetate (10 mL) was added to the solution, giving a precipitate in suspension. The suspension was filtered and an excess of ethyl ether was added to the filtrate, giving a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried/vacuum to give ethyl 5-guanidino-1H-benzoimidazol-2-yl acetate hydrochloride (14.1 g, 94% yield) as an off-white solid; <1>H-NMR (300 MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t). (e) A mixture comprising 4-nitro-3-methoxybenzoic acid (5.0 g, 25.4 mmol) and aqueous methylamine (40%, 15 mL) in a sealed tube was heated in an oil bath at 100 °C for 12 h , was allowed to cool to room temperature and was then poured into a stirred slurry of 1M aqueous hydrochloric acid and ice, yielding an orange precipitate. The precipitate was collected by filtration, rinsed with water and recrystallized from hot ethanol to give 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); <1>H-NMR (300 MHz, DMSO-d6): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d). (f) A mixture comprising 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenztriazole hydrate (9.9 g, 73.0 mmol), dimethylformamide (100 mL) and N-methylmorpholine (18.3 mL) were stirred at room temperature for 15 minutes and then 2-naphthylen-1-ylethylamine (13.8 g, 66.3 mmol) was added. The mixture was stirred for an additional 30 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, 0.1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by recrystallization from hot ethanol to give 3-methylamino-N-(2-naphthalen-1-yl-ethyl)-4-nitrobenzamide as a bright red crystalline solid (21.3 g, 92% yield ); <1>H-NMR (300 MHz, DMSO-d6): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 ( d). (g) A mixture comprising 3-methylamino-N-(2-naphth-1-ylethyl)-4-nitrobenzamide (21.3 g, 61 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 ml) and methanol (100 ml) were hydrogenated at one atmosphere, filtered and concentrated / vacuum to give 4-amino-3-methylamino-N-(2-naphth-1-ylethyl)-4-benzamide (18.4 g, 95% yield) as a bleached, amorphous solid; <1>H-NMR (300 MHz, DMSO-d6): 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q), 3.2 (t), 2.7 ( s). (h) A mixture comprising ethyl 5-guanidino-1H-benzoimidazol-2-yl acetate hydrochloride (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N-(2-naphth-1 -ylethyl)-4-benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 mL) were heated in an oil bath at 185 °C and stirred under a nitrogen atmosphere for 3.5 h, cooled to room temperature and poured into stirred acetonitrile (150 mL), which gave a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 mL), collected by filtration and dried under vacuum to give an off-white solid. The solid was purified by preparative reverse phase HPLC to give 2-(5-guanidino-1N-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl)-3-methyl-3H-benzoimidazol-5 -carboxamide as a white solid (0.5 g, 57%); LRMS(ESI): Calcd for C30H28N6O: 516.6; Found (MH<+>): 517.2.

EKSEMPEL 7 EXAMPLE 7

Etyl-2-(4-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oksobutyl)benzoat Ethyl-2-(4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5- yl}-4-oxobutyl)benzoate

(Forbindelse 29) (Compound 29)

(a) En løsning omfattende etyl-2-cyanopropionat (100 g, 0,29 mol.) i etanol (65 mL) ble avkjølt til 0°C og deretter mettet med tørr hydrogenklorid-gass. Blandingen fikk oppvarmes til romtemperatur, ble omrørt i 24 timer, avkjølt til 0°C og mettet med hydrogenklorid-gass. Blandingen fikk oppvarmes til romtemperatur og ble omrørt ytterligere 24 timer. Etyleter:heksan (1:1) ble satt til blandingen, hvilket ga et presipitat. Presipitatet ble isolert ved filtrering og tørket /' vakuum, hvilket ga etyl-2-(A/-etoksyamidino)propionat-hydroklorid (119,6 g, 73% utbytte) som et hvitt, fast stoff; <*>H NMR (300 MHz, DMSO-d6): 12,05 (br s, 2H), 4,50 (q, 2H), 4,15 (m, 3H), 1,30 (m, 6H), 1,20 (tr, 3H). (b) En blanding omfattende 3,4-diaminopyridin (51,7 g, 0,46 mol), etyl-2-(A/-etoksyamidino)propionoat-hydroklorid (125 g, 0,69 mol) og iseddik (200 mL) ble oppvarmet ved 85°C og omrørt i 18 timer og deretter oppvarmet ved 120°C og omrørt i en ytterligere time. Blandingen ble avkjølt til romtemperatur og konsentrert / vakuum. Residuet ble nøytralisert ved tilsetning av et overskudd av 5M vandig ammoniumhydroksyd og blandingen ble ekstrahert med etylacetat. Det organiske laget ble vasket med mettet vandig natrium-hydrogenkarbonat og deretter mettet vandig natriumklorid, tørket (MgS04), filtrert og konsentrert / vakuum, hvilket ga etyl-1/-/-imidazo[4,5-c]pyridin-2-karboksylat (60,4 g, 58% utbytte); <*>H NMR (300 MHz, CDCI3): 9,00 (s, 1H), 8,45 (d, 1H), 7,50 (d, 1H), 4,25 (q, 2H), 3,90 (q, 1H), 1,75 (d, 3H), 1,25 (tr, 3H). (c) En blanding omfattende etyl-1H-imidazo[4,5-c]pyridin-2-karboksyiat (34,7 g, 158 mmol), trifluoreddiksyre (50 mL) og platinaoksyd (2,5 g) i et Parr hydrogenerings-apparat ble hydrogenert ved 3,5 kg/cm<2> i 24 timer, filtrert og konsentrert / vakuum. Det oljeaktige residuet ble oppløst i et minimum av etanol og tørr hydrogenklorid i dioksan-løsning (4M, 120 mL, 475 mmol) ble satt til løsningen. Et overskudd av etyleter ble satt til løsningen, hvilket ga et presipitat. Fellingen ble oppsamlet ved filtrering og tørket / vakuum, hvilket ga etyl-1,4,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-karboksylat-dihydroklorid (30,7 g, 66% utbytte); <1>H NMR (300 MHz, DMSO-d6): 10,00 (br s, 2H), 4,35 (q, 1H), 4,20 (br s, 2H), 4,10 (m, 2H), 3,35 (m, 2H), 2,90 (br s, 2H), 1,55 (d, 3H), 1,15 (tr, 3H). (d) En blanding omfattende etyl-1,4,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-karboksylat-dihydroklorid (60,2 g, 0,20 mol), acetonitril (500 mL) og diisopropyletylamin (100 mL, 0,60 mol) ble avkjølt til 0°C og omrørt mens benzylklorformiat (58 mL, 0,40 mol) ble tilsatt langsomt. Blandingen ble langsomt oppvarmet til romtemperatur, omrørt i ytterligere 16 timer og konsentrert / vakuum. Residuet ble oppløst i etyleter (500 mL) og løsningen ble vasket med 0,1 M vandig saltsyre, mettet vandig natrium-hydrogenkarbonat og mettet vandig natriumklorid, tørket over vannfritt natriumsulfat, filtrert og konsentrert / vakuum, hvilket ga en farveløs olje. Residuet ble oppløst i etanol (320 mL) og løsningen ble avkjølt til 0°C og deretter ble natriumetoksyd i etanol-løsning (2,6M, 85 mL, 0,22 mol.) langsomt tilsatt. Blandingen ble omrørt i én time ved 0"C og deretter ble hydrogenklorid-løsning i dioksan (4M, 50 mL) (a) A solution comprising ethyl 2-cyanopropionate (100 g, 0.29 mol) in ethanol (65 mL) was cooled to 0°C and then saturated with dry hydrogen chloride gas. The mixture was allowed to warm to room temperature, was stirred for 24 hours, cooled to 0°C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and was stirred for a further 24 hours. Ethyl ether:hexane (1:1) was added to the mixture, which gave a precipitate. The precipitate was isolated by filtration and dried under vacuum to give ethyl 2-(N-ethoxyamidino)propionate hydrochloride (119.6 g, 73% yield) as a white solid; <*>H NMR (300 MHz, DMSO-d6): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H) , 1.20 (tr, 3H). (b) A mixture comprising 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2-( N -ethoxyamidino)propionoate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 mL ) was heated at 85°C and stirred for 18 hours and then heated at 120°C and stirred for a further hour. The mixture was cooled to room temperature and concentrated/vacuum. The residue was neutralized by the addition of an excess of 5M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (MgSO 4 ), filtered and concentrated / vacuum to give ethyl 1 H (60.4 g, 58% yield); <*>H NMR (300 MHz, CDCl 3 ): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3, 90 (q, 1H), 1.75 (d, 3H), 1.25 (tr, 3H). (c) A mixture comprising ethyl 1H-imidazo[4,5-c]pyridine-2-carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 mL) and platinum oxide (2.5 g) in a Parr hydrogenation -apparatus was hydrogenated at 3.5 kg/cm<2> for 24 hours, filtered and concentrated / vacuum. The oily residue was dissolved in a minimum of ethanol and dry hydrogen chloride in dioxane solution (4M, 120 mL, 475 mmol) was added to the solution. An excess of ethyl ether was added to the solution, which gave a precipitate. The precipitate was collected by filtration and dried / vacuum to give ethyl 1,4,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylate dihydrochloride (30.7 g, 66% yield ); <1>H NMR (300 MHz, DMSO-d6): 10.00 (br s, 2H), 4.35 (q, 1H), 4.20 (br s, 2H), 4.10 (m, 2H ), 3.35 (m, 2H), 2.90 (br s, 2H), 1.55 (d, 3H), 1.15 (tr, 3H). (d) A mixture comprising ethyl 1,4,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylate dihydrochloride (60.2 g, 0.20 mol), acetonitrile ( 500 mL) and diisopropylethylamine (100 mL, 0.60 mol) were cooled to 0°C and stirred while benzyl chloroformate (58 mL, 0.40 mol) was added slowly. The mixture was slowly warmed to room temperature, stirred for an additional 16 hours and concentrated/vacuum. The residue was dissolved in ethyl ether (500 mL) and the solution was washed with 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated/vacuum to give a colorless oil. The residue was dissolved in ethanol (320 mL) and the solution was cooled to 0°C and then sodium ethoxide in ethanol solution (2.6M, 85 mL, 0.22 mol.) was slowly added. The mixture was stirred for one hour at 0°C and then hydrogen chloride solution in dioxane (4M, 50 mL)

tilsatt. Blandingen ble konsentrert / vakuum og residuet ble oppløst i etylacetat (250 mL) og mettet vandig natrium-hydrogenkarbonat. Det organiske laget ble separert og vasket med mettet vandig natriumklorid, tørket over vannfritt natriumsulfat, filtrert og konsentrert / vakuum, hvilket ga 5-benzyl-2-etyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2,5-dikarboksylat som et gult, amorft materiale (52 g, 72% utbytte); * H NMR (300 MHz, DMSO-d6): 11,75 (br s, 1H), 7,30 (s, 5H), 5,10 (s, 2H), 4,40 (br s, 2H), 4,05 (m, 2H), 3,75 (q, 1H), 3,65 (br s, 2H), 1,40 (d, 3H), 1,15 (tr, 3H). (e) En blanding omfattende 4-klorbutyrylklorid (12,6 g, 89,2 mmol), rerf-butanol (25 mL), pyridin (6,9 g, 86,5 mmol) og 4-dimetylaminopyridin (1,0 g, 8,2 mmol) ble oppvarmet ved 50°C under en atmosfære av tørr nitrogen i 12 timer, hvilket ga en hvit suspensjon. Suspensjonen ble fordelt mellom etyleter (250 mL) og vann og det organiske laget ble separert og vasket gjentatte ganger med vann og deretter 0,1M vandig saltsyre, mettet vandig natriumkarbonat og mettet vandig natriumklorid, tørket over vannfritt magnesiumsulfat, filtrert og konsentrert / vakuum til en farveløs olje. Oljen ble destillert ved 0,5 mmHg (51°C), hvilket ga fe/t-butyl-4-klorbutyrat som en farveløs væske (11,27 g; 73% utbytte); <*>H NMR (300 MHz, CDCI3): 3,60 (tr, 2H), 2,40 (tr, 2H), 2,10 (m, 2H), 1,45 (s, 9H). (f) En blanding omfattende etyl-salicylat (3,14 g, 18,9 mmol) og cesiumkarbonat (6,2 g, 18,9 mmol), dimetylformamid (25 mL) og fert-butyl-4-klorbutyrat (4,08 g, 22,8 mmol) ble oppvarmet ved 70°C og omrørt i 12 timer. Blandingen ble fordelt mellom etyleter (100 mL) og vann og det organiske laget ble separert og vasket med ytterligere vann (3x) og mettet vandig natriumklorid, tørket over vannfritt magnesiumsulfat, filtrert og konsentrert / vakuum, hvilket ga en farveløs olje. Residuet ble renset ved silikagel "flash" kromatografi ved anvendelse av ren heksan til (10:1) heksan:etylacetat, hvilket ga etyl-2-(3-rerf-butoksykarbonylpropoksy)benzoat (3,6 g, 62% utbytte) som en farveløs olje; <1>H NMR (300 MHz, CDCI3): 7,80 (d, 1H), 7,49 (tr, 1H), 7,00 (m, 2H), 4,40 (q, 2H), 4,10 (tr, 2H), 2,50 (tr, 2H), 2,10 (m, 2H), 1,45 (s, 9H), 1,40 (tr, 3H). (g) Etyl-2-(3-fe/f-butoksykarbonylpropoksy)benzoat (3,60 g, 11,7 mmol) ble behandlet med et overskudd av trifluoerddiksyre ved romtemperatur over én time. Løsningen ble konsentrert /' vakuum og det oljeaktige residuet ble renset ved silikagel "flash" kromatografi ved anvendelse av (10:1) heksan:etylacetat til ren etyleter, hvilket ga 4-(2-etoksykarbonylfenoksy)smørsyre som et farveløst, krystallinsk fast stoff (2,81 g, 95% utbytte); <1>H NMR (300 MHz, CDCI3): 7,80 (d, 1H), 7,50 (tr, 1H), 7,00 (m, 2H), 4,40 (q, 2H), 4,15 (tr, 2H), 2,65 (tr, 2H), 2,20 (m, 2H), 1,40 (tr, 3H). (h) En blanding omfattende benzyl-2-etoksykarbonylmetyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (1,7 g, 4,8 mmol), A/-(3,4-diaminofenyl)guanidin-hydroklorid (0,8 g, 4,0 mmol) og dimetylformamid (2 mL) ble oppvarmet i et oljebad ved 185°C og omrørt under en nitrogen-atmosfære i 2,5 timer. Blandingen ble avkjølt til romtemperatur og hellet i omrørt acetonitril (150 mL), hvilket ga et presipitat. Fellingen ble vasket med ytterligere acetonitril og dietyleter (150 mL), oppsamlet ved filtrering og tørket / vakuum, hvilket ga et gråhvitt, fast stoff. Det faste stoffet ble renset ved preparativ revers fase HPLC, hvilket ga benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat som et hvitt, fast stoff (1,0 g, 55% utbytte); LRMS(ESI): Beregnet for C24H26N8O2: 458,5; Funnet (MH<+>): 459,2. (i) En blanding omfattende benzyl-2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (1,0 g, 2,2 mmol), 10% palladium på karbon (0,5g), tetrahydrofuran (50 mL) og metanol (50 mL) ble hydrogenert ved én atmosfære, filtrert og konsentrert / vakuum, hvilket ga A/-{2-[1-(4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-2-yl)etyl]-1H-benzoimidazol-5-yl)-guanidin (0,69 g, 97% utbytte); LRMS(ESI): Beregnet for Ci6H2oN8: 324,4; Funnet (MH<+>): 325,2. added. The mixture was concentrated / vacuum and the residue was dissolved in ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated / vacuum to give 5-benzyl-2-ethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine -2,5-dicarboxylate as a yellow, amorphous material (52 g, 72% yield); * H NMR (300 MHz, DMSO-d6): 11.75 (br s, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (br s, 2H), 4.05 (m, 2H), 3.75 (q, 1H), 3.65 (br s, 2H), 1.40 (d, 3H), 1.15 (tr, 3H). (e) A mixture comprising 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), r -butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g , 8.2 mmol) was heated at 50 °C under an atmosphere of dry nitrogen for 12 h, yielding a white suspension. The suspension was partitioned between ethyl ether (250 mL) and water and the organic layer was separated and washed repeatedly with water and then 0.1M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated/vacuum to a colorless oil. The oil was distilled at 0.5 mmHg (51°C) to give fe/t-butyl-4-chlorobutyrate as a colorless liquid (11.27 g; 73% yield); <*>H NMR (300 MHz, CDCl 3 ): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H). (f) A mixture comprising ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL) and tert-butyl-4-chlorobutyrate (4, 08 g, 22.8 mmol) was heated at 70°C and stirred for 12 hours. The mixture was partitioned between ethyl ether (100 mL) and water and the organic layer was separated and washed with additional water (3x) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated/vacuum to give a colorless oil. The residue was purified by silica gel "flash" chromatography using neat hexane to (10:1) hexane:ethyl acetate to give ethyl 2-(3-rerf-butoxycarbonylpropoxy)benzoate (3.6 g, 62% yield) as a colorless oil; <1>H NMR (300 MHz, CDCl 3 ): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4, 10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H). (g) Ethyl 2-(3-fe/f-butoxycarbonylpropoxy)benzoate (3.60 g, 11.7 mmol) was treated with an excess of trifluoroacetic acid at room temperature over one hour. The solution was concentrated in vacuo and the oily residue was purified by silica gel flash chromatography using (10:1) hexane:ethyl acetate to pure ethyl ether to give 4-(2-ethoxycarbonylphenoxy)butyric acid as a colorless crystalline solid (2.81 g, 95% yield); <1>H NMR (300 MHz, CDCl 3 ): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4, 15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H). (h) A mixture comprising benzyl 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.7 g, 4.8 mmol), A/-(3 ,4-diaminophenyl)guanidine hydrochloride (0.8 g, 4.0 mmol) and dimethylformamide (2 mL) were heated in an oil bath at 185°C and stirred under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature and poured into stirred acetonitrile (150 mL), which gave a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 mL), collected by filtration and dried/vacuum to give an off-white solid. The solid was purified by preparative reverse phase HPLC to give benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c ]pyridine-5-carboxylate as a white solid (1.0 g, 55% yield); LRMS(ESI): Calcd for C 24 H 26 N 8 O 2 : 458.5; Found (MH<+>): 459.2. (i) A mixture comprising benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.0 g, 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL) were hydrogenated at one atmosphere, filtered and concentrated / vacuum to give A / -{2-[1-(4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-2-yl)ethyl]-1H-benzoimidazol-5-yl)-guanidine (0.69 g , 97% yield); LRMS(ESI): Calcd for C16H20N8: 324.4; Found (MH<+>): 325.2.

(j) En blanding omfattende 4-(2-etoksykarbonylfenoksy)smørsyre (155 mg, 0,61 mmol), PyBOP (360 mg, 0,69 mmol), hydroksybenztriazol-hydrat (87 mg, 0,64 mmol), W-metylmorfolin (0,16 mL, 0,92 mmol) og dimetylformamid (2,5 mL) ble omrørt ved romtemperatur i 10 minutter og deretter ble W-{2-[1-(4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-2-yl)etyl]-3H-benzimidazol-5-yljguanidin (203 mg, 0,63 mmol) tilsatt. Blandingen ble omrørt i 3 timer ved romtemperatur og konsentrert /' vakuum. Residuet ble oppløst i 5% vandig acetonitril og produktet ble renset ved preparativ revers fase HPLC. De samlede rene fraksjoner ble deretter lyofilisert, hvilket ga etyl-2-(4-{2-[1-{5-guanidino-1W-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro- (j) A mixture comprising 4-(2-ethoxycarbonylphenoxy)butyric acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), W- methylmorpholine (0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) were stirred at room temperature for 10 min and then W-{2-[1-(4,5,6,7-tetrahydro-imidazo [4,5-c]pyridin-2-yl)ethyl]-3H-benzimidazol-5-ylguanidine (203 mg, 0.63 mmol) added. The mixture was stirred for 3 hours at room temperature and concentrated under vacuum. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by preparative reverse phase HPLC. The pooled pure fractions were then lyophilized, yielding ethyl 2-(4-{2-[1-{5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydro-

imidazo[4,5-c]pyridin-5-yl}-4-oksobutyl)benzoat; LRMS (Bioion): Beregnet for C29H34N8O4: 558,6; Funnet: 559,3. imidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate; LRMS (Bioion): Calculated for C29H34N8O4: 558.6; Found: 559.3.

EKSEMPEL 8 EXAMPLE 8

2- [1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-W-[2-(2-metoksyfenoksy)etyl]-3- metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 30) 2- [1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 30)

(a) En oppløsning av ferf-butyl-2-hydroksyetylkarbamat (25 mL, 161,6 mmol) i diklormetan (60 mL) ble avkjølt til 0°C og omrørt mens først diisopropyletylamin (33,8 mL, 193,9 mmol) og deretter mesylklorid (13,7 mL, 177,8 mmol) dråpevis ble tilsatt. Blandingen fikk oppvarmes til 23°C, ble omrørt i 18 timer, hellet i diklormetan (200 mL) og vasket med vandig saltsyre (3M, 3x 25 mL) og mettet vandig natrium-hydrogenkarbonat (2 x 25 mL). Det organiske laget ble separert, tørket (MgS04) og konsentrert / vakuum, hvilket ga ferf-butyl-2-metylsulfonyloksyetylkarbamat (37,39 g, 97% utbytte) som en brun olje; MS (PB-PCI) C8H17N05S m/e beregnet 239,08; funnet 240 (Mh<f>). (b) Litiumbromid (136 g, 1,56 mol.) ble oppløst i tetrahydrofuran (600 mL) ved 0°C. Blandingen fikk oppvarmes til 23°C og deretter ble fert-butyl-2-metylsulfonyloksy-etylkarbamat (37,39 g, 156 mmol) tilsatt dråpevis. Blandingen ble omrørt ved 23°C i 18 timer og konsentrert;' vakuum. Residuet ble oppløst i heksaner og det organiske laget ble vasket med vann og saltvann, tørket (Na2S04) og konsentrert / vakuum, hvilket ga ferf-butyl-2-brometylkarbamat (33,48 g, 96% utbytte) som en brun olje; MS (PB-PCI) C7Hi4BrN02 m/e beregnet 224,10; funnet 225 (MH<+>). (c) En blanding av 2-metoksyfenol (9,8 mL, 89,3 mmol), dimetylformamid (100 mL) og kaliumkarbonat (61,5 g, 445 mmol) ble omrørt ved 23°C mens noe ferf-butyl-2-brometylkarbamat (20 g, 89,3 mmol) ble tilsatt. Blandingen ble omrørt i 24 timer og deretter hellet i etyleter:heksaner (1:1, 400 mL) og ble vasket med vann (5x 50 mL). Det vandige laget ble ekstrahert med etyleter:heksaner (1:1, 3x 40 mL) og de samlede organiske lag ble tørket (Na2S04) og konsentrert /' vakuum, hvilket ga ferf-butyl-2-(2-metoksyfenoksy)etylkarbamat (23,22 g, 97% utbytte) som en gul olje; MS (PB-PCI) C14H21N04 m/e beregnet 267,32; funnet 268 (MH<+>). (d) fert-butyl-2-(2-metoksyfenoksy)etylkarbamat (23,8 g, 89 mmol) ble avkjølt til 0°C og omrørt mens en blanding av trifluoreddiksyre:diklormetan (1:1, 40 mL) ble tilsatt dråpevis. Blandingen fikk oppvarmes til 23°C, ble omrørt i 2 timer og konsentrert / vakuum. Residuet ble tatt tilbake i diklormetan (100 ml) og løsningen ble vasket med mettet vandig natrium-hydrogenkarbonat (3x 20 mL) og vandig natriumhydroksyd (10%, 3x 20 mL), tørket (Na2SC*4), filtrert og konsentrert / vakuum, hvilket ga 2-(2-metoksyfenoksy)etylamin (13 g, 88% utbytte) som et lysegult, fast stoff; MS (PB-PCI) C9H13NO2 m/e beregnet 167,21; funnet 168 (MH<+>). (e) En heterogen blanding omfattende 3-metoksy-4-nitrobenzosyre (15,42 g, 78,2 mmol) og tionylklorid (70 mL, 391 mmol) ble oppvarmet ved tilbakeløp i én time. Overskudd av tionylklorid ble fjernet ved destillasjon og residuet ble konsentrert / vakuum, hvilket ga 3-metoksy-4-nitrobenzoylklorid (16,8 g, 99% utbytte) som et lysegult, fast stoff; MS (PB-PCI) C8H6CIN04 m/e beregnet 215,59; funnet 216 (MH<+>). (f) En blanding omfattende 2-(2-metoksyfenoksy)etylamin (10 g, 59,9 mmol), diisopropyletylamin (13,9 mL, 81,6 mmol) og diklormetan (80 mL) ble avkjølt til 0°C og deretter ble en oppløsning av 3-metoksy-4-nitrobenzoylklorid (11,76 g, 54,4 mmol) i diklormetan (50 mL) tilsatt dråpevis. Blandingen fikk oppvarmes til 23°C over to timer, ble behandlet med vandig saltsyre (3M, 20 mL), vasket med vann (3x 20 mL), tørket (Na2S04) og konsentrert /' vakuum, hvilket ga A/-[2-(2-metoksyfenoksy)etyl]-3-metoksy-4-nitrobenzamid (14 g, 74% utbytte) som et gråhvitt, fast stoff; MS (PB-PCI) Ci7H18N206 m/e beregnet 346,34; funnet 347 (MH<+>). (g) En blanding omfattende A/-[2-(2-metoksyfenoksy)etyl]-3-metoksy-4-nitrobenzamid (4,0 g, 11,6 mmol), vandig metylamin (40%, 10 mL) og DMSO (2 mL) i et forseglet rør ble oppvarmet ved 110"C i 4 timer, avkjølt og deretter hellet i vann (25 mL). Fortynningen ble behandlet med 3M vandig saltsyre,. hvilket ga et oransje, fast stoff. Det faste stoffet ble isolert ved filtrering, hvilket ga A/-[2-(2-metoksyfenoksy)etyl]-3-metylamino-4-nitrobenzamid (3,56 g, 89% utbytte); MS (PB-PCI) C17H19N3O5 m/e beregnet 345,35; funnet 346 (MH<+>). (h) En blanding omfattende W-[2-(2-metoksyfenoksy)etyl]-3-metylamino-4-nitrobenzamid (3,56 g, 10,3 mmol), suspendert palladium på karbon (10%, 0,5 g) i metanol (100 mL) og tetrahydrofuran (50 mL) ble omrørt under en hydrogenatmosfære ved omgivelsestrykk i 2,5 timer. Blandingen ble filtrert og løsningen ble konsentrert / vakuum, hvilket ga 4-amino-W-[2-(2-metoksyfenoksy)etyl]-3-metylaminobenzamid (3,37 g, 100% utbytte) som et grønt skum; MS (PB-PCI) Ci7H21N303 m/e beregnet 315,37; funnet 316 (MH<+>). (i) En blanding omfattende 4-amino-3-nitrofenol (5,0 g, 32,4 mmol), palladium på karbon (10%, 1,0 g) og metanol (50 mL) i et Parr-apparat ble hydrogenert ved 3,5 kg/cm<2> i 3 timer, filtrert gjennom celite og konsentrert / vakuum, hvilket ga 3,4-diaminofenol (4,02 g, 91% utbytte) som et mørkt, fast stoff; MS (PB-PCI) C6H8N20 m/e beregnet 124,16; funnet 125 (MH<+>). (a) A solution of tert -butyl 2-hydroxyethyl carbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0 °C and stirred while first diisopropylethylamine (33.8 mL, 193.9 mmol) and then mesyl chloride (13.7 mL, 177.8 mmol) was added dropwise. The mixture was allowed to warm to 23°C, was stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3M, 3 x 25 mL) and saturated aqueous sodium bicarbonate (2 x 25 mL). The organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo to give tert -butyl-2-methylsulfonyloxyethyl carbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17N05S m/e calcd 239.08; found 240 (Mh<f>). (b) Lithium bromide (136 g, 1.56 mol.) was dissolved in tetrahydrofuran (600 mL) at 0°C. The mixture was allowed to warm to 23°C and then tert-butyl-2-methylsulfonyloxy-ethyl carbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23°C for 18 hours and concentrated; vacuum. The residue was dissolved in hexanes and the organic layer was washed with water and brine, dried (Na 2 SO 4 ) and concentrated in vacuo to give tert -butyl 2-bromomethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI) C7Hi4BrN02 m/e calcd 224.10; found 225 (MH<+>). (c) A mixture of 2-methoxyphenol (9.8 mL, 89.3 mmol), dimethylformamide (100 mL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23°C while some tert-butyl-2 -bromomethyl carbamate (20 g, 89.3 mmol) was added. The mixture was stirred for 24 h and then poured into ethyl ether:hexanes (1:1, 400 mL) and washed with water (5x 50 mL). The aqueous layer was extracted with ethyl ether:hexanes (1:1, 3x 40 mL) and the combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to give tert -butyl 2-(2-methoxyphenoxy)ethyl carbamate (23 .22 g, 97% yield) as a yellow oil; MS (PB-PCI) C14H21N04 m/e calcd 267.32; found 268 (MH<+>). (d) tert -butyl 2-(2-methoxyphenoxy)ethyl carbamate (23.8 g, 89 mmol) was cooled to 0 °C and stirred while a mixture of trifluoroacetic acid:dichloromethane (1:1, 40 mL) was added dropwise . The mixture was allowed to warm to 23°C, was stirred for 2 hours and concentrated/vacuum. The residue was taken back into dichloromethane (100 mL) and the solution was washed with saturated aqueous sodium bicarbonate (3x 20 mL) and aqueous sodium hydroxide (10%, 3x 20 mL), dried (Na2SC*4), filtered and concentrated / vacuum, which gave 2-(2-methoxyphenoxy)ethylamine (13 g, 88% yield) as a pale yellow solid; MS (PB-PCI) C9H13NO2 m/e calcd 167.21; found 168 (MH<+>). (e) A heterogeneous mixture comprising 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was heated at reflux for one hour. Excess thionyl chloride was removed by distillation and the residue was concentrated/vacuum to give 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a pale yellow solid; MS (PB-PCI) C8H6CINO4 m/e calcd 215.59; found 216 (MH<+>). (f) A mixture comprising 2-(2-methoxyphenoxy)ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0 °C and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23°C over two hours, treated with aqueous hydrochloric acid (3M, 20 mL), washed with water (3x 20 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to give A/-[2- (2-Methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14 g, 74% yield) as an off-white solid; MS (PB-PCI) C 17 H 18 N 2 O 6 m/e calcd 346.34; found 347 (MH<+>). (g) A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 mL) and DMSO (2 mL) in a sealed tube was heated at 110°C for 4 h, cooled and then poured into water (25 mL). The dilution was treated with 3M aqueous hydrochloric acid, which gave an orange solid. The solid was isolated by filtration to give N -[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m/e calcd 345 .35; found 346 (MH<+>). (h) A mixture comprising W-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), suspended palladium on carbon (10%, 0.5 g) in methanol (100 mL) and tetrahydrofuran (50 mL) was stirred under a hydrogen atmosphere at ambient pressure for 2.5 h.The mixture was filtered and the solution was concentrated/vacuum to give 4-Amino-W-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) Ci7H21N303 m /e calculated 315.37; found 316 (MH<+>). (i) A mixture comprising 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 mL) in a Parr apparatus was hydrogenated at 3.5 kg/cm<2> for 3 h, filtered through celite and concentrated / vacuum to give 3,4-diaminophenol (4.02 g, 91% yield) as a dark solid; MS (PB-PCI) C 6 H 8 N 2 O m/e calcd 124.16; found 125 (MH<+>).

(j) En blanding omfattende 3,4-diaminofenol (3,661 g, 29,5 mL), etyl-2-(/v-etoksy-amidino)propionat (7,423 g, 38,4 mmol) og etanol (30 mL) ble oppvarmet ved tilbakeløp i 6 timer og konsentrert / vakuum. Residuet ble oppløst i etylacetat (200 mL) og løsningen ble vasket med mettet vandig natriumhydrogenkarbonat (3x 20 mL) og saltvann (1x 20 mL), tørket (MgSCU) og konsentrert;' vakuum, hvilket ga etyl-2-(5-hydroksy-1 W-benzoimidazol-2-yl)propionat (6,3 g, 91% utbytte) som et mørkt, fast stoff. Det faste stoffet ble ytterligere renset ved silikagel "flash" kromatografi (100% etylacetat); MS (PB-PCI) C12HMN203 m/e beregnet 234,28; funnet 235 (MH<+>). (j) A mixture comprising 3,4-diaminophenol (3.661 g, 29.5 mL), ethyl 2-(/v-ethoxyamidino)propionate (7.423 g, 38.4 mmol) and ethanol (30 mL) was heated at reflux for 6 hours and concentrated / vacuum. The residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated aqueous sodium bicarbonate (3x 20 mL) and brine (1x 20 mL), dried (MgSCU) and concentrated; vacuum to give ethyl 2-(5-hydroxy-1N-benzoimidazol-2-yl)propionate (6.3 g, 91% yield) as a dark solid. The solid was further purified by silica gel "flash" chromatography (100% ethyl acetate); MS (PB-PCI) C12HMN203 m/e calcd 234.28; found 235 (MH<+>).

(k) En blanding omfattende etyl-2-(5-hydroksy-1H-benzoimidazol-2-yljpropionat (148 mg, 0,63 mmol), 4-amino-A/-[2-(2-metoksyfenoksy)etyl]-3-metylaminobenzamid (200 mg, 0,63 mmol) og 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon (0,5 mL) ble omrørt ved romtemperatur inntil den var homogen, avgasset under vakuum og konsentrert ved oppvarmning ved 170°C i 2 timer under en strøm av N2. Residuet ble avkjølt til romtemperatur og skyllet med et overskudd av etyleter. Det resulterende amorfe materiale ble tatt opp i 50% vandig acetonitril og renset ved preparativ revers fase HPLC (2-50% CH3CN/H20), hvilket ga 2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-W-[2-(2-metoksyfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (40 mg, 13% utbytte) som et lys rosa, fast stoff; MS (Biolon) C27H27N504 m/e beregnet 485,59; funnet 486,5 (MH<+>). (k) A mixture comprising ethyl 2-(5-hydroxy-1H-benzoimidazol-2-ylpropionate (148 mg, 0.63 mmol), 4-amino-N-[2-(2-methoxyphenoxy)ethyl]- 3-Methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (0.5 mL) were stirred at room temperature until homogeneous, degassed under vacuum and concentrated by heating at 170°C for 2 h under a stream of N2. The residue was cooled to room temperature and rinsed with an excess of ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN/H2O), which gave 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-methoxyphenoxy)ethyl]-3- methyl 3H-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a pale pink solid, MS (Biolon) C27H27N504 m/e calcd 485.59; found 486.5 (MH<+>).

På samme måte som i Eksempel 8 ble de følgende forbindelser ifølge foreliggende oppfinnelse fremstilt: In the same way as in Example 8, the following compounds according to the present invention were prepared:

metyl-2-(2-{2-[1 -(5-fluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 31), MS (Biolon) C26H26N5O4F m/e beregnet 515,54; funnet 516 (Mh<T>); 2-(2-{2-[1 -(5-fluoM H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 32) MS (Biolon) C27H24N5O4F m/e beregnet 501,52; funnet 502,1 (Mh<T>); etyl-2-(2-{2-[1-(5-hydroksy-1W-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 33), MS (Biolon) C29H29N505 m/e beregnet 527,58; funnet 528,1 (MH<+>); 2-(2-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 34), MS (Biolon) C27H25N5O5 m/e beregnet 499,53; funnet 500,1 (MH<+>); A/-etyl-2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 35), MS (Biolon) C20H21N5O2 m/e beregnet 363,42; funnet 364,1 (MH<+>); 2- [1-(5-hydroksy:1H-benzoimidazol-2-yl)etyl]-/v'-(2-metoksyetyl)-3-metyl-3H-benzoimidazoI-5-karboksamid (Forbindelse 36), MS (Biolon) C21H23N5O3. m/e beregnet 393,45; funnet 394,1 (MH<+>); methyl 2-(2-{2-[1-(5-fluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 31), MS (Biolon) C26H26N5O4F m/e calcd 515.54; found 516 (Mh<T>); 2-(2-{2-[1 -(5-fluoroM H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 32) MS (Biolon) C27H24N5O4F w/e calculated 501.52; found 502.1 (Mh<T>); ethyl 2-(2-{2-[1-(5-hydroxy-1N-benzoimidazol-2-yl)ethyl]-3-methyl-3N-benzoimazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 33), MS (Biolon) C29H29N505 m/e calcd 527.58; found 528.1 (MH<+>); 2-(2-{2-[1 -(5-Hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 34), MS ( Biolon) C27H25N5O5 m/e calculated 499.53; found 500.1 (MH<+>); N-ethyl-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 35), MS (Biolon) C20H21N5O2 w/ e calculated 363.42; found 364.1 (MH<+>); 2-[1-(5-hydroxy:1H-benzoimidazol-2-yl)ethyl]-[v'-(2-methoxyethyl)-3-methyl-3H-benzoimidazoI-5-carboxamide (Compound 36), MS (Biolon ) C21H23N5O3. m/e calculated 393.45; found 394.1 (MH<+>);

butyI-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 37), MS (Biolon) C31H33N505 m/e beregnet 555,64; funnet 555,7 (MH<+>); butyI-2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 37), MS (Biolon) C31H33N505 m/e calcd 555.64; found 555.7 (MH<+>);

3- {2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-6-[2-(2-metoksyfenoksy)etylkarbamoyl]benzimidazol-1-yl}propan-1-sulfonsyre (Forbindelse 38), MS (LCMS) C3oH35N806S m/e beregnet 635,72; funnet 635,4 3- {2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-6-[2-(2-methoxyphenoxy)ethylcarbamoyl]benzimidazol-1-yl}propane-1-sulfonic acid (Compound 38 ), MS (LCMS) C 3 o H 35 N 8 O 6 S m/e calcd 635.72; found 635.4

(MH<+>); (MH<+>);

A/-[2-(2-etoksyfenoksy)etyl]-2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 39), MS (Biolon) C2BH29N504 m/e beregnet 499,58; funnet 500,4 (MH<+>); N -[2-(2-ethoxyphenoxy)ethyl]-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 39) , MS (Biolon) C2BH29N504 m/e calcd 499.58; found 500.4 (MH<+>);

2-[1 -(5-hydroksy-1 W-benzoimidazol-2-yl)etyl]-A/-[2-(2-isopropoksyfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 40), MS (Biolon) C29H31N5O4 m/e b*eregnet 513,61; funnet 514,5 (Mh<T>); 2-[1 -(5-Hydroxy-1 N -benzoimidazol-2-yl)ethyl]- N -[2-(2-isopropoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 40 ), MS (Biolon) C29H31N5O4 m/e b*calcd 513.61; found 514.5 (Mh<T>);

2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-propoksyfenoksy)etyl]-3H-benzoimidazbl-5-karboksamid 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-propoxyphenoxy)ethyl]-3H-benzoimidazbl-5-carboxamide

(Forbindelse 41), MS (Biolon) C29H31N504 m/e beregnet 513,61; funnet 514,2 (Compound 41), MS (Biolon) C 29 H 31 N 5 O 4 m/e calcd 513.61; found 514.2

(MH<+>); (MH<+>);

propyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 42), MS (ESI) C30H31N5O5 m/e beregnet 541,61; funnet 542,2 (Mh<T>); propyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 42), MS (ESI) C30H31N5O5 m/e calcd 541.61; found 542.2 (Mh<T>);

isobutyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 43), MS (Biolon) C31H33N5O5 m/e beregnet 555,64; funnet 556,3 (Mh<f>); isobutyl-2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 43), MS (Biolon) C31H33N5O5 m/e calcd 555.64; found 556.3 (Mh<f>);

etyl-4-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylaminobutyrat (Forbindelse 44), MS (Biolon) C24H27N5O4 m/e beregnet 449,51; funnet 449,9 (MH<+>); ethyl 4-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5-ylcarbonylaminobutyrate (Compound 44), MS (Biolon) C24H27N5O4 m/e calculated 449.51; found 449.9 (MH<+>);

4-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-ylkarbonylamino}smørsyre (Forbindelse 45), MS (Biolon) C22H23N504 m/e beregnet 421,46; funnet 422,1 (MH<+>); 4-{2-[1 -(5-Hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3W-benzoimidazol-5-ylcarbonylamino}butyric acid (Compound 45), MS (Biolon) C22H23N504 w/ e calculated 421.46; found 422.1 (MH<+>);

isopropyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 46), MS (ESI) C3oH3iN505 m/e beregnet 541,61; funnet 542,2 (Mh<T>); isopropyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 46), MS (ESI) C 3 o H 3 i N 5 O 5 m/e calcd 541.61; found 542.2 (Mh<T>);

A/-{2-[2-(1 -etylpropoksy)fenoksy]etyl}-2-[1 -(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 47), MS (Biolon) C31H35N5O4 m/e beregnet 541,65; funnet 542,5 N -{2-[2-(1 -ethylpropoxy)phenoxy]ethyl}-2-[1 -(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5- carboxamide (Compound 47), MS (Biolon) C31H35N5O4 m/e calcd 541.65; found 542.5

(MH<+>); (MH<+>);

etyl-2-{2-{2-[1 -(5-fluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 48), MS (Biolon) C2gH28N504F m/e beregnet 529,57; funnet 529,5 (Mh<T>); ethyl 2-{2-{2-[1-(5-fluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 48), MS (Biolon) C 2 g H 28 N 5 O 4 F m/e calcd 529.57; found 529.5 (Mh<T>);

2-metoksyetyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 49), MS (Biolon) C30H31N5O6 m/e beregnet 557,61; funnet 58,2 (MH<+>); 2-Methoxyethyl-2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 49) , MS (Biolon) C30H31N5O6 m/e calcd 557.61; found 58.2 (MH<+>);

W-(3-metoksypropyl)-2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-karboksamid (Forbindelse 50), MS (Biolon) C22H25N503 m/e beregnet 407,47; funnet 408,0 (Mh<T>); W-(3-Methoxypropyl)-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3W-benzoimidazol-5-carboxamide (Compound 50), MS (Biolon) C22H25N503 m/e calculated 407.47; found 408.0 (Mh<T>);

2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-W-[2-(2-metoksymetylfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 51), MS (Biolon) C28H29N5O4 m/e beregnet 499,57; funnet 499,8 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-methoxymethylphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 51) , MS (Biolon) C28H29N5O4 m/e calcd 499.57; found 499.8

(MH<T>); (MH<T>);

A/-[2-(2-etoksymetylfenoksy)etyl]-2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 52), MS (Biolon) C29H31N5O4 m/e beregnet 513,60; funnet 514,1 (MH<+>); N -[2-(2-Ethoxymethylphenoxy)ethyl]-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 52) , MS (Biolon) C29H31N5O4 m/e calcd 513.60; found 514.1 (MH<+>);

etyl-2-(2-{2-[1-(6-fluor-5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 53), MS (ESI) C29H28N5O5F m/e beregnet 545,57; funnet 546,3 (Mh<T>); ethyl 2-(2-{2-[1-(6-fluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 53), MS (ESI) C29H28N5O5F m/e calcd 545.57; found 546.3 (Mh<T>);

etyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)cykloheksankarboksyat (Forbindelse 54), MS (Biolon) C29H35N5O5 m/e beregnet 533,63; funnet 534 ethyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3 H -benzoimidazol-5-ylcarbonylamino}ethoxy)cyclohexanecarboxylate (Compound 54 ), MS (Biolon) C29H35N5O5 m/e calcd 533.63; found 534

(MH<+>); (MH<+>);

2-[1-(5-hydroksy-1/-/-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-propoksymetylfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 55), MS (Biolon) C30H33N5O4 m/e beregnet 527,62; funnet 527,6 2-[1-(5-hydroxy-1/-/-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-propoxymethylphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 55), MS (Biolon) C30H33N5O4 m/e calcd 527.62; found 527.6

(MH<+>); (MH<+>);

2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-W-[2-(2-isopropoksy-metylfenoksy)etyl]-3-metyl-3W-benzoimidazol-5-karboksamid (Forbindelse 56), MS (Biolon) C3oH33N504 m/e beregnet 527,62; funnet 527,9 (MH<+>); 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-isopropoxy-methylphenoxy)ethyl]-3-methyl-3W-benzoimidazol-5-carboxamide (Compound 56 ), MS (Biolon) C30H33N504 m/e calcd 527.62; found 527.9 (MH<+>);

2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-W-{2-[2-(2-metoksyetoksy-metyl)fenoksy]etyl}-3-metyl-3H-benzoimidazol-5-karboksamid, 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-{2-[2-(2-methoxyethoxy-methyl)phenoxy]ethyl}-3-methyl-3H-benzoimidazol-5 -carboxamide,

(Forbindelse 57), MS (Biolon) C30H33N5O5 m/e beregnet 543,62; funnet 543,4 (Compound 57), MS (Biolon) C30H33N5O5 m/e calcd 543.62; found 543.4

(MH<+>); (MH<+>);

2-[1-(1H-benzoimidazol-2-yl)etyl]-A/-[2-(2-metoksymetylfenoksy)etyl]-3-metyl-3W-benzoimidazol-5-karboksamid (Forbindelse 58), MS (Biolon) C28H29N503 m/e beregnet 483,57; funnet 484 (MhT); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-A/-[2-(2-methoxymethylphenoxy)ethyl]-3-methyl-3N-benzoimidazol-5-carboxamide (Compound 58), MS (Biolon ) C28H29N503 m/e calculated 483.57; found 484 (MhT);

A/-[2-(2-etoksymetylfenoksy)etyl]-2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 59), MS (Biolon) C29H31N5O3 m/e beregnet 497,6; funnet 498,3 (MH<+>); N -[2-(2-ethoxymethylphenoxy)ethyl]-2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 59), MS (Biolon ) C29H31N5O3 m/e calculated 497.6; found 498.3 (MH<+>);

2-[1 -(1 H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-propoksymetylfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 60), MS (Biolon) C30H33N5O3 m/e beregnet 511,62; funnet 511,5 (MH<+>); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-propoxymethylphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 60), MS (Biolon ) C30H33N5O3 m/e calculated 511.62; found 511.5 (MH<+>);

2-[1-(1W-benzoimidazol-2-yl)etyl]-W-[2-(2-isopropoksymetylfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 61), MS (Biolon) C30H33N5O3 m/e beregnet 511,62; funnet 511,6 (MH<+>); 2-[1-(1N-benzoimidazol-2-yl)ethyl]-W-[2-(2-isopropoxymethylphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 61), MS (Biolon) C30H33N5O3 m/e calculated 511.62; found 511.6 (MH<+>);

2-[1 -(1 H-benzoimidazol-2-yl)etyl]-A/-{2-[2-(2-metoksyetoksymetyl)fenoksy]etyl}-3-metyl-3H-benzoimidazol-5-karboksarnid (Forbindelse 62), MS (Biolon) C3oH33N504 m/e beregnet 527,62; funnet 527,7 2-[1-(1H-benzoimidazol-2-yl)ethyl]-N-{2-[2-(2-methoxyethoxymethyl)phenoxy]ethyl}-3-methyl-3H-benzoimidazol-5-carboxarnide (Compound 62), MS (Biolon) C 3 o H 3 3 N 5 O 4 m/e calcd 527.62; found 527.7

(MH<+>); (MH<+>);

2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-[2-(2-morfolin-4-ylfenoksy)etyl]-3H-benzoimidazo!-5-karboksamid (Forbindelse 63), MS (Biolon) C30H32N6O4 m/e beregnet 540,73; funnet 541,8 (MH<+>); 2-[1-(5-Hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-[2-(2-morpholin-4-ylphenoxy)ethyl]-3H-benzoimidazo!-5- carboxamide (Compound 63), MS (Biolon) C30H32N6O4 m/e calcd 540.73; found 541.8 (MH<+>);

W-(2-fenylsulfonyletyl)-2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 64), MS (Biolon) C26H25N5O4S m/e beregnet 503,59; funnet 504,2 (MH<+>); W-(2-phenylsulfonylethyl)-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 64), MS (Biolon) C26H25N5O4S m/e calculated 503.59; found 504.2 (MH<+>);

2-(2-{2-[1-(6-fluor-5-hydroksy-1H-benzoimidazol-2-yl)etylJ-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy]benzosyre (Forbindelse 65), MS (ESI) C27H24N5O5F m/e beregnet 517,52; funnet 518,2 (MH<+>); 2-(2-{2-[1-(6-fluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl J-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy]benzoic acid (Compound 65), MS (ESI) C27H24N5O5F m/e calcd 517.52, found 518.2 (MH<+>);

etyl-2-hydroksy-5-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3f/-benzoimidazol-5-ylkarbonyamino}benzoat (Forbindelse 66), MS (Biolon) C27H25N505 m/e beregnet 499,52; funnet 500,2 (MH<+>); ethyl 2-hydroxy-5-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3f/-benzoimidazol-5-ylcarbonylamino}benzoate (Compound 66), MS (Biolon) C27H25N505 m/e calcd 499.52; found 500.2 (MH<+>);

2-[1-(5-fluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-morfolin-4-yl-fenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 67), MS (Biolon) C30H31N6O3F m/e beregnet 542,62; funnet 543,4 (Mh<T>); 2-[1-(5-fluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-morpholin-4-yl-phenoxy)ethyl]-3H-benzoimidazol-5- carboxamide (Compound 67), MS (Biolon) C30H31N6O3F m/e calcd 542.62; found 543.4 (Mh<T>);

A/-(2-fenylsulfonyletyl)-2-[1-(5-fluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 68), MS (Biolon) C26H24N503FSm/e beregnet 505,58; funnet 506,5 (MH<+>); N-(2-phenylsulfonylethyl)-2-[1-(5-fluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 68), MS (Biolon) C26H24N503FSm/e calculated 505.58; found 506.5 (MH<+>);

etyl-2-(-2-{2-[1-(4,6-difluor-5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 69), MS (Biolon) C29H27N5O5F2 m/e beregnet 563,52; funnet 563,4 (MH<+>); ethyl-2-(-2-{2-[1-(4,6-difluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy) benzoate (Compound 69), MS (Biolon) C29H27N5O5F2 m/e calcd 563.52; found 563.4 (MH<+>);

2-(2-{2-[1-(4,6-difluor-5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy)benzosyre (Forbindelse 70), MS (Biolon) C27H23N5O5F2 m/e beregnet 536,51; funnet 563 (MhT); 2-(2-{2-[1-(4,6-difluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy)benzoic acid (Compound 70), MS (Biolon) C27H23N5O5F2 m/e calcd 536.51; found 563 (MhT);

etyl-2-(-2-{2-[1-(4,6-difluor-5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 71), MS (Biolon) C32H29N704F2 m/e beregnet 613,62; funnet 614,3 (MH<+>); ethyl-2-(-2-{2-[1-(4,6-difluoro-5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5- ylcarbonylamino}ethoxy)benzoate (Compound 71), MS (Biolon) C32H29N704F2 m/e calcd 613.62; found 614.3 (MH<+>);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl)-3-metyl-A/-{2-[2-(3-metyl-[1,2,4]oksadiazol-5-yl)fenoksy]etyl}-3/-/-benzoimidazol-5-karboksamid 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl)-3-methyl-N-{2-[2-(3-methyl-[1,2,4]oxadiazole-5- yl)phenoxy]ethyl}-3 H -benzoimidazole-5-carboxamide

(Forbindelse 72), MS (Biolon) C30H30N10O3 m/e beregnet 578,63; funnet 579,4 (MH<+>); og (Compound 72), MS (Biolon) C30H30N10O3 m/e calcd 578.63; found 579.4 (MH<+>); and

2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-{2-[2-(3-metyl-[1,2,4]oksadiazol-5-yl)fenoksy]etyiy-3H-benzoimidazol-5-karboksamid (Forbindelse 73), MS (Biolon) C32H29N9O3 m/e beregnet 587,64; funnet 588,2 (MH<+>). 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-{2-[2-(3-methyl-[1,2,4] Oxadiazol-5-yl)phenoxy]ethyl-3H-benzoimidazole-5-carboxamide (Compound 73), MS (Biolon) C32H29N9O3 m/e calcd 587.64; found 588.2 (MH<+>).

EKSEMPEL 9 EXAMPLE 9

2- [2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3- metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre 2- [2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3 - methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid

(Forbindelse 74) (Compound 74)

(a) En løsning omfattende 3,4-diaminopyridin ((51,7 g, 0,46 mol) i eddiksyre (400 ml) ble oppvarmet til 85°C og deretter ble dietyl-metyl-1-iminomalonat (125 g, 0,60 mol) tilsatt i 3 ekvivalente porsjoner over 6 timer. Blandingen ble oppvarmet ved 85°C i 12 timer og ved 120°C i ytterligere en time, avkjølt og konsentrert under redusert trykk. Residuet ble avkjølt til 0°C og nøytralisert med 5N ammoniumhydroksyd. Det vandige laget ble ekstrahert med flere porsjoner etylacetat og de samlede ekstrakter ble vasket suksessivt med natriumbikarbonat og natriumklorid, tørket (Na2S04), filtrert og konsentrert under redusert trykk, hvilket ga etyl-2-(1H-imidazo[4,5-c]pyridin-2-yl)propionat (60,4 g, 58%) som et ravgult, fast stoff. 1 H-N MR (300 MHz, CDCl3) 5 ppm: 9,00 (s, 1H), 8,35 (d, 1H, J = 9,4 Hz), 7,50 (d, 1H, J = 9,4 Hz), 4,25 (m, 3H), 1,78 (d, 3H, J = 7,8 Hz), 1,30 (t, 3H, J = 4,7 Hz). (b) En løsning omfattende etyl-2-(1H-imidazo[4,5-c]pyridin-2-yl)propionat (60,4 g, 0,28 mol) i trifluoreddiksyre (100 ml) ble hydrogenert ved 3,5 kg/cm<2> i nærvær av platina(IV)oksyd (5 g) i 2 dager. Blandingen ble filtrert og konsentrert under redusert trykk. Residuet ble avkjølt til 0°C, behandlet med 4 M HCI/dioksan, suspendert i eter, isolert ved filtrering og tørket. Løsninger omfattende residuet (15-20 g hver) i frisk trifluoreddiksyre (50 ml hver) ble hydrogenert ved 3,5 kg/cm<2> i nærvær av platina(IV)oksyd (5 g hver) i 24 timer. Blandingene ble filtrert og konsentrert under redusert trykk. Residuene ble azeotropt tørket med en blanding av toluen/ etano] -1:1, med 4 M HCI/dioksan, suspendert i eter, isolert ved filtrering og tørket under vakuum, hvilket ga etyl-2- (415,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionat-dihydroklorid (61,80 g, 75% utbytte); <1>H-NMR (300 MHz, DMSO-d6) d ppm: 10,00 (br s, 2H), 4,35 (q, 1H, J = 7,1 Hz), 4,25 (br s, 2H), 4,15 (m, 2H), 3,35 (m, 2H), 2,90 (br s, 2H), 1,60 (d, 3H, J = 7,1 Hz), 1,20 (t, 3H, J = 6,9 Hz). (c) En løsning omfattende etyl-2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionat-dihydroklorid (60,2 g, 0,20 mol) i acetonitril (400 ml) ble avkjølt til 0°C under nitrogen, behandlet med A/.AV-diisopropyletylamin (35 ml, 0,20 mol), videre avkjølt til - -5°C (is/aceton) og deretter behandlet med benzylklorformiat (58 ml, 0,41 mol) og W,W-diisopropyletylamin (70 ml, 0,40 mol) i skiftende porsjoner over 30 minutter. Blandingen ble avkjølt ved -5°C i 1 time, fikk oppvarmes til 20"C og, etter 16 timer, ble konsentrert under redusert trykk. Residuet ble suspendert i eter og suspensjonen ble vasket suksessivt med natriumbikarbonat, natriumklorid, 0,1 M saltsyre og natriumklorid, tørket (Na2S04), filtrert og konsentrert under redusert trykk. Residuet ble oppløst i etanol (320 ml) og løsningen ble avkjølt til -5°C under nitrogen og deretter ble natriumetoksyd.(21 vékt%, 85 ml, 0,22 mol) tilsatt dråpevis over 1 time mens reaksjonstemperaturen ble holdt under 0°C. Blandingen ble avkjølt ved -5°C i 1 time, regulert til nøytral pH med 50 ml 4M saltsyre og konsentrert under redusert trykk. Residuet ble oppløst i etylacetat og løsningen ble vasket med natriumbikarbonat og natriumklorid, tørket (Na2S04), filtrert og konsentrert under redusert trykk. Residuet ble renset ved silikagel-kromatografi (heksaner/etylacetat), hvilket ga benzyl- 2-(1 -etoksykarbonyletyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (52 g, 72%) som en blekgul olje; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11,72 (br s, 1H), 7,32 (s, 5H), 5,07 (s, 2H), 4,32 (br s, 2H), 4,02 (q, 2H, J = 9,3 Hz), 3,77 (q, 1H, J = 8,3 Hz), 3,66 (s, 2H), 2,55 (s, 2H), 1,38 (d, 3H, J = 8,3 Hz), 1,13 (t, 3H, J = 9,3 Hz). (d) En blanding omfattende benzyl 2-(1-etoksykarbonyletyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (6,37 g, 0,018 mol), 4-amino-3- (A/-metylamino)benzosyre (2,70 g, 0,016 mol) og DMPU (20 ml) ble avgasset kort under vakuum, oppvarmet ved 185°C under nitrogen i 4 timer, avkjølt og kombinert med et ekvivalent volum av benzen. Eter ble deretter satt til blandingen, hvilket ga et presipitat. Fellingen ble isolert ved filtrering, tørket kort under vakuum og ytterligere renset ved gjenutfelling fra varm etanol/vann. (a) A solution comprising 3,4-diaminopyridine ((51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85°C and then diethyl-methyl-1-iminomalonate (125 g, 0 .60 mol) added in 3 equivalent portions over 6 hours. The mixture was heated at 85°C for 12 hours and at 120°C for a further hour, cooled and concentrated under reduced pressure. The residue was cooled to 0°C and neutralized with 5N ammonium hydroxide The aqueous layer was extracted with several portions of ethyl acetate and the combined extracts were washed successively with sodium bicarbonate and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give ethyl 2-(1H-imidazo[4,5 -c]pyridin-2-yl)propionate (60.4 g, 58%) as an amber solid 1 H-N MR (300 MHz, CDCl 3 ) 5 ppm: 9.00 (s, 1H), 8.35 (d, 1H, J = 9.4 Hz), 7.50 (d, 1H, J = 9.4 Hz), 4.25 (m, 3H), 1.78 (d, 3H, J = 7, 8 Hz), 1.30 (t, 3H, J = 4.7 Hz). (b) A solution comprising ethyl 2-(1H-imidazo[4,5-c]pyridin-2-yl)propionate (60 .4 g, 0.28 mol) in trifluoride Acetic acid (100 ml) was hydrogenated at 3.5 kg/cm<2> in the presence of platinum(IV) oxide (5 g) for 2 days. The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0°C, treated with 4 M HCl/dioxane, suspended in ether, isolated by filtration and dried. Solutions comprising the residue (15-20 g each) in fresh trifluoroacetic acid (50 ml each) were hydrogenated at 3.5 kg/cm<2> in the presence of platinum(IV) oxide (5 g each) for 24 hours. The mixtures were filtered and concentrated under reduced pressure. The residues were azeotropically dried with a mixture of toluene/ethane] -1:1, with 4 M HCl/dioxane, suspended in ether, isolated by filtration and dried under vacuum to give ethyl 2-(415,6,7-tetrahydroimidazo [4,5-c]pyridin-2-yl)propionate dihydrochloride (61.80 g, 75% yield); <1>H-NMR (300 MHz, DMSO-d6) d ppm: 10.00 (br s, 2H), 4.35 (q, 1H, J = 7.1 Hz), 4.25 (br s, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (br s, 2H), 1.60 (d, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 6.9 Hz). (c) A solution comprising ethyl 2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile ( 400 ml) was cooled to 0°C under nitrogen, treated with A/.AV-diisopropylethylamine (35 ml, 0.20 mol), further cooled to - -5°C (ice/acetone) and then treated with benzyl chloroformate (58 ml, 0.41 mol) and W,W-diisopropylethylamine (70 ml, 0.40 mol) in alternating portions over 30 minutes. The mixture was cooled at -5°C for 1 hour, allowed to warm to 20°C and, after 16 hours, concentrated under reduced pressure. The residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution was cooled to -5°C under nitrogen and then sodium ethoxide. (21 wt%, 85 mL, 0, 22 mol) added dropwise over 1 hour while maintaining the reaction temperature below 0°C. The mixture was cooled at -5°C for 1 hour, adjusted to neutral pH with 50 ml of 4M hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography (hexanes/ethyl acetate) to give benzyl-2-(1-ethoxycarbonylethyl)-1,4,6 ,7-tetrahydroimidazo[4,5-c]pyridine-5-carbox sylate (52 g, 72%) as a pale yellow oil; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H ), 4.02 (q, 2H, J = 9.3 Hz), 3.77 (q, 1H, J = 8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H ), 1.38 (d, 3H, J = 8.3 Hz), 1.13 (t, 3H, J = 9.3 Hz). (d) A mixture comprising benzyl 2-(1-ethoxycarbonylethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino- 3-( N -methylamino)benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) were degassed briefly under vacuum, heated at 185°C under nitrogen for 4 h, cooled and combined with an equivalent volume of benzene . Ether was then added to the mixture, which gave a precipitate. The precipitate was isolated by filtration, dried briefly under vacuum and further purified by reprecipitation from hot ethanol/water.

Fellingen ble isolert og gjenvunnet ved filtrering og tørket, hvilket ga 2-[1-(5-benzyloksykarbonyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksylsyre (4,73 g, 58 %); <1>H-NMR (300 MHz, DMSO-d6) d ppm: 12,70 (br s, 1H), 11,80 (s, 1H), 8,15 (s, 1H), 7,78 (d, 1H, J = 8,3 Hz), 7,64 (d, 1H, J = 8,3 Hz), 7,31 (s, 5H), 5,09 (s, 2H), 4,66 (q, 1H, J = 5,2 Hz), 4,32 (br s, 2H), 3,78 (s, 3H), 3,65 (br s, 2H), 2,52 (br s, 2H), 1,73 (d, 3H, J = 5,2 Hz). (e) En blanding omfattende 2-[1-(5-benzyloksykarbonyl-4,5,6,7-tetrahydro-^-imidazo[4,5-c]pyridin-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksylsyre (0,75 g, 1,6 mmol), DMF (6,5 ml), metyl-2-(2-aminoetoksy)benzoat (0,38 g, 1,6 mmol) og HOBT (0,22 g, 1,6 mmol) ble avkjølt under nitrogen til -40°C, behandlet med EDC (0,32 g, 1,6 mmol) og /V,A/-diisopropyletylamin (0,29 ml, 1,6 mmol) og 15 minutter senere med ytterligere W,W-diisopropyletylamin (0,29 ml), fikk oppvarmes til 20°C og ble omrørt i 16 timer. Blandingen ble deretter avkjølt til -40°C, behandlet med ytterligere EDC (0,080 g) og W./V-diisopropyletylamin (0,050 ml), omrørt i 15 minutter ved -40°C og 2 timer ved 20°C og konsentrert ved kortveis destillering. Residuet ble fordelt mellom kloroform og natriumbikarbonat og det organiske laget ble vasket med natriumklorid, 0,5 M kaliumsulfat og natriumklorid, tørket (Na2S04), filtrert og konsentrert under redusert trykk. Residuet ble renset ved silikagel-kromatografi (CHCIa/MeOH/AcOH : 95/5/1), hvilket ga benzyl 2-(1-{6-[2-(2-metoksykarbonylfenoksy)etylkarbamoyl]-1 -metyl-1 W-benzoimidazol-2-yl}etyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (0,69 g, 66 %) som et glassaktig, brunt skum; <1>H-NMR (300 MHz, DMSO-d6) d ppm: 11,92 (s, 1H), 8,49 (t, 1H, J = 5,0 Hz), 8,02 (s, 1H), 7,69 (d, 1H, J = 9,9 Hz), 7,60 (m, 2H), 7,50 (t, 1H, J = 8,3 Hz), 7,30 (m, 5H), 7,19 (d, 1H, J = 9,9 Hz), 6,99 (t, 1H, J = 8,3 Hz), 5,04 (s, 2H), 4,61 (q, 1H, J = 8,8 Hz), 4,30 (br s, 2H), 4,20 (t, 2H, J = 5,0 Hz), 3,74 (s, 3H), 3,68 (s, 3H), 3,63 (m, 4H), 2,55 (br s, 2H), 1,67 (d, 3H, J = 8,8 Hz). (f) En løsning omfattende benzyl 2-(1-{6-[2-(2-metoksykarbonylfenoksy)-etylkarbamoyl]-1-metyl-1H-benzoimidazol-2-yl}etyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-karboksylat (0,69 g, 1,1 mmol) i THF (2 ml) og vann (2 ml) ble avkjølt til 0°C under nitrogen, behandlet med 2N litiumhydroksyd (1,1 ml, 2,2 mmol), fikk oppvarmes til 20°C og ble omrørt i 8 timer. Blandingen ble deretter avkjølt til 0°C, behandlet med ytterligere 2N litiumhydroksyd (1,1 ml), fikk oppvarmes til 20°C, ble omrørt i 6 timer, avkjølt til 0°C, regulert til pH 7 med 1M saltsyre og konsentrert under redusert trykk. Residuet ble forsiktig vasket med kaldt natriumklorid og vann og deretter tørket under vakuum, hvilket ga 5-benzyloksykarbonyl-2-(2-{3-metyl-2-[1-(4,5l6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)etyl]-3H-benzoimidazol-5-ylkarbonylamino}-etoksy)benzosyre (0,56 g, 83 %) som et glassaktig residuum; ^-NMR (300 MHz, DMSO-d6) d ppm: 11,87 (brs, 1H), 9,74 (s, 1H), 8,45 (s, 1H), 7,84 (d, 1H, J = 9,7 Hz), 7,56 (d, 1H, J = 9,7 Hz), 7,42 (d, 1H, J = 7,7 Hz), 7,32 (s, 5H), 7,23 (t, 1H, J = 7,7 Hz), 7,06 (d, 1H, J = 7,7 Hz), 6,90 (t, 1H, J = 7,7 Hz), 5,08 (s, 2H), 4,63 (q, 1H, J = 7,7 Hz), 4,32 (s, 2H), 4,19 (m, 2H), 3,84 (s, 3H), 3,64 (m, 4H), 2,55 (s, 2H), 1,71 (d, 3H, J = 7,7 Hz). (g) En løsning omfattende 5-benzyloksykarbonyl-2-(2-{3-metyl-2-[1-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)etyl]-3H-benzoimidazol-5-ylkarbonylamino}-etoksy)benzosyre (0,561 g, 0,90 mmol) i iseddik (2 ml) ble oppvarmet under nitrogen i et vannbad til 10°C, behandlet med hydrogenbromid i eddiksyre (2 ml av en 30 % løsning) og fikk oppvarmes til 20CC og, én time senere, konsentrert med en strøm av nitrogen. Residuet ble oppløst i en liten mengde etanol og løsningen ble satt dråpevis til eter under omrøring, hvilket ga et blekbrunt presipitat. Fellingen ble isolert ved filtrering og tørket, hvilket ga 2-(2-{3-metyl-2-[4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)etyl]-3W-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre-hydrobromid (0,651 g); 'H-NMR (300 MHz, DMSO-d6) d ppm: 9,31 (br s, 2H), 8,63 (rn, 1H), 8,24 (s, 1H), 7,79 (d, 1H, J = 7,9 Hz), 7,63 (m, 2H), 7,47 (t, 1H, J = 7,9 Hz), 7,21 (d, 1H, J = 7,9 Hz), 7,00 (t, 1H, J = 7,9 Hz), 5,21 (q, 1H, J = 6,3 Hz), 4,29 (s, 2H), 4,21 (s, 2H), 3,91 (s, 3H), 3,68 (m, 2H), 3,43 (m, 2H), 2,89 (s, 2H), 1,79 (d, 3H, J = 6,3 Hz). (h) En løsning omfattende 2-(2-{3-metyl-2-[4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridin-2-yl)etyl]-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre-hydrobromid (0,30 g, 0,46 mmol) i DMF (1,5 ml) ble avkjølt under nitrogen til 0°C, behandlet med etyl-acetimidat (0,12 g, 0,92 mmol) og A/.W-diisopropyletylamin (0,25 ml, 1,4 mmol), avkjølt ved 0°C i 30 minutter og fikk deretter oppvarmes til 20°C og ble omrørt i 20 timer. Blandingen ble deretter avkjølt til 0<6>C, behandlet med ytterligere etyl-acetimidat (0,06 g) og W./V-diisopropyletylamin (0,16 ml), fikk oppvarmes til 20°C og ble omrørt i 2 timer. Blandingen ble avkjølt til 0°C, behandlet med ytterligere etyl-acetimidat (0,03 g ), fikk oppvarmes til 20°C og ble omrørt i 2 timer. Blandingen ble deretter satt dråpevis til omrørt eter, hvilket ga et presipitat. Fellingen ble isolert ved dekantering av oppløsningsmidlet og tørket under vakuum. Residuet ble utfelt fra etanol/eter og renset ved preparativ RP-HPLC: 2 50 % MeCN/H20 (20 mM HCI) over 50 minutter. Fraksjonene ble lyofilisert, hvilket ga 2-[2-(2-{1-[5-(1-iminoetyl)-4I5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (0,145 g, 52 %); <1>H-NMR (300 MHz, DMSO-cfe) d ppm: 9,77 (s, 1H), 9,34 (2s, 1H), 8,81 (m, 1H), 8,36 (s, 1H), 7,89 (d, 1H, J = 8,6 Hz), 7,71 (d, 1H, J = 8,6 Hz), 7,60 (d, 1H, J = 7,7 Hz), 7,49 (t, 1H, J = 7,7 Hz), 7,21 (d, 1H, J = 7,7 Hz), 6,99 (t, 1H, J = 7,7 Hz), 5,37 (m, 1H), 4,71 (2s, 2H), 4,23 (s, 2H), 3,97 (s, 3H), 3,82 (s, 1H), 3,66 (m, 2H), 2,83 (m, 2H), 2,49 (s, 1H), 2,40 (d, 3H, J = 3,5 Hz), 1,85 (d, 3H, J = 5,1 Hz). MS (ESI) C28H31N7O4 m/e beregnet. 529,61, observert 530,3 (MH<+>). The precipitate was isolated and recovered by filtration and dried to give 2-[1-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl] -3-methyl-3H-benzoimidazole-5-carboxylic acid (4.73 g, 58%); <1>H-NMR (300 MHz, DMSO-d6) d ppm: 12.70 (br s, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d , 1H, J = 8.3 Hz), 7.64 (d, 1H, J = 8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q , 1H, J = 5.2 Hz), 4.32 (br s, 2H), 3.78 (s, 3H), 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J = 5.2 Hz). (e) A mixture comprising 2-[1-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-^-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3H -benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmol), DMF (6.5 mL), methyl 2-(2-aminoethoxy)benzoate (0.38 g, 1.6 mmol) and HOBT ( 0.22 g, 1.6 mmol) was cooled under nitrogen to -40°C, treated with EDC (0.32 g, 1.6 mmol) and /V,A/-diisopropylethylamine (0.29 mL, 1, 6 mmol) and 15 minutes later with additional W,W-diisopropylethylamine (0.29 ml), was allowed to warm to 20°C and was stirred for 16 hours. The mixture was then cooled to -40°C, treated with additional EDC (0.080 g) and W./V-diisopropylethylamine (0.050 mL), stirred for 15 min at -40°C and 2 h at 20°C and concentrated at distillation. The residue was partitioned between chloroform and sodium bicarbonate and the organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCIa/MeOH/AcOH : 95/5/1) to give benzyl 2-(1-{6-[2-(2-methoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1 W- benzoimidazol-2-yl}ethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (0.69 g, 66%) as a glassy brown foam; <1>H-NMR (300 MHz, DMSO-d6) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J = 5.0 Hz), 8.02 (s, 1H) , 7.69 (d, 1H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J = 8.3 Hz), 7.30 (m, 5H) , 7.19 (d, 1H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz), 4.30 (br s, 2H), 4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H ), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J = 8.8 Hz). (f) A solution comprising benzyl 2-(1-{6-[2-(2-methoxycarbonylphenoxy)-ethylcarbamoyl]-1-methyl-1H-benzoimidazol-2-yl}ethyl)-1,4,6,7- Tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (0.69 g, 1.1 mmol) in THF (2 mL) and water (2 mL) was cooled to 0 °C under nitrogen, treated with 2N lithium hydroxide ( 1.1 ml, 2.2 mmol), was allowed to warm to 20°C and was stirred for 8 hours. The mixture was then cooled to 0°C, treated with additional 2N lithium hydroxide (1.1 mL), allowed to warm to 20°C, stirred for 6 hours, cooled to 0°C, adjusted to pH 7 with 1M hydrochloric acid and concentrated under reduced pressure. The residue was carefully washed with cold sodium chloride and water and then dried under vacuum to give 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[1-(4,5l6,7-tetrahydro-1H-imidazo[4 ,5-c]pyridin-2-yl)ethyl]-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (0.56 g, 83%) as a glassy residue; ^-NMR (300 MHz, DMSO-d6) d ppm: 11.87 (brs, 1H), 9.74 (s, 1H), 8.45 (s, 1H), 7.84 (d, 1H, J = 9.7 Hz), 7.56 (d, 1H, J = 9.7 Hz), 7.42 (d, 1H, J = 7.7 Hz), 7.32 (s, 5H), 7, 23 (t, 1H, J = 7.7 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.90 (t, 1H, J = 7.7 Hz), 5.08 ( s, 2H), 4.63 (q, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3, 64 (m, 4H), 2.55 (s, 2H), 1.71 (d, 3H, J = 7.7 Hz). (g) A solution comprising 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[1-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- yl)ethyl]-3H-benzoimidazol-5-ylcarbonylamino}-ethoxy)benzoic acid (0.561 g, 0.90 mmol) in glacial acetic acid (2 mL) was heated under nitrogen in a water bath to 10 °C, treated with hydrogen bromide in acetic acid ( 2 ml of a 30% solution) and allowed to warm to 20CC and, one hour later, concentrated with a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the solution was added dropwise to ether with stirring, which gave a pale brown precipitate. The precipitate was isolated by filtration and dried to give 2-(2-{3-methyl-2-[4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl ]-3N-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid hydrobromide (0.651 g); 1H-NMR (300 MHz, DMSO-d6) d ppm: 9.31 (br s, 2H), 8.63 (rn, 1H), 8.24 (s, 1H), 7.79 (d, 1H , J = 7.9 Hz), 7.63 (m, 2H), 7.47 (t, 1H, J = 7.9 Hz), 7.21 (d, 1H, J = 7.9 Hz), 7.00 (t, 1H, J = 7.9 Hz), 5.21 (q, 1H, J = 6.3 Hz), 4.29 (s, 2H), 4.21 (s, 2H), 3.91 (s, 3H), 3.68 (m, 2H), 3.43 (m, 2H), 2.89 (s, 2H), 1.79 (d, 3H, J = 6.3 Hz ). (h) A solution comprising 2-(2-{3-methyl-2-[4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridin-2-yl)ethyl]-3H -benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid hydrobromide (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled under nitrogen to 0 °C, treated with ethyl acetimidate (0.12 g , 0.92 mmol) and A/.W-diisopropylethylamine (0.25 mL, 1.4 mmol), cooled at 0°C for 30 minutes and then allowed to warm to 20°C and stirred for 20 hours. The mixture was then cooled to 0<6>C, treated with additional ethyl acetimidate (0.06 g) and N/V-diisopropylethylamine (0.16 ml), allowed to warm to 20°C and stirred for 2 hours. The mixture was cooled to 0°C, treated with additional ethyl acetimidate (0.03 g), allowed to warm to 20°C and stirred for 2 hours. The mixture was then added dropwise to stirred ether, which gave a precipitate. The precipitate was isolated by decanting the solvent and dried under vacuum. The residue was precipitated from ethanol/ether and purified by preparative RP-HPLC: 2 50% MeCN/H 2 O (20 mM HCl) over 50 min. The fractions were lyophilized to give 2-[2-(2-{1-[5-(1-iminoethyl)-4N5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl] ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (0.145 g, 52%); <1>H-NMR (300 MHz, DMSO-cfe) d ppm: 9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 7.60 (d, 1H, J = 7.7 Hz) , 7.49 (t, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 7.7 Hz), 6.99 (t, 1H, J = 7.7 Hz), 5 .37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.82 (s, 1H), 3.66 (m, 2H), 2.83 (m, 2H), 2.49 (s, 1H), 2.40 (d, 3H, J = 3.5 Hz), 1.85 (d, 3H, J = 5.1 Hz). MS (ESI) C28H31N7O4 m/e calcd. 529.61, observed 530.3 (MH<+>).

EKSEMPEL 10 EXAMPLE 10

Etyl-2-(2-{2-[1-(4,6,7-trifluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karbonylamino}etoksy}benzoat (Forbindelse 75) Ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carbonylamino}ethoxy}benzoate (Compound 75)

(a) En løsning omfattende 2,3,4,6-tetrafluornitrobenzen (0,6 g, 3,1 mmol) og ammoniakk i dioksan (Aldrich, 0,5 M, 7,5 mmol) ble omrørt ved romtemperatur i 3 timer, hvilket ga et fint, hvitt presipitat. Blandingen ble fortynnet med et likt volum av vann for å oppløse det hvite presipitat, hvilket ga gule krystaller. Krystallene ble isolert, oppsamlet og tørket, hvilket ga 2,3,5-t rifl u or-6-n itro a n i I i n (307 mg, 51%) som gule nåler; sm.p. 66°C; <1>H NMR (CDCI3) d 6,4 (1H, m), d 6,0 (2H, s). (b) En blanding av 2,3,5-trifl uor-6- n itroa n i I i n (300 mg, 1,56 mmol) og 10% palladium på karbon i absolutt etanol ble hydrogenert natten over ved atmosfærisk trykk, filtrert under nitrogen og konsentrert, hvilket ga 1,2-diamino-3,4,6-trifluorbenzen (219 mg, 87% utbytte) som et blårødt, krystallinsk, fast stoff; MS M<+> 162,7, +41. +82 (+ACN, +2ACN). (beregnet for C6H5F3N2: 162,11). (c) En blanding av 1,2-diamino-3,4,6-trifluorbenzen (1,92 g, 11,8 mmol), etyl-2-etoksykarbonimidoylpropionat (3,1 g, 14,7 mmol) og absolutt etanol (6 ml) ble oppvarmet ved tilbakeløp inntil ingen videre utvikling i reaksjonen ble vist ved TLC, filtrert fra NH4CI og konsentrert. Residuet ble renset ved kromatografi på silika (heksan: metylenklorid: etylacetat, 5:5:1), hvilket ga etyl-2-(4,6,7-trifluor-1H-benzoimidazol-2-yl)propionat (1,37 g, 42%) som et gyldenbrunt, krystallinsk, fast stoff; NMR (CDCI3): d 10,35 (s, 1/2 H), d 7,05 (s, 1/2 H), 6,7 (m, 1H), d 4,25 (dd, 2H), d 4,15 (dd, 1H), d 1,73 (d, 3H), d 1,31 (t, 3H); M<+> 272,9 (beregnet for C12H11F3N2O2: 272,23). (d) Etyl-2-(4,6,7-trifluor-1H-benzoimidazol-2-yl)propionat (988 mg, 3,63 mmol) og etyl-2-[2-(4-amino-3-metylaminobenzoylamino)etoksy]benzoat (1,3 g, 3,63 mmol) ble samlet og plassert under vakuum i 4 timer og deretter videre kombinert med DMPU (4 ml). Blandingen ble omrørt inntil løsning, evakuert natten over under høyvakuum for å fjerne gjenværende gasser, oppvarmet til 195°C under en nitrogenstrøm i 4 timer, avkjølt til romtemperatur og fordelt mellom etylacetat og vann. Det organiske laget ble separert og vasket med saltvann, tørket over natriumsulfat og konsentrert. Residuet ble renset ved kromatografi på silika (trinnvis gradient av 100% heksan til 100% etylacetat) og ytterligere renset ved krystallisering fra MeOH/THF/vann, hvilket ga etyl-2-(2-{2-[1-(4,6,7-trifluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karbonylamino}etoksy}benzoat (1,0 g, 49%) som et hvitt, krystallinsk fast stoff: NMR (CDCI3): d 6,84-8,07 (m, 8H), d 4,93 (dd, 1H), d 4,34 (dd, 2H), d 4,27 (m, 2H), d 3,95 (m, 2H), d 3,9 (s, 3H), d 1,93 (d, 3H), d 1,78 (s, 2H), d 1,38 (t, 3H); LCMS M<+> 566,2 Biolon M<+> 565,7 (beregnet for CzgHzeFsNgCM: 565,55). (a) A solution comprising 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was stirred at room temperature for 3 h , which gave a fine white precipitate. The mixture was diluted with an equal volume of water to dissolve the white precipitate, which gave yellow crystals. The crystals were isolated, collected and dried to give 2,3,5-t rif u or-6-n itro a n i I i n (307 mg, 51%) as yellow needles; sm.p. 66°C; <1>H NMR (CDCl3 ) d 6.4 (1H, m), d 6.0 (2H, s). (b) A mixture of 2,3,5-trifl uoro-6-nitroa n i I i n (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol was hydrogenated overnight at atmospheric pressure, filtered under nitrogen and concentrated to give 1,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a bluish-red crystalline solid; MS M<+> 162.7, +41. +82 (+ACN, +2ACN). (calcd for C6H5F3N2: 162.11). (c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2-ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at reflux until no further development of the reaction was shown by TLC, filtered from NH 4 Cl and concentrated. The residue was purified by chromatography on silica (hexane: methylene chloride: ethyl acetate, 5:5:1) to give ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (1.37 g , 42%) as a golden brown crystalline solid; NMR (CDCl3): d 10.35 (s, 1/2 H), d 7.05 (s, 1/2 H), 6.7 (m, 1H), d 4.25 (dd, 2H), d 4.15 (dd, 1H), d 1.73 (d, 3H), d 1.31 (t, 3H); M<+> 272.9 (calcd for C12H11F3N2O2: 272.23). (d) Ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (988 mg, 3.63 mmol) and ethyl 2-[2-(4-amino-3-methylaminobenzoylamino )ethoxy]benzoate (1.3 g, 3.63 mmol) was collected and placed under vacuum for 4 h and then further combined with DMPU (4 mL). The mixture was stirred until solution, evacuated overnight under high vacuum to remove residual gases, heated to 195°C under a stream of nitrogen for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (stepwise gradient of 100% hexane to 100% ethyl acetate) and further purified by crystallization from MeOH/THF/water to give ethyl 2-(2-{2-[1-(4.6 ,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carbonylamino}ethoxy}benzoate (1.0 g, 49%) as a white crystalline solid: NMR ( CDCl3): d 6.84-8.07 (m, 8H), d 4.93 (dd, 1H), d 4.34 (dd, 2H), d 4.27 (m, 2H), d 3, 95 (m, 2H), d 3.9 (s, 3H), d 1.93 (d, 3H), d 1.78 (s, 2H), d 1.38 (t, 3H); LCMS M< +> 566.2 Biolon M<+> 565.7 (calcd for CzgHzeFsNgCM: 565.55).

På samme måte som i Eksempel 10 ble de følgende forbindelser ifølge foreliggende oppfinnelse fremstilt: etyl-2-(2-{2-[1 -(5,6-difluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 76), MS (Biolon) C29H27N5O4F2 m/e beregnet 547,56; funnet 548,1 (MH<+>); In the same way as in Example 10, the following compounds according to the present invention were prepared: ethyl-2-(2-{2-[1-(5,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3- methyl 3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 76), MS (Biolon) C29H27N5O4F2 m/e calcd 547.56; found 548.1 (MH<+>);

etyl-2-(2-{2-[1-(4,6-difluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 77, MS (LCMS) C29H27F2N5O4 m/e beregnet 547,56; funnet 548,3 (Mh<T>); ethyl 2-(2-{2-[1-(4,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate ( Compound 77, MS (LCMS) C29H27F2N5O4 m/e calcd 547.56, found 548.3 (Mh<T>);

etyl-2-(2-{2-[1-(4,5,6-trifluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 78), MS (LCMS) C29H26F3N5O4 m/e beregnet 565,55; funnet 566,2 (MH<T>); og ethyl 2-(2-{2-[1-(4,5,6-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 78), MS (LCMS) C29H26F3N5O4 m/e calcd 565.55; found 566.2 (MH<T>); and

etyl-2-{2-[3-metyl-2-(4,6,7-trifluor-1H-benzoimidazol-2-ylmetyl)-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzoat (Forbindelse 79), MS (Biolon) C28H24F3N504 m/e beregnet 551,52; funnet 551,2. ethyl 2-{2-[3-methyl-2-(4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl)-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 79), MS ( Biolon) C28H24F3N504 m/e calcd 551.52; found 551.2.

EKSEMPEL 11 EXAMPLE 11

2-(2-{2-[1-(4,6,7-trifluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 80) 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 80)

En blanding omfattende etyl-2-(2-{2-[1-(4,6l7-trifluor-1H-benzoimidazol-2- yl)etyl]-3-metyl-3H-benzoimidazol-5-karbonylamino}etoksy}benzoat (118 mg, 0,21 mmol), metanol (4 ml) og 2N natriumhydroksyd (2,1 ml) ble omrørt ved romtemperatur i 4 timer, nøytralisert med 2N saltsyre (2,1 ml) og fordelt mellom etylacetat og mettet ammoniumklorid. Det vandige laget ble separert og ekstrahert med etylacetat (X3). De samlede organiske lag ble vasket med saltvann, tørket over natriumsulfat og konsentrert til et hvitt, fast stoff. Residuet ble oppløst i varm etanol (10 ml) og 4M hydrogenklorid/dioksan-løsning. Løsningen ble fortynnet med etyleter, hvilket ga et presipitat. Fellingen ble isolert og tørket, hvilket ga 2-(2-{2-[1-(4,6,7-trifluor-1H-benzoimidazol-2-yl)etyl]-3- metyl-3H-benzoimidazol-5-ylkarbonylamino}-etoksy)benzosyre som et hvitt, fast stoff; MS (LCMS) C27H22F3N5O4 m/e beregnet 537,50; funnet 538,4 (MH<+>). A mixture comprising ethyl 2-(2-{2-[1-(4,6l7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carbonylamino}ethoxy}benzoate ( 118 mg, 0.21 mmol), methanol (4 mL) and 2N sodium hydroxide (2.1 mL) were stirred at room temperature for 4 hours, neutralized with 2N hydrochloric acid (2.1 mL) and partitioned between ethyl acetate and saturated ammonium chloride. the aqueous layer was separated and extracted with ethyl acetate (X3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to a white solid. The residue was dissolved in hot ethanol (10 mL) and 4M hydrogen chloride/dioxane solution .The solution was diluted with ethyl ether to give a precipitate.The precipitate was isolated and dried to give 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino}-ethoxy)benzoic acid as a white solid, MS (LCMS) C27H22F3N5O4 m/e calcd 537.50; found 538.4 (MH<+>).

På samme måte som i Eksempel 11 ble de følgende forbindelser ifølge foreliggende oppfinnelse fremstilt: 2-(2-{2-[1 -(5,6-difluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 81), MS (LCMS) C27H23N504F2 m/e beregnet 519,51; funnet 520,2 (MhT); In the same way as in Example 11, the following compounds according to the present invention were prepared: 2-(2-{2-[1-(5,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl- 3N-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 81), MS (LCMS) C27H23N504F2 m/e calcd 519.51; found 520.2 (MhT);

2-(2-{2-[1 -(4,6-difluor-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 82), MS (LCMS) C27H23F2N5O4 m/e beregnet 519,51; funnet 520,2 (MH<+>); og 2-(2-{2-[1-(4,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 82), MS (LCMS) C27H23F2N5O4 m/e calcd 519.51; found 520.2 (MH<+>); and

2-(2-{2-[1-(4,5,6-trifluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karbonylamino}etoksy)benzosyre (Forbindelse 83), MS (Biolon) C27H22F3N504 m/e beregnet 537,5; funnet 537,7 (Mh<T>). 2-(2-{2-[1-(4,5,6-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy)benzoic acid (Compound 83) , MS (Biolon) C27H22F3N504 m/e calcd 537.5; found 537.7 (Mh<T>).

EKSEMPEL 12 EXAMPLE 12

Etyl-2-(2-{2-[1-(1-isobutyryl-5-metoksykarbonyloksy-1W-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat Ethyl 2-(2-{2-[1-(1-isobutyryl-5-methoxycarbonyloxy-1N-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate

(Forbindelse 84) (Compound 84)

En blanding omfattende etyl-2-(2-{2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-karbonylamino}etoksy)benzoat (0,50 g, 0,95 mmol), dimetylformamid (5 mL), cesiumkarbonat (0,93 g, 2,85 mmol) og isosmørsyreanhydrid (0,17 ml, 1,05 mmol) ble omrørt i 2 timer, deretter fortynnet med diklormetan (50 ml) og passert gjennom en celite-pute. Oppløsningsmidlene ble fjernet / vakuum og residuet ble oppløst i diklormetan (5 ml). Løsningen ble kombinert med diisopropyletylamin (0,47 ml, 2,7 mmol) og metyl-klorformiat (0,1 ml, 1,3 mmol) og blandingen ble omrørt i 1 time. Oppløsningsmidlene ble fjernet / vakuum og residuet ble renset ved silikagel-kromatografi ved anvendelse av etanol og diklormetan som elueringsmiddel, hvilket ga etyl-2-(2-{2-[1-(1 -isobutyrl-5-metoksykarbonyloksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (0,20 g, 32% utbytte) som et farveløst, amorft, fast stoff; MS (Biolon) C35H37N5O8 m/e beregnet 655,72; funnet 656,1 (Mh<T>). A mixture comprising ethyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3W-benzoimidazole-5-carbonylamino}ethoxy)benzoate (0, 50 g, 0.95 mmol), dimethylformamide (5 mL), cesium carbonate (0.93 g, 2.85 mmol) and isobutyric anhydride (0.17 mL, 1.05 mmol) were stirred for 2 h, then diluted with dichloromethane (50 ml) and passed through a celite pad. The solvents were removed / vacuum and the residue was dissolved in dichloromethane (5 ml). The solution was combined with diisopropylethylamine (0.47 mL, 2.7 mmol) and methyl chloroformate (0.1 mL, 1.3 mmol) and the mixture was stirred for 1 hour. The solvents were removed / vacuum and the residue was purified by silica gel chromatography using ethanol and dichloromethane as eluent to give ethyl 2-(2-{2-[1-(1-isobutyrl-5-methoxycarbonyloxy-1H-benzoimidazole) -2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (0.20 g, 32% yield) as a colorless, amorphous solid; MS (Biolon) C35H37N5O8 m/e calcd 655.72; found 656.1 (Mh<T>).

På samme måte som i Eksempel 12 ble de følgende prodrug-derivater ifølge foreliggende oppfinnelse ble fremstilt: metyl-2-(1-{6-[2-(2-etoksykarbonylfenoksy)etylkarbamoyl]-1-metyl-1H-benzoimidazol-2-yl}etyl)-5-hydroksybenzoimidazol-1-karboksylat (Forbindelse 85), MS (ESI) C3iH31N507 m/e beregnet 585,62; funnet 586,2 In the same way as in Example 12, the following prodrug derivatives according to the present invention were prepared: methyl-2-(1-{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1H-benzoimidazole-2- yl}ethyl)-5-hydroxybenzoimidazole-1-carboxylate (Compound 85), MS (ESI) C 3 i H 3 1 N 5 O 7 m/e calcd 585.62; found 586.2

(MH<+>); (MH<+>);

etyl-2-( 1 -{6-[2-(2-etoksykarbonylfenoksy)etylkarbamoyl]-1 -metyl-1/-/-benzoimidazol-2-yl}etyl)-5-metoksykarbonyloksybenzoimidazol-1-karboksylat (Forbindelse 86), MS (ESI) C33H33N5O7 m/e beregnet 643,66; funnet 644,2 (MH<+>); ethyl 2-( 1 -{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-1 -methyl-1/-/-benzoimidazol-2-yl}ethyl)-5-methoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 86) , MS (ESI) C33H33N5O7 m/e calcd 643.66; found 644.2 (MH<+>);

etyl-2-(2-{2-[1 -(5-hydroksy-1 -isobutyryl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 87), MS (ESI) CssHssNgOe m/e beregnet 597,68; funnet 598,2 (Mh<T>); ethyl 2-(2-{2-[1-(5-hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate ( Compound 87), MS (ESI) CssHssNgOe m/e calcd 597.68; found 598.2 (Mh<T>);

etyl-2-(2-{2-[1-(1-benzoyl-5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 88), MS (ESI) C36H33N5O6 m/e beregnet 631,69; funnet 632,3 (MH<+>); ethyl 2-(2-{2-[1-(1-benzoyl-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 88), MS (ESI) C36H33N5O6 m/e calcd 631.69; found 632.3 (MH<+>);

etyl-2-(2-{2-[1 -(1 -dimetylkarbamoyl-5~hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy}benzoat (Forbindelse 89), MS (ESI) C32H34N6O6 m/e beregnet 598,66; funnet 599,3 ethyl 2-(2-{2-[1 -(1 -dimethylcarbamoyl-5~hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy}benzoate ( Compound 89), MS (ESI) C 32 H 34 N 6 O 6 m/e calcd 598.66; found 599.3

(MH<+>); (MH<+>);

etyl-2-(2-{2-[1 -(1 -acetoksymetyl-5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 90), MS (Biolon) C32H33N507 m/e beregnet 599,65; funnet 600,7 (MH<+>); ethyl-2-(2-{2-[1 -(1-acetoxymethyl-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5-ylcarbonylamino}ethoxy )benzoate (Compound 90), MS (Biolon) C32H33N507 m/e calcd 599.65; found 600.7 (MH<+>);

etyl-2-[2-(2-{1 -[1 -(2,2-dimetylpropionyloksymetyl)-5-hydroksy-1H-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzoat (Forbindelse 91), MS (ESI) C35H39N5O7 m/e beregnet 641,74; funnet 642,3 (MH<+>); ethyl-2-[2-(2-{1 -[1 -(2,2-dimethylpropionyloxymethyl)-5-hydroxy-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino )ethoxy]benzoate (Compound 91), MS (ESI) C35H39N5O7 m/e calcd 641.74; found 642.3 (MH<+>);

etyl-2-(2-{2-[1-(1-isobutyrl-5-metoksykarbonyloksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 92), MS (Biolon) C35H37N508 m/e beregnet 655,72; funnet 656,1 ethyl 2-(2-{2-[1-(1-isobutyrl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 92), MS (Biolon) C35H37N508 m/e calcd 655.72; found 656.1

(MH<+>); (MH<+>);

etyl-5-etoksykarbonyloksy-2-(1-{6-[2-(2-etoksykarbonylfenoksy)etylkarbamoyl]-1-metyl-1 H-benzoimidazol-2-yl}etyl)benzoimidazol-1-karboksylat (Forbindelse 93), MS (ESI) C35H37N5O9 m/e beregnet 671,72; funnet 672,4 (MH<+>); ethyl 5-ethoxycarbonyloxy-2-(1-{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1H-benzoimidazol-2-yl}ethyl)benzoimidazole-1-carboxylate (Compound 93), MS (ESI) C35H37N5O9 m/e calcd 671.72; found 672.4 (MH<+>);

isopropyl 2-(1-{6-[2-(2-etoksykarbonylfenoksy)etylkarbamoyl]-1-metyl-1H-benzoimidazol-2-yl}etyl)-5-isopropoksykarbonyloksy-benzoimidazol-1-karboksylat (Forbindelse 94), MS (ESI) C37H41N5O9 m/e beregnet 699,79; funnet 700,4 (Mh<T>); og isopropyl 2-(1-{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1H-benzoimidazol-2-yl}ethyl)-5-isopropoxycarbonyloxy-benzoimidazole-1-carboxylate (Compound 94), MS (ESI) C37H41N5O9 m/e calcd 699.79; found 700.4 (Mh<T>); and

etyl-2-(2-{2-[1 -(1 -acetyl-5-hydroksy-1 tf-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 95), MS (ESI) C31H31N5O6 m/e beregnet 569,62; funnet 570,1 (Mh<T>). ethyl 2-(2-{2-[1 -(1 -acetyl-5-hydroxy-1 tf-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate ( Compound 95), MS (ESI) C31H31N5O6 m/e calcd 569.62; found 570.1 (Mh<T>).

På samme måte som beskrevet i denne søknaden eller ved metoder kjent for fagfolk, ble de følgende ytterligere forbindelser ifølge foreliggende oppfinnelse fremstilt: C-[2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3H-benzoimidazol-5-yl]metylamin (Forbindelse 96); C-[2-(1tf-nafto[2,3-d]imidazol-2-ylmetyl)-1H-benzoimida n (Forbindelse 97), MS (Biolon) C20H17N5 m/e beregnet 327,4; funnet 328,1 In the same manner as described in this application or by methods known to those skilled in the art, the following additional compounds according to the present invention were prepared: C-[2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3H-benzoimidazol-5- yl]methylamine (Compound 96); C-[2-(1tf-naphtho[2,3-d]imidazol-2-ylmethyl)-1H-benzoimida n (Compound 97), MS (Biolon) C20H17N5 m/e calcd 327.4; found 328.1

(MH<+>); (MH<+>);

C-[2-(5-metyl-1H-benzoimidazol-2-ylmetyl)-1H-benzoimidazol-5-yl]metyla min (Forbindelse 98), MS (Biolon) Ci7H17N5 m/e beregnet 291,4; funnet 292,3 C-[2-(5-methyl-1H-benzoimidazol-2-ylmethyl)-1H-benzoimidazol-5-yl]methylamine (Compound 98), MS (Biolon) C17H17N5 m/e calcd 291.4; found 292.3

(MH<+>); (MH<+>);

2- (5-aminometyl-1 H-benzoimidazol-2-ylmetyl)-1 tf-benzoimidazol-5-karboksylsyre (Forbindelse 99); 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-1t-benzoimidazol-5-carboxylic acid (Compound 99);

3- [2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-1H-benzoimidazol-5-yl-karbonylamino]propionsyre (Forbindelse 100), 'H-NMR (300 MHz, CD3OD): 1,92 (m, 2H, J=7,2Hz), 2,38 (t, 2H, J = 7,2 Hz), 3,47 (t, 2H, J=7,2 Hz), 4,30 (s, 2H), 7,54 (d, 1H, J=10,0 Hz), 7,69 (d, 1H, J = 8,6 Hz), 7,75 (d, 1H, J=10,0 Hz), 7,81 (s, 1H), 7,87 (d, 1H, J=8,6 Hz), 8,12 (s, 1H); 3-[2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-1H-benzoimidazol-5-yl-carbonylamino]propionic acid (Compound 100), 1H-NMR (300 MHz, CD3OD): 1.92 ( m, 2H, J=7.2Hz), 2.38 (t, 2H, J = 7.2 Hz), 3.47 (t, 2H, J=7.2 Hz), 4.30 (s, 2H ), 7.54 (d, 1H, J=10.0 Hz), 7.69 (d, 1H, J = 8.6 Hz), 7.75 (d, 1H, J=10.0 Hz), 7.81 (s, 1H), 7.87 (d, 1H, J=8.6 Hz), 8.12 (s, 1H);

2-(5-aminometyl-1/7-benzoimidazol-2-ylmetyl)-A/-(2-naft-1-yletyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 101), 'H-NMR (300 2-(5-aminomethyl-1/7-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl)-1H-benzoimidazol-5-carboxamide (Compound 101), 1 H-NMR (300

MHz, CD3OD): 3,42 (t, 2H, J=7,5 Hz), 3,75 (t, 2H, J = 7,5 Hz), 7,39-7,81 (m, 12H), 8,08 (s, 1H), 8,27 (d, 1H, J=10,0 Hz); MHz, CD3OD): 3.42 (t, 2H, J=7.5 Hz), 3.75 (t, 2H, J = 7.5 Hz), 7.39-7.81 (m, 12H), 8.08 (s, 1H), 8.27 (d, 1H, J=10.0 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 102), 'H-NMR (300 2-(5-Aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 102), 1 H-NMR (300

MHz, CD3OD): 3,41 (t, 2H, J=7,4 Hz), 3,72 (t, 2H, J=7,4 Hz), 3,96 (s, 3H), 4,27 (s, 2H), 7,37-7,54 (m, 5H), 7,67 (d, 1H, J=8,7 Hz), 7,71-7,77 (m, 2H), 7,80-7,85 (m, 2H), 8,70 (d, 1H, J=0,9 Hz), 8,24 (d, 1H, J = 8,1 Hz); MHz, CD3OD): 3.41 (t, 2H, J=7.4 Hz), 3.72 (t, 2H, J=7.4 Hz), 3.96 (s, 3H), 4.27 ( s, 2H), 7.37-7.54 (m, 5H), 7.67 (d, 1H, J=8.7 Hz), 7.71-7.77 (m, 2H), 7.80 -7.85 (m, 2H), 8.70 (d, 1H, J = 0.9 Hz), 8.24 (d, 1H, J = 8.1 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-4-karboksamid (Forbindelse 103), <1>H-NMR(300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-4-carboxamide (Compound 103), <1>H- NMR (300

MHz, CD3OD): 3,45 (t, 2H, J=7,2 Hz), 3,74 (s, 3H), 3,83 (t, 2H, J=7,2 Hz), 4,27 (s, 2H), 7,36-7,55 (m, 7H), 7,71-7,77 (m, 3H), 7,83-7,86 (m, 2H), 8,24 (d, 1H, J=8,1 Hz); MHz, CD3OD): 3.45 (t, 2H, J=7.2 Hz), 3.74 (s, 3H), 3.83 (t, 2H, J=7.2 Hz), 4.27 ( s, 2H), 7.36-7.55 (m, 7H), 7.71-7.77 (m, 3H), 7.83-7.86 (m, 2H), 8.24 (d, 1H, J=8.1 Hz);

(S)-2-[2-(5-aminometyl-1/-/-benzoimidazol-2-ylmetyl)-1H-benzoimidazol-5-ylkarbonylamino]-3-indol-3-ylpropionsyre (Forbindelse 104), 1 H-N MR (300 MHz, CD3OD): 3,36 (dd, 1H, J = 14,6, 8,1 Hz), 3,53 (dd, 1H, J=14,6, 5,0 Hz), 3,92 (s, 3H), 4,27 (s, 2H), 6,97 (t, 1H, J = 7,4 Hz), 7,07 (t, 1H, J=7,4 Hz), 7,16 (s, 1H), 7,33 (d, 1H J=7,8 Hz), 7,51 (dd, 1H, J = 8,4, 1,5 Hz), 7,60-7,66 (m, 2H), 7,73-7,80 (m, 3H), 7,96 (d, 1H, J=0,9 Hz), 8,39 (d, J = 7,5 Hz, delvis utskiftet); (S)-2-[2-(5-aminomethyl-1/-/-benzoimidazol-2-ylmethyl)-1H-benzoimidazol-5-ylcarbonylamino]-3-indol-3-ylpropionic acid (Compound 104), 1 H-N MR (300 MHz, CD3OD): 3.36 (dd, 1H, J = 14.6, 8.1 Hz), 3.53 (dd, 1H, J=14.6, 5.0 Hz), 3.92 (s, 3H), 4.27 (s, 2H), 6.97 (t, 1H, J = 7.4 Hz), 7.07 (t, 1H, J=7.4 Hz), 7.16 (s, 1H), 7.33 (d, 1H J=7.8 Hz), 7.51 (dd, 1H, J = 8.4, 1.5 Hz), 7.60-7.66 (m , 2H), 7.73-7.80 (m, 3H), 7.96 (d, 1H, J=0.9 Hz), 8.39 (d, J = 7.5 Hz, partially substituted);

(R)-2-[2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-1H-benzoimid 5-ylkarbonylamino]-3-indol-3-ylpropionsyre (Forbindelse 105),1 H-N MR (300 MHz, CD3OD): 3,35 (dd, 1H, J = 14,5, 8,1 Hz), 3,51 (dd, 1H, J=14,4, 4,8 Hz), 3,90 (s, 3H), 4,23 (s, 2H), 6,96 (t, 1H, J = 7,4 Hz), 7,06 (t, 1H, J=7,4 Hz), 7,14 (s, 1H), 7,31 (d, 1H, J=7,8 Hz), 7,44 (d, 1H, J = 7,8 Hz), 7,58-7,74 (m, 5H), 7,94 (s, 1H), 8,33 (d, J=8,1 Hz, delvis utskiftet); (R)-2-[2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-1H-benzoimide 5-ylcarbonylamino]-3-indol-3-ylpropionic acid (Compound 105), 1 H-N MR (300 MHz, CD3OD): 3.35 (dd, 1H, J = 14.5, 8.1 Hz), 3.51 (dd, 1H, J=14.4, 4.8 Hz), 3.90 (s, 3H ), 4.23 (s, 2H), 6.96 (t, 1H, J = 7.4 Hz), 7.06 (t, 1H, J=7.4 Hz), 7.14 (s, 1H ), 7.31 (d, 1H, J=7.8 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.58-7.74 (m, 5H), 7.94 (s, 1H), 8.33 (d, J=8.1 Hz, partially replaced);

2-(1W-benzoimidazol-2-ylmetyl)-N-(2-naft-1-yletyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 106), <1>H-NMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,4 Hz), 3,76 (t, 2H, J = 7,4 Hz), 3,97 (s, 3H), 7,38-7,60 (m, 5H), 7,65 (d, 1H, J=8,7Hz), 7,72-7,79 (m, 4H), 7,85 (dd, 1H, J=8,6, 1,5 Hz), 8,04 (d, 1H, J=1,2 Hz), 8,26 (d, 1H, J=8,4 Hz); 2-(1N-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl)-1H-benzoimidazol-5-carboxamide (Compound 106), <1>H-NMR (300 MHz, CD3OD): 3 .42 (t, 2H, J=7.4 Hz), 3.76 (t, 2H, J = 7.4 Hz), 3.97 (s, 3H), 7.38-7.60 (m, 5H), 7.65 (d, 1H, J=8.7Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J=8.6, 1.5 Hz) , 8.04 (d, 1H, J=1.2 Hz), 8.26 (d, 1H, J=8.4 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-(4-aminobutyl)-3H-benzoimidazol-4-karboksamid (Forbindelse 107), MS (Biolon) C22H27N7O1 m/e beregnet 405,4; funnet 406,5 (MH<+>); 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-A/-(4-aminobutyl)-3H-benzoimidazole-4-carboxamide (Compound 107), MS (Biolon) C22H27N7O1 m/e calcd. 405.4; found 406.5 (MH<+>);

2-[1-(5-aminometyl-1H-benzoimidazol-2-yl)etyl]-3-metyl-A<y->(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 108), MS (Biolon) CsiHsoNeO! m/e beregnet 502,6; funnet 503,3 (MH<+>); 2-[1-(5-aminomethyl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-α-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 108 ), MS (Biolon) CsiHsoNeO! m/e calculated 502.6; found 503.3 (MH<+>);

2-(1 H-imidazo[4,5-c]pyridin-2-ylmetyl)-3-metyl-W-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 109), MS (Biolon) C28H24N6O1 m/e beregnet 460,5; funnet 461,3 (MH<+>); 2-(1H-imidazo[4,5-c]pyridin-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 109), MS (Biolon) C28H24N6O1 m/e calcd 460.5; found 461.3 (MH<+>);

2-(5-aminometyl-1/-/-benzoimidazol-2-ylkarbonyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 110), MS (Biolon) C3oH26N602 m/e beregnet 502,6; funnet 503,6 (MH<+>); 2-(5-Aminomethyl-1 H -benzoimidazol-2-ylcarbonyl)-3-methyl- N -(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 110), MS ( Biolon) C3oH26N602 m/e calculated 502.6; found 503.6 (MH<+>);

2-(5-karbamoyl-1 H-benzoimidazol-2-ylmetyl)-W-(2-naft-1 -yletyl)- 2-(5-carbamoyl-1H-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl)-

1 H-benzoimidazol-5-karboksamid (Forbindelse 111), 1 H -benzoimidazole-5-carboxamide (Compound 111),

2-(5-aminometyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 112), <1>H-NMR (300 MHz, CD3OD): 1,67 (m, 1H), 2,14 (m, 1H), 2,24 (m, 1H), 2,47 (dd, 1H, J=15,3, 9,3 Hz), 2,76 (m, 2H), 2,90 (dd, 1H, J = 15,7, 7,5 Hz), 3,05 (d, 2H, J=6,9 Hz), 3,41 (t, 2H, J=7,4 Hz), 3,75 (t, 2H, J=7,4 Hz), 3,90 (s, 3H), 7,35-7,53 (m, 5H), 7,61 (d, 1H, J=8,4 Hz), 7,72-7,75 (rn, 2H), 7,85 (dd, 1H, J = 8,1,1,2 Hz), 7,99 (d, 1H, J=0,9 Hz), 8,26 (d, 1H, J=8,4 Hz); 2-(5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ( Compound 112), <1>H-NMR (300 MHz, CD3OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J=15.3, 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7, 7.5 Hz), 3.05 (d, 2H , J=6.9 Hz), 3.41 (t, 2H, J=7.4 Hz), 3.75 (t, 2H, J=7.4 Hz), 3.90 (s, 3H), 7.35-7.53 (m, 5H), 7.61 (d, 1H, J=8.4 Hz), 7.72-7.75 (rn, 2H), 7.85 (dd, 1H, J = 8.1,1.2 Hz), 7.99 (d, 1H, J=0.9 Hz), 8.26 (d, 1H, J=8.4 Hz);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-(3-fenylpropyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 113), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(3-phenylpropyl)-3H-benzoimidazole-5-carboxamide (Compound 113), <1>H-NMR (300

MHz, CD3OD): 1,98 (m, 2H), 2,72 (t, 2H, J=7,6 Hz), 3,46 (t, 2H, J=7,2 Hz), 4,01 (s, 3H), 4,29 (s, 2H), 7,12-7,17 (m, 1H), 7,21-7,28 (m, 4H), 7,56 (d, 1H, J=8,1 Hz), 7,70 (d, 1H, J=8,7 Hz), 7,77 (d, 1H, J=8,4 Hz), 7,85-7,88 (m, 2H), 8,16 (s, 1H, J=1H); MHz, CD3OD): 1.98 (m, 2H), 2.72 (t, 2H, J=7.6 Hz), 3.46 (t, 2H, J=7.2 Hz), 4.01 ( s, 3H), 4.29 (s, 2H), 7.12-7.17 (m, 1H), 7.21-7.28 (m, 4H), 7.56 (d, 1H, J= 8.1 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.85-7.88 (m, 2H) , 8.16 (s, 1H, J=1H);

2-(5-aminometyl-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-fenoksyet^ 3H-benzoimidazol-5-karboksamid (Forbindelse 114), <1>H-NMR (300 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-phenoxyet^ 3H-benzoimidazole-5-carboxamide (Compound 114), <1>H-NMR (300

MHz, CD3OD): 3,80 (t, 2H, J=5,0 Hz), 3,99 (s, 3H), 4,17 (t, 2H, J=5,0Hz), 4,27 (s, 2H), 6,88 (t, 1H, J=7,5Hz), 6,92 (d, 2H, J=7,5 Hz), 7,22 (t, 2H, J=7,5 Hz), 7,55 (d, 1H, J=8,7 Hz), 7,68 (d, 1H, J=6,6 Hz), 7,77 (d, 1H, J = 8,4 Hz), 7,84 (s, 1H), 7,88 (d, 1H, J=8,7 Hz), 8,18 (s, 1H); MHz, CD3OD): 3.80 (t, 2H, J=5.0 Hz), 3.99 (s, 3H), 4.17 (t, 2H, J=5.0Hz), 4.27 (s , 2H), 6.88 (t, 1H, J=7.5Hz), 6.92 (d, 2H, J=7.5 Hz), 7.22 (t, 2H, J=7.5 Hz) , 7.55 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=6.6 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7 .84 (s, 1H), 7.88 (d, 1H, J=8.7 Hz), 8.18 (s, 1H);

2-[5-(1-iminoetyl)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 115), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,96 (m, 2H), 3,42 (t, 2H, J=7,4 Hz), 3,75 (t, 2H, J=7,4 Hz), 3,93 (s, 3H), 3,98 (m, 2H), 4,70 (4,80, s, 2H), 7,38-7,53 (m, 4H), 7,63-7,87 (m, 4H), 8,04 (d, J=1,5 Hz, 8,08, s, 1H), 8,26 (d, 1H, J=8,0Hz); 2-[5-(1-iminoethyl)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-(2-naphth-1- ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 115), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3.42 (t, 2H, J=7.4 Hz), 3.75 (t, 2H, J=7.4 Hz), 3.93 (s, 3H), 3.98 (m, 2H), 4.70 (4.80, s, 2H), 7.38-7.53 (m, 4H), 7.63-7.87 (m, 4H), 8.04 (d, J=1.5 Hz, 8.08, s, 1H), 8.26 (d, 1H, J=8.0Hz);

2-[5-(i-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylkarbony l]-3-metyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 116), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 3,03 (m, 2H), 3,41 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, J=7,4 Hz), 3,97 (m, 2H), 4,18 (4,18, s, 3H), 4,66 (4,80, s, 2H), 7,38-7,54 (m, 4H), 7,72-7,92 (m, 4H), 8,04 (s, 1H), 8,26 (d, 1H, J=7,8 Hz); 2-[5-(i-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylcarbonyl]-3-methyl-N-(2-naphth- 1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 116), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 3.03 (m, 2H ), 3.41 (t, 2H, J=7.4 Hz), 3.74 (t, 2H, J=7.4 Hz), 3.97 (m, 2H), 4.18 (4.18 , s, 3H), 4.66 (4.80, s, 2H), 7.38-7.54 (m, 4H), 7.72-7.92 (m, 4H), 8.04 (s , 1H), 8.26 (d, 1H, J=7.8 Hz);

2-(5-iminometyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 117), <1>H-NMR (300 MHz, CD3OD): 2,95 (m, 2H), 3,40 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, 2-(5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 117), <1>H-NMR (300 MHz, CD3OD): 2.95 (m, 2H), 3.40 (t, 2H, J=7.4 Hz) , 3.74 (t, 2H,

J = 7,4 Hz), 3,90 (3,89, s, 3H), 3,98 (m, 2H), 4,70 (4,82, s, 2H), 7,39-7,52 (m, 4H), 7,63-7,84 (m, 4H), 8,03 (s, 1H), 8,16 (8,18, s, 1H), 8,24 (d, 1H, J=8,4 Hz); J = 7.4 Hz), 3.90 (3.89, s, 3H), 3.98 (m, 2H), 4.70 (4.82, s, 2H), 7.39-7.52 (m, 4H), 7.63-7.84 (m, 4H), 8.03 (s, 1H), 8.16 (8.18, s, 1H), 8.24 (d, 1H, J =8.4 Hz);

2-(5-aminometyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylkarbonyl)-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 118), <1>H-NMR (300 MHz, CD3OD): 1,69 (m, 1H), 2,15 (m, 1H), 2,20 (m, 1H), 2,55 (dd, 1H, J=15,0, 11,4 Hz), 2,81-3,08 (m, 5H), 3,44 (t, 2H, J=7,5 Hz), 3,74 (m, 2H), 4,23 (s, 3H), 7,39-7,52 (m, 4H), 7,75 (dd, 1H, J=6,1, 3,2 Hz), 7,83-7,88 (m, 2H), 7,97 (d, 1H, J=8,7 Hz), 8,10 (s, 1H), 8,27 (d, 1H, J=8,1 Hz); 2-(5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbonyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 118), <1>H-NMR (300 MHz, CD3OD): 1.69 (m, 1H), 2.15 (m, 1H), 2.20 (m, 1H), 2.55 (dd , 1H, J=15.0, 11.4 Hz), 2.81-3.08 (m, 5H), 3.44 (t, 2H, J=7.5 Hz), 3.74 (m, 2H), 4.23 (s, 3H), 7.39-7.52 (m, 4H), 7.75 (dd, 1H, J=6.1, 3.2 Hz), 7.83-7 .88 (m, 2H), 7.97 (d, 1H, J=8.7 Hz), 8.10 (s, 1H), 8.27 (d, 1H, J=8.1 Hz);

2-[5-(1-iminoetyl)-4,5,6J-tetrahydro-1W-imidazo[4,5-c]pyridin-2-ylm 2-[5-(1-iminoethyl)-4,5,6J-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl

-metyl-A/-(2-fenoksyetyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 119), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,95 (m, 2H), 3,80 (t, 2H, J=5,6 Hz), 3,95 (s, 3H), 3,98 (m, 2H), 4,17 (t, 2H, J=5,6 Hz), 4,71 (4,81, s, 2H), 6,89 (t, 1H, J=7,3 Hz), 6,93 (d, 2H, J=8,6 Hz), 7,23 (dd, 2H, J=8,6f 7,3 Hz), 7,66 (d, 1H, J=7,8 Hz), 7,85 (d, 1H, J=7,8 Hz), 8,13 (s, 1H); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-(2-benzo[1,3]dioksol-4-yletyl)-3W-benzoimidazol-5-karboksamid (Forbindelse 120), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,89-2,97 (m, 4H), 3,65 (t, 2H, J = 7,1 Hz), 3,94 (s, 3H), 3,98 (m, 2H), 4,71 (4,81, s, 2H), 5,83 (s, 2H), 6,65-6,74 (m, 3H), 7,64 (d, 1H, J=7,8 Hz), 7,76-7,79 (m, 1H), 8,06 (m, 1H); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-(-benzoimidazol-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 121), <1>H-NMR (300 MHz, CD3OD): 2,46 (2,44, s, 3H), 2,96 (m, 2H), 3,92 (s, 3H), 3,95-4,01 (m, 4H), 4,73 (4,79, s, 2H), 4.80 (m, 2H), 7,54-7,64 (m, 4H), 7,83 (dd, 1H, J=6,5, 2,2 Hz), 7,93 (s, 1H), 7,98 (dd, J=6,5, 2,1 Hz), 9,49 (s,1H); A/-[2-(5-hydroksy-1H-indol-2-yl)etyl]-2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1/-/-imidazo[4,5-c]pyridin-2-ylmetyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 122), 'H-NMR (300 MHz, CD3OD): 2,42 (2,39, s, 3H), 2,90 (m, 2H), 2,99 (t, 2H, J=7,1 Hz), 3,67 (t, 2H, J=7,1 Hz), 3,75 (s, 3H), 3,93 (m, 2H), 4,66 (4,76, s, 2H), 6,61 (dd, 1H, J=8,5, 2,3 Hz), 6,94 (d, 1H, J=2,3 Hz), 7,06 (s, 1H), 7,12 (d, 1H, J=8,5 Hz), 7,59 (d, 1H, J=8,4 Hz), 7,76 (dd, 1H, J=8,4, 1,2 Hz), 7,87 (d, 1H, J=1,2 Hz); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-[2-(2-klorfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 123), MS (Biolon) C26H28N7O2CI m/e beregnet 506,0; funnet 506,3 (MH<+>); 2-[5-(1-iminoetyl)-4,5,6>7-tetrahydro-1H-imidazot4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-[2-(3-klorfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 124), MS (Biolon) C26H28N7O2CI m/e beregnet 506,0; funnet 506,7 (MH<+>); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 125), <1>H-NMR (300 MHz, CD3OD): 2,48 (2,46, s, 3H), 3,00 (m, 2H), 3,60 (t, 2H, J=6,6 Hz), 3,90-4,05 (m, 7H), 4,76 (4,76, s, 2H), 6,64 (6,66, s, delvis utskiftet), 7,45-7,95 (m, 9H), 8,02 (m, delvis echanged), 8,17 (d, 1H, J=8,1 Hz), 8,96 (s, delvis utskiftet); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-(2-hydroksy-2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 126), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,94 (m, 2H), 3,55 (dd, 1H, J=13,6, 8,3 Hz), 3,91-3,99 (m, 6H), 4,70 (4,80, s, 2H), 5,78 (dd, 1H, J=8,3, 3,6 Hz), 7,44-7,54 (m, 3H), 7,66 (d, 1H, J=8,4 Hz), 7,76-7,88 (m, 4H), 8,08 (rn, 1H), 8,39 (d, 1H, J=8,4Hz); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yimetyl]-3 -metyl-A/-[2-(2-hydroksynaft-1-yl)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 127), 'H-NMR (300 MHz, CD3OD): 2,43 (2,41, s, 3H), 2,92 (m, 2H), 3,41 (t, 2H, J=7,1 Hz), 3,69 (t, 2H, J=7,1 Hz), 3,85 (s, 3H), 3,93-3,96 (m, 2H), 4,68 (4,78, s, 2H), 7,11 (d, 1H, J=8,7 Hz), 7,21 (t, 1H, J=7,5 Hz), 7,38 (dt, 1H, J=1,2, 7,6 Hz), 7,50-7,61 (m, 2H), 7,69-7,75 (m, 2H), 7,93 (s, 1H), 8,07 (d, 1H, J=8,4 Hz); 2-[5-(1-iminoetyl)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-[2-(4-hydroksynaftal-1-yl)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 128), 'H-NMR (300 MHz, CD3OD): 2,42 (2,40, s, 3H), 2,89 (m, 2H), 3,27 (m, 2H), 3,69 (t, 2H, J=7,2 Hz), 3,82 (3,83, s, 3H), 3,93 (m, 2H), 4,64 (4,76, s, 2H), 6,72 (d, 1H, J=7,8 Hz), 7,17 (d, 1H, J=7,5 Hz), 7,37 (t, 1H, J=7,5 Hz), 7,46 (dt, 1H, J=0,9, 6,9 Hz), 7,62 (d, 1H, J=8,5 Hz), 7,77 (d, 1H, J=8,5 Hz), 7,95 (s, 1H), 8,12 (d, 1H, J=8,4 Hz), 8,17 (d, 1H, J = 8,4 Hz); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-[2-(2-metoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 129), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,95 (m, 2H), 3,80 (rn, 5H), 3,95 (s, 3H), 3,98 (m, 2H), 4,17 (t, 2H, J=5,4 Hz), 4,71 (4,81, s, 2H), 6,85-7,00 (m, 4H), 7,66 (d, 1H, J = 8,7 Hz), 7,84 (m, 1H), 8,13 (s, 1H); -methyl- N -(2-phenoxyethyl)-3H-benzoimidazole-5-carboxamide (Compound 119), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (t, 2H, J=5.6 Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H , J=5.6 Hz), 4.71 (4.81, s, 2H), 6.89 (t, 1H, J=7.3 Hz), 6.93 (d, 2H, J=8, 6 Hz), 7.23 (dd, 2H, J=8.6f 7.3 Hz), 7.66 (d, 1H, J=7.8 Hz), 7.85 (d, 1H, J=7 .8 Hz), 8.13 (s, 1H); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-(2-benzo[ 1,3]dioxol-4-ylethyl)-3N-benzoimidazol-5-carboxamide (Compound 120), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2 .89-2.97 (m, 4H), 3.65 (t, 2H, J = 7.1 Hz), 3.94 (s, 3H), 3.98 (m, 2H), 4.71 ( 4.81, s, 2H), 5.83 (s, 2H), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 7.76 -7.79 (m, 1H), 8.06 (m, 1H); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-(-benzoimidazole-1 -ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 121), <1>H-NMR (300 MHz, CD3OD): 2.46 (2.44, s, 3H), 2.96 (m, 2H) , 3.92 (s, 3H), 3.95-4.01 (m, 4H), 4.73 (4.79, s, 2H), 4.80 (m, 2H), 7.54-7.64 (m, 4H), 7.83 (dd, 1H, J=6.5, 2.2 Hz), 7.93 (s, 1H), 7.98 (dd, J=6.5, 2.1 Hz), 9.49 (s, 1H); N-[2-(5-Hydroxy-1H-indol-2-yl)ethyl]-2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1 H -imidazo[ 4,5-c]pyridin-2-ylmethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 122), 1H-NMR (300 MHz, CD 3 OD): 2.42 (2.39, s, 3H), 2.90 (m, 2H), 2.99 (t, 2H, J=7.1 Hz), 3.67 (t, 2H, J=7.1 Hz), 3.75 (s, 3H), 3.93 (m, 2H), 4.66 (4.76, s, 2H), 6.61 (dd, 1H, J=8.5, 2.3 Hz), 6.94 (d , 1H, J=2.3 Hz), 7.06 (s, 1H), 7.12 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.4 Hz ), 7.76 (dd, 1H, J=8.4, 1.2 Hz), 7.87 (d, 1H, J=1.2 Hz); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-[2-(2 -chlorophenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 123), MS (Biolon) C 26 H 28 N 7 O 2 Cl m/e calcd 506.0; found 506.3 (MH<+>); 2-[5-(1-iminoethyl)-4,5,6>7-tetrahydro-1H-imidazot4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-[2-(3-chlorophenoxy )ethyl]-3H-benzoimidazole-5-carboxamide (Compound 124), MS (Biolon) C 26 H 28 N 7 O 2 Cl m/e calcd 506.0; found 506.7 (MH<+>); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-(2-naphth- 1 -ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 125), <1>H-NMR (300 MHz, CD3OD): 2.48 (2.46, s, 3H), 3.00 (m, 2H ), 3.60 (t, 2H, J=6.6 Hz), 3.90-4.05 (m, 7H), 4.76 (4.76, s, 2H), 6.64 (6, 66, s, partially echanged), 7.45-7.95 (m, 9H), 8.02 (m, partially echanged), 8.17 (d, 1H, J=8.1 Hz), 8.96 (s, partially replaced); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-(2-hydroxy- 2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 126), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2.94 (m, 2H), 3.55 (dd, 1H, J=13.6, 8.3 Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H ), 5.78 (dd, 1H, J=8.3, 3.6 Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H, J=8.4 Hz) , 7.76-7.88 (m, 4H), 8.08 (rn, 1H), 8.39 (d, 1H, J=8.4Hz); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-[2-(2 -hydroxynaphth-1-yl)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 127), 1H-NMR (300 MHz, CD3OD): 2.43 (2.41, s, 3H), 2.92 ( m, 2H), 3.41 (t, 2H, J=7.1 Hz), 3.69 (t, 2H, J=7.1 Hz), 3.85 (s, 3H), 3.93- 3.96 (m, 2H), 4.68 (4.78, s, 2H), 7.11 (d, 1H, J=8.7 Hz), 7.21 (t, 1H, J=7, 5 Hz), 7.38 (dt, 1H, J=1.2, 7.6 Hz), 7.50-7.61 (m, 2H), 7.69-7.75 (m, 2H), 7.93 (s, 1H), 8.07 (d, 1H, J=8.4 Hz); 2-[5-(1-iminoethyl)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-[2-(4-hydroxynaphthalene -1-yl)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 128), 1H-NMR (300 MHz, CD3OD): 2.42 (2.40, s, 3H), 2.89 (m, 2H), 3.27 (m, 2H), 3.69 (t, 2H, J=7.2 Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H), 4.64 (4.76, s, 2H), 6.72 (d, 1H, J=7.8 Hz), 7.17 (d, 1H, J=7.5 Hz), 7.37 (t , 1H, J=7.5 Hz), 7.46 (dt, 1H, J=0.9, 6.9 Hz), 7.62 (d, 1H, J=8.5 Hz), 7.77 (d, 1H, J=8.5 Hz), 7.95 (s, 1H), 8.12 (d, 1H, J=8.4 Hz), 8.17 (d, 1H, J = 8, 4Hz); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-[2-(2 -methoxyphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 129), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (rn, 5H), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J=5.4 Hz), 4.71 ( 4.81, s, 2H), 6.85-7.00 (m, 4H), 7.66 (d, 1H, J = 8.7 Hz), 7.84 (m, 1H), 8.13 (s, 1H);

2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3

-metyl-A/-naft-2-ylmetyl-3H-benzoimidazol-5-karboksamid (Forbindelse 130), <1>H-NMR (300 MHz, CD3OD): 2,44 (2,42, s, 3H), 2,92 (m, 2H), 3,91 (s, 3H), 3,95 -methyl- N -naphth-2-ylmethyl-3H-benzoimidazol-5-carboxamide (Compound 130), <1>H-NMR (300 MHz, CD3OD): 2.44 (2.42, s, 3H), 2.92 (m, 2H), 3.91 (s, 3H), 3.95

(m, 2H), 4,68 (4,78, s, 2H), 4,77 (s, 2H), 7,41-7,44 (m, 2H), 7,50 (dd, 1h, J=8,6, 1,1 Hz), 7,67 (d, 1H, J=8,4 Hz), 7,78-7,83 (m, 4H), 7,90 (m, 1H), 8,16 (m, 1H); (m, 2H), 4.68 (4.78, s, 2H), 4.77 (s, 2H), 7.41-7.44 (m, 2H), 7.50 (dd, 1h, J =8.6, 1.1 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.78-7.83 (m, 4H), 7.90 (m, 1H), 8 .16 (m, 1H);

2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3

-metyl-A/-(3-pyird-4-ylpropyl)-3H-benzoimidazol-5-karboksarnid (Forbindelse 131), <1>H-NMR (300 MHz, CD3OD): 2,11 (m, 2H), 2,46 (2,43, s, 3H), 2,96 (m, 2H), 3,06 (t, 2H, J=7,7 Hz), 3,51 (t, 2H, J=6,8 Hz), 3,98 (m, 5H), 4,72 (4,82, s, 2H), 7,67 (d, 1H, J=8,5 Hz), 7,83 (dd, 1H, J=8,5, 1,3 Hz), 8,00 (d, 2H, J=6,6 Hz), 8,15 (d, 1H, J=1,3 Hz), 8,70 (d, 2H, J=6,6 Hz); 2-(5-guanidino-1/-/-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 132), MS (Biolon) C32H32N8O3 m/e beregnet 576,6; funnet 577,5 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3,41 (t, 2H, J=7,5 Hz), 3,58-3,76 (m, 4H), 4,05 (m, 1H), 4,45 (dd, 1H, J=14,9, 8,5 Hz), 4,61 (dd, 1H, J = 14,9, 3,2 Hz), 7,36-7,52 (m, 4H), 7,66-7,85 (m, 4H), 8,14 (s, 1H), 8,25 (d, 1H, J=7,8 Hz); 2-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-A/-[2-(4-metoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 133), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,95 (m, 2H), 3,70 (m, 2H), 3,77 (t, 2H, J=5,6 Hz), 3,95 (s, 3H), 3,98 (m, 2H), 4,12 (t, 2H. J=5,6 Hz), 4,71 (4,81, s, 2H), 6,78-6,89 (m, 4H), 7,66 (d, 1H, J=8,4 Hz), 7,84 (m, 1H), 8,13 (d, 1H, J=1.2 Hz); 2-(5-guanidino-1H-benzoimidazol-2-ylkarbonyl)-3-(2,3-dihydroksy)propyl-A/-(2-naft-1-ytetyl)-3/V-benzoimidazol-5-karboksamid (Forbindelse 134), MS (Biolon) C32H30N7O4 m/e beregnet 590,6; funnet 590,7 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, J=7,4 Hz), 4,00 (d, 2H, J=4,2 Hz), 4,38 (t, 1H, J=11,7 Hz), 4,56 (dd, 1H, J=12,5, 3,5 Hz), 7,34-7,51 (m, 5H), 7,61-7,65 (m, 2H), 7,72-7,86 (m, 4H), 8,05 (d, 1H, J=1,2Hz), 8,25 (d, 1H, J=8,1 Hz); 2-t5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-/v-[2-(1,2,3,4-tetrahydronaft-1-yl)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 135), 'H-NMR (300 MHz, CD3OD): 1,69-2,11 (m, 6H), 2,45 (2,43, s, 3H), 2,73 (m, 2H). 2,88 (rn, 1H), 2,95 (rn 2H), 3,52 (t, 2H, J=7,4 Hz), 3,97 (m, 5H), 4,72 (4,81, s, 2H), 6,99-7,06 (m, 3H), 7,15-7,18 (m, 1H), 7,67 (d, 1H, J=8,7 Hz), 7,82-7,86 (m, 1H), 8,14 (d, 1H, J = 0,9 Hz); 2-[5-(1-iminoetyl)-4,5,6J-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmetyl]-3 -metyl-W-[2-(3-metoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 136), <1>H-NMR (300 MHz, CD3OD): 2,45 (2,42, s, 3H), 2,95 (m, 2H), 3,71 (s, 3H), 3,78 (t, 2H, J=5,6 Hz), 3,94 (s, 3H), 3,97 (m, 2H), 4,15 (t, 2H, J=5,6 Hz), 4,71 (4,80, s, 2H), 6,46-6,54 (m, 3H), 7,12 (t, 1H, J=8,0 Hz), 7,66 (d, 1H, J=8,4 Hz), 7,83 (m, 1H), 8,12 (m, 1H, J=1,2 Hz); -methyl- N -(3-pyrid-4-ylpropyl)-3H-benzoimidazol-5-carboxarnide (Compound 131), <1>H-NMR (300 MHz, CD3OD): 2.11 (m, 2H), 2.46 (2.43, s, 3H), 2.96 (m, 2H), 3.06 (t, 2H, J=7.7 Hz), 3.51 (t, 2H, J=6, 8 Hz), 3.98 (m, 5H), 4.72 (4.82, s, 2H), 7.67 (d, 1H, J=8.5 Hz), 7.83 (dd, 1H, J=8.5, 1.3 Hz), 8.00 (d, 2H, J=6.6 Hz), 8.15 (d, 1H, J=1.3 Hz), 8.70 (d, 2H, J=6.6 Hz); 2-(5-guanidino-1/-/-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ( Compound 132), MS (Biolon) C32H32N8O3 m/e calcd 576.6; found 577.5 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3.41 (t, 2H, J=7.5 Hz), 3.58-3.76 (m, 4H), 4.05 (m, 1H) , 4.45 (dd, 1H, J=14.9, 8.5 Hz), 4.61 (dd, 1H, J = 14.9, 3.2 Hz), 7.36-7.52 (m , 4H), 7.66-7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d, 1H, J=7.8 Hz); 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A/-[2-(4 -methoxyphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 133), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.70 (m, 2H), 3.77 (t, 2H, J=5.6 Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.12 ( t, 2H. J=5.6 Hz), 4.71 (4.81, s, 2H), 6.78-6.89 (m, 4H), 7.66 (d, 1H, J=8, 4 Hz), 7.84 (m, 1H), 8.13 (d, 1H, J=1.2 Hz); 2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3N-benzoimidazol-5-carboxamide ( Compound 134), MS (Biolon) C32H30N7O4 m/e calcd 590.6; found 590.7 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3.42 (t, 2H, J=7.4 Hz), 3.74 (t, 2H, J=7.4 Hz), 4.00 (d , 2H, J=4.2 Hz), 4.38 (t, 1H, J=11.7 Hz), 4.56 (dd, 1H, J=12.5, 3.5 Hz), 7.34 -7.51 (m, 5H), 7.61-7.65 (m, 2H), 7.72-7.86 (m, 4H), 8.05 (d, 1H, J=1.2Hz) , 8.25 (d, 1H, J=8.1 Hz); 2-t5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-[2-(1, 2,3,4-tetrahydronaphth-1-yl)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 135), 1 H-NMR (300 MHz, CD 3 OD): 1.69-2.11 (m, 6H) , 2.45 (2.43, s, 3H), 2.73 (m, 2H). 2.88 (rn, 1H), 2.95 (rn 2H), 3.52 (t, 2H, J=7.4 Hz), 3.97 (m, 5H), 4.72 (4.81, s, 2H), 6.99-7.06 (m, 3H), 7.15-7.18 (m, 1H), 7.67 (d, 1H, J=8.7 Hz), 7.82 -7.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz); 2-[5-(1-iminoethyl)-4,5,6J-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-W-[2-(3-methoxyphenoxy) ethyl]-3H-benzoimidazole-5-carboxamide (Compound 136), <1>H-NMR (300 MHz, CD3OD): 2.45 (2.42, s, 3H), 2.95 (m, 2H), 3.71 (s, 3H), 3.78 (t, 2H, J=5.6 Hz), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (t, 2H , J=5.6 Hz), 4.71 (4.80, s, 2H), 6.46-6.54 (m, 3H), 7.12 (t, 1H, J=8.0 Hz) , 7.66 (d, 1H, J=8.4 Hz), 7.83 (m, 1H), 8.12 (m, 1H, J=1.2 Hz);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-W-(3-fenylpropyl)-1H-benzoimidazol-5-karboksamid (Forbindelse 137), 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-N-(3-phenylpropyl)-1H-benzoimidazole-5-carboxamide (Compound 137),

2-(5-guanidino-1/-/-benzoimidazol-2-ylmetyl)-3-(3-hydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 138), <1>H-NMR (300 MHz, CD3OD): 2,09 (m, 2H), 3,44 (t, 2H, J=7,4 Hz), 3,58 (t, 2H, J=5,6 Hz), 3,77 (t, 2H, J=7,4 Hz), 4,55 (t, 2H, J = 7,1 Hz), 7,32 (dd, 1H, J=8,6, 1,9 Hz), 7,37-7,55 (m, 4H), 7,61 (d, 1H, J=1,9 Hz), 7,69 (d, 1H, J=8,4 Hz), 7,73-7,88 (m, 4H), 8,11 (s, 1H), 8,28 (d, 1H, J=8,1Hz); 2-(5-guanidino-1/-/-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 138 ), <1>H-NMR (300 MHz, CD3OD): 2.09 (m, 2H), 3.44 (t, 2H, J=7.4 Hz), 3.58 (t, 2H, J= 5.6 Hz), 3.77 (t, 2H, J=7.4 Hz), 4.55 (t, 2H, J = 7.1 Hz), 7.32 (dd, 1H, J=8, 6, 1.9 Hz), 7.37-7.55 (m, 4H), 7.61 (d, 1H, J=1.9 Hz), 7.69 (d, 1H, J=8.4 Hz), 7.73-7.88 (m, 4H), 8.11 (s, 1H), 8.28 (d, 1H, J=8.1Hz);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)propyl-W-[2-(2-metoksy)fenoksyetyl]-3/-/-benzoimidazol-5-karboksamid 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-N-[2-(2-methoxy)phenoxyethyl]-3/-/-benzoimidazol-5-carboxamide

(Forbindelse 139), MS (Biolon) C2gH32Na05 m/e beregnet 572,62; funnet 573,3 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3,58-3,69 (m, 2H), 3,80 (m, 5H), 4,07 (m, 1H), 4,17 (t, 2H, J=5,3 Hz), 4,47 (dd, 1H, J=15,0, 8,4 Hz), 4,64 dd, 1H, J=15,0, 3,0 Hz), 6,66-7,00 (m, 4H), 7,38 (dd, 1H, J=8,6, 1,7 Hz), 7,66 (d, 1H, J=1,7Hz), 7,70 (d, 1H, J=8,6 Hz), 7,78 (d, 1H, J=8,6 Hz), 7,87 (dd, 1H, J=8,6,1,5 Hz), 8,24 (d, 1H, J=1,5 Hz); (Compound 139), MS (Biolon) C 2 g H 3 2 NaO 5 m/e calcd 572.62; found 573.3 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3.58-3.69 (m, 2H), 3.80 (m, 5H), 4.07 (m, 1H), 4.17 (t, 2H, J=5.3 Hz), 4.47 (dd, 1H, J=15.0, 8.4 Hz), 4.64 dd, 1H, J=15.0, 3.0 Hz), 6 .66-7.00 (m, 4H), 7.38 (dd, 1H, J=8.6, 1.7 Hz), 7.66 (d, 1H, J=1.7Hz), 7.70 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.87 (dd, 1H, J=8.6,1.5 Hz), 8 .24 (d, 1H, J=1.5 Hz);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-(2,3-dihydroksypropyl)-A/-(2-naft-1-yletyl)-3/-/-benzoimidazol-5-karboksamid (Forbindelse 140), MS (Biolon) C33H34N803 m/e beregnet 590,7; funnet 591,3 (MH<+>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-(2,3-dihydroxypropyl)-N-(2-naphth-1-ylethyl)-3/-/-benzoimidazol -5-carboxamide (Compound 140), MS (Biolon) C 33 H 34 N 8 O 3 m/e calcd 590.7; found 591.3 (MH<+>);

2-(5-guanidino-1H-benzoimidazol-2-ylkarbonyl)-3-(2,3-dihydroksypropyl)-W-[2-(2-metoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid 2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxypropyl)-W-[2-(2-methoxyphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide

(Forbindelse 141), MS (Biolon) C29H3oN806 m/e beregnet 586,6; funnet 587,5 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3,33 (m, 1H), 3,81 (m, 5H), 3,98 (d, 2H, J=4,5 Hz), 4,18 (t, 2H, J=5,4 Hz), 4,38 (t, 1H, J=12,0 Hz), 4,57 (dd, 1H, J=12,0, 3,5Hz), 6,85-7,00 (m, 4H), 7,30 (dd, 1H, J=8,7, 2,2 Hz), 7,60 (d, 1H, J=2,2Hz), 7,64 (d, 1H, J=8,4 Hz), 7,74 (d, 1H, J=8,7 Hz), 7,80 (dd, 1H, J=8,4, 1,5 Hz), 8,14 (d, 1H, J=1,5 Hz); (Compound 141), MS (Biolon) C 29 H 3 o N 8 O 6 m/e calcd 586.6; found 587.5 (MH<+>); <1>H-NMR (300 MHz, CD3OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H, J=4.5 Hz), 4.18 (t, 2H, J=5.4 Hz), 4.38 (t, 1H, J=12.0 Hz), 4.57 (dd, 1H, J=12.0, 3.5Hz), 6, 85-7.00 (m, 4H), 7.30 (dd, 1H, J=8.7, 2.2 Hz), 7.60 (d, 1H, J=2.2Hz), 7.64 ( d, 1H, J=8.4 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.80 (dd, 1H, J=8.4, 1.5 Hz), 8, 14 (d, 1H, J=1.5 Hz);

2-[5-(1 -iminoetyl)aminometyl-1 H-benzoimidazol-2-ylmetyl]-3-(2,3-dihydroksy)propyl-A/-[2-(2-metoksy)fenoksyetyl]-3H-benzoirnidazol-5-karboksamid (Forbindelse 142), <1>H-NMR (300 MHz, CD3OD): 2,28 (s, 3H), 3,64 (m, 2H), 3,80 (s, 3H), 3,79-3,85 (m, 2H), 4,05 (m, 1H), 4,18 (t, 2H, J=5,4 Hz), 4,46 (dd, 1H, J=15,0, 8,7 Hz), 4,62-4,66 (m 3H), 6,86-7,00 (m, 4H), 7,53 (dd, 1H, J=8,7,1,2 Hz), 7,68 (d, 1H, J=8,4 Hz), 7,77-7,80 (m, 2H), 7,84 (dd, 1H, J=8,4, 1,4 Hz), 8,21 (d, 1H, J=1,4 Hz); 2-[5-(1-iminoethyl)aminomethyl-1H-benzoimidazol-2-ylmethyl]-3-(2,3-dihydroxy)propyl-[2-(2-methoxy)phenoxyethyl]-3H-benzoirnidazole -5-carboxamide (Compound 142), <1>H-NMR (300 MHz, CD3OD): 2.28 (s, 3H), 3.64 (m, 2H), 3.80 (s, 3H), 3 .79-3.85 (m, 2H), 4.05 (m, 1H), 4.18 (t, 2H, J=5.4 Hz), 4.46 (dd, 1H, J=15.0 , 8.7 Hz), 4.62-4.66 (m 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H, J=8.7,1.2 Hz ), 7.68 (d, 1H, J=8.4 Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, J=8.4, 1.4 Hz) , 8.21 (d, 1H, J=1.4 Hz);

metyl-2-{2-[2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzoat (Forbindelse 143), MS (Biolon) C28H28N804 m/e beregnet 54,56; funnet 541,4 (MH<+>); methyl 2-{2-[2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 143), MS (Biolon) C28H28N804 m /e calculated 54.56; found 541.4 (MH<+>);

2-{-2-[2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzosyre (Forbindelse 144); 2-{-2-[2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoic acid (Compound 144);

metyl-3-{-2-[2-(5-guanidino-1W-benzoimidazol-2-ylmetyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzoat (Forbindelse 145), MS (Biolon) C2eH28N804 m/e beregnet 540,5; funnet 541,4 methyl 3-{-2-[2-(5-guanidino-1W-benzoimidazol-2-ylmethyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 145), MS (Biolon) C2eH28N804 m/e calculated 540.5; found 541.4

(MH<+>); (MH<+>);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-[2-(2,6-dimetoksy)-fenoksyetyl]-3/-/-benzoimidazol-5-karboksamid (Forbindelse 146),1 H-N MR (300 MHz, CD3OD): 3,71 (t, 2H, J=5,3 Hz), 3,73 (s, 6H), 4,01 (s, 3H), 4,13 (t, 2H, J=5,3 Hz), 6,63 (d, 2H, J=8,4 Hz), 6,99 (t, 1H, J=8,4 Hz), 7,33 (dd, 1H, J=8,6, 1,9 Hz), 7,63 (d, 1H, J=1,9 Hz), 7,74 (d, 1H, J=8,7 Hz), 7,75 (d, 1H, J=8,6 Hz), 7,90 (dd, 1H, J=8,7,1,5 Hz), 8,21 (d, 1H, J=1,5Hz); 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-[2-(2,6-dimethoxy)-phenoxyethyl]-3/-/-benzoimidazol-5-carboxamide (Compound 146) .1 H-N MR (300 MHz, CD3OD): 3.71 (t, 2H, J=5.3 Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t , 2H, J=5.3 Hz), 6.63 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.4 Hz), 7.33 (dd, 1H , J=8.6, 1.9 Hz), 7.63 (d, 1H, J=1.9 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.75 (d , 1H, J=8.6 Hz), 7.90 (dd, 1H, J=8.7,1.5 Hz), 8.21 (d, 1H, J=1.5Hz);

2-(5-guanidinometyl-1H-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)propyl-W-[2-(2-metoksyfenoksy)etyl]-3/-/-benzoimidazol-5-karboksamid (Forbindelse 147), 'H-NMR (300 MHz, CD3OD): 3,57-3,69 (m, 2H), 3,80 (m, 5H), 4,05 (m, 1H), 4,17 (t, 2H, j=5,4 Hz), 4,45 (dd, 1H, J=15,0, 8,7 Hz), 4,58^,65 (m, 3H), 6,85-7,00 (m, 4H), 7,50 (dd, 1H, J=8,7,1,5 Hz), 7,67 (d, 1H, J=8,5 Hz), 7,72 (d, 1H, J=1,5 Hz), 7,76 (d, 1H, J=8,7 Hz), 7,82 (dd, 1H, J=8,5, 1,4 Hz), 8,19 (d, 1H, J=1,4 Hz); 2-(5-guanidinomethyl-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-W-[2-(2-methoxyphenoxy)ethyl]-3/-/-benzoimidazol-5-carboxamide (Compound 147), 1H-NMR (300 MHz, CD 3 OD): 3.57-3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 4.17 (t, 2H, j=5.4 Hz), 4.45 (dd, 1H, J=15.0, 8.7 Hz), 4.58^,65 (m, 3H), 6.85-7 .00 (m, 4H), 7.50 (dd, 1H, J=8.7,1.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.72 (d, 1H, J=1.5 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.82 (dd, 1H, J=8.5, 1.4 Hz), 8.19 ( d, 1H, J=1.4 Hz);

2-(5-iminometylaminometyl-1H-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)-propyl-A/-[2-(2-metoksy)fenoksyetyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 148), 1H-NMR (300 MHz, CD3OD): 3.58-3,70 (m, 2-(5-Iminomethylaminomethyl-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)-propyl-[2-(2-methoxy)phenoxyethyl]-3H-benzoimidazol-5-carboxamide ( Compound 148), 1H-NMR (300 MHz, CD3OD): 3.58-3.70 (m,

2H), 3,81 (m, 5H), 4,06 (m, 1H), 4,19 (t, 2H, J=5,4 Hz), 4,46 (dd, 1H, J=15,0, 8,7 Hz), 4,64 (dd, 1H, J=15,0, 3,0 Hz), 4,69 (4,73, s, 2H), 6,86-7,01 (m, 4H), 7,51 (dd, 1H, J=8,1,1,5 Hz), 7,69 (d, 1H, J=8,6 Hz), 7,76-7,79 (m, 2H), 7,84 (dd, 1H, J=8,6,1,3 Hz), 7,96 (8,12, s, 1H), 8,21 (d, 1H, J=1,3Hz); 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 (t, 2H, J=5.4 Hz), 4.46 (dd, 1H, J=15.0 , 8.7 Hz), 4.64 (dd, 1H, J=15.0, 3.0 Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, J=8.1,1.5 Hz), 7.69 (d, 1H, J=8.6 Hz), 7.76-7.79 (m, 2H ), 7.84 (dd, 1H, J=8.6,1.3 Hz), 7.96 (8.12, s, 1H), 8.21 (d, 1H, J=1.3Hz);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-hydroksy-2-kinol-4-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 149), 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-hydroxy-2-quinol-4-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 149),

<1>H-NMR (300 MHz, CD3OD): 3,60 (dd, 1H, J=13,8, 7,5 Hz), 3,97-4,06 (m, 4H), 5,99 (dd, 1H, J=7,5, 3,6 Hz), 7,35 (dd, 1H, J=8,7, 2,0 Hz), 7,65 (d, 1H, J=2,0 Hz), 7,69 (d, 1H, J=8,7 Hz), 7,77 (d, 1H, J=8,7 Hz), 7,84 (dd, 1H, J=8,7, 1,5 Hz), 7,99 (m, 1H), 8,11-8,18 (m, 2H), 8,26 (d, 1H, J=8,4 Hz), 8,33 (d, 1H, J=5,7Hz), 8,88 (d, 1H, J=8,7 Hz), 8,15 (d, 1H, J=5,7 Hz); <1>H-NMR (300 MHz, CD3OD): 3.60 (dd, 1H, J=13.8, 7.5 Hz), 3.97-4.06 (m, 4H), 5.99 ( dd, 1H, J=7.5, 3.6 Hz), 7.35 (dd, 1H, J=8.7, 2.0 Hz), 7.65 (d, 1H, J=2.0 Hz ), 7.69 (d, 1H, J=8.7 Hz), 7.77 (d, 1H, J=8.7 Hz), 7.84 (dd, 1H, J=8.7, 1, 5 Hz), 7.99 (m, 1H), 8.11-8.18 (m, 2H), 8.26 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=5.7Hz), 8.88 (d, 1H, J=8.7Hz), 8.15 (d, 1H, J=5.7Hz);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-/V-[2-(3-metyl-2,4-dioksokinazolin-1-yl)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 150), MS (Biolon) C29H28N10O3 m/e beregnet 564,6; funnet 565,5 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-/V-[2-(3-methyl-2,4-dioxoquinazolin-1-yl)ethyl]-3H-benzoimidazol-5- carboxamide (Compound 150), MS (Biolon) C29H28N10O3 m/e calcd 564.6; found 565.5

(MH<+>); (MH<+>);

metyl-2-{2-[2-(5-guanidino-1H-benzoimidazol-2-ylkarbonyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzoat (Forbindelse 151), MS (Biolon) C28H26N805 m/e beregnet 554,5; funnet 554,8 (MH<+>); methyl 2-{2-[2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 151), MS (Biolon) C28H26N805 m /e calculated 554.5; found 554.8 (MH<+>);

2-(5-guanidino-1/7-benzoimidazol-2-ylmetyl)-3-(2-hydroksy)etyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 152), <1>H-NMR (300 MHz, CD3OD): 3,44 (t, 2H, J=7,4 Hz), 3,77 (t, 2H, J=7,4 Hz), 3,95 (t, 2H, J=4,9 Hz), 4,56 (t, 2H, J = 4,9 Hz), 7,32 (dd, 1H, J=8,7, 1,8 Hz), 7,40-7,54 (m, 4H), 7,61 (d, 1H, J=1,8 Hz), 7,67-7,89 (m, 5H), 8,09 (d, 1H, J=1,2 Hz), 8,28 (d, 1H, J=8,1 Hz); 2-(5-guanidino-1/7-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 152) , <1>H-NMR (300 MHz, CD3OD): 3.44 (t, 2H, J=7.4 Hz), 3.77 (t, 2H, J=7.4 Hz), 3.95 ( t, 2H, J=4.9 Hz), 4.56 (t, 2H, J = 4.9 Hz), 7.32 (dd, 1H, J=8.7, 1.8 Hz), 7, 40-7.54 (m, 4H), 7.61 (d, 1H, J=1.8 Hz), 7.67-7.89 (m, 5H), 8.09 (d, 1H, J= 1.2 Hz), 8.28 (d, 1H, J=8.1 Hz);

2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-A/-[2-(3-okso-2,3-dihydrobenzo[1,4]oksazin-4-yl)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 153); 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-[2-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)ethyl]- 3H-benzoimidazole-5-carboxamide (Compound 153);

2-(5-guanidino-1H-benzoimidazol-2-ylkarbonyl]-3-(2-hydroksyetyl)-A/-(2-naft-2-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 154), <1>H-NMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,3 Hz), 3,75 (t, 2H, J=7,3 Hz), 4,48-4,51 (m, 2H), 7,29 (dd, 1H, J=8,6, 1,9 Hz), 7,38-7,52 (m, 4H), 7,58 (d, 1H, J=1,9 Hz), 7,62 (d, 1H, J=8,7 Hz), 7,71-7,76 (m, 3H), 7,86 (d, 1H, J=8,6 Hz), 8,06 (s, 1H), 8,26 (d, 1H, J=8,1 Hz); 2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl]-3-(2-hydroxyethyl)-N-(2-naphth-2-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 154), < 1>H-NMR (300 MHz, CD3OD): 3.42 (t, 2H, J=7.3 Hz), 3.75 (t, 2H, J=7.3 Hz), 4.48-4, 51 (m, 2H), 7.29 (dd, 1H, J=8.6, 1.9 Hz), 7.38-7.52 (m, 4H), 7.58 (d, 1H, J= 1.9 Hz), 7.62 (d, 1H, J=8.7 Hz), 7.71-7.76 (m, 3H), 7.86 (d, 1H, J=8.6 Hz) , 8.06 (s, 1H), 8.26 (d, 1H, J=8.1 Hz);

2-(5-guanidino-1 H-benzoimidazo^ yletyt)-3H-benzoimidazol-5-karboksamid (Forbindelse 155), 2-(5-guanidino-1H-benzoimidazo^ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 155),

2-(5-guanidino-1H-benzoimidazol-2-ylkarbonyl)-3-(3-hydroksypropyl)-A/-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 156); 2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl)-3-(3-hydroxypropyl)-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 156);

2-(5-imidazol-1 -yl-1 W-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1 - yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 157); 2-(5-imidazol-1-yl-1N-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 157);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 158), MS (Biolon) C31H30N8O1 m/e beregnet 530,6; funnet 531,1 (Mh<T>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 158), MS (Biolon) C31H30N8O1 m/e calcd 530.6; found 531.1 (Mh<T>);

2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-Ay-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 159), MS (Biolon) C33H29N7CM m/e beregnet 539,6; funnet 540,1 (MH<+>); 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-α-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 159), MS (Biolon) C33H29N7CM m/e calcd 539.6; found 540.1 (MH<+>);

2-{1 -[5-(2-aminoimidazol-1 -yl)-1 H-benzoimidazol-2-yl]etyl}-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 160), MS (Biolon) CæHaoNaOi m/e beregnet 554,7; funnet 555,2 (MH<+>); 2-{1-[5-(2-aminoimidazol-1-yl)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol -5-carboxamide (Compound 160), MS (Biolon) CaHaoNaOi m/e calcd 554.7; found 555.2 (MH<+>);

1- (5-guanidino-1H-benzoimidazol-2-yl)-3-hydroksy-1-metyl-W-(2-naft-1-yl etyl) 3,4-dihydro-1H-2-oksa-4a,9-diazafluoren-6-karboksamid (Forbindelse 161); 1-(5-guanidino-1H-benzoimidazol-2-yl)-3-hydroxy-1-methyl-N-(2-naphth-1-yl ethyl) 3,4-dihydro-1H-2-oxa-4a, 9-diazafluorene-6-carboxamide (Compound 161);

2- [1-(5-guanidino-1W-benzoimidazol-2-yl)etyl]-3-(4-hydroksybutyl)-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 162), MS (Biolon) C34H36N802 m/e beregnet 588,7; funnet 589,3 (MH<+>); 2- [1-(5-guanidino-1N-benzoimidazol-2-yl)ethyl]-3-(4-hydroxybutyl)-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ( Compound 162), MS (Biolon) C 34 H 36 N 8 O 2 m/e calcd 588.7; found 589.3 (MH<+>);

3- [2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-6-(2-naft-1-yletylkarbamoyl)benzoimidazol-1-yl]propan-1-sulfonsyre (Forbindelse 163), MS (Biolon) C33H34N804S m/e beregnet 638,7; funnet 639,2 3-[2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-6-(2-naphth-1-ylethylcarbamoyl)benzoimidazol-1-yl]propane-1-sulfonic acid (Compound 163 ), MS (Biolon) C33H34N804S m/e calcd 638.7; found 639.2

(MH<+>); (MH<+>);

3-[2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-6-(2-naft-1-yletylkarbamoyl)benzoimidazol-1-yl]propan-1-sulfonsyre (Forbindelse 164), MS (Biolon) C35H33N704S m/e beregnet 647,8; funnet 648,2 3-[2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-6-(2-naphth-1-ylethylcarbamoyl)benzoimidazol-1-yl]propane-1-sulfonic acid (Compound 164), MS (Biolon) C 35 H 33 N 7 O 4 S m/e calcd 647.8; found 648.2

(MH<+>); (MH<+>);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)-2-metylpropyl]-3-metyl-A/-(2-naft-1-yletyl)-3/-/-benzoimidazol-5-karboksamid (Forbindelse 165), MS (Biolon) C33H34N80i m/e beregnet 558,7; funnet 559,6 (Mh<T>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)-2-methylpropyl]-3-methyl-N-(2-naphth-1-ylethyl)-3/-/-benzoimidazol-5- carboxamide (Compound 165), MS (Biolon) C33H34N80i m/e calcd 558.7; found 559.6 (Mh<T>);

2-[1-(1 H-imidazo[4,5-c]pyridin-2-yl)etyl]-3-metyl-rV-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 166), MS (Biolon) C29H26N6O1 m/e beregnet 474,6; funnet 475,2 (MhT); 2-[1-(1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-rN-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide ( Compound 166), MS (Biolon) C29H26N6O1 m/e calcd 474.6; found 475.2 (MhT);

2-{5-[1-(A/-metylimino)etyl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2- ylmetyl}-3-metyl-W-(2-naft-1-yletyl)-3W-benzoimidazol-5-karboksamid (Forbindelse 167), MS (Biolon) C31H33N7O m/e beregnet 519,71; funnet 520,9 (Mh<T>);2-{5-[1-(N-methylimino)ethyl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl}-3-methyl-W- (2-Naphth-1-ylethyl)-3N-benzoimidazol-5-carboxamide (Compound 167), MS (Biolon) C31H33N7O m/e calcd 519.71; found 520.9 (Mh<T>);

imino(2-{1 -[1 -metyl-6-(2-naft-1 -yletylkarbamoyl)- imino(2-{1-[1-methyl-6-(2-naphth-1-ylethylcarbamoyl)-

1 H-benzoimidazol-2-yl]etyl}-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)eddiksyre (Forbindelse 168), MS (Biolon) C31H31N7O3 m/e beregnet 549,6; funnet 550,2 (Mh<T>); 2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-/V-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 169), MS (Biolon) C3iH33N70i m/e beregnet 519,6; funnet 520,3 (MH<+>); 2-{1-[5-(W-metylamidino)-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 170), MS (Biolon) C31H34N8O1 m/e beregnet 534,7; funnet 535,1 (MH<+>); 2-(2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)-5-metoksybenzosyre (Forbindelse 171), MS (Biolon) C29H3oN805 m/e beregnet 570,6; funnet 571,2 (MH<+>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)isoftalic syre (Forbindelse 172), MS (Biolon) C29H3oN805 m/e beregnet 570,6; funnet 571,3 (Mh<T>); 2-(2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)-1 -hydroksyetyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)-6-metoksybenzosyre (Forbindelse 173), MS (Biolon) C29H30N8O6 m/e beregnet 586,6; funnet 587,2 (MH<+>); etyl-2-[2-(2-{1-[5-(A/-acetylguanidino)-1H-benzoimidazol-2-yl]etyl}-3- metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzoat (Forbindelse 174), MS (Biolon) C3iH32N805 m/e beregnet 596,6; funnet 597,2 (MH<+>); 2-{1-[5-(A/,W-dimetylamidino)-4l5l6,7-tetrahydro- 1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-A/-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 175); 2-{1 -[5-(2-amino-1,1 -dimetyletyl)-1 H-benzoimidazol-2-yl]etyl}-3-metyl-A/-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 176); 2-{1-[5-(1-iminoetyl)-4,5,67-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl} -W-etyl-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 177); 2-[2-(2-{1-[5-(W-acetylguanidino)-1H-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 178), MS (Biolon) C30H30N8O5 m/e beregnet 582,6; funnet 583,3 (MhT); 2-[2-(2-{1-[5-(1-aminocyklopropyl)-1W-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 179), MS (Biolon) C30H30N6O4 m/e beregnet 538,6; funnet 539,3 (MH<+>); 2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-A/- (3-metylbutyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 180), MS (Biolon) CzeHz<g>N<y>O, m/e beregnet 455,6; funnet 456,2 (MH<+>); 2-(1H-benzoimidazol-2-yletyl)-3-metyl-W-(2-fenoksyetyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 181), MS (Biolon) C26H25N6O2 m/e beregnet 439,5; funnet 440,2 (MH<+>); etyl-2-[2-(2-{1-[5-(1-iminoeryl)-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzoat (Forbindelse 182); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-[2-(2,4-diokso-3,4-dihydro-2W-kinazolin-1-yl)etyl]-3/-/-benzoimidazol-5-karboksamid (Forbindelse 183); 2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl} -W-(3-metoksypropyl)-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 184); W-etyl-2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 185), MS (Biolon) C23H23N7O1 m/e beregnet 413,5; funnet 414,1 (MH<+>); 2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-W-(2-metoksyetyl)-3-metyl-3/-/-benzoimidazol-5-karboksamid (Forbindelse 186), MS (Biolon) C24H25N7O2 m/e beregnet 443,5; funnet 444,2 (MH<+>); 1 -(2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)-4-metylpentansyre (Forbindelse 187), MS (Biolon) C27H29N7O3 m/e beregnet 499,6; funnet 500,3 (Mh<T>); 1 H-benzoimidazol-2-yl]ethyl}-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)acetic acid (Compound 168), MS (Biolon) C31H31N7O3 m/e calcd 549 ,6; found 550.2 (Mh<T>); 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro- 1H-Imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl- N -(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 169), MS ( Biolon) C3iH33N70i m/e calculated 519.6; found 520.3 (MH<+>); 2-{1-[5-(N-methylamidino)-4,5,6,7-tetrahydro- 1H-Imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 170), MS ( Biolon) C31H34N8O1 m/e calculated 534.7; found 535.1 (MH<+>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)-5-methoxybenzoic acid (Compound 171) , MS (Biolon) C 29 H 3 o N 8 O 5 m/e calcd 570.6; found 571.2 (MH<+>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)isophthalic acid (Compound 172), MS ( Biolon) C29H3oN805 m/e calculated 570.6; found 571.3 (Mh<T>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)-1-hydroxyethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)-6-methoxybenzoic acid ( Compound 173), MS (Biolon) C29H30N8O6 m/e calcd 586.6; found 587.2 (MH<+>); ethyl 2-[2-(2-{1-[5-(N-acetylguanidino)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate ( Compound 174), MS (Biolon) C 3 i H 3 2 N 8 O 5 m/e calcd 596.6; found 597.2 (MH<+>); 2-{1-[5-(N,N-dimethylamidino)-4l5l6,7-tetrahydro- 1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl- N -(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide (Compound 175); 2-{1-[5-(2-amino-1,1-dimethylethyl)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-A/-(2-naphth-1-ylethyl)-3H -benzoimidazole-5-carboxamide (Compound 176); 2-{1-[5-(1-iminoethyl)-4,5,67-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-N-ethyl-3-methyl-3H -benzoimidazole-5-carboxamide (Compound 177); 2-[2-(2-{1-[5-(N-acetylguanidino)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 178) , MS (Biolon) C30H30N8O5 m/e calcd 582.6; found 583.3 (MhT); 2-[2-(2-{1-[5-(1-aminocyclopropyl)-1N-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 179) , MS (Biolon) C30H30N6O4 m/e calculated 538.6; found 539.3 (MH<+>); 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-(3-methylbutyl)-3H-benzoimidazol-5-carboxamide (Compound 180) , MS (Biolon) CzeHz<g>N<y>O, m/e calcd 455.6; found 456.2 (MH<+>); 2-(1H-benzoimidazol-2-ylethyl)-3-methyl-N-(2-phenoxyethyl)-3H-benzoimidazole-5-carboxamide (Compound 181), MS (Biolon) C26H25N6O2 m/e calcd 439.5; found 440.2 (MH<+>); ethyl-2-[2-(2-{1-[5-(1-iminoaryl)-4,5,6,7-tetrahydro- 1H-Imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate (Compound 182); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-A/-[2-(2,4-dioxo-3,4-dihydro-2N-quinazolin-1- yl)ethyl]-3 H -benzoimidazole-5-carboxamide (Compound 183); 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-N-(3-methoxypropyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 184); N-ethyl-2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 185), MS (Biolon) C23H23N7O1 m/e calculated 413.5; found 414.1 (MH<+>); 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-N-(2-methoxyethyl)-3-methyl-3/-/-benzoimidazol-5-carboxamide (Compound 186), MS (Biolon) C24H25N7O2 m/e calcd 443.5; found 444.2 (MH<+>); 1-(2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)-4-methylpentanoic acid (Compound 187), MS (Biolon) C27H29N7O3 m/e calcd 499.6; found 500.3 (Mh<T>);

2-(2-{2-[1-(5-imidazol-1-yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 188), MS (Biolon) C30H27N7O4 m/e beregnet 549,6; funnet 550,2 (Mh<T>); 2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 188 ), MS (Biolon) C30H27N7O4 m/e calcd 549.6; found 550.2 (Mh<T>);

2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)-4-metylpentansyre (Forbindelse 189); 2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl- 3H-benzoimidazol-5-ylcarbonylamino)-4-methylpentanoic acid (Compound 189);

2-{1-[5-(A/,A/-dimetylamidino)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2- yl]-etyl}-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 190), MS (Biolon) C39H34N8O4 m/e beregnet 558,6; funnet 559,3 2-{1-[5-(N,N-dimethylamidino)-4,5,6l7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]-ethyl}-3-methyl- 3/-/-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 190), MS (Biolon) C39H34N8O4 m/e calcd 558.6; found 559.3

(MH<+>); (MH<+>);

2-[2-(2-{1-[5-(2-karboksy-1-iminoetyl)-4,5,6,7-tetrahydro- 2-[2-(2-{1-[5-(2-carboxy-1-iminoethyl)-4,5,6,7-tetrahydro-

1 H-imidazo[4,5-c]-pyridin-2-yl]etyl}-3- metyl-3H-benzoimidazol-5-ylkarbonylåmino)etoksy]benzosyre (Forbindelse 181), MS (Biolon) C29H31N7O6 m/e beregnet 573,6; funnet 530,3 (MH<+>), tap av C02; 1 H-imidazo[4,5-c]-pyridin-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 181), MS (Biolon) C29H31N7O6 m/e calcd. 573.6; found 530.3 (MH<+>), loss of CO 2 ;

2-(2-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-(2-metoksyetyl)-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 192), MS (Biolon) C32H31N7O5 m/e beregnet 593,6; funnet 594,2 (Mh<T>); 2-(2-{2-[1 -(5-imidazol-1 -yl-1H-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-3H-benzoimidazol-5-ylcarbonylamino}ethoxy) benzoic acid (Compound 192), MS (Biolon) C32H31N7O5 m/e calcd 593.6; found 594.2 (Mh<T>);

2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-(2-metoksyetyl)-N-(2-metoksyetyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 193), MS (Biolon) C26H29N7O3 m/e beregnet 487,6; funnet 488,2 (MH<+>); 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-N-(2-methoxyethyl)-3H-benzoimidazol-5-carboxamide (Compound 193), MS (Biolon) C26H29N7O3 m/e calcd 487.6; found 488.2 (MH<+>);

2- [2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1W-imidazo[4,5-c]pyridin-2-y l]etyl}-3-(2-metoksyetyl)-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 194); 2- [2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1N-imidazo[4,5-c]pyridin-2-yl]ethyl}-3 -(2-Methoxyethyl)-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 194);

3- (2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzotmidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 185), MS (Biolon) C28H28N804 m/e beregnet 540,6; funnet 541,3 (MH<+>); 3-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzotmidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 185), MS ( Biolon) C28H28N804 m/e calculated 540.6; found 541.3 (MH<+>);

2-(2-{2-[1-(5-guanidino-1W-benzoimidazol-2-yl)etyl]-3-(2-metoksyetyl)-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 196), MS (Biolon) C30H32N8O5 m/e beregnet 584,6; funnet 585,3 (MH<+>); 2-(2-{2-[1-(5-guanidino-1N-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 196) , MS (Biolon) C30H32N8O5 m/e calcd 584.6; found 585.3 (MH<+>);

2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-(3-sulfopropyl)-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse .197), MS (Biolon) C30H32N8O7S m/e beregnet 648,7; funnet 649,6 (MH<+>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-(3-sulfopropyl)-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound .197 ), MS (Biolon) C30H32N8O7S m/e calcd 648.7; found 649.6 (MH<+>);

2-(2-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-(3-sulfopropyl)-3/-/-benzoimidazol-6-ylkarbonylamino}etoksy)benzosyre (Forbindelse 198), MS (Biolon) C32H31N7O7S m/e beregnet 657,7; funnet 658,4 (Mh<T>); 2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-(3-sulfopropyl)-3/-/-benzoimidazol-6-ylcarbonylamino }ethoxy)benzoic acid (Compound 198), MS (Biolon) C32H31N7O7S m/e calcd 657.7; found 658.4 (Mh<T>);

2-(2-{2-[1-(5-imidazol-1-yl-3-metyl-3H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 199), MS (Biolon) C31H29N7O4 m/e beregnet 563,6; funnet 564,2 (MH<+>); 2-(2-{2-[1-(5-imidazol-1-yl-3-methyl-3H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 199), MS (Biolon) C31H29N7O4 m/e calcd 563.6; found 564.2 (MH<+>);

2-(2-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-(2-hydroksypropyl)-3W-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 200), MS (Biolon) C32H31N7O5 m/e beregnet 593,6; funnet 594,3 2-(2-{2-[1 -(5-imidazol-1 -yl-1H-benzoimidazol-2-yl)ethyl]-3-(2-hydroxypropyl)-3N-benzoimidazol-5-ylcarbonylamino}ethoxy) benzoic acid (Compound 200), MS (Biolon) C32H31N7O5 m/e calcd 593.6; found 594.3

(MH<+>); (MH<+>);

2-{2-[2-(1 -{5-[1 -(W-hydroksyimino)etyl]-4,5,6,7-tetrahydro- 2-{2-[2-(1 -{5-[1 -(N-Hydroxyimino)ethyl]-4,5,6,7-tetrahydro-

1 H-imidazo[4,5-c]-pyridin-2-yl}etyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzosyre (Forbindelse 201); 1H-Imidazo[4,5-c]-pyridin-2-yl}ethyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoic acid (Compound 201);

etyl-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 202), MS (Biolon) C3oH32N804 m/e beregnet 568,6; funnet 569,5 (Mh<T>); ethyl 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 202), MS (Biolon) C3oH32N8O4 m/e calcd 568.6; found 569.5 (Mh<T>);

etyl-2-[2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylkarbonylamino)etoksy]benzoat (Forbindelse 203), MS (Biolon) C28H36N804 m/e beregnet 549,0; funnet 548,2 ethyl-2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl} -1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)ethoxy]benzoate (Compound 203), MS (Biolon) C28H36N804 m/e calcd 549.0; found 548.2

(MH<+>); (MH<+>);

etyl-4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}butyrat (Forbindelse 204), MS (Biolon) C25H3oN803 m/e beregnet 490,57; funnet 491,3 (MH<+>); ethyl 4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}butyrate (Compound 204), MS (Biolon) C25H3oN803 m /e calculated 490.57; found 491.3 (MH<+>);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-[2-(2-tetrazol-1-ylfenoksy)etyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 205), MS (Biolon) C28H28N12O2 m/e beregnet 564,56; funnet 565,3 (MH<+>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-A/-[2-(2-tetrazol-1-ylphenoxy)ethyl)-3H-benzoimidazol-5-carboxamide (Compound 205), MS (Biolon) C 28 H 28 N 12 O 2 m/e calcd 564.56; found 565.3 (MH<+>);

2-[2-(2-{1-[5-(1-iminoetylamino)-1H-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 206), MS (Biolon) Q31H33N7O4 m/e beregnet 567,6; funnet 568,4 (MH<+>); 2-[2-(2-{1-[5-(1-iminoethylamino)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 206) , MS (Biolon) Q31H33N7O4 m/e calculated 567.6; found 568.4 (MH<+>);

etyl-4-(2-{2-[1-(5-guanidino-1H-ben2oimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 207), MS (Biolon) C30H32N8O4 m/e beregnet 568,6; funnet 569,4 (MH<+>); ethyl 4-(2-{2-[1-(5-guanidino-1H-ben2oimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 207), MS (Biolon) C30H32N8O4 m/e calcd 568.6; found 569.4 (MH<+>);

5-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)isoftalsyre (Forbindelse 208), MS (Biolon) C29H28N8O6 m/e beregnet 584,6; funnet 585,3 (MH<+>); 5-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)isophthalic acid (Compound 208), MS (Biolon ) C29H28N8O6 m/e calculated 584.6; found 585.3 (MH<+>);

4-(2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 209), MS (Biolon) C28H28N8O4 m/e beregnet 540,6; funnet 541,2 (Mh<T>); 4-(2-{2-[1 -(5-guanidino-1 H -benzoimidazol-2-yl)ethyl]-3-methyl-3 H -benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 209) , MS (Biolon) C28H28N8O4 m/e calcd 540.6; found 541.2 (Mh<T>);

2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-(2-hydroksypropyl)-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 210), MS (Biolon) C30H32N8O5 m/e beregnet 584,6; funnet 585,4 (Mh<T>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-(2-hydroxypropyl)-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 210) , MS (Biolon) C30H32N8O5 m/e calcd 584.6; found 585.4 (Mh<T>);

2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-metoksy-fenoksy)etyl]-3H-benzoimidazol-5-karboksamid 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-methoxy-phenoxy)ethyl]-3H-benzoimidazol-5- carboxamide

(Forbindelse 211), MS (Biolon) C3oH29N702 m/e beregnet 535,6; funnet 536,3 (Compound 211), MS (Biolon) C30H29N702 m/e calcd 535.6; found 536.3

(MH<+>); (MH<+>);

2-(2-{2-[1 -(5-guanidino-1 W-benzoimidazol-2-yl)etylJ-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 212), MS (Biolon) C27H26N8O4 m/e beregnet 526,6; funnet 527,2 (MH<+>); 2-(2-{2-[1 -(5-guanidino-1 N -benzoimidazol-2-yl)ethyl J-3-methyl-3 H -benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 212), MS (Biolon) C27H26N8O4 m/e calcd 526.6; found 527.2 (MH<+>);

2-[1 -(5-imidazol-1 -yl-1 /-/-benzoimidazol-2-yl)etyl]-3-metyl-A/-(2-fenoksyetyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 213), MS (Biolon) C29H27N7O2 m/e beregnet 505,6; funnet 506,2 (MhT); 2-[1-(5-imidazol-1-yl-1/-/-benzoimidazol-2-yl)ethyl]-3-methyl-N-(2-phenoxyethyl)-3H-benzoimidazol-5-carboxamide (Compound 213), MS (Biolon) C29H27N7O2 m/e calcd 505.6; found 506.2 (MhT);

2-(2-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-1H-benzoimidazol-5-yl-karbonylamino}etoksy)benzosyre (Forbindelse 214), MS (Biolon) C29H25N7O4 m/e beregnet 535,6; funnet 536,4 (Mh<T>); 2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-1H-benzoimidazol-5-yl-carbonylamino}ethoxy)benzoic acid (Compound 214), MS (Biolon) C29H25N7O4 m/e calcd 535.6; found 536.4 (Mh<T>);

etyl-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-ylkarbonylamino}etoksy)-4-metylbenzoat (Forbindelse 215), MS (Biolon) C3iH34N804 m/e beregnet 582,7; funnet 583,5 ethyl 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3W-benzoimidazol-5-ylcarbonylamino}ethoxy)-4-methylbenzoate (Compound 215 ), MS (Biolon) C3iH34N8O4 m/e calcd 582.7; found 583.5

(MH<+>); (MH<+>);

2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-benzoimidazol-5-ylkarbonylamino}etoksy)-4-metylbenzosyre (Forbindelse 216), MS (Biolon) C29H30N8O4 m/e beregnet 554,6; funnet 555,5 (Mh<T>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-benzoimidazol-5-ylcarbonylamino}ethoxy)-4-methylbenzoic acid (Compound 216), MS ( Biolon) C29H30N8O4 m/e calculated 554.6; found 555.5 (Mh<T>);

2-[2-(2-{1-[S-tl-iminoetylM.S.ej-tetrahydro-IH-imidazo^.S-cJpyridin^-ylletyl}-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylkarbonylamino)etoksy]benzoat (Forbindelse 217), MS (ESI) C26H32N8O4 m/e beregnet 520,58; funnet 521,3 2-[2-(2-{1-[S-1-iminoethyl M.S.ej-tetrahydro-1H-imidazo^.S-cJpyridin^-ylethyl}-1,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-ylcarbonylamino)ethoxy]benzoate (Compound 217), MS (ESI) C 26 H 32 N 8 O 4 m/e calcd 520.58; found 521.3

(MH<+>); (MH<+>);

etyl-2-(2-{2-{5-(A/-metylamidino)-1H-benzoimidazol-2-ylmetyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 218), MS (Biolon) C30H31N7O4 m/e beregnet 553,6; funnet 554,3 (MH<+>); ethyl 2-(2-{2-{5-(N-methylamidino)-1H-benzoimidazol-2-ylmethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 218), MS (Biolon) C30H31N7O4 m/e calcd 553.6; found 554.3 (MH<+>);

2-[2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-(3-sulfopropyl)-3H-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 219), MS (Biolon) C3oH35N707 m/e beregnet 637,7; funnet 638,3 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3 -(3-sulfopropyl)-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 219), MS (Biolon) C30H35N707 m/e calcd 637.7; found 638.3

(MH<+>); (MH<+>);

etyl-2-(2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)-4-metylvalerat (Forbindelse 220); ethyl-2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3- methyl (3H-benzoimidazol-5-ylcarbonylamino)-4-methylvalerate (Compound 220);

etyl-2-{2-[2-(1-{5-[1-(A/-hydroksyimino)etyl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridin-2-yl}etyl)-3-metyl-3H-benzoimidazol-5-ylkarbonylamino]etoksy}benzoat (Forbindelse 221); ethyl-2-{2-[2-(1-{5-[1-(N-hydroxyimino)ethyl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine -2-yl}ethyl)-3-methyl-3H-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 221);

2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-[2-(2-metoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 222), MS (Biolon) C27H27N503 m/e beregnet 469,5; funnet 469,5 (MH<+>); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-A/-[2-(2-methoxyphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 222), MS (Biolon ) C27H27N503 m/e calculated 469.5; found 469.5 (MH<+>);

2-(2-etoksykarbonylfenoksy)etyl-2-[1-(6-guanidino-1H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4r5-c]pyridin-5-karboksyat (Forbindelse 223), MS (Biolon) C28H32N805 m/e beregnet 560,62; funnet 561,3 (MH<+>); 2-(2-ethoxycarbonylphenoxy)ethyl-2-[1-(6-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4r5-c]pyridine-5-carboxylate ( Compound 223), MS (Biolon) C 28 H 32 N 8 O 5 m/e calcd 560.62; found 561.3 (MH<+>);

4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}smørsyre (Forbindelse 224), MS (Biolon) C23H26N8O3 m/e beregnet 462,52; funnet 462,8 (Mh<T>); 4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}butyric acid (Compound 224), MS (Biolon) C23H26N8O3 m/e calculated 462.52; found 462.8 (Mh<T>);

2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-A/-[2-(2-tetrazolylfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 225), MS (ESI) C28H3iNn02 m/e beregnet 553,6; funnet 553,5 (MH<+>); 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-A/- [2-(2-Tetrazolylphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 225), MS (ESI) C 28 H 3 iNnO 2 m/e calcd 553.6; found 553.5 (MH<+>);

isopropyl 2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 226), MS (Biolon) C33H33N704 m/e beregnet 591,3; funnet 591,4 (Mh<T>); isopropyl 2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 226), MS (Biolon) C 33 H 33 N 7 O 4 m/e calcd 591.3; found 591.4 (Mh<T>);

2-{1-[5-(1-iminoetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-W-[2-(3-tetrazolylfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 227), MS (Biolon) C28H31N11O2 m/e beregnet 553,59; funnet 553,5 (MH<+>); 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-W-[ 2-(3-Tetrazolylphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 227), MS (Biolon) C28H31N11O2 m/e calcd 553.59; found 553.5 (MH<+>);

2-{1-[5-(1-iminoetyl)-4)5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]etyl}-3-metyl-A/-[2-(4-tetrazolylfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 228), MS (ESI) C28H31N11O2 m/e beregnet 553,59; funnet 553,5 (Mh<T>); 2-{1-[5-(1-iminoethyl)-4)5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-A/- [2-(4-Tetrazolylphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide (Compound 228), MS (ESI) C28H31N11O2 m/e calcd 553.59; found 553.5 (Mh<T>);

cykloheksyl-2-(2-{2-[1 -(5-imidazol-1 -yl)-1 H-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-ylkarbonylamino)etoksybenzoat (Forbindelse 229), MS (ESI) C36H37N704 m/e beregnet 631,3; funnet 631,5 (MH<+>); cyclohexyl-2-(2-{2-[1 -(5-imidazol-1 -yl)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxybenzoate (Compound 229), MS (ESI) C 36 H 37 N 7 O 4 m/e calcd 631.3; found 631.5 (MH<+>);

2-[2-(2-{1-[5-(A/-metylamidino)-1H-benzoimidazol-2-yl]etyl}-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 230), MS (Biolon) C28H27N704 m/e beregnet 525,6; funnet 525,5 (MH<+>); 2-[2-(2-{1-[5-(N-methylamidino)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3/-/-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 230), MS (Biolon) C 28 H 27 N 7 O 4 m/e calcd 525.6; found 525.5 (MH<+>);

2-[2-(2-{1 -[5-( 1 -iminoetylamino)-1 H-benzoimidazol-2-yl]etyl}-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino)etoksy]benzosyre (Forbindelse 231), MS (Biolon) C29H29N704 m/e beregnet 539,6; funnet 539,8 (MH<+>); 2-[2-(2-{1 -[5-( 1 -iminoethylamino)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3/-/-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 231), MS (Biolon) C 29 H 29 N 7 O 4 m/e calcd 539.6; found 539.8 (MH<+>);

2-(3-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-ylkarbonyl}propoksy)benzosyre (Forbindelse 232), MS (Biolon) C27H3oN804 m/e beregnet 530,60; funnet 531,7 (MH<+>); 2-(3-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-ylcarbonyl }propoxy)benzoic acid (Compound 232), MS (Biolon) C 27 H 3 o N 8 O 4 m/e calcd 530.60; found 531.7 (MH<+>);

2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-ylformyloksy}etoksy)benzosyre (Forbindelse 233), MS (Biolon) C26H28N8O5 m/e beregnet 532,56; funnet 533,2 (MH<+>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-ylformyloxy }ethoxy)benzoic acid (Compound 233), MS (Biolon) C26H28N8O5 m/e calcd 532.56; found 533.2 (MH<+>);

2-metoksyetyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 234), MS (Biolon) C33H33N705 m/e beregnet 607,3; funnet 607,4 (MH<+>); 2-Methoxyethyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 234), MS (Biolon) C 33 H 33 N 7 O 5 m/e calcd 607.3; found 607.4 (MH<+>);

isobutyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 235), MS (Biolon) C34H35N704 m/e beregnet 605,3; funnet 605,4 (Mh<T>); isobutyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 235), MS (Biolon) C 34 H 35 N 7 O 4 m/e calcd 605.3; found 605.4 (Mh<T>);

2-(2-metoksyetoksy)etyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)etyl]-3-metyl- 2-(2-Methoxyethoxy)ethyl-2-(2-{2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-

3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 236), MS (Biolon) C35H37N7O6 m/e beregnet 651,3; funnet 651,3 (Mh<T>); 3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 236), MS (Biolon) C35H37N7O6 m/e calcd 651.3; found 651.3 (Mh<T>);

butyl-2-(2-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 237), MS (Biolon) C34H35N7O4 m/e beregnet 605,3; funnet 605,4 (MH<+>); butyl 2-(2-{2-[1 -(5-imidazol-1 -yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate ( Compound 237), MS (Biolon) C34H35N7O4 m/e calcd 605.3; found 605.4 (MH<+>);

2-[1 -(1 H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(3-okso-2,3-dihydrobenzo[1,4]-oksazin-4-yl)etyl]-3W-benzoimidazol-5-karboksamid (Forbindelse 238), MS (Biolon) C28H26N603 m/e beregnet 494,2; funnet 494,5 (MH<+>); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(3-oxo-2,3-dihydrobenzo[1,4]-oxazin-4-yl)ethyl ]-3N-benzoimidazole-5-carboxamide (Compound 238), MS (Biolon) C 28 H 26 N 6 O 3 m/e calcd 494.2; found 494.5 (MH<+>);

2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-[2-(2-fluorfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 239); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-[2-(2-fluorophenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 239);

2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(3-fluorfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 240); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(3-fluorophenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 240);

2-[1 -(1 H-benzoimidazol-2-yl)etyl]-3-metyl-N-[2-(2-isopropoksyfenoksy)etyl]-3H-benzoimidazol-5-karboksamid (Forbindelse 241), MS (Biolon) C29H31N503 m/e beregnet 497,2; funnet 497,6 (Mh<T>); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-[2-(2-isopropoxyphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide (Compound 241), MS (Biolon ) C29H31N503 m/e calculated 497.2; found 497.6 (Mh<T>);

2-[1-(1 H-benzoimidazol-2<->yl)etyl]-3-metyl-A/-[2-(2-met<y>lfenoksy)et<y>l]-3H-benzoimidazol-5-karboksamid (Forbindelse 242), MS (Biolon) C27H27N5C*2 m/e beregnet 453,2; funnet 453,5 (Mh<T>); 2-[1-(1H-benzoimidazol-2<->yl)ethyl]-3-methyl-[2-(2-methylphenoxy)ethyl]-3H-benzoimidazol- 5-carboxamide (Compound 242), MS (Biolon) C27H27N5C*2 m/e calcd 453.2; found 453.5 (Mh<T>);

2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyi-A/-[2-(2-etoksyfenoksy)etyl]-3W-benzoimidazol-5-karboksamid (Forbindelse 243), MS (Biolon) C28H29N5O3 m/e beregnet 483,2; funnet 483,5 (MhT); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-[2-(2-ethoxyphenoxy)ethyl]-3N-benzoimidazol-5-carboxamide (Compound 243), MS (Biolon ) C28H29N5O3 m/e calculated 483.2; found 483.5 (MhT);

2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-W-[2-(2-metoksyfenoksy)-etyl]-3H-benzoimidazol-5-karboksamid 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-W-[2-(2-methoxyphenoxy)ethyl]-3H-benzoimidazol-5-carboxamide

(Forbindelse 244), MS (Biolon) C28H30N8O3 m/e beregnet 526,6; funnet 526,8 (Mh<T>); (Compound 244), MS (Biolon) C 28 H 30 N 8 O 3 m/e calcd 526.6; found 526.8 (Mh<T>);

etyl-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-l^.e^-tetrahydro-imidazo^.S-clpyridin-S-ylkarbonylamihoJetoksyJbenzoat (Forbindelse 245), MS (Biolon) C28H33N904 m/e beregnet 559,6; funnet 559,6 ethyl 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1^.e^-tetrahydro-imidazo^.S-clpyridin-S-ylcarbonylamihoJethoxyJbenzoate (Compound 245 ), MS (Biolon) C28H33N904 m/e calcd 559.6; found 559.6

(MH<+>); (MH<+>);

2-metoksyetyl-2-(2-{2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 246), MS (Biolon) C30H31N5O4 m/e beregnet 541,6; funnet 541,5 (MH<+>); 2-Methoxyethyl-2-(2-{2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 246), MS (Biolon ) C30H31N5O4 m/e calculated 541.6; found 541.5 (MH<+>);

etyl-2-{2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzo-imidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 247), MS (Biolon) C2gH3oN804 m/e beregnet 554,6; funnet 555,4 (MhT); ethyl 2-{2-{2-[1 -(5-guanidino-1 H -benzoimidazol-2-yl)ethyl]-3-methyl-3 H -benzo-imidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 247 ), MS (Biolon) C 2 g H 3 o N 8 O 4 m/e calcd 554.6; found 555.4 (MhT);

2-{2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 248), MS (Biolon) C28H28N804 m/e beregnet 540,6; funnet 541,3 (Mh<T>); 2-{2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 248), MS (Biolon ) C28H28N804 m/e calculated 540.6; found 541.3 (Mh<T>);

2-[1-(5-guanidino-1/-/-benzoimidazol-2-yl)etyl]-W-[2-(2-karbamoylfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 249), MS (Biolon) C28H29N903 m/e beregnet 539,6; funnet 540,5 (Mh<T>); 2-[1-(5-guanidino-1/-/-benzoimidazol-2-yl)ethyl]-W-[2-(2-carbamoylphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 249), MS (Biolon) C 28 H 29 N 9 O 3 m/e calcd 539.6; found 540.5 (Mh<T>);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-A/-[2-(2-karbamoyl-4- klorfenoksy)-etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 250), MS (Biolon) C28H28N903CI m/e beregnet 574,0; funnet 574,2 (Mh<T>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-A/-[2-(2-carbamoyl-4-chlorophenoxy)-ethyl]-3-methyl-3H-benzoimidazol-5- Carboxamide (Compound 250), MS (Biolon) C 28 H 28 N 9 O 3 Cl m/e calcd 574.0; found 574.2 (Mh<T>);

4- klor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 251), MS (Biolon) C28H27N8O4CI m/e beregnet 575,0 funnet 575,2 (MH<+>); 4-chloro-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 251) , MS (Biolon) C28H27N8O4CI m/e calcd 575.0 found 575.2 (MH<+>);

5- klor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 252), MS (Biolon) C2BH27N804CI m/e beregnet 575,0; funnet 575,2 (Mh<T>); 5-chloro-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 252) , MS (Biolon) C2BH27N804CI m/e calcd 575.0; found 575.2 (Mh<T>);

6- klor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 253), MS (Biolon) C28H27N8O4CI m/e beregnet 575,0; funnet 575,2 (Mh<T>); 6-chloro-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 253) , MS (Biolon) C28H27N8O4CI m/e calcd 575.0; found 575.2 (Mh<T>);

4,6-diklor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 254), MS (Biolon) C28H26NB04CI2 m/e beregnet 609,5; funnet 609,1 (MH<+>); 4,6-Dichloro-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 254), MS (Biolon) C28H26NB04Cl2 m/e calcd 609.5; found 609.1 (MH<+>);

etyl-2-(2-{2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5- karbonylamino}etoksy)benzoat (Forbindelse 255), MS (Biolon) C29H29N5O4 m/e beregnet 511,6; funnet 512,2 (Mh<T>); ethyl 2-(2-{2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy)benzoate (Compound 255), MS (Biolon) C29H29N5O4 m/e calculated 511.6; found 512.2 (Mh<T>);

2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-A/-{2-[2,4-diokso-3-(2-trimetylsilanyletyl)-3,4-dihydro-2W-kinazolin-1-yl]etyl}-3H-benzoimidazol-5-karboksamid (Forbindelse 256), MS (Biolon) C34H4oN1o03Si m/e beregnet 664,8; funnet 665,4 (Mh<T>); 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-{2-[2,4-dioxo-3-(2-trimethylsilanylethyl)-3,4- dihydro-2N-quinazolin-1-yl]ethyl}-3H-benzoimidazol-5-carboxamide (Compound 256), MS (Biolon) C34H40N1003Si m/e calcd 664.8; found 665.4 (Mh<T>);

2-[1-(5-guanidinc-1H-benzoimidazo 3,4-dihydro-2H-kinazolin-1-yl]etyl}-3H-benzoimidazol-5-karboksamid (Forbindelse 257), MS (Biolon) C29H28N10O3 m/e beregnet 564,6; funnet 565,2 2-[1-(5-guanidinc-1H-benzoimidazo 3,4-dihydro-2H-quinazolin-1-yl]ethyl}-3H-benzoimidazole-5-carboxamide (Compound 257), MS (Biolon) C29H28N10O3 m/e calculated 564.6; found 565.2

(MH<+>); (MH<+>);

2-[1-(1H-benzoimidazol-2-yl)etyl]-A/-[2-(2-cyanofenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 258), MS (Biolon) C27H24N6O2 m/e beregnet 454,5; funnet 465,1 (MH<+>); 2-[1-(1H-benzoimidazol-2-yl)ethyl]-A/-[2-(2-cyanophenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 258), MS (Biolon ) C27H24N6O2 m/e calculated 454.5; found 465.1 (MH<+>);

5-(2-{2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5- ylkarbonylamino}etoksy)isoftalic syre (Forbindelse 259), MS (Biolon) C28H25N5O6 m/e beregnet 527,5; funnet 528,4 (MH<+>); 5-(2-{2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)isophthalic acid (Compound 259), MS (Biolon) C28H25N5O6 m /e calculated 527.5; found 528.4 (MH<+>);

2-(2-metoksyetoksy)etyl-2-(2-{2-[1-(1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 260), MS (Biolon) C32H35N5O6 m/e beregnet 585,7; funnet 585,4 (Mh<T>); 2-(2-Methoxyethoxy)ethyl-2-(2-{2-[1-(1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 260 ), MS (Biolon) C32H35N5O6 m/e calcd 585.7; found 585.4 (Mh<T>);

2-(2-{2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyrid-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 261), MS (Biolon) C2gH29N904 m/e beregnet 531,6; funnet 531,5 (Mh<T>); 2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyrid-5- ylcarbonylamino}ethoxy)benzoic acid (Compound 261), MS (Biolon) C2gH29N904 m/e calcd 531.6; found 531.5 (Mh<T>);

2-[1-(1H-imidazo[4,5-c]pyridin-2-yl)etyl]-A/-[2-(2-metoksyfenoksy)etyl]-3-metyl-3ft-benzoimidazol-5-karboksamid (Forbindelse 262), MS (Biolon) C26H26N603 m/e beregnet 470,54; funnet 471,4 (MH<+>); 2-[1-(1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-N-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide (Compound 262), MS (Biolon) C 26 H 26 N 6 O 3 m/e calcd 470.54; found 471.4 (MH<+>);

2-[1-(5-fluor-1H-benzoimidazol-2-yl)etyl]-/\/-[2-(2-metoksyfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 263), MS (Biolon) C27H26N503F m/e beregnet 487,54; funnet 486,1 (MH<+>); 2-[1-(5-fluoro-1H-benzoimidazol-2-yl)ethyl]-/\/-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazol-5-carboxamide (Compound 263 ), MS (Biolon) C27H26N503F m/e calcd 487.54; found 486.1 (MH<+>);

2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-3-metyl-A/-(2-tetrazol-1-yletyl)-3H-benzoimidazol-5-karboksamid (Forbindelse 264), MS (ESI) C24H23NHO m/e beregnet 481,47; funnet 482,6 (MH<+>); 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-(2-tetrazol-1-ylethyl)-3H-benzoimidazol-5-carboxamide (Compound 264), MS (ESI) C 24 H 23 NHO m/e calcd 481.47; found 482.6 (MH<+>);

2-[1 -(4-hydroksy-1 H-benzoimidazol-2-yl)etyl]-W-[2-(2-metoksyfenoksy)etyl]- 3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 265), MS (Biolon) C27H27N504 m/e beregnet 485,59; funnet 486,3 (Mh<T>); 2-[1-(4-hydroxy-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-methoxyphenoxy)ethyl]- 3-methyl-3H-benzoimidazol-5-carboxamide (Compound 265) , MS (Biolon) C 27 H 27 N 5 O 4 m/e calcd 485.59; found 486.3 (Mh<T>);

2- [1-(4-aminobenzoksazol-2-yl)etyl]-A/-[2-(2-metoksyfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 266), MS (Biolon) C27H27N504 m/e beregnet 485.59; funnet 486,1 (Mh<T>); 2- [1-(4-Aminobenzoxazol-2-yl)ethyl]-A/-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide (Compound 266), MS (Biolon ) C27H27N504 m/e calculated 485.59; found 486.1 (Mh<T>);

3- {2-[1 -(1 H-benzoimidazol-2-yl)etyl]-6- [2-(2-metoksyfenoksy)etylkarbamoyl]-benzoimidazol-1-yl}propan-1-sulfonsyre 3- {2-[1 -(1 H -benzoimidazol-2-yl)ethyl]-6- [2-(2-methoxyphenoxy)ethylcarbamoyl]-benzoimidazol-1-yl}propane-1-sulfonic acid

(Forbindelse 267), MS (Biolon) C29H31N506S m/e beregnet 577,66; funnet 577,4 (Mh<T>); (Compound 267), MS (Biolon) C 29 H 31 N 5 O 6 S m/e calcd 577.66; found 577.4 (Mh<T>);

3-{2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-6-[2-(2-metoksyfenoksy)-etylkarbamoyl]benzoimidazol-1-yl}propan-1-sulfonsyre (Forbindelse 268), MS (Biolon) C32H33N7O6S m/e beregnet 643,72; funnet 644,6 (Mh<T>); 3-{2-[1 -(5-imidazol-1 -yl-1H-benzoimidazol-2-yl)ethyl]-6-[2-(2-methoxyphenoxy)ethylcarbamoyl]benzoimidazol-1-yl}propane- 1-sulfonic acid (Compound 268), MS (Biolon) C32H33N7O6S m/e calcd 643.72; found 644.6 (Mh<T>);

etyl-2-[2-(2-{1 -[1 -(2-metoksyetyl)-1 H-benzoimidazol-2-yl]etyl}-3-metyl-3H-benzoimidazol-5-karbonylamino)etoksy]benzoat (Forbindelse 269), MS (Biolon) C32H35N5O5 m/e beregnet 569,66; funnet 570,5 (MH<+>); ethyl 2-[2-(2-{1 -[1 -(2-methoxyethyl)-1H-benzoimidazol-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-carbonylamino)ethoxy]benzoate ( Compound 269), MS (Biolon) C32H35N5O5 m/e calcd 569.66; found 570.5 (MH<+>);

benzyl-2-[1 -(5-imidazol-1 -yl-1 H-benzoimidazol-2-yl)etyl]-l^.ej-tetrahydro-imidazo^.S-cjpyridin-S-karboksylat (Forbindelse 270), MS (Biolon) C29H3oN806 m/e beregnet 586,6; funnet 587,2 (MH<+>); benzyl 2-[1-(5-imidazol-1-yl-1H-benzoimidazol-2-yl)ethyl]-1H-tetrahydro-imidazo-S-pyridine-S-carboxylate (Compound 270), MS (Biolon) C 29 H 3 o N 8 O 6 m/e calcd 586.6; found 587.2 (MH<+>);

etyl-2-(4-{2-[1 -(1 H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4,5-c]-pyridin-5-yl}-4-oksobutoksy)benzoat (Forbindelse 271); ethyl-2-(4-{2-[1-(1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]-pyridin-5-yl}- 4-oxobutoxy)benzoate (Compound 271);

1- {2-[1 -(1 H-benzoimidazol-2-yl)etyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-(2-metoksyfenoksy)butan-1-on (Forbindelse 272); 1- {2-[1 -(1 H -benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-(2-methoxyphenoxy )butan-1-one (Compound 272);

2- (5-guanidino-1H-benzoimidazol-2-ylmetyl)-W-(2-naft-1-yletyl)imidazo[1,2-a]-pyridin-6-karboksamid (Forbindelse 273); 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-N-(2-naphth-1-ylethyl)imidazo[1,2-a]-pyridine-6-carboxamide (Compound 273);

W-[3-(2-etoksyfenyl)propyl]-2-[1-(5-hydroksy-1/-/-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-karboksamid (Forbindelse 274), MS (Biolon) C29H31N503 m/e beregnet 497,62; funnet 497,4; W-[3-(2-ethoxyphenyl)propyl]-2-[1-(5-hydroxy-1/-/-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5- Carboxamide (Compound 274), MS (Biolon) C 29 H 31 N 5 O 3 m/e calcd 497.62; found 497.4;

A/-[3-(2-butoksyfenyl)propyl]-2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-karboksamid (Forbindelse 275), MS (Biolon) C3iH35N503 m/e beregnet 525,65; funnet 526,3; N -[3-(2-butoxyphenyl)propyl]-2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3N-benzoimidazol-5-carboxamide (Compound 275) , MS (Biolon) C 3 iH 35 N 5 O 3 m/e calcd 525.65; found 526.3;

2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yI)etyl]-3-metyl-A/-[3-(2-propoksyfenyl)-propyl]-3A7-benzoimidazol-5-karboksamid 2-[1-(5-Hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-N-[3-(2-propoxyphenyl)-propyl]-3N7-benzoimidazole-5-carboxamide

(Forbindelse 276), MS (Biolon) C3oH33N503 m/e beregnet 511,62; funnet 512,3; (Compound 276), MS (Biolon) C30H33N503 m/e calcd 511.62; found 512.3;

2-[1-(5-hydroksy-1H-benzoimidazol-2-yl)etyl]-A/-{2-[2-(3-metyl-[1,2,4]oksadiazol-5-yl)fenoksy]etyl}-3-metyl-3H-benzoimidazol-5-karboksamid (Forbindelse 277), MS (Biolon) C29H27N7O4 m/e beregnet 538,1; funnet 537,58; 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-N-{2-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)phenoxy] ethyl}-3-methyl-3H-benzoimidazole-5-carboxamide (Compound 277), MS (Biolon) C29H27N7O4 m/e calcd 538.1; found 537.58;

etyl-2-(2-{2-t1-(4-fluor-5-hydroksy-1W-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 278), MS (ESI) C29H2BN5O5 m/e beregnet 545,57 funnet 545,6; ethyl 2-(2-{2-t1-(4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 278 ), MS (ESI) C29H2BN5O5 m/e calcd 545.57 found 545.6;

2-(2-{2-[1-(4-fluor-5-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 279), MS (Biolon) C27H24N5O5F m/e beregnet 517,52 funnet 517,4; 2-(2-{2-[1-(4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 279) , MS (Biolon) C27H24N5O5F m/e calcd 517.52 found 517.4;

etyl-2-(2-{2-[1 -(6-fluor-4-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 280), MS (Biolon) C29H28N5O5F m/e beregnet 545,57 funnet 545,9; ethyl 2-(2-{2-[1 -(6-fluoro-4-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate ( Compound 280), MS (Biolon) C29H28N5O5F m/e calcd 545.57 found 545.9;

2-(2-{2-[1-(6-fluor-4-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 280), MS (Biolon) C27H24N505F m/e beregnet 517,52 funnet 517,6; 2-(2-{2-[1-(6-fluoro-4-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 280) , MS (Biolon) C27H24N505F m/e calcd 517.52 found 517.6;

etyl-2-(2-{2-[1 -(4,5-d ifluor-7-hyd roksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat (Forbindelse 281), MS (Biolon) C29H27N5O5F2 m/e beregnet 563,56 funnet 563,9; og ethyl-2-(2-{2-[1 -(4,5-difluoro-7-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3/-/-benzoimidazol-5 -ylcarbonylamino}ethoxy)benzoate (Compound 281), MS (Biolon) C29H27N5O5F2 m/e calcd 563.56 found 563.9; and

2-(2-{2-[1-(4,5-difluor-7-hydroksy-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre (Forbindelse 282), MS (ESI) C29H27N505F2 m/e beregnet 536,1 funnet 535,51. 2-(2-{2-[1-(4,5-difluoro-7-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 282), MS (ESI) C 29 H 27 N 5 O 5 F 2 m/e calcd 536.1 found 535.51.

EKSEMPEL 13 EXAMPLE 13

In vitro tryptase-hemningsforsøk In vitro tryptase inhibition assay

Tryptaseløsning (60 g/ml) ble fremstilt ved oppløsning av tryptase renset fra menneske-lunge- eller hud-vev-preparater eller human mastcellelinje (HMC-1) eller oppnådd fra kommersielle kilder, f.eks. ICN Biomeidals, Irvin, California, Athens Research & Technology, Athens, Georgia, etc, i en oppløsningsmiddelblanding omfattende: 10 mM 2-W-morfolinoetansulfonsyre, 2 mM CaCI2, 20% glycerol og 50 g/ml heparin. Substratløsning inneholdende 2 mM syntetisk tripeptid (tosyl-Gly-Pro-Lys-p-nitroanilid) ble anskaffet fra Sigma. Testforbindelse-løsninger ble fremstilt ved fortynning av en lagerløsning (1 mg testforbindelse i 200 ml dimetylsulfoksyd (DMSO)) med ti-ganger forsøksbuffer (omfattende: Tris-HCI (pH 8,2), 50 mM; NaCI, 100 mM; Tryptase solution (60 g/ml) was prepared by dissolving tryptase purified from human lung or skin tissue preparations or human mast cell line (HMC-1) or obtained from commercial sources, e.g. ICN Biomeidals, Irvin, California, Athens Research & Technology, Athens, Georgia, etc, in a solvent mixture comprising: 10 mM 2-W-morpholinoethanesulfonic acid, 2 mM CaCl 2 , 20% glycerol and 50 g/ml heparin. Substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys-p-nitroanilide) was purchased from Sigma. Test compound solutions were prepared by diluting a stock solution (1 mg of test compound in 200 mL of dimethyl sulfoxide (DMSO)) with tenfold assay buffer (comprising: Tris-HCl (pH 8.2), 50 mM; NaCl, 100 mM;

0,05% polyoksyetylensorbitan-monolaurat (Tween-20®); og sinkklorid, 150 mM) og deretter fremstilling av syv ytterligere tre-ganger fortynninger i 10% DMSO i forsøksbuffer. 0.05% polyoxyethylene sorbitan monolaurate (Tween-20®); and zinc chloride, 150 mM) and then making seven additional three-fold dilutions in 10% DMSO in assay buffer.

Aliquoter (50 ml) fra hver av de åtte fortynninger av testforbindelse-løsning ble satt til separate brønner i en 96-brønn U-bunnet mikrotiter-plate. Tryptase-løsning (25 ml) ble satt til hver brønn og løsningene ble blandet 1 time ved romtemperatur. Substrat-løsning (25 ml) ble tilsatt for å initiere den enzymatiske reaksjon og mikrotiter-platene ble umiddelbart overført til en UV/MAX kinetisk mikroplateleser (Molecular Devices). Hydrolyse av det kromogene substrat ble fulgt spektrofotometrisk ved 405 nanometer i fem minutter. Initielle hastighets-målinger ble beregnet fra utviklingskurvene med et kinetisk analyse program ( BatchKi; Petr Kuzmic, University of Wisconsin, Madison, Wl). Klare hemningskonstanter (Kj) ble beregnet fra enzym-utviklingskurvene ved anvendelse av standard matematiske modeller. Aliquots (50 ml) from each of the eight dilutions of test compound solution were added to separate wells in a 96-well U-bottom microtiter plate. Tryptase solution (25 ml) was added to each well and the solutions were mixed for 1 hour at room temperature. Substrate solution (25 ml) was added to initiate the enzymatic reaction and the microtiter plates were immediately transferred to a UV/MAX kinetic microplate reader (Molecular Devices). Hydrolysis of the chromogenic substrate was followed spectrophotometrically at 405 nanometers for five minutes. Initial velocity measurements were calculated from the development curves with a kinetic analysis program (BatchKi; Petr Kuzmic, University of Wisconsin, Madison, WI). Apparent inhibition constants (Kj) were calculated from the enzyme development curves using standard mathematical models.

Ved å gå frem som beskrevet i denne søknaden eller ved metoder kjent for fagfolk ble de følgende forbindelser ifølge foreliggende oppfinnelse testet for tryptase-hemmende aktivitet: Forbindelse 1, Kj=0,09^M; Forbindelse 12, K;=29 uM; Forbindelse 26, Ki=33^iM; Forbindelse 27, KpO.6 uM; Forbindelse 28, Ki=0,00007 uM; Forbindelse 29, Kj=0,0008 uM; Forbindelse 30, Kj=0,009 jjM; Proceeding as described in this application or by methods known to those skilled in the art, the following compounds of the present invention were tested for tryptase inhibitory activity: Compound 1, Kj=0.09 µM; Compound 12, K;=29 µM; Compound 26, Ki = 33 µM; Compound 27, KpO.6 µM; Compound 28, Ki=0.00007 µM; Compound 29, Kj=0.0008 µM; Compound 30, Kj=0.009 jjM;

Forbindelse 37, Kj=0,002 uM; Forbindelse 42, Ki=0,008 uM; Compound 37, Kj=0.002 µM; Compound 42, Ki=0.008 µM;

Forbindelse 43, Kj=0,002 \ M; Forbindelse 74, Kj=0,006 uM; Forbindelse 75, Kj=0,03 uM; Forbindelse 80, Ki=0,01 ^iM; Forbindelse 81, Ki=0,01 ^tM; Forbindelse 84, Ki=2,6 ^M; Forbindelse 102, Ki=0,00007 ^M; Compound 43, Kj=0.002 \ M; Compound 74, Kj=0.006 µM; Compound 75, Kj=0.03 µM; Compound 80, Ki=0.01 µM; Compound 81, Ki=0.01 µM; Compound 84, Ki=2.6 µM; Compound 102, Ki=0.00007 µM;

Forbindelse 112, Kj=0,00005^iM; Forbindelse 115, Ki=0,003^iM; Compound 112, Kj=0.00005 µM; Compound 115, Ki=0.003 µM;

Forbindelse 116, Kj=0,006 jiM; Forbindelse 117, Kr0,008 \ iM; Compound 116, Kj=0.006 µM; Compound 117, Kr0.008 \ iM;

Forbindelse 126, Kj=0,008 uM; Forbindelse 127, Ki=0,006 uM; Compound 126, Kj=0.008 µM; Compound 127, Ki=0.006 µM;

Forbindelse 128, Kj=0,002^M; Forbindelse 169, Ki=0,001 uM; Compound 128, Kj=0.002^M; Compound 169, Ki=0.001 µM;

Forbindelse 132, Kj=0,00002^M; Forbindelse 134, Ki=0,00002 uM; Forbindelse 138, Kj=0,0002 uM; Forbindelse 152, Ki=0,0005 ^M; Compound 132, Kj=0.00002^M; Compound 134, Ki=0.00002 µM; Compound 138, Kj=0.0002 µM; Compound 152, Ki=0.0005 µM;

Forbindelse 182, Kj=0,004 ^M; Forbindelse 194, Kj=0,009 uM; Compound 182, Kj=0.004 µM; Compound 194, Kj=0.009 µM;

Forbindelse 203, Kj=0,008 uM; Forbindelse 225, K^O.008 uM; Compound 203, Kj=0.008 µM; Compound 225, K^O.008 µM;

Forbindelse 249, Ki=0,0007 uM; Forbindelse 250, Kj=0,0004 uM; Compound 249, Ki=0.0007 µM; Compound 250, Kj=0.0004 µM;

Forbindelse 251, Kj=0,0008 uM; og Forbindelse 252, Kf0,0004 \ xM. Compound 251, Kj=0.0008 µM; and Compound 252, Kf0.0004 \ xM.

EKSEMPEL 14 EXAMPLE 14

Saue-modell av astma Sheep model of asthma

Den allergiske saue-modell av astma ble anvendt for in vivo evaluering av forbindelsene ifølge foreliggende oppfinnelse som antiastmatiske midler. Disse metoder er publisert tidligere (se Abraham et al. (1983) Am. Rev. Respir. Dis. 128:839-844; Allegra et al. (1983) J. Appl. Physiol. 55:726-730; Russi et al. The allergic sheep model of asthma was used for in vivo evaluation of the compounds of the present invention as antiasthmatic agents. These methods have been published previously (see Abraham et al. (1983) Am. Rev. Respir. Dis. 128:839-844; Allegra et al. (1983) J. Appl. Physiol. 55:726-730; Russi et al .

(1985) J. Appl. Physiol. 59:1416-1422; Soler et al. ((1989) J. Appl. Physiol. 67:406-413. Hver sau tjener som sin egen kontroll. Kroppsvektene til disse dyrene var fra 20-50 kg. I disse undersøkelsene ble 1 mg av Forbindelse 13 oppløst i 3 ml destillert vann og den totale løsning levert som en aerosol 0,5 timer før, 4 timer etter og 24 timer etter antigen-utfordring (total dose = 1 mg; n = 3). Resultatene av disse forsøk er oppsummert i Figur 1. 24 timer etter antigen-utfordringen i både kontroll- og medikament-forsøket, utviklet sauene luftveis-hyper-responsivitet. Luftveis-hyper-responsivitet er uttrykt som PC400, konsentrasjonen av karbachol som forårsaker en 400% økning i SRL; og en reduksjon i PC400 indikerer derfor hyper-responsivitet. Forbindelse 13 ble funnet å stanse begynnelse av hyper-responsivitet. Som vist i Figur 2 holdt denne forbindelsen PC400 hovedsakelig ved basisverdien på 15 pusteenheter. Antallet pusteenheter falt til 7 for dyrene i kontrollgruppen. Således resulterte behandling med Forbindelse 13 i en betydelig forbedring i luftveisfunksjon hos antigen-påvirkede sauer. Således tilveiebringer foreliggende oppfinnelse forbindelser og preparater som er nyttige for forebygging og behandling av immunomedierte inflammatoriske lidelser, spesielt de forbundet med luftveiene, omfattende astma og hyper-responsivitets-fase forbundet med kronisk astma, i tillegg til allergisk rhinitt. Foreliggende oppfinnelse er også ansett å tilveiebringe en metode for behandling av immunomedierte inflammatoriske lidelser som er mottagelige for behandling med en forbindelse ifølge foreliggende oppfinnelse. Det skal forstås at beskrivelsen ovenfor skal være illustrativ og ikke begrensende. Mange utførelsesformer vil være klare for fagfolk på området etter lesing av beskrivelsen ovenfor. Omfanget av foreliggende oppfinnelse skal derfor ikke være bestemt av beskrivelsen ovenfor, men skal istedet bestemmes av de følgende krav, samt de totale omfanget av ekvivalenter som hører inn under kravene. (1985) J. Appl. Physiol. 59:1416-1422; Soler et al. ((1989) J. Appl. Physiol. 67:406-413. Each sheep serves as its own control. The body weights of these animals ranged from 20-50 kg. In these studies, 1 mg of Compound 13 was dissolved in 3 ml of distilled water and the total solution delivered as an aerosol 0.5 h before, 4 h after, and 24 h after antigen challenge (total dose = 1 mg; n = 3). The results of these experiments are summarized in Figure 1. 24 h after antigen -challenge in both the control and drug trials, the sheep developed airway hyper-responsiveness. Airway hyper-responsiveness is expressed as PC400, the concentration of carbachol that causes a 400% increase in SRL; and a decrease in PC400 therefore indicates hyper- responsiveness. Compound 13 was found to arrest the onset of hyper-responsiveness. As shown in Figure 2, this compound maintained PC400 mainly at the baseline value of 15 respiratory units. The number of respiratory units dropped to 7 for the animals in the control group. Thus, treatment with Compound 13 resulted in a significant improvement in respiratory function in antigen-affected sheep. Thus, the present invention provides compounds and preparations useful for the prevention and treatment of immune-mediated inflammatory disorders, especially those associated with the respiratory tract, including asthma and hyper-responsiveness phase associated with chronic asthma, in addition to allergic rhinitis. The present invention is also considered to provide a method for the treatment of immune-mediated inflammatory disorders that are amenable to treatment with a compound according to the present invention. It is to be understood that the above description shall be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art after reading the above description. The scope of the present invention shall therefore not be determined by the description above, but shall instead be determined by the following claims, as well as the total scope of equivalents that fall under the claims.

Claims (21)

1. Forbindelse, karakterisert ved formel I: hvor: n1 er 0 eller 1, n2 er 0, 1, 2, 3 eller 4; A sammen med B er 1 H-benzoimidazol-2-yl eller 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl; X<1> og X<2> er nabostilte ringelementer i en aromatisk ring,og X<1> er en heteroatom-gruppe valgt fra -N=, -NR<5->, hvor R<5> har samme betydning som R<6>; C er 1 H-benzoimidazol-2-yl eller4,5,6,7-tetrahydro-1H-benzoimidazol-2-yi. X<4> og X<5> er nabostilte ringelementer i en aromatisk ring, X<5> er en heteroatom-gruppe valgt fra -N=, og -NR<6->, hvor R6 er hydrogen, en gruppe valgt fra eventuelt med én eller flere hydroksy substituert (Ci-8)alkyl, benzoyl, Ci-C6-alkoksy-Ci-C6-alkyl, (Ci^)alkanoyloksy, (Ci.6)alkylkarbamoyl, di(Ci.6)alkylkarbamoyl, (Ci.6)alkyloksykarbonyl eller (Ci-6)alkyloksysulfonyl; X<3> er -CR<7>R<8>-, hvor R7 er hydrogen eller (Ci^)alkyl; og R<8> er hydrogen eller (Ci.6)alkyl, R<1> er imidazolyl, -{CH2)XNHC(NR<9>)R<9>, -(CH2)xNHC(NH)NR<9>R<9>, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<1>0R10 eller -(CR<11>R<11>)yNH2, og er bundet til hvilket som helst ringatom med en tilgjengelig valens i B, hvor x er 0 eller 1, y er 0, 1, 2 eller 3, hver R<9> uavhengig er hydrogen eller (C^Jalkyl, hver R<10> uavhengig er {Ci-ejalkyl, og hver R<11> uavhengig er hydrogen, (Ci_3>alkyl eller sammen med en annen R<11> og et karbonatom til hvilket begge er tilknyttet, danner cyklopropyl, hver R2 uavhengig er: (Ci-6)alkyl, (C^Jalkyloksykarbonyl, (Ci^)alkanoyloksy, halogen eller hydroksy, og er bundet til hvilket som helst ringatom med en tilgjengelig valens i B, eller R<1> og R<2> sammen med to naboliggende karbonatomer i ring B danner en fenylring; og R4 er: (CH2)Y-NH2, eller -C(0)N(R<13>)R<12>, og er bundet til hvilket som helst ringkarbonatom med en tilgjengelig valens i C, hvor: R<12> er -R<15> eller -X<6->{R<15>)„i5, hvor n15 er 1 eller 2, X<6> er (Cioojalkylen, oksy(C2-io)alkylen, og hver R<15> er hydrogen, Ci-C6-alkoksy, amino. OH, karboksy Ci-C6-alkoksykarbonyl, fenyl-Ci-04-alkoksykarbonyl, tetrazolyl, eventuelt med OH substituert kinolyl, eventuelt med okso og/eller CrC6-alkyl subsituert kinazolinyl, eventuelt med OH eller Ci-C6-alkoksy substituert indolyl, benzoksazolinyl, pyridyl, C3-C7-cykloalkyl, eventuelt med Ci-C6-alkoksykarbonyl substituert C3-C7-cykloalkoksy, tetrahydronaftyl, eventuelt med OH substituert naftyl, fenyl eventuelt substituert med én eller flere substituenter valgt blant halogen, C1-C6-karbonyl, amino-Ci-Ce-alkyl, karboksy, Ci-Ce-alkoksy eller Ci-C3-alkylendioksy, fenoksy eventuelt substituert med én eller flere substituenter valgt blant Ci-C6-alkoksy, Ci-C6-alkoksykarbonyl, karboksy, Ci-C6-alkoksy-CrC6-alkoksy-Ci-C6-alkyl, CrC6-alkoksy-Ci-C6-alkyl, eventuelt med Ci-Ce-alkyl substituert oksadiazolyl, morfolinyl, halogen, tetrazolyl, C3-C7-cykloalkoksykarbonyl, CrC6-alkoksy-CrCe-alkoksykarbonyl, CN eller karbamoyl, R<13> er hydrogen eller (d.6)alkyl; eller et /V-oksyd-derivat, blanding av isomer og farmasøytisk godtagbart salt derav.1. Compound, characterized by formula I: where: n1 is 0 or 1, n2 is 0, 1, 2, 3 or 4; A together with B is 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl; X<1> and X<2> are adjacent ring elements in an aromatic ring, and X<1> is a heteroatom group selected from -N=, -NR<5->, where R<5> has the same meaning as R <6>; C is 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl. X<4> and X<5> are adjacent ring elements in an aromatic ring, X<5> is a heteroatom group selected from -N=, and -NR<6->, where R6 is hydrogen, a group selected from optionally with one or more hydroxy-substituted (Ci-8)alkyl, benzoyl, Ci-C6-alkoxy-Ci-C6-alkyl, (Ci-6)alkanoyloxy, (Ci-6)alkylcarbamoyl, di(Ci-6)alkylcarbamoyl, (Ci .6)alkyloxycarbonyl or (C1-6)alkyloxysulfonyl; X<3> is -CR<7>R<8>-, where R7 is hydrogen or (C1-4)alkyl; and R<8> is hydrogen or (Ci-6)alkyl, R<1> is imidazolyl, -{CH2)XNHC(NR<9>)R<9>, -(CH2)xNHC(NH)NR<9> R<9>, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<1>0R10 or -(CR<11>R<11>) yNH2, and is attached to any ring atom with an available valence in B, where x is 0 or 1, y is 0, 1, 2 or 3, each R<9> independently is hydrogen or (C₁₋₆alkyl, each R <10> independently is {Ci-ejalkyl, and each R<11> independently is hydrogen, (Ci_3>alkyl or together with another R<11> and a carbon atom to which both are attached form cyclopropyl, each R2 independently is: (Ci-6)alkyl, (Ci-6)alkyloxycarbonyl, (Ci-6)alkanoyloxy, halogen or hydroxy, and is attached to any ring atom with an available valence in B, or R<1> and R<2> together with two neighboring carbon atoms in ring B form a phenyl ring; and R4 is: (CH2)Y-NH2, or -C(0)N(R<13>)R<12>, and is attached to any ring carbon atom with an available valence at C, where: R<12> is -R<15> or -X<6->{R<15>)„i5, where n15 is 1 or 2, X<6> is (C100 alkylene, oxy(C2-10) alkylene, and each R<15> is hydrogen, C1-C6 alkoxy, amino. OH, carboxy C1-C6-alkoxycarbonyl, phenyl-C1-04-alkoxycarbonyl, tetrazolyl, optionally with OH substituted quinolyl, optionally with oxo and/or CrC6-alkyl substituted quinazolinyl, optionally with OH or C1-C6-alkoxy substituted indolyl, benzoxazolinyl . -Ci-C6-alkyl, carboxy, C1-C6-alkoxy or C1-C3-alkylenedioxy, phenoxy optionally substituted with one or more substituents selected from C1-C6-alkyl, C1-C6-alkyloxycarbonyl, carboxy, C1-C6-alkyl -CrC6-Alkoxy-Ci-C6-alkyl, CrC6-Alkoxy-Ci-C6-alkyl, optionally with Ci-Ce-Alkyl substituted oxadiazolyl, morpholinyl, halogen, tetrazolyl, C3-C7-Cycloalkoxycarbonyl, CrC6-Alkoxy-CrCe-Alkoxycarbonyl , CN or carbamoyl, R<13> is hydrogen or (d.6)alkyl; or a /V-oxide derivative, mixture of isomer and pharmaceutically acceptable salt thereof. 2. Forbindelse ifølge krav 1,karakterisert ved formel II: hvor: de stiplede linjer uavhengig representerer eventuelle bindinger; hver R<2> uavhengig er: (Ci.6)alkyl, halogen eller hydroksy; hverX<3> er -CR7R<8->; hvor R<7> og R<8> uavhengig er hydrogen eller (Ci-C6)alkyl; X<8> er -CH(R<1>)n1- eller -C(R<1>)n1<=> , hvor R<1> er: imidazolyl, -NHC(NH)NR<9>R<9>, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<1>0R10 eller -(CR11R11)yNH2, hvor hver R<9> uavhengig er hydrogen eller (Ci-e)alkyl og hver R<10> uavhengig er (Ci-e)alkyl; og X<9> er -CH(R<4>)- eller -C(R<4>)=, hvor R<4> er: <CH2)Y-NH2; eller -C(0)N(R13)R1<2>, hvori y er 0, 1,2 eller 3.2. Compound according to claim 1, characterized by formula II: where: the dashed lines independently represent any bonds; each R<2> independently is: (C1-6)alkyl, halogen or hydroxy; eachX<3> is -CR7R<8->; where R<7> and R<8> are independently hydrogen or (C1-C6)alkyl; X<8> is -CH(R<1>)n1- or -C(R<1>)n1<=> , where R<1> is: imidazolyl, -NHC(NH)NR<9>R<9 >, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<1>0R10 or -(CR11R11)yNH2, where each R<9> is independently hydrogen or (Ci-e)alkyl and each R<10> independently is (Ci-e)alkyl; and X<9> is -CH(R<4>)- or -C(R<4>)=, where R<4> is: <CH2)Y-NH2; or -C(0)N(R13)R1<2>, wherein y is 0, 1,2 or 3. 3. Forbindelse if ølge krav 2, karakterisert ved at R<5> er hydrogen eller (Ci.4)alkyl, R6 er hydrogen eller (d^alkyl, hvilken alkylgruppe eventuelt er substituert med én til to hydroksy, R7 er hydrogen eller metyl, og R<8> er hydrogen eller metyl; X8er-C(R1)m= , hvor R<1> er: aminometyl, 2-amino-1,1 -d imetyletyl, imidazolyl, -C{NR<9>)R<9>, hvor hver R<9> uavhengig er hydrogen eller metyl; X9 er-C(R4)=, hvor R4 er: -C(0)N(R13)R<12>, hvor R<13> er hydrogen eller (Ci^)alkyl; R<12> er -R<15> eller -X<6->(R<15>)ni5, hvor X<6> er (Ci-io)alkylen eller hetero(C2-io)alkylen, og hver R<15> uavhengig er som forut definert, eller et W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbare salter derav.3. Compound according to claim 2, characterized in that R<5> is hydrogen or (Ci-4)alkyl, R 6 is hydrogen or (C 1-4 alkyl), which alkyl group is optionally substituted with one to two hydroxy, R 7 is hydrogen or methyl, and R<8> is hydrogen or methyl; X8 is-C(R1)m= , where R<1> is: aminomethyl, 2-amino-1,1-dimethylethyl, imidazolyl, -C{NR<9>)R<9>, where each R<9> is independently hydrogen or methyl; X9 is -C(R4)=, where R4 is: -C(O)N(R13)R<12>, where R<13> is hydrogen or (C1-6)alkyl; R<12> is -R<15> or -X<6->(R<15>)n15, where X<6> is (C1-10)alkylene or hetero(C2-10)alkylene, and each R< 15> independently is as previously defined, or a W-oxide derivative, mixture of isomers or pharmaceutically acceptable salts thereof. 4. Forbindelse ifølge krav 3, karakterisert ved at A sammen med B danner 1/-/-benzoimidazol-2-yl eller 4,5,6,7-tetrahydro-1H-benzoimidazot-2-yl, hvor R<1> er aminometyl, og hver R<2> uavhengig er halogen eller hydroksy; C er 1H-benzoimidazol-2-yl, hvor R<4>, X6 og R<15> er som forut definert; eller et W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbare salter derav.4. Compound according to claim 3, characterized in that A together with B forms 1/-/-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazot-2-yl, where R<1> is aminomethyl, and each R<2> independently is halogen or hydroxy; C is 1H-benzoimidazol-2-yl, where R<4>, X6 and R<15> are defined as before; or a W-oxide derivative, mixture of isomers or pharmaceutically acceptable salts thereof. 5. Forbindelse ifølge krav 4, karakterisert ved at A sammen med B danner 1H-benzoimidazol-2-yl og hver R<2> uavhengig er halogen eller hydroksy; eller et A/-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav.5. Compound according to claim 4, characterized in that A together with B forms 1H-benzoimidazol-2-yl and each R<2> independently is halogen or hydroxy; or an A/-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof. 6. Forbindelse ifølge krav 5, karakterisert ved at n1 er 0; eller et A/-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav.6. Compound according to claim 5, characterized in that n1 is 0; or an A/-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof. 7. Forbindelse ifølge krav 6, karakterisert ved at den er valgt fra: (a) 2-(2-{2-[1-(4,6,7-trifluor-1H-benzoimidazol-2-yl)etyl]-3-mety!-3/-/-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre; (forb. 80) (b) 2-(2-{2-[1-(5,6-difluor-1H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzosyre; (forb. 81) (c) butyl-2-(2-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 37) (d) propyl-2-(2-{2-[1 -(5-hydroksy-1 tf-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 42), og (e) isobutyl-2-(2-{2-[1 -(5-hydroksy-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3W-benzoimidazol-5-ylkarbonylamino}etoksy)benzoat; (forb. 43), W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav.7. Compound according to claim 6, characterized in that it is selected from: (a) 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3 -methyl-3 H -benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid; (comp. 80) (b) 2-(2-{2-[1-(5,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy )benzoic acid; (comp. 81) (c) butyl-2-(2-{2-[1 -(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoate; (comp. 37) (d) propyl-2-(2-{2-[1 -(5-hydroxy-1 tf-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoate; (comp. 42), and (e) isobutyl-2-(2-{2-[1 -(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3N-benzoimidazol-5- ylcarbonylamino}ethoxy)benzoate; (comp. 43), W-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof. 8. Forbindelse ifølge krav 4, karakterisert ved at R<1> er aminometyl eller et W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav.8. Compound according to claim 4, characterized in that R<1> is aminomethyl or a W-oxide derivative, mixture of isomers or a pharmaceutically acceptable salt thereof. 9. Forbindelse ifølge krav 8, karakterisert ved at den er valgt fra: (a) 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 28); (b) 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-(2,3-dihydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 132); (c) 2-(5-guanidino-1/-/-benzoimidazol-2-ylkarbonyl)-3-(2,3-dihydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 134); (d) 2-(5-guanidino-1/-/-benzoimidazol-2-ylmetyl)-3-(3-hydroksy)propyl-W-(2-naft-1-yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 138); (e) 2-(5-guanidino-1H-benzoimidazol-2-ylmetyl)-3-(2-hydroksy)etyl-W-(2-naft-1-yletyl)-3W-benzoimidazol-5-karboksamid; (forb. 152); (f) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-W-[2-(2-karbamoyl-fenoksy)etyl]-3-metyl-3/-/-benzoimidazol-5-karboksamid; (forb. 249); (g) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-W-[2-(2-karbamoyl-4-klorfenoksy)etyl]-3-metyl-3H-benzoimidazol-5-karboksamid; (forb. 250); (h) 4-klor-2-[2-({2-[1-(5-guanidino-1H-benzoimidazol-2-yl)etyl]-3-metyl-3tf-benzoimidazol-5-ylkarbonyl}amino)etoksy]benzosyre; (forb. 251); (i) 5-klor-2-[2-({2-[1 -(5-guanidino-1 H-benzoimidazol-2-yl)etyl]-3-metyl-3H-benzoimidazol-5-ylkarbonyl}amino)etoksy]benzosyre; (forb. 2 52); Q) 2-(5-aminometyl-1 H-benzoimidazol-2-ylmetyl)-3-metyl-W-(2-naft-1 -yletyl)-3H-benzoimidazol-5-karboksamid; (forb. 102); og (k) 2-(5-aminometyl-4,5,6,7-tetrahydro-1/-/-benzoimidazol-2-ylmetyl)-3- metyl-W-(2-naft-1-yletyl)-3W-benzoimidazol-5-karboksamid (forb. 112); eller et W-oksyd-derivat, blanding av isomerer eller farmasøytisk godtagbart salt derav.9. Compound according to claim 8, characterized in that it is selected from: (a) 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)- 3H-benzoimidazole-5-carboxamide; (prob. 28); (b) 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide; (prob. 132); (c) 2-(5-guanidino-1/-/-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5 -carboxamide; (prob. 134); (d) 2-(5-guanidino-1/-/-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide ; (prob. 138); (e) 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl-N-(2-naphth-1-ylethyl)-3N-benzoimidazol-5-carboxamide; (prob. 152); (f) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-carbamoyl-phenoxy)ethyl]-3-methyl-3/-/-benzoimidazol- 5-carboxamide; (prob. 249); (g) 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-W-[2-(2-carbamoyl-4-chlorophenoxy)ethyl]-3-methyl-3H-benzoimidazol-5 -carboxamide; (prob. 250); (h) 4-chloro-2-[2-({2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3tf-benzoimidazol-5-ylcarbonyl}amino)ethoxy ]benzoic acid; (prob. 251); (i) 5-Chloro-2-[2-({2-[1 -(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonyl}amino) ethoxy]benzoic acid; (prob. 2 52); Q) 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazol-5-carboxamide; (prob. 102); and (k) 2-(5-aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl)-3- methyl N-(2-naphth-1-ylethyl)-3N-benzoimidazole-5-carboxamide (comp. 112); or a W-oxide derivative, mixture of isomers or pharmaceutically acceptable salt thereof. 10. Farmasøytisk preparat, karakterisert ved at det omfatter en forbindelse ifølge hvert av krav 1-9 sammen med en farmasøytisk godtagbar bærer.10. Pharmaceutical preparation, characterized in that it comprises a compound according to each of claims 1-9 together with a pharmaceutically acceptable carrier. 11. Farmasøytisk preparat ifølge krav 10, karakterisert ved at det videre omfatter en B-adrenerg agonist-forbindelse.11. Pharmaceutical preparation according to claim 10, characterized in that it further comprises a B-adrenergic agonist compound. 12. Farmasøytisk preparat ifølge krav 11, karakterisert ved at nevnte B-adrenerge agonist-forbindelse er valgt fra gruppen bestående av albuterol, terbutalin, formoterol, fenoterol og prenalin.12. Pharmaceutical preparation according to claim 11, characterized in that said B-adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formoterol, fenoterol and prenaline. 13. Farmasøytisk preparat ifølge krav 10, karakterisert ved at nevnte preparat omfatter en farmasøytisk godtagbar topisk bærer.13. Pharmaceutical preparation according to claim 10, characterized in that said preparation comprises a pharmaceutically acceptable topical carrier. 14. Farmasøytisk preparat ifølge krav 10, karakterisert ved at nevnte preparat omfatter en farmasøytisk godtagbar oral bærer.14. Pharmaceutical preparation according to claim 10, characterized in that said preparation comprises a pharmaceutically acceptable oral carrier. 15. Farmasøytisk preparat ifølge krav 15, karakterisert ved at nevnte preparat omfatter en farmasøytisk godtagbar aerosol-bærer.15. Pharmaceutical preparation according to claim 15, characterized in that said preparation comprises a pharmaceutically acceptable aerosol carrier. 16. Forbindelse for anvendelse som en medisin, karakterisert ved at den er en forbindelse ifølge krav 1-9.16. Compound for use as a medicine, characterized in that it is a compound according to claims 1-9. 17. Anvendelse av en forbindelse ifølge krav 1 - 9 til fremstilling av et terapeutisk preparat for behandling av en immunomediert inflammatorisk lidelse hos et pattedyr.17. Use of a compound according to claims 1 - 9 for the preparation of a therapeutic preparation for the treatment of an immunomediated inflammatory disorder in a mammal. 18. Anvendelse av en forbindelse ifølge krav 1 - 9 til fremstilling av et terapeutisk preparat for behandling av en immunomediert inflammatorisk lidelse i luftveiene hos et pattedyr.18. Use of a compound according to claims 1 - 9 for the preparation of a therapeutic preparation for the treatment of an immunomediated inflammatory disorder in the respiratory tract of a mammal. 19. Anvendelse av en forbindelse ifølge krav 1 - 9 til fremstilling av et terapeutisk preparat for behandling av revmatoid artritt hos et pattedyr.19. Use of a compound according to claims 1 - 9 for the production of a therapeutic preparation for the treatment of rheumatoid arthritis in a mammal. 20. Anvendelse av en forbindelse ifølge krav 1 - 9 til fremstilling av et terapeutisk preparat for behandling av konjunktivitt hos et pattedyr.20. Use of a compound according to claims 1 - 9 for the production of a therapeutic preparation for the treatment of conjunctivitis in a mammal. 21. Anvendelse av en forbindelse ifølge krav 1 - 9 til fremstilling av et terapeutisk preparat for behandling av syncytial-virus-infeksjoner hos et pattedyr.21. Use of a compound according to claims 1 - 9 for the preparation of a therapeutic preparation for the treatment of syncytial virus infections in a mammal.
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