NO313879B1 - Disubstituted bicyclic heterocycles, use and preparation thereof and drug - Google Patents

Disubstituted bicyclic heterocycles, use and preparation thereof and drug Download PDF

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NO313879B1
NO313879B1 NO19993945A NO993945A NO313879B1 NO 313879 B1 NO313879 B1 NO 313879B1 NO 19993945 A NO19993945 A NO 19993945A NO 993945 A NO993945 A NO 993945A NO 313879 B1 NO313879 B1 NO 313879B1
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methyl
amide
carboxylic acid
aminomethyl
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NO19993945A
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NO993945L (en
NO993945D0 (en
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Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean Marie Stassen
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Boehringer Ingelheim Pharma
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Priority claimed from DE19706229A external-priority patent/DE19706229A1/en
Priority claimed from DE1997151939 external-priority patent/DE19751939A1/en
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Publication of NO993945D0 publication Critical patent/NO993945D0/en
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Description

Foreliggende oppfinnelse vedrører disubstituerte bisykliske heterosykler, anvendelse og fremstilling derav samt legemiddel The present invention relates to disubstituted bicyclic heterocycles, their use and production as well as medicine

Gjenstand ifølge foreliggende oppfinnelse er følgelig nye disubstituerte bisykliske heterosykler med generell formel (I) Object according to the present invention are consequently new disubstituted bicyclic heterocycles of general formula (I)

hvor where

A er en med benzo-, pyrido- eller tienodel av resten Het koplet karbonyl- eller sulfonylgruppe, idet de ovennevnte delene dessuten ikke kan inneholde resten Ri, A is one with a benzo-, pyrido- or thieno part of the residue Het coupled carbonyl or sulfonyl group, the above-mentioned parts also cannot contain the residue Ri,

B er en etylengruppe, hvor en metylengruppe, som enten er koplet med resten Het eller Ar, kan bli erstattet med et oksygen- eller svovelatom, med en sulfinyl-, sulfonyl-, karbonyl-eller -NRi-gruppe, idet B is an ethylene group, where a methylene group, which is either linked to the residue Het or Ar, can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl or -NRi group, as

Ri er et hydrogenatom eller en Ci-4-alkylgruppe, R 1 is a hydrogen atom or a C 1-4 alkyl group,

E er en RbNH-C(=NH)-gruppe hvor E is a RbNH-C(=NH) group where

Rb er et hydrogenatom, en hydroksygruppe, en Ci-3-alkylgruppe eller eventuelt med Ci-C6-alkylsulfonyl eller Ci-C6-alkoksy-Ci-C6-alkyl substituert Ci-C9-alkoksykarbonyl, C3-C7-cykloalkoksykarbonyl, fenyl-Ci-C4-alkoksykarbonyl, eventuelt med C]-C4-alkyl substituert med benzoyl eller pyridinoyl, Rb is a hydrogen atom, a hydroxy group, a C 1-3 alkyl group or optionally with C 1-C 6 alkylsulfonyl or C 1-C 6 alkoxy-C 1-C 6 alkyl-substituted C 1-C 9 alkoxycarbonyl, C 3-C 7 cycloalkylcarbonyl, phenyl-C 1 -C4-Alkoxycarbonyl, optionally with C1-C4-alkyl substituted with benzoyl or pyridinoyl,

Ar er fenylengruppe eventuelt substituert med et fluor-, klor- eller bromatom, med en trifluormetyl-, Ci-3-alkyl- eller Ci-3-alkoksygruppe, Ar is phenylene group optionally substituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, C 1-3 alkyl or C 1-3 alkoxy group,

en eventuelt i karbonskjelettet tienylen-, tiazolylen, pyridinylen-, pyrimidinylen-, pyrazinylen- eller pyridazinylengruppe eventuelt substituert med en Ci-3-alkyl-gruppe, an optional thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton with a C 1-3 alkyl group,

Het er en bisyklisk heterosyklus med formelen Het is a bicyclic heterocycle with the formula

hvor where

X er et nitrogenatom og X is a nitrogen atom and

Y er et oksygen- eller svovelatom eller en eventuelt med en Ci-6-alkyl- eller C3-7-sykloalkylgruppe substituert nitrogenatom, Y is an oxygen or sulfur atom or a nitrogen atom optionally substituted with a C1-6 alkyl or C3-7 cycloalkyl group,

eller X er en eventuelt med resten Ri substituert metingruppe, idet Ri er definert som ovenfor, og or X is a methine group optionally substituted with the residue Ri, Ri being defined as above, and

Y er et nitrogenatom eventuelt substituert med en Ci-6-alkyl- eller C3-7-syklo-alkylgruppe, eller Het er en gruppe med formlene eller Y is a nitrogen atom optionally substituted with a C 1-6 alkyl or C 3-7 cycloalkyl group, or Het is a group of the formulas or

idet while

Ri er definert som ovenfor og Ri is defined as above and

R er et hydrogenatom eller en Ci^-alkyl, eller C3-7-sykloalkylgruppe, og R is a hydrogen atom or a C 1-6 alkyl, or C 3-7 cycloalkyl group, and

Ra er en Ci-6-alkylgruppe, en eventuelt med en Ci-3-alkylgruppe substituert C3.7-sykloalkylgruppe, idet Ci-3-alkylgruppen i tillegg kan være substituert med en karboksylgruppe eller Ci-Cé-alkoksykarbonyl, eller en R2NR3-gruppe, hvor Ra is a C1-6 alkyl group, a C3.7-cycloalkyl group optionally substituted with a C1-3 alkyl group, the C1-3 alkyl group can additionally be substituted with a carboxyl group or C1-C6 alkoxycarbonyl, or an R2NR3- group, where

R2 er en Ci-4-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, Ci-3-alkylsulfonylaminokarbonyl-, fenyl-sulfonyl-aminokarbonyl-, trifluorsulfonylamino, trifluorsulfonylaminokarbonyl- eller lH-tetrazolyl-gruppe, eller R2 is a C1-4 alkyl group, which may be substituted with a carboxy-, C1-6-alkyloxycarbonyl, benzyloxycarbonyl-, C1-3-alkylsulfonylaminocarbonyl-, phenyl-sulfonyl-aminocarbonyl-, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl- or 1H-tetrazolyl- group, or

med hydroksy-, fenyl-Ci-3-akoksy, karboksy-Ci-3-alkylamino-, Ci-3-alkoksy-karbonyl-Ci-3alkylamino-, N-(Ci-3-alkyl)-karboksy-Ci-3-alkylamino eller N-(Ci-3-alkyl)-Ci.3-alkoksykarbonyl-Ci.3-alkylaminogruppe substituert C2-4-alkylgruppe, idet i den ovenfor angitte gruppen a-karbonatomet som står ved siden av nitrogen-atomet ikke kan være substituert, eller with hydroxy-, phenyl-Ci-3-alkoxy, carboxy-Ci-3-alkylamino-, Ci-3-alkoxy-carbonyl-Ci-3-alkylamino-, N-(Ci-3-alkyl)-carboxy-Ci-3- alkylamino or N-(Ci-3-alkyl)-Ci-3-alkoxycarbonyl-Ci-3-alkylamino group substituted C2-4-alkyl group, in that in the above-mentioned group the a-carbon atom standing next to the nitrogen atom cannot be substituted, or

en eventuelt med en Ci-3-alkylgruppe substituert piperidinylgruppe og a piperidinyl group optionally substituted with a C 1-3 alkyl group and

R3 er en eventuelt med en Ci-3-alkyl-gruppe substituert C3-7-sykloalkylgruppe, en C3-6-alkenyl- eller alkinylgruppe, idet den umettede delen ikke kan være direkte koplet til nitrogenatomet i R2NR3-gruppen, en fenylgruppe eventuelt substituert med et fluor, Mor-eller bromatom, med en Ci-3-alkyl- eller Ci-3-alkoksygruppe, en even-tuelt med en C1-3-alkylgruppe substituert benzyl-, oksazolyl-, isoksazolyl-, tiazolyl, isotiazolyl-, pyrazolyl-, pyrrolyl-, tienyl-, pyrimidinyl-, pyrazinyl-, pyridazinyl-, imidazolyl- eller piperidinylgruppe eller R3 is a C3-7 cycloalkyl group optionally substituted with a C1-3 alkyl group, a C3-6 alkenyl or alkynyl group, the unsaturated part cannot be directly linked to the nitrogen atom in the R2NR3 group, a phenyl group optionally substituted with a fluorine, Mor or bromine atom, with a C 1-3 alkyl or C 1-3 alkoxy group, an optionally with a C 1-3 alkyl group substituted benzyl-, oxazolyl-, isoxazolyl-, thiazolyl, isothiazolyl-, pyrazolyl, pyrrolyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl or piperidinyl group or

R2 og R3 sammen med nitrogenatomet som ligger derimellom er 5- til 7-leddet sykloalkyleniminogruppe valgt blant dihydroindolyl, isoindolinyl eller pyrrolidinyl eventuelt substituert med en karboksy- eller Ci^-alkoksykarbonygruppe, tautomerer, stereoisomerer og salter derav. R2 and R3 together with the nitrogen atom which lies between them is a 5- to 7-membered cycloalkyleneimino group selected from dihydroindolyl, isoindolinyl or pyrrolidinyl optionally substituted with a carboxy- or C1-4-alkyloxycarbonyl group, tautomers, stereoisomers and salts thereof.

Forbindelsene med ovennevnte generelle formel (I) som innholder en in vivo avspaltbar rest tilveiebringer dermed såkalte promedikamenter og forbindelser med generell formel (I), såkalte dobbeltpromedikamenter som inneholder to in vivo avspaltbare rester. The compounds with the above-mentioned general formula (I) which contain an in vivo cleavable residue thus provide so-called prodrugs and compounds with general formula (I), so-called double prodrugs which contain two in vivo cleavable residues.

Foreliggende oppfinnelse vedrører videre de substituerte bisykliske heterosykler med gernerell formel I ifølge krav 1, kjennetegnet ved at The present invention further relates to the substituted bicyclic heterocycles of general formula I according to claim 1, characterized in that

A er en karbonyl- eller sulfonylgruppe koplet med benzo-, pyrido- eller tienodelen av resten Het, idet de ovennevnte delene dessuten ikke kan inneholde resten Ri, A is a carbonyl or sulfonyl group linked to the benzo, pyrido or thieno part of the residue Het, the above-mentioned parts also cannot contain the residue Ri,

B er en etylengruppe, hvor metylengruppen, som er koplet til rest Ar, kan bli erstattet med et oksygen- eller svovelatom eller med en -NRi -gruppe idet B is an ethylene group, where the methylene group, which is connected to the residue Ar, can be replaced by an oxygen or sulfur atom or by an -NRi group as

Ri er et hydrogenatom eller en Ci-4-alkylgruppe, R 1 is a hydrogen atom or a C 1-4 alkyl group,

E er en RbNH-C(=NH)-gruppe idet E is a RbNH-C(=NH) group in that

Rb er et hydrogenatom, en hydroksy-, Ci-9-alkoksykarbonyl-, sykloheksyl-oksykarbonyl-, fenyl-Ci-3-alkoksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller pyridinoylgruppe, idet etoksydelen i 2-stillingen til ovenfor angitte Ci-9-alkoksykarbonyl-gruppe i tillegg kan være substituert med en Ci_3-alkyl-sulfonyl- eller 2-(Ci-3-alkoksy)-etyl-gruppe, Rb is a hydrogen atom, a hydroxy-, C1-9-alkyloxycarbonyl-, cyclohexyl-oxycarbonyl-, phenyl-C1-3-alkoxycarbonyl-, benzoyl-, p-C1-3-alkylbenzoyl or pyridinoyl group, the ethoxy moiety in the 2-position to the C 1-9 -alkoxycarbonyl group specified above can additionally be substituted with a C 1-3 -alkyl-sulfonyl- or 2-(C 1-3 - alkoxy)-ethyl group,

Ar er en eventuelt med et kloratom, eller en metoksygruppe, substituert 1,4-fenylengruppe eller en 2,5-tienylengruppe, Ar is a substituted 1,4-phenylene group or a 2,5-thienylene group, optionally with a chlorine atom, or a methoxy group,

Het er en l-(Ci.3-alkyl)-2,5-benzimidazolylen-, l-sykopropyl-2,5-benzimidazo-lylen-, 2,5-benztiazolylen-, l-(Ci_3-alkyl)-2,5-indolylen-, l-(Ci-3-alkyl)-2,5-imidazo[4,5-b]-pyridinylen-, 3-(Ci-3-alkyl)-2,7-imidazo[l,2-a]pyridinylen- eller l-(Ci_3-aIkyl)-2,5-tieno-[2,3-d]imidazolylengruppe og Het is a l-(Ci-3-alkyl)-2,5-benzimidazolylene-, l-cyclopropyl-2,5-benzimidazolylene-, 2,5-benzthiazolylene-, l-(Ci_3-alkyl)-2, 5-Indolylene-, 1-(Ci-3-alkyl)-2,5-imidazo[4,5-b]-pyridinylene-, 3-(Ci-3-alkyl)-2,7-imidazo[l,2 -a]pyridynylene or 1-(Ci-3-alkyl)-2,5-thieno-[2,3-d]imidazolylene group and

Ra er en R2NR3-gruppe, hvor R a is an R 2 NR 3 group, where

R2 er en Ci-4-alkylgruppe, som kan være substituert med en karboksy-, Ci-6-alkyloksykarbonyl, benzyloksykarbonyl-, Ci-3-alkylsulfonylaminokarbonyl- eller R2 is a C1-4 alkyl group, which may be substituted with a carboxy-, C1-6-alkyloxycarbonyl, benzyloxycarbonyl-, C1-3-alkylsulfonylaminocarbonyl- or

1 H-tetrazol-5-ylgruppe, 1 H-tetrazol-5-yl group,

en C2^-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci-3-alkylamino-, Ci-3-alkoksykarbonyl-Ci-3-alkylamino-, N-(Ci.3-alkyl)-karboksy-Ci-3-alkylamino eller N-(Ci-3-alkyl)-Ci.3-alkoksykarbonyl-Ci.3-alkylaminogruppe, idet i den ovennevnte gruppen a-karbonatomet som står ved siden av nitrogenatomet ikke være substituert, a C 2-3 -alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C 1-3 -alkylamino-, C 1-3 -carboxycarbonyl-C 1-3 -alkylamino-, N -(C 1-3 -alkyl)-carboxy-C 1-3 -alkylamino or N-(Ci-3-alkyl)-Ci-3-Alkoxycarbonyl-Ci-3-alkylamino group, whereby in the above-mentioned group the α-carbon atom standing next to the nitrogen atom is not substituted,

R3 er en C3-7-sykloalkylgruppe, en propargylgruppe, idet den umettede delen ikke direkte kan være koplet med nitrogenatomet til R2NR3-gruppen, en fenylgruppe eventuelt substituert med et fluor- eller kloratom, med en metyl- eller R3 is a C3-7 cycloalkyl group, a propargyl group, the unsaturated part cannot be directly linked to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with a fluorine or chlorine atom, with a methyl or

metoksygruppe, en eventuelt med en metylgruppe substituert pyrazolyl-, pyridazolyl- eller pyridinylgruppe eller methoxy group, a pyrazolyl, pyridazolyl or pyridinyl group optionally substituted with a methyl group or

R2 og R3 sammen med det mellomliggende nitrogenatomet er 5- til 7-leddet sykloalkyleniminogruppe eventuelt substituert med en karboksy- eller Ci-4-alkoksy-karbonylgruppe, hvortil i tillegg en fenylring kan være påkondensert, R2 and R3 together with the intervening nitrogen atom is a 5- to 7-membered cycloalkylenimino group optionally substituted with a carboxy- or C1-4-alkyloxy-carbonyl group, to which a phenyl ring can additionally be condensed,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Det er videre beskrevet disubstituerte bisykliske heterosykler med generell formel I ifølge krav 1, kjennetegnet ved at It is further described disubstituted bicyclic heterocycles of general formula I according to claim 1, characterized by that

A er karbonyl- eller sulfonylgruppe koplet med benzo-, pyrido- eller tienodel av resten Het, idet de ovennevnte delene dessuten ikke kan inneholde resten Ri, A is a carbonyl or sulfonyl group coupled with a benzo-, pyrido- or thieno part of the residue Het, the above-mentioned parts also cannot contain the residue Ri,

B er en etylengruppe, hvor metylengruppen som er koplet med rest Ar, kan være erstattet med et oksygen- eller svovelatom eller med en -NRj -gruppe idet B is an ethylene group, where the methylene group which is connected to the residue Ar, can be replaced by an oxygen or sulfur atom or by a -NRj group as

Ri er et hydrogenatom eller en metylgruppe, R 1 is a hydrogen atom or a methyl group,

E er en RbNH-C(=NH)-gruppe, hvor E is a RbNH-C(=NH) group, where

Rb er et hydrogenatom, en hydroksy-, Ci-9-alkoksykarbonyl-, sykloheksyloksy-karbonyl-, benzyloksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller nikotinoylgruppe, idet etoksydelen i 2-stillingen av ovennevnte Ci-9-alkoksykarbonylgruppe i tillegg kan være substituert med en Ci-3-alkylsulfonyl- eller 2-(Ci-3-alkoksy)-etylgruppe, Rb is a hydrogen atom, a hydroxy-, C1-9-alkyloxycarbonyl-, cyclohexyloxy-carbonyl-, benzyloxycarbonyl-, benzoyl-, p-C1-3-alkylbenzoyl or nicotinoyl group, the ethoxy part in the 2-position of the above-mentioned C1-9- Alkoxycarbonyl group can additionally be substituted with a C1-3-alkylsulfonyl- or 2-(C1-3-alkoxy)-ethyl group,

Ar er en eventuelt med et kloratom med en metyl-, etyl- eller metoksygruppe substituert 1,4-fenylengruppe eller en 2,5-tienylengruppe, Ar is a 1,4-phenylene group optionally substituted by a chlorine atom with a methyl, ethyl or methoxy group or a 2,5-thienylene group,

Het er en l-metyl-2,5-benzimidazolylen, l-syklopropyl-2,5-benzimida-zolylen-, 2,5-benztiazolylen-, l-metyl-2,5-indolylen-, l-metyl-2,5-imidazo[4,5-b]-pyridinylen-, 3-metyl-2,7-imidazo[l,2-a]pyirdinylen- eller l-metyl-2,5-tieno[2,3-d]-imidazolylengruppe og Ra er en R2NR3-gruppe, hvor Het is a l-methyl-2,5-benzimidazolylene, l-cyclopropyl-2,5-benzimidazolylene-, 2,5-benzthiazolylene-, l-methyl-2,5-indolylene-, l-methyl-2, 5-imidazo[4,5-b]-pyridinylene-, 3-methyl-2,7-imidazo[l,2-a]pyridinylene- or l-methyl-2,5-thieno[2,3-d]- imidazolylene group and R a is an R 2 NR 3 group, where

R2 er en Ci.3-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, metylsulfonylaminokarbonyl- eller lH-tetrazol-5-ylgruppe, R 2 is a C 1-3 alkyl group, which may be substituted with a carboxy, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,

C2-3-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci-3-alkylamino-, C1.3-alkoksykarbonyl-C 1.3-alkylamino-, N-(Ci _3-alkyl)-karboksy-C 1.3-alkylamino eller N-(Ci.3-alkyl)-Ci-3-alkoksykarbonyl-Ci.3-alkylaminogruppe, idet i de ovennevnte gruppene a-karbonatomet som står ved siden av nitrogen-atomet ikke kan være substituert, C 2-3 -alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C 1-3 -alkylamino-, C 1-3 -carboxycarbonyl-C 1-3 -alkylamino-, N -(C 1-3 -alkyl)-carboxy-C 1-3 -alkylamino or N-(Ci-3-alkyl)-Ci-3-Alkoxycarbonyl-Ci-3-alkylamino group, in that in the above-mentioned groups the α-carbon atom which stands next to the nitrogen atom cannot be substituted,

og R3 er en propargylgruppe, idet den umettede delen ikke kan være direkte koplet med nitrogenatomet til R2NR3-gruppen, en eventuelt med et fluor- eller kloratom med en metyl- eller metoksygruppe substituert fenylgruppe eller en pyridinylgruppe, and R3 is a propargyl group, the unsaturated part cannot be directly linked to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with a fluorine or chlorine atom with a methyl or methoxy group or a pyridinyl group,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Foreliggende oppfinnelse vedrører videre disubstituerte bisykliske heterosykler med generell formel 1 ifølge krav 1, kjennetegnet ved at The present invention further relates to disubstituted bicyclic heterocycles of general formula 1 according to claim 1, characterized in that

A er en karbonylgruppe koplet med benzo- eller tienodelen av resten Het, A is a carbonyl group linked to the benzo or thieno part of the residue Het,

B er en etylengruppe, idet metylengruppen, som er koplet med resten Ar, kan bli erstattet med en -NRi-gruppe, idet B is an ethylene group, the methylene group, which is connected to the residue Ar, can be replaced by a -NRi group, since

Ri er et hydrogenatom eller en metylgruppe, R 1 is a hydrogen atom or a methyl group,

E er en RbNH-C(=NH)-gruppe, idet E is a RbNH-C(=NH) group, wherein

Rb er et hydrogenatom, en hydroksy-, Ci-g-alkoksykarbonyl-, sykloheksyl-oksykarbonyl-, benzyloksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller nikotino-yl-gruppe hvor etoksydelen i 2-stillingen til ovennevnte Ci-9-alkoksy-karbonylgruppe i tillegg kan være substituert med en metylsulfonyl- eller 2-etoksyetylgruppe, Rb is a hydrogen atom, a hydroxy, C 1-6 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C 1-3 -alkylbenzoyl or nicotinoyl group where the ethoxy part in the 2-position of the above Ci -9-Alkoxycarbonyl group can additionally be substituted with a methylsulfonyl or 2-ethoxyethyl group,

Ar er en eventuelt med en metoksygruppe substituert 1,4-fenylengruppe eller en 2,5 -tienylengruppe, Ar is a 1,4-phenylene group optionally substituted with a methoxy group or a 2,5-thienylene group,

Het er en l-metyl-2,5-benzimidazolylen, 2,5-benztiazolylen-, l-metyl-2,5-indolylen- eller l-metyl-2,5-tieno[2,3-d]-imidazolylengruppe og Het is a 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]-imidazolylene group and

Ra er en R2NR3-gruppe, idet R a is an R 2 NR 3 group, wherein

R2 er en Ci-3-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, metylsulfonylaminokarbonyl- eller lH-tetrazol-5-ylgruppe, R 2 is a C 1-3 alkyl group, which may be substituted with a carboxy, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,

en C2-3-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci.3-alkylamino-, C1 -3-alkoksykarbonyl-Ci .3-alkylamino-, N-(C 1 -3-alkyl)-karboksy-Ci .3-alkylamino eller N-(Ci-3-alkyl)-Ci.3-alkoksykarbonyl-Ci-3-alkylaminogruppe, idet i de ovennevnte gruppene kan a-karbonatomet som står ved siden av nitrogen-atomet ikke være substituert, a C 2-3 alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C 1-3 -alkylamino-, C 1 -3-carboxycarbonyl-C 1-3 -alkylamino-, N-(C 1-3-alkyl)-carboxy-Ci .3-alkylamino or N-(Ci-3-alkyl)-Ci.3-alkoxycarbonyl-Ci-3-alkylamino group, in that in the above-mentioned groups the α-carbon atom standing next to the nitrogen atom cannot be substituted,

og R3 er en eventuelt med et fluoratom substituert fenylgruppe eller en 2-pyridinylgruppe, and R3 is a phenyl group optionally substituted with a fluorine atom or a 2-pyridinyl group,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Følgende er eksempler på spesielt foretrukne forbindelser: The following are examples of particularly preferred compounds:

(a) 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-karboksy-etyl)-amid, (b) 2-[N-(4-amidinfenyl)-N-metylaminometyl]-benztiazol-5-yl- karboksylsyre -N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (c) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyre -N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (d) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyre-N-fenyl-N-(3-hydroksykarbonylpropyl)-amid, (e) l-metyl-2-[N-(4-amidinfenyl)-aminom (a) 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxy-ethyl)-amide, (b) 2-[N-(4- amidinephenyl)-N-methylaminomethyl]-benzthiazol-5-yl- carboxylic acid -N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (c) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl] -benzimidazol-5-yl-carboxylic acid -N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (d) 1 -methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, (e) 1-methyl-2-[N-(4-amidinephenyl)-aminom

pyridyl)-N-(hydroksykarbonylmetyl)-arnid, pyridyl)-N-(hydroxycarbonylmethyl)-arnide,

(f) l-metyl-2-[2-(2-amidintiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (g) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyre-N-(2-pyridy])-N-(2-hydroksykarbonyletyl)-amid, (h) 1 -metyl-2-[2-(4-arnidinfenyl)-etyl]-benzimidazol-5-yl- karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (f) 1-methyl-2-[2-(2-amidinthiopen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide , (g) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridy])-N-(2-hydroxycarbonylethyl)-amide, ( h) 1-methyl-2-[2-(4-arnidinphenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,

(i) l-metyl-2-[2-(4-amidinfenyl)-etyl]-be^ (i) 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-be^

hydroksykarbonyletyl)-amid, hydroxycarbonylethyl)-amide,

(j) 1 -metyl-2-[2-(4-arnidinfenyl)-etyl]-benzimidazol-5-yl- karboksylsyre-N-fenyl-N-[2-(1 H-tetrazol-5 -yl)etyl] -amid, (j) 1-methyl-2-[2-(4-arnidinphenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl] -amide,

(k) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid, (1) 1 -metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl] -benzimidazol-5-yl- karboksylsyreN-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (m) 1 -metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl- karboksylsyreN-(3-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (k) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]- amide, (1) 1 -methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide , (m) 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,

(n) 1 -metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl- karboksylsyreN-fenyl-N-(2-hydroksykarbonyletyl)-amid, (n) 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-hydroxycarbonylethyl)-amide,

(o) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[(N-hydroksykarbonyletyl-N-metyl)-2-aminoetyl]amid, (o) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl] amide,

(p) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyre-N-(3-fluorfenyl)-N-(2-hydroksykarbonyletyl)-amid, (p) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide,

(q) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-berizimidazol-5-yl-karboksylsyre-N-(4-fluorfenyl)-N-(2-hydroksykarbonyletyl)-amid, (q) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-berizimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide,

(r) 1 -metyl-2- [N-(4-amidin-2-metoksyfenyl)-aminometyl] -benzimidazol-5 -yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (r) 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide,

(s) l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (s) 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide ,

(t) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid og (t) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and

(u) 1 -met<y>l-2-[N-(4-amidinfen<y>l)-aminomet<y>l]-tieno[23-d]-imidazol-5-yl- karboksylsyreN-fenyl-N-(2-hydroksykarbonyletyl)-amid, (u) 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-thieno[23-d]-imidazol-5-yl-carboxylic acid N-phenyl- N-(2-hydroxycarbonylethyl)-amide,

tautomerer, promedikamenter, dobbeltpromedikamenter, stereoisomerer og salter derav. tautomers, prodrugs, double prodrugs, stereoisomers and salts thereof.

Foreliggende oppfinnelse beskriver videre følgende forbindelser l-metyl-2-[N-(4-amidinfenyl)-aminonietyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksy-karbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav; The present invention further describes the following compounds 1-methyl-2-[N-(4-amidinephenyl)-aminoniethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-carbonylethyl)-amide, prodrugs, double prodrugs and salts thereof;

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav; 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, prodrugs, double prodrugs and salts thereof ;

l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav; 1 -metyl-2- [N- [4-(N-n-heksyloksykarbonylamidin)fenyl)-aminometyl] -benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og salter derav. 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, prodrugs, double prodrugs and salts thereof; 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and salts hence.

Det er videre beskrevet fysiologisk tålbare salter av forbindelser ifølge krav 1 til 9, kjennetegnet ved at E er en RbNH-C(=NH)-gruppe. Physiologically tolerable salts of compounds according to claims 1 to 9 are further described, characterized in that E is an RbNH-C(=NH) group.

Foreligende oppfinnelse vedrører følgelig fremgangsmåte for fremstilling av forbindelser ifølge kravene 1-10, kjennetegnet ved at The present invention therefore relates to a method for producing compounds according to claims 1-10, characterized in that

a. for fremstilling av en forbindelse med generell formel I, hvor E er en RbNH-C(=NH)-gruppe, hvor Rb er et hydrogenatom, en hydroksy- eller Ci-3-alkylgruppe, blir en eventuelt i reaksjonsblandingen dannet forbindelse med generell formel a. for the preparation of a compound of general formula I, where E is a RbNH-C(=NH) group, where Rb is a hydrogen atom, a hydroxy or C 1-3 alkyl group, a compound is optionally formed in the reaction mixture with general formula

hvor where

A, B, Ar, Het og Ra er som definert i kravene 1 til 9 og A, B, Ar, Het and Ra are as defined in claims 1 to 9 and

Zi er en alkoksy-, aralkoksy-, alkyltio eller aralkyltiogruppe omsatt med et amin med generell formel Zi is an alkoxy, aralkylthio, alkylthio or aralkylthio group reacted with an amine of general formula

hvor where

Rb' er et hydrogenatom, en hydroksy- eller C].3-alkylgruppe, eller Rb' is a hydrogen atom, a hydroxy or C1-3 alkyl group, or

b. for fremstilling av en forbindelse med generell formel I, hvor Ra-A-gruppen og E b. for the preparation of a compound of general formula I, where the Ra-A group and E

med den forutsetningen som i kravene 1 til 9 er definert, idet Ra-A-gruppen innholder en karboksygruppe og E er som definert i krav 1 til 9 eller Ra-A-gruppen with the premise defined in claims 1 to 9, that the Ra-A group contains a carboxy group and E is as defined in claims 1 to 9 or the Ra-A group

er som definert i kravene 1 til 9 og E er en NH2-C(=NH)-gruppe eller Ra-A-gruppen inneholder en karboksygruppe og E er en NH2-C(=NH)-gruppe, blir en forbindelse med generell formel is as defined in claims 1 to 9 and E is an NH2-C(=NH) group or the Ra-A group contains a carboxy group and E is an NH2-C(=NH) group, becomes a compound of general formula

hvor where

A, B, Ar og Het er definert som i kravene 1 til 9 og A, B, Ar and Het are defined as in claims 1 to 9 and

Ra'-A-gruppen og E' har de for Ra-A-gruppen og E i kravene 1 til 9 nevnte betydning med den forutsetningen at Ra'-A-gruppen inneholder en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i en karboksylgruppe overførbar gruppe og E er definert som i kravene 1 til 9 eller E' er en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i NH2-C(=NH)-gruppe overførbar gruppe og Ra'-A-gruppen er de for Ra-A-gruppen i kravene 1 til 9 nevnte betydning eller Ra'-A-gruppen inneholder en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i en karboksylgruppe overførbar gruppe og E' er en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse til en NH2-C(=NH)-gruppe overførbar gruppe, ved hjelp av hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse blir overført til en forbindelse med generell formel I, idet Ra-A-gruppen og E er definert som angitt i kravene 1 til 9, idet Ra-A-gruppen inneholder en karboksygruppe og E er som definert i kravene 1 til 9 eller Ra-A-gruppen oppviser betydningen angitt i kravene 1 til 9 og E er en NH2-C(=NH)-gruppe eller Ra-A-gruppen inneholder en karboksygruppe og E er en NH2-C(=NH)-gruppe, blir The Ra'-A group and E' have the meanings mentioned for the Ra-A group and E in claims 1 to 9, with the proviso that the Ra'-A group contains a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a carboxyl group transferable group and E is defined as in claims 1 to 9 or E' is a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in NH2-C(=NH) group transferable group and Ra'- The A group is the meaning mentioned for the Ra-A group in claims 1 to 9 or the Ra'-A group contains a group transferable by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a carboxyl group and E' is a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis to an NH2-C(=NH) group transferable group, by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis is transferred to a compound of general formula I, in that the Ra-A group and E are defined as stated in claims 1 to 9, in that the Ra-A group contains a carboxy group and E is as defined in claims 1 to 9 or the Ra-A group has the meaning stated in claims 1 to 9 and E is an NH2-C(=NH) group or Ra - The A group contains a carboxy group and E is an NH2-C(=NH) group, becomes

overført eller transferred or

c. for fremstilling av en forbindelse med generell formel I hvor Ra-A-gruppen inneholder en i definisjonen av Ra-A-gruppen i kravene 1 til 9 nevnte estergrupper, blir en forbindelse med generell formel c. for the preparation of a compound of general formula I where the Ra-A group contains an ester group mentioned in the definition of the Ra-A group in claims 1 to 9, a compound of general formula becomes

hvor where

B, E, Ar og Het er som definert i kravene 1 til 9 og B, E, Ar and Het are as defined in claims 1 to 9 and

Ra"-A-gruppen har betydningen som Ra-A-gruppen i kravene 1 til 9 med den forutsetningen at Ra"-A-gruppen inneholder en karboksylgruppe eller en ved hjelp av en alkohol i en tilsvarende estergruppe ovenførbar gruppe, med en alkohol med generell formel The Ra"-A group has the same meaning as the Ra-A group in claims 1 to 9 with the proviso that the Ra"-A group contains a carboxyl group or a group that can be added using an alcohol in a corresponding ester group, with an alcohol with general formula

hvor where

R7 er alkyldelen av en av kravene 1 til 9 nevnte in vivo avspaltbar rest med unntak av R4-CO-0-(R5CR6)-gruppen er en karboksylgruppe, eller med formamidacetaler derav R7 is the alkyl part of one of claims 1 to 9 mentioned in vivo cleavable residue with the exception of the R4-CO-0-(R5CR6) group is a carboxyl group, or with formamide acetals thereof

eller med en forbindelse med generell formel or with a compound of general formula

hvor where

R7 er alkyldelen av en i kravene 1 til 9 nevnte in vivo avspaltbare rester med unntakelse av R^CO-O-CRsCR^-gruppen med en karboksylgruppe og R7 is the alkyl part of an in vivo cleavable residue mentioned in claims 1 to 9 with the exception of the R^CO-O-CRsCR^ group with a carboxyl group and

Z2 er en utgående gruppe eller Z2 is an outgoing group or

d. for fremstilling av en forbindelse med generell formel I, hvor Rb utgjør en in vivo avspaltbar rest, blir en forbindelse med generell formel d. for the preparation of a compound of general formula I, where Rb constitutes an in vivo cleavable residue, becomes a compound of general formula

hvor where

Ra, A, Het, B og Ar er definert som i kravene 1 til 9, omsatt med en forbindelse med generell formel Ra, A, Het, B and Ar are defined as in claims 1 to 9, reacted with a compound of general formula

hvor where

Rg er en in vivo avspaltbar rest og Rg is an in vivo cleavable residue and

Z2 er en nukleofil utgående gruppe, eller Z2 is a nucleophilic leaving group, or

e. fremstilling av en forbindelse med generell formel I hvor B er en etylengruppe, idet en metylengruppe er erstattet med en sulfinyl- eller sulfonyl-gruppe, blir en forbindelse med generell formel e. preparation of a compound of general formula I where B is an ethylene group, in that a methylene group is replaced by a sulfinyl or sulfonyl group, a compound of general formula becomes

hvor where

A, E, Ar, Het og Ra er definert som i kravene 1 til 9 og A, E, Ar, Het and Ra are defined as in claims 1 to 9 and

B' er en etylengruppe, hvor en metylengruppe er erstattet med en sulfenyl- eller sulfinylgruppe, oksydert eller f. fremstilling av en forbindelse med generell formel I, hvor E er en cyanogruppe og B B' is an ethylene group, where a methylene group is replaced by a sulfenyl or sulfinyl group, oxidized or f. preparation of a compound of general formula I, where E is a cyano group and B

er en etylengruppe, hvor en metylengruppe, som enten er koplet med resten Het eller Ar er erstattet med et oksygen- eller svovelatom, med en sulfinyl-, sulfonyl-, karbonyl- eller -NR]-gruppe, blir en forbindelse med generell formel is an ethylene group, where a methylene group, which is either linked to the residue Het or Ar is replaced by an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR] group, becomes a compound of general formula

omsatt med en forbindelse med generell formel reacted with a compound of general formula

hvor where

Ra, A, Ar og Het er som definert i kravene 1 til 9, en av restene U eller V er en HO-, HS-, HOSO-, HOS02- eller HNRi -gruppe og den andre av restene er en Z3CH2-gruppe, idet Ri er definert som i kravene 1 til 9 og Z3 er en nukleofil utgangsgruppe, eller Ra, A, Ar and Het are as defined in claims 1 to 9, one of the residues U or V is a HO, HS, HOSO, HOS02 or HNRi group and the other of the residues is a Z3CH2 group, wherein Ri is defined as in claims 1 to 9 and Z3 is a nucleophilic leaving group, or

g. For fremstilling av en forbindelse med generell formel I hvor E er en cyanogruppe og Ra er en R2NR3-gruppe blir en forbindelse med generell formel g. For the preparation of a compound of general formula I where E is a cyano group and Ra is an R2NR3 group, a compound of general formula becomes

hvor where

A, B, Het og Ar er definert som angitt i kravene 1 til 10, omsatt med et amin med generell formel A, B, Het and Ar are defined as stated in claims 1 to 10, reacted with an amine of general formula

hvor where

R2 og R3 er definert som i kravene 1 til 9, eller omsatt med reaksjonsdyktige R2 and R3 are defined as in claims 1 to 9, or substituted with reactive

derivater derav, eller derivatives thereof, or

h. fremstilling av en benzimidazolyl-, benztiazolyl- eller benzoksazolylforbindelse med generell formel I, hvor B er en etylengruppe, blir en forbindelse med generell formel h. preparation of a benzimidazolyl, benzthiazolyl or benzoxazolyl compound of general formula I, where B is an ethylene group, becomes a compound of general formula

hvor where

Ra, A og Y er definert som i kravene 1 til 9 omsatt med en forbindelse med generell formel Ra, A and Y are defined as in claims 1 to 9 reacted with a compound of general formula

hvor where

Ar og E er definert som angitt i kravene 1 til 9, eller blir omsatt med reaksjonsdyktige derivater derav, Ar and E are defined as stated in claims 1 to 9, or are reacted with reactive derivatives thereof,

i. for fremstilling av en kinoksalin-2-on-forbindelse med generell formel blir en forbindelse med generell formel i. for the preparation of a quinoxalin-2-one compound of general formula becomes a compound of general formula

hvor where

Ra, Ri og A er definert som angitt i kravene 1 til 9, omsatt med en forbindelse med generell formel Ra, Ri and A are defined as stated in claims 1 to 9, reacted with a compound of general formula

hvor where

Ar og E er definert som angitt i kravene 1 til 9, eller blir omsatt med reaksjonsdyktige derivater derav, eller Ar and E are defined as stated in claims 1 to 9, or are reacted with reactive derivatives thereof, or

j. for fremstilling av en forbindelse med generell formel I, idet R2 er en Ci-4-alkylgruppe, som er substituert med en alkylsulfonylaminokarbonylgruppe, blir en forbindelse med generell formel j. for the preparation of a compound of general formula I, wherein R 2 is a C 1-4 alkyl group, which is substituted with an alkylsulfonylaminocarbonyl group, becomes a compound of general formula

hvor where

R3, A, B, E og Het er som definert i kravene 1 til 9 og R3, A, B, E and Het are as defined in claims 1 to 9 and

R2' er en Ci_4-alkylgruppe, som er substituert med en karboksygruppe, eller reaksjonsdyktige derivater derav, omsatt med et salt av en forbindelse med generell formel og dersom en i løpet av omsetningen for beskyttelse av reaktive grupper anvendte beskyttelsesrester blir avspaltet og/eller det deretter er ønskelig å separere en slik oppnådd forbindelse med generell formel I til stereoisomerer derav og/eller blir en på denne måten oppnådd forbindelse med generell formel I overført til salter derav, spesielt for farmasøytisk anvendelse i deres fysiologisk tålbare salter med en uorganisk eller organisk syre eller base. R2' is a Ci_4 alkyl group, which is substituted with a carboxy group, or reactive derivatives thereof, reacted with a salt of a compound of general formula and if a protective residue used during the reaction for the protection of reactive groups is split off and/or the then it is desirable to separate such an obtained compound of general formula I into stereoisomers thereof and/or a thus obtained compound of general formula I is transferred to salts thereof, especially for pharmaceutical use in their physiologically tolerable salts with an inorganic or organic acid or base.

Omsetningen i a. ovenfor foregår hensiktsmessig i et oppløsningsmiddel som metanol, etanol, n-propanol, vann, metanol/vann, tetrahydrofuran eller dioksan ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 20 og 120°C, med en forbindelse med generell formel ni eller med et tilsvarende syreaddisjonssalt som eksempelvis ammoniumkarbonat. The reaction in a. above conveniently takes place in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0 and 150°C, preferably at temperatures between 20 and 120°C, with a compound with general formula nine or with a corresponding acid addition salt such as, for example, ammonium carbonate.

En forbindelse med generell formel II oppnås eksempelvis ved omsetning av en forbindelse med generell formel I, hvor E er en cyanogruppe, med en tilsvarende alkohol som metanol, etanol, n-propanol, isopropanol eller benzylalkohol i nærvær av en syre som saltsyre eller ved omsetning av et tilsvarende amid med et trialkyloksoniumsalt som trietyloksonium-tetrafluorkarbonat i et oppløsningsmiddel som metylenklorid, tetrahydrofuran eller dioksan ved temperaturer mellom 0 og 50°C, fortrinnsvis derimot ved 20°C, eller et tilsvarende nitril med svovelhydrogen fortrinnsvis i et oppløsningsmiddel som pyridin eller dimetylformamid og i nærvær av en base som trietylamin og deretter alkylering av det dannede tioamidet med et tilsvarende alkyl- eller aralkylhalogenid. A compound of general formula II is obtained, for example, by reacting a compound of general formula I, where E is a cyano group, with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting of a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluorocarbonate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50°C, preferably at 20°C, or a corresponding nitrile with hydrogen sulphide preferably in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and then alkylating the formed thioamide with a corresponding alkyl or aralkyl halide.

En karboksygruppe overførbar gruppe i b. ovenfor er eksempelvis en gjennom en beskyttelsesrest beskyttet karboksylgruppe som deres funksjonelle derivater, f.eks deres usubstituerte eller substituerte amider, ester, tioester, trimetylsilylester, ortoester eller iminoester, som om ønskelig blir overført ved hjelp av hydrolyse til en karboksylgruppe, estere derav med tertiære alkoholer, f.eks tert.butylester som hensiktsmessig blir overført ved behandling med en syre eller termolyse til en karboksylgruppe, og esteren derav ved aralkanoler, f.eks benzylester, som hensiktsmessig ved hjelp av hydrogenolyse blir overført til en karboksylgruppe. A carboxy group transferable group in b. above is, for example, a carboxyl group protected through a protective residue as their functional derivatives, e.g. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, which, if desired, are transferred by means of hydrolysis to a carboxyl group, esters thereof with tertiary alcohols, e.g. tert.butyl ester which is conveniently transferred by treatment with an acid or thermolysis to a carboxyl group, and the ester thereof by aralkanols, e.g. benzyl ester, which is conveniently transferred by means of hydrogenolysis to a carboxyl group.

Hydrolysen blir hensiktsmessig gjennomført enten i nærvær av en syre som saltsyre, svovelsyre, fosforsyre, eddiksyre, trikloreddiksyre, trifluoreddiksyre eller blandinger derav eller i nærvær av en base som litiumhydroksid, natriumhydroksid eller kaliumhydroksid i et egnet oppløsningsmiddel som vann, vann/metanol, vann/etanol, vann/isopropanol, The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ ethanol, water/isopropanol,

metanol, etanol, vann/tetrahydrofuran eller vann/dioksan ved temperaturer mellom -10 og methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and

120°C, f.eks ved temperaturer mellom romtemperatur og koketemperaturen til reaksjonsblandingen. 120°C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture.

Omsetning med en alkohol med generell formel VI i c. ovenfor blir hensiktsmessig utført i et oppløsningsmiddel eller oppløsningsmiddelblanding som metylenklorid, benzen, toluen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran eller dioksan, fortrinnsvis derimot i en alkohol med generell formel VI, eventuelt i nærvær av en syre som saltsyre eller i nærvær av et vannuttrekkende middel, f.eks i nærvær av klormausyreisobutylester, tionylklorid, trimetylklorsilan, saltsyre, svovelsyre, metansulfonsyre, p-toluensulfonsyre, fosfortriklorid, fosforpentoksid, N,N'-disykloheksylkarbodiimid, N,N'-disykloheksylkarbodiimid/N-hydroksysuksinimid, N,N'-karbonyldiimidazol- eller N,N'-tionyldi-imidazol, trifenylfosfin, tetraklorkarbon eller trifenylfosfin/azodikarboksylsyredietylester eventuelt i nærvær av en base som kaliumkarbonat, N-etyldiisopropylamin eller N,N-dimetylaminopyridin fortrinnsvis ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 0 og 80°C. Reaction with an alcohol of general formula VI in c. above is suitably carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, preferably in an alcohol of general formula VI, optionally in the presence of an acid such as hydrochloric acid or in the presence of a water-extracting agent, e.g. in the presence of chloroformate isobutyl ester, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N' -dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine, carbon tetrachloride or triphenylphosphine/azodicarboxylic acid diethyl ester optionally in the presence of a base such as potassium carbonate, N-ethyldiisopropylamine or N,N-dimethylaminopyridine preferably at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.

Med en forbindelse med generell formel VU blir omsetningen hensiktsvis utført i et oppløsningsmiddel som metylenklorid, tetrahydrofuran, dioksan, dimetylsulfoksid, dimetylformamid eller aceton eventuelt i nærvær av et reaksjonsøkende middel som natrium- eller kaliumjodid og fortrinnsvis i nærvær av en base som natriumkarbonat eller kaliumkarbonat eller i nærvær av en tertiær organisk base som N-etyldiisopropylamin eller N-metylmorfolin, som samtidig også kan tjene som oppløsningsmiddel eller eventuelt i nærvær av sølvkarbonat eller sølvoksid ved temperaturer mellom -30 og 100°C, fortrinnsvis derimot ved temperaturer mellom -10 og 80°C. With a compound of general formula VU, the reaction is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction-enhancing agent such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methylmorpholine, which at the same time can also serve as a solvent or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100°C, preferably at temperatures between -10 and 80 °C.

Omsetningen i d. ovenfor blir fortrinnsvis gjennomført i et oppløsningsmiddel som metanol, etanol, metlenklorid, tetrahydrofuran, toluen, dioksan, dimetylsulfoksid eller dimetyl-formamid i nærvær av en uorganisk eller en tertiær organisk base, fortrinnsvis ved temperaturer mellom 20°C og koketemperaturen til anvendte oppløsningsmiddel. The reaction in d. above is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiling temperature of solvent used.

Med en forbindelse med generell formel IX hvor Z2 er en nukleofil utgangsgruppe, blir omsetningen fortrinnsvis gjennomført i et oppløsningsmiddel som metylenklorid, acetonitril, tetrahydrofuran, toluen, dimetylformamid eller dimetylsulfoksid eventuelt i nærvær av en base som natriumhydrid, kaliumkarbonat, kalium-tert.butylat eller N-etyldiisopropylamin ved temperaturer mellom 0 og 60°C. With a compound of general formula IX where Z2 is a nucleophilic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyldiisopropylamine at temperatures between 0 and 60°C.

Oksidasjonen i e. ovenfor blir fortrinnsvis gjennomført i et oppløsningsmiddel eller en oppløsningsmiddelblanding, f.eks i vann, vann/pyridin, aceton, metylenklorid, iseddik, iseddik/acetanhydrid, fortynnet svovelsyre eller trifluoreddiksyre, og alt etter anvendt oksidasjonsmiddel fortrinnsvis ved temperaturer mellom -80 og 100°C. The oxidation in e. above is preferably carried out in a solvent or a solvent mixture, for example in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and depending on the oxidizing agent used, preferably at temperatures between - 80 and 100°C.

For fremstilling av en tilsvarende sulfinylforbindelse med generell formel I blir oksidasjonen fortrinnsvis gjennomført med en ekvivalent av det anvendte oksidasjonsmiddelet, f.eks med hydrogenperoksid i iseddik, trifluoreddiksyre eller maursyre ved 0 til 20°C eller i aceton ved 0 til 60°C, med en persyre som permaursyre i iseddik eller trifluoreddiksyre ved 0 til 50°C eller med m-klorperbenzosyre i metylenklorid, kloroform eller dioksan ved -20 til 80°C, med natriummetaperjodat i vandig metanol eller etanol ved -15 til 25°C, med brom i iseddik eller vandig eddiksyre eventuelt i nærvær av en svak base som natriumacetat, med N-bromsuksinimid i etanol, med tert.butylhypokloritt i metanol ved -80 til -30°C, med jodbenzodiklorid i vandig pyridin ved 0 til 50°C, med saltpetersyre i iseddik ved 0 til 20°C, med kromsyre i iseddik eller i aceton ved 0 til 20°C og med sulfurylklorid i metylenklorid ved -70°C, blir det derved oppnådde tioeter-klor-komplekset fortrinnsvis hydrolysert med vandig etanol. For the preparation of a corresponding sulfinyl compound of general formula I, the oxidation is preferably carried out with an equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20°C or in acetone at 0 to 60°C, with a peracid such as permauric acid in glacial acetic acid or trifluoroacetic acid at 0 to 50°C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80°C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25°C, with bromine in glacial acetic acid or aqueous acetic acid optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.butyl hypochlorite in methanol at -80 to -30°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic acid in glacial acetic acid or in acetone at 0 to 20°C and with sulfuryl chloride in methylene chloride at -70°C, the thioether-chlorine complex thus obtained is preferably hydrolyzed with aqueous e tanol.

For fremstilling av en sulfonylforbindelse med generell formel I blir oksidasjonen utgående fra en tilsvarende sulfinylforbindelse hensiktsmessig gjennomført med ett eller flere ekvivalenter av det anvendte oksidasjonsmiddelet eller utgående fra en tilsvarende sulfinylforbindelse fortrinnsvis med to eller flere ekvivalenter av anvendte oksidasjonsmiddel, f.eks med hydrogenperoksid i iseddik/acetanhydrid, trifluoreddiksyre eller i maursyre ved 20 til 100°C eller i aceton ved 0 til 60°C, med en persyre som permaursyre eller m-klorperbenzosyre i iseddik, trifluoreddiksyre, metylenklorid eller kloroform ved temperaturer mellom 0 og 60°C, med saltpetersyre i iseddik ved 0 til 20°C, med kromsyre eller kaliumpermanganat i iseddik, vann/svovelsyre eller i aceton ved 0 til 20°C. Således oppnår man eksempelvis ved oksidasjon utgående fra en tilsvarende sulfenylforbindelse fortrinnsvis i metylenklorid gjennom behandling med en tilsvarende mengde m-klor-benzosyre ved temperaturer mellom 20°C og tilbakeløpstemperaturen til reaksjonsblandingen en tilsvarende sulfonylforbindelse med generell formel I, som kan inneholde en ytterligere liten mengde av den tilsvarende sulfinylforbindelsen. For the preparation of a sulfonyl compound of general formula I, the oxidation starting from a corresponding sulfinyl compound is suitably carried out with one or more equivalents of the oxidizing agent used or starting from a corresponding sulfinyl compound preferably with two or more equivalents of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid /acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100°C or in acetone at 0 to 60°C, with a peracid such as performate or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid or in acetone at 0 to 20°C. Thus, for example, by oxidation starting from a corresponding sulfenyl compound, preferably in methylene chloride, through treatment with a corresponding amount of m-chloro-benzoic acid at temperatures between 20°C and the reflux temperature of the reaction mixture, a corresponding sulfonyl compound of general formula I is obtained, which may contain a further small amount of the corresponding sulfinyl compound.

Omsetningen i f. ovenfor gjennomføres fortrinnsvis i et oppløsningsmiddel som metanol, etanol, metylenklorid, tetrahydrofuran, toluen, dioksan, dimetylsulfoksid eller dimetylformamid eventuelt i nærvær av en uorganisk eller en tertiær organisk base som trietylamin, N-etyldiisopropylamin eller dimetylaminopyridin, fortrinnsvis ved temperaturer mellom 20°C og koketemperaturen til anvendte oppløsningsmiddel, idet en forbindelse med generell formel XI eller XII hvor Z3 er et halogenatom også kan bli fremstilt i reaksjonsblandingen. The reaction in f. above is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or dimethylaminopyridine, preferably at temperatures between 20°C and the boiling temperature of the solvent used, a compound of general formula XI or XII where Z3 is a halogen atom can also be prepared in the reaction mixture.

Omsetningen av en syre i g. ovenfor med generell formel XIII blir eventuelt gjennomført i et oppløsningsmiddel eller oppløsningsmiddelblanding som metylenklorid, dimetylformamid, benzen, toluen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran eller dioksan eller i et tilsvarende amin med generell formel HI eventuelt i nærvær av et vannuttrekkende middel, f.eks i nærvær av klormaursyreisobutylester, ortokarboksylsyretetraetylester, ortoeddiksyretrimetylester, 2,2-dimetoksypropan, tetrametoksysilan, tionylklorid, trimetylklorsilan, fosfortriklorid, fosforpentoksid, N,N'-disykloheksylkarbodiimid, N,N'-disykloheksylkarbodiimid/N-hydroksysuksinimid, N,N'-disykloheksylkarbodiimid/1 -hydroksybenztriazol, 2-( 1 H-benzotriazol-1 -yl)-1,1,3,3-tetra-metyluroniumtetrafluorborat, 2-(lH-benzotriazol-1 -yl)-1,1,3,3,-tetrametyluronium-tetrafluorborat/1 -hydroksybenztriazol, N,N'-karbonyldiimidazol eller trifenylfosfin/- tetraklorkarbon og eventuelt under tilsetning av en base som pyridin, 4-dimetylaminopyridin, N-metylmorfolin eller trietylamin hensiktsmessig ved temperaturer mellom 0 The reaction of an acid in g. above with general formula XIII is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or in a corresponding amine with general formula HI optionally in the presence of a water-extracting agent, e.g. in the presence of chloroformic acid isobutyl ester, orthocarboxylic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide , N,N'-dicyclohexylcarbodiimide/1-hydroxybenztriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1 . laminopyridine, N-methylmorpholine or triethylamine appropriately at temperatures between 0

og 150°C, fortrinnsvis ved temperaturer mellom 0 og 100°C. and 150°C, preferably at temperatures between 0 and 100°C.

Omsetning av en tilsvarende reaksjonsdyktig forbindelse med generell formel XHI som ester, imidazolider eller halogenider derav med et amin med generell formel XIV blir fortrinnsvis utført i et tilsvarende amin som oppløsningsmiddel eventuelt i nærvær av et ytterligere oppløsningsmiddel som metylenklorid eller eter og fortrinnsvis i nærvær av en tertiær organisk base som trietylamin, N-etyldiisopropylamin eller N-metylmorfolin ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 100°C. Reaction of a corresponding reactive compound of general formula XHI as ester, imidazolides or halides thereof with an amine of general formula XIV is preferably carried out in a corresponding amine as solvent optionally in the presence of a further solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methylmorpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Omsetningen i h. ovenfor gjennomføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som metylenklorid, dimetylformamid, benzen, toluen, The reaction in h. above is suitably carried out in a solvent or a solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene,

klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran eller dioksan eventuelt i nærvær av et vannuttrekkende middel, f.eks i nærvær av klormaursyreisobutylester, ortokarboksylsyretetraetylester, ortoeddiksyretrimetylester, 2,2-dimetoksypropan, tetrametoksysilan, tionylklorid, trimetylklorsilan, fosfortriklorid, fosforpentoksid, N,N'-disykloheksylkarbodiimid, N,N'-disykloheksylkarbodiimid/N-hydroksysuksinimid, N,N'-disykloheksylkarbodiimid/ 1 -hydroksybenztriazol, 2-( 1 H-benzotriazol-1 -yl)-1,1,3,3-tetrametyluroniumtetrafluorborat, 2-(lH-benzotriazol-1 -yl)-1,1,3,3,-tetrametyluroniumtetrafluorborat/l -hydroksybenztriazol, N,N'-karbonyldiimidazol eller trifenylfosfin/tetraklorkarbon og eventuelt under tilsetning av en base som pyridin, 4-dimetylaminopyridin, N-metylmorfolin eller trietylamin hensiktsmessig ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 0 og 100°C. chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of a water-extracting agent, e.g. in the presence of chloroformic acid isobutyl ester, orthocarboxylic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'- dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/ 1 -hydroxybenzotriazole, 2-( 1 H -benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-( lH-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate/l-hydroxybenztriazole, N,N'-carbonyldiimidazole or triphenylphosphine/tetrachlorocarbon and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N- methylmorpholine or triethylamine suitably at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.

Omsetning av en tilsvarende reaksjonsdyktig forbindelse med generell formel XVI som deres estere, imidazolider eller halogenider med et amin med generell formel XV blir fortrinnsvis gjennomført i et oppløsningsmiddel som metylenklorid, eter eller tetrahydrofuran og fortrinnsvis i nærvær av en tertiær organisk base som trietylamin, N-etyldiisopropylamin eller N-metylmorfolin, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 100°C. Reaction of a correspondingly reactive compound of general formula XVI as their esters, imidazolides or halides with an amine of general formula XV is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N- ethyldiisopropylamine or N-methylmorpholine, which can also serve as a solvent, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Omsetningen i i. ovenfor gjennomføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som metylenklorid, dimetylformamid, benzen, toluen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran, etanol eller dioksan eventuelt i nærvær av et vannuttrekkende middel, f.eks i nærvær av klormaursyreisobutylester, ortokarboksylsyretetraetylester, ortoeddiksyretrimetylester, 2,2-dimetoksypropan, tetrametoksysilan, tionylklorid, trimetylklorsilan, fosfortriklorid, fosforpentoksid, N,N'-disykloheksylkarbodiimid, N,N'-disykloheksylkarbodiimid/N-hydroksysuksiriimid, N,N' -disykloheksylkarbodiimid/1 -hydroksybenztriazol, 2-( 1 H-benzotriazol-1 -yl)-1,1,3,3-tetrametyluroniumtetrafluorborat, 2-( 1 H-benzotirazol-1 -yl)-1,1,3,3,-tetrametyluronium-tetrafluorborat/1 -hydroksybenztriazol, N,N'-karbonyldiimidazol eller trifenylfosfin/tetra-. klorkarbon og eventuelt under tilsetning av en base som pyridin, 4-dimetylaminopyridin, N-metylmorfolin eller trietylamin hensiktsmessig ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 0 og 100°C. The reaction in i. above is conveniently carried out in a solvent or a solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, ethanol or dioxane, optionally in the presence of a water-extracting agent, e.g. in the presence of chloroformate isobutyl ester, orthocarboxylic acid tetraethyl ester , orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccirimide, N,N'-dicyclohexylcarbodiimide/1-hydroxybenztriazole, 2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate/1-hydroxybenztriazole , N,N'-carbonyldiimidazole or triphenylphosphine/tetra-. chlorocarbon and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.

Omsetningen blir derimot fortrinnsvis gjennomført med en tilsvarende reaksjonsdyktig forbindelse med generell formel XVII som deres estere, imidazolider eller halogenider med et amin med generell formel XVI i et oppløsningsmiddel som metylenklorid, eter, etanol eller tetrahydrofuran og fortrinnsvis i nærvær av en tertiær organisk base som trietylamin, N-etyldiisopropylamin eller N-metylmorfolin, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 100°C. The reaction, on the other hand, is preferably carried out with a correspondingly reactive compound of general formula XVII as their esters, imidazolides or halides with an amine of general formula XVI in a solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine , N-ethyldiisopropylamine or N-methylmorpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Omsetningen i j. ovenfor blir fortrinnsvis gjennomført med en tilsvarende reaksjonsdyktig forbindelse med generell formel IXX som deres ester, imidazolider eller halogenider med et salt av en forbindelse med generell formel XX, fortrinnsvis med alkalisaltet derav som natriumsaltet derav i et oppløsningsmiddel som metylenklorid, eter, etanol, tetrahydrofuran eller dimetylformamid ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 100°C. The turnover in j. above is preferably carried out with a correspondingly reactive compound of general formula IXX as their ester, imidazolides or halides with a salt of a compound of general formula XX, preferably with the alkali salt thereof as the sodium salt thereof in a solvent such as methylene chloride, ether, ethanol, tetrahydrofuran or dimethylformamide at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Ved den ovenfor angitte omsetningen kan eventuelt tilstedeværende reaktive grupper som hydroksy-, karboksy, amino-, alkylamino eller iminogruppen i løpet av omsetningen bli beskyttet med vanlige beskyttelsesgrupper som etter omsetningen igjen blir avspaltet. In the reaction indicated above, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups can be protected during the reaction with normal protective groups which are cleaved off again after the reaction.

Eksempler på beskyttelsesrester for en hydroksygruppe trimetylsilyl-, acetyl-, benzoyl-, tert.butyl-, trityl-, benzyl- eller tetrahydropyranylgruppe, som beskyttelsesrest for en karboksylgruppe trimetylsilyl-, metyl-, etyl-, tert.butyl-, benzyl eller tetrahydropyranylgruppe og beskyttelsesrest for en amino-, alkylamino- eller iminogruppe acetyl-, trifluoracetyl-, benzoyl-, etoksykarbonyl-, tertbutoksykarbonyl-, benzyloksykarbonyl-, benzyl-, metoksybenzyl- eller 2,4-dimetoksybenzylgruppe og for aminogruppen i tillegg ftalylgruppen. Examples of protective residues for a hydroxy group trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, as a protective residue for a carboxyl group trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protective residue for an amino, alkylamino or imino group acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group.

Den eventuelt tilhørende avspaltningen av en anvendt beskyttelsesrest foregår eksempelvis hydrolytisk i et vandig oppløsningsmiddel, f.eks i vann, isopropanol/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre som trifluoreddiksyre, saltsyre eller svovelsyre eller i nærvær av en alkalibase som litiumhydroksid, natriumhydroksid eller kaliumhydroksid eller ved hjelp av eterspaltning, f.eks i nærvær av jodtrimetylsilan, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 10og50°C. The possibly associated cleavage of an applied protective residue takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of a alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

Avspaltning av en benzyl-, metoksybenzyl- eller benzyloksykarbonylrest foregår derimot eksempelvis hydrogenolytisk, f.eks med hydrogen i nærvær av en katalysator som palladium/kull i et oppløsningsmiddel som metanol, etanol, eddiksyreetylester, dimetyl-formamid, dimetylformamid/aceton eller iseddik eventuelt under tilsetning av en syre som saltsyre ved temperaturer mellom 0 og 50°C, fortrinnsvis derimot ved romtemperatur, og ved et hydrogentrykk på 1 til 7 bar, fortrinnsvis derimot på 3 til 5 bar. Cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl residue, on the other hand, takes place, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally under addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably at 3 to 5 bar.

Avspaltning av en metoksybenzylgruppe kan også foregå i nærvær av et oksidasjonsmiddel som Cer (IV) ammoniumnitrat i et oppløsningsmiddel som metylenklorid, acetonitril eller acetonitril/vann ved temperaturer mellom 0 og 50°C, fortrinnsvis derimot ved romtemperatur. Cleavage of a methoxybenzyl group can also take place in the presence of an oxidizing agent such as Cer (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50°C, preferably at room temperature.

Avspaltning av en 2,4-dimetoksybenzylrest foregår derimot fortrinnsvis i trifluoreddiksyre i nærvær av anisol. Cleavage of a 2,4-dimethoxybenzyl residue, on the other hand, preferably takes place in trifluoroacetic acid in the presence of anisole.

Avspaltning av tert.butyl- eller tert.butyloksykarbonylrest foregår fortrinnsvis ved behandling med en syre som trifluoreddiksyre eller saltsyre eventuelt ved anvendelse av et oppløsningsmiddel som metylenklorid, dioksan eller eter. Cleavage of the tert-butyl or tert-butyloxycarbonyl residue takes place preferably by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally by using a solvent such as methylene chloride, dioxane or ether.

Avspaltning av en ftalylrest foregår fortrinnsvis i nærvær av hydrozin eller et primært amin som metylamin, etylamin eller n-butylamin i et oppløsningsmiddel som metanol, etanol, isopropanol, toluen/vann eller dioksan ved temperaturer mellom 20 og 50°C. Cleavage of a phthalyl residue preferably takes place in the presence of hydrozine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.

Avspaltning av en allyloksykarbonylrest foregår ved behandling med en katalytisk mengde tetrakis-(trifenylfosfin)-palladium(0) fortrinnsvis i et oppløsningsmiddel som tetrahydrofuran og fortrinnsvis i nærvær av et overskudd av en base som morfolin eller 1,3-dimedon ved temperaturer mellom 0 og 100°C, fortrinnsvis ved romtemperatur og under inert gass, eller ved behandling med en katalytisk mengde tris-(trifenylfosfin)-rhodium(I)klorid i et oppløsningsmiddel som vandig etanol og eventuelt i nærvær av en base som l,4-diazabisyklo[2,2,2]oktan ved temperaturer mellom 20 og 70°C. Cleavage of an allyloxycarbonyl residue takes place by treatment with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris-(triphenylphosphine)rhodium(I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[ 2,2,2]octane at temperatures between 20 and 70°C.

Forbindelser med generelle formler II til XX som anvendes som utgangsforbindelser og som er delvis kjent fra litteraturen oppnås ifølge fremgangsmåter kjent innenfor litteraturen og fremstillingen derav blir beskrevet i eksemplene. Compounds with general formulas II to XX which are used as starting compounds and which are partially known from the literature are obtained according to methods known within the literature and their preparation is described in the examples.

Således oppnår man eksempelvis en forbindelse med generell formel II ved omsetning av et tilsvarende nitril, som fortrinnsvis blir oppnådd ifølge fremgangsmåtene f til h med en tilsvarende tio- eller alkohol i nærvær av klor- eller bromhydrogen. Thus, for example, a compound of general formula II is obtained by reacting a corresponding nitrile, which is preferably obtained according to methods f to h, with a corresponding thio or alcohol in the presence of hydrogen chloride or bromine.

En forbindelse anvendt som utgangsforbindelse med generelle formler IV, V, VHI, X og DCX oppnår man hensiktsmessig ifølge fremgangsmåten i foreliggende oppfinnelse. A compound used as starting compound with general formulas IV, V, VHI, X and DCX is conveniently obtained according to the method of the present invention.

En utgangsforbindelse med generell formel XI hvor U er en halogenmetylgruppe oppnår man fortrinnsvis gjennom ringslutning av en tilsvarende ester som er substituert i o-stillingen med et egnet halogenatom og en metoksyacetarnidgruppe, til en tilsvarende bisyklisk 2-alkoksymetylforbindelse, og eventuelt påfølgende hydrolyse og eventuelt påfølgende amidering av en på denne måten oppnådd karboksylsyre med et tilsvarende amin, overføring av den på denne måten oppnådde alkoksymetylforbindelsen til den tilsvarende halogenmetylforbindelsen, og som om ønskelig deretter kan bli overført ved hjelp av en tilsvarende forbindelse til den ønskede forbindelsen. Gjennomfører man ringslutningen med et egnet karbondioksid oppnår man en utgangsforbindelse med generell formel XI hvor U er en hydroksy-, merkapto- eller aminogruppe. A starting compound of general formula XI where U is a halomethyl group is preferably obtained through cyclization of a corresponding ester which is substituted in the o-position with a suitable halogen atom and a methoxyacetarnide group, to a corresponding bicyclic 2-alkoxymethyl compound, and optionally subsequent hydrolysis and optionally subsequent amidation of a carboxylic acid obtained in this way with a corresponding amine, transfer of the alkoxymethyl compound obtained in this way to the corresponding halomethyl compound, and which, if desired, can then be transferred by means of a corresponding compound to the desired compound. If the ring closure is carried out with a suitable carbon dioxide, a starting compound of general formula XI is obtained where U is a hydroxy, mercapto or amino group.

En utgangsforbindelse med generell formel XIII oppnår man ved ringslutning av en tilsvarende o-disubstituert ester, påfølgende forsåpning av den på denne måten oppnådde esteren og påfølgende amidering av den på denne måten oppnådde karboksylsyren med et tilsvarende amin. A starting compound of general formula XIII is obtained by cyclization of a corresponding o-disubstituted ester, subsequent saponification of the ester obtained in this way and subsequent amidation of the carboxylic acid obtained in this way with a corresponding amine.

Videre kan en gjennom ringslutning oppnådd i 5-stilling imidazopyridin substituert med en metylgruppe over tilsvarende N-oksid bli overført til tilsvarende hydroksymetyl-forbindelse som blir overført ved hjelp av oksidasjon til ønsket karboksylsyre med generell formel Xm. Furthermore, a through ring closure obtained in the 5-position imidazopyridine substituted with a methyl group above the corresponding N-oxide can be transferred to the corresponding hydroxymethyl compound which is transferred by oxidation to the desired carboxylic acid of general formula Xm.

Forbindelser anvendt som utgangsforbindelser med generelle formler HI, VI, VE, IX og XII oppnår man ifølge trivielle fremgangsmåter, eksempelvis ved reduksjon av en aromatisk ester som i o-stillingen er substituert med en eventuelt substituert aminogruppe og en nitrogruppe, og eventuelt påfølgende ringslutning av den på denne måten oppnådde o-diaminoforbindelsen med en tilsvarende karboksylsyre. Compounds used as starting compounds with general formulas HI, VI, VE, IX and XII are obtained according to trivial methods, for example by reduction of an aromatic ester that is substituted in the o-position with an optionally substituted amino group and a nitro group, and optionally subsequent ring closure of the o-diamino compound thus obtained with a corresponding carboxylic acid.

Videre kan de oppnådde forbindelsene med generell formel I bli separert til deres enantiomerer og/eller diastereomerer. Furthermore, the obtained compounds of general formula I can be separated into their enantiomers and/or diastereomers.

Således er det eksempelvis mulig å separere de oppnådde forbindelsene med generell formel I, som opptrer i racemater ifølge i seg selv kjente fremgangsmåter (se Allinger N.L. og Eliel E.L. i "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971) til deres optiske antipoder og forbindelser med generell formel I med minst 2 asymmetriske karbonatomer pga deres fysikalsk-kjemiske forskjeller ifølge i seg selv kjente fremgangsmåter, f.eks ved kromatografi og/eller fraksjonert krystallisering, separeres til deres diastereomerer som dersom de forekommer i racemisk form deretter som nevnt ovenfor kan bli separert til deres enantiomerer. Thus, for example, it is possible to separate the obtained compounds of general formula I, which occur in racemates according to methods known per se (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, e.g. by chromatography and/or fractional crystallization, are separated into their diastereomers which if they occur in racemic form then as mentioned above can be separated into their enantiomers.

Enantiomersepareringen foregår fortrinnsvis ved kolonneseparasjon på kirale faser eller ved omkrystallisering fra et optisk aktivt oppløsningsmiddel eller ved omsetning med racemisk forbindelse, salter eller derivater som f.eks ester eller amid dannende optiske aktive forbindelser, spesielt syrer og deres aktive derivater eller alkoholer, og separeringen av de på denne måten oppnådde diastereomeere saltblandingene eller derivatene, f.eks pga forskjellig løselighet, idet det fra de rene diastereomersaltene eller derivatene kan bli frigjort frie antipoder gjennom innvirkning av egnet middel. Spesielt brukbare, optiske aktive syrer er f.eks D- og L-formene av vinsyre eller dibenzoylvinsyre, di-o-tolylvinsyre, appelsinsyre, mandelsyre, kamfersulfonsyre, glutaminsyre, asparaginsyre eller kinasyre. Som optiske aktive alkoholer kommer eksempelvis (+)- eller (-)-mentol og som optiske aktive acylrester kommer amider eksempelvis (+)- eller (-)-mentyloksykarbonylrester i betrakning. The enantiomer separation takes place preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a racemic compound, salts or derivatives such as ester or amide forming optically active compounds, especially acids and their active derivatives or alcohols, and the separation of the diastereomeric salt mixtures or derivatives obtained in this way, for example due to different solubility, as free antipodes can be released from the pure diastereomer salts or derivatives through the action of a suitable agent. Particularly useful optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, mandelic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Optically active alcohols include, for example, (+)- or (-)-menthol, and as optically active acyl residues, amides, for example (+)- or (-)-menthyloxycarbonyl residues, are considered.

Videre kan de oppnådde forbindelsene med formel I bli overført til salter derav, spesielt for farmasøytisk anvendelse i deres fysiologiske tålbare salter med uorganiske eller organiske syrer. Som syrer kommer eksempelvis saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, fumarsyre, Bernsteinsyre, melkesyre, sitronsyre, vinsyre eller maleinsyre i betraktning. Furthermore, the obtained compounds of formula I can be converted into salts thereof, especially for pharmaceutical use in their physiologically tolerable salts with inorganic or organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, Bernstein acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration.

Dessuten er det mulig å overføre de på denne måten oppnådde nye forbindelsene med formel I, dersom de inneholder en karboksygruppe om ønskelig deretter i deres salter med uorganiske eller organiske baser, spesielt for farmasøytisk anvendelse av deres fysiologiske tålbare salter. Som baser kan det her eksempelvis nevnes natriumhydroksid, kaliumhydroksid, sykloheksylamin, etanolamin, dietanolamin og trietanolarnin. Moreover, it is possible to transfer the thus obtained new compounds of formula I, if they contain a carboxy group, if desired then in their salts with inorganic or organic bases, especially for pharmaceutical use of their physiologically tolerable salts. Examples of bases that can be mentioned here are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Som allerede nevnt utviser de nye forbindelsene med generell formel I og salter derav verdifulle egenskaper. Dermed tilveiebringer forbindelsene med generell formel I, hvor E er en cyanogruppe, verdifulle mellomprodukter for fremstilling av de øvrige forbindelsene med generell formel I og forbindelsene med generell formel I, hvor E er en RbNH-C(=NH)-gruppe, samt deres tautomerer, stereoisomerer, fysiologisk tålbare salter verdifulle farmakologiske egenskaper, spesielt en trombinhemmende virkning, en trombin-tidforlengende virkning og en hemning av kjente serinproteaser som f.eks trypsin, urokinase, faktor Vila, faktor Xa, faktor DC, faktor XI og faktor XH, idet også noen forbindelser som eksempelvis forbindelsene i eksempel 16 samtidig også utviser en lavere trombocyttaggregasjonshemmende virkning. As already mentioned, the new compounds of general formula I and their salts exhibit valuable properties. Thus, the compounds of general formula I, where E is a cyano group, provide valuable intermediates for the preparation of the other compounds of general formula I and the compounds of general formula I, where E is a RbNH-C(=NH) group, as well as their tautomers , stereoisomers, physiologically tolerable salts valuable pharmacological properties, in particular a thrombin-inhibiting effect, a thrombin-time-prolonging effect and an inhibition of known serine proteases such as, for example, trypsin, urokinase, factor Vila, factor Xa, factor DC, factor XI and factor XH, as also some compounds such as the compounds in example 16 at the same time also exhibit a lower platelet aggregation inhibitory effect.

Eksempelvis ble forbindelsene For example, the connections were

A = 2- [N-(4-amidinfenyl)-aminometyl] -benztiazol-5 -karboksylsyre-N-fenyl-N-(2-karboksyetyl)-amid, A = 2- [N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide,

B = 1 -metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-hydroksykarbonylpropyl)-amid, B = 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide,

C = 1 -metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(hydroksykarbonylmetyl)-amid, C = 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide,

D = 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-ka D = 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-ka

fenyl-N-(2-hydroksykarbonylmetyl)-amid, phenyl-N-(2-hydroxycarbonylmethyl)-amide,

E = 1 -metyl-2-[N-(4-amidinfenyl)-amm^ E = 1-methyl-2-[N-(4-amidinephenyl)-amm^

pyridyl)-N-(hydroksykarbonyletyl)-amid, pyridyl)-N-(hydroxycarbonylethyl)-amide,

F = 1 -metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-(lH-tetrazol-5-yl)etyl]-amid og F = 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-(1H-tetrazol-5-yl)ethyl]-amide and

G = 1 -metyl-2-[N-(4-amidinfenyl)-amm^ G = 1-methyl-2-[N-(4-amidinephenyl)-amm^

pyridyl)-N-(2-hydroksykarbonyletyl)-amid pyridyl)-N-(2-hydroxycarbonylethyl)-amide

undersøkt når det gjelder deres virkning på trombintiden: investigated in terms of their effect on thrombin time:

Materiale: Plasma, av humant sitratblod, Material: Plasma, of human citrated blood,

Test-trombin (okse), 30 U/ml, Behring Werke, Marburg Dietylbarbituratacetat-buffer, ORWH 60/61, Behring Werke, Marburg Test thrombin (bovine), 30 U/ml, Behring Werke, Marburg Diethylbarbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg

Biomatic B10 Koagulometer, Sarstedt Biomatic B10 Coagulometer, Sarstedt

Gjennomføring: Bestemmelse av trombintiden foregår med et Biomatic B10-Koagulometer fra Firma Sarstedt. Implementation: Determination of the thrombin time takes place with a Biomatic B10-Coagulometer from Firma Sarstedt.

Testforbindelsen ble tilsatt i testbeholderene foreskrevet av fremstilleren med 0,1 ml humant sitrat-plasma og 0,1 ml dietylbarbiturat-buffer (DBA-buffer). Blandingen ble inkubert i ett minutt ved 37°C. Ved tilsetning av 0,3 U test-trombin i 0,1 ml DBA-buffer ble koaguleringsreaksjonen startet. Apparatmessig fører tilsetning av trombin til måling av tiden helt til koagulasjon av blandingen. Som kontroller anvendes blandinger hvor det blir tilsatt 0,1 ml DBA-buffer. The test compound was added to the test containers prescribed by the manufacturer with 0.1 ml human citrate plasma and 0.1 ml diethylbarbiturate buffer (DBA buffer). The mixture was incubated for one minute at 37°C. By adding 0.3 U test thrombin in 0.1 ml DBA buffer, the coagulation reaction was started. Apparatus-wise, the addition of thrombin leads to measurement of the time until coagulation of the mixture. Mixtures to which 0.1 ml of DBA buffer is added are used as controls.

Ifølge definisjonen ble den effektive forbindelseskonsentrasjonen formidlet over en dose-virkningskurve hvor trombintiden i forhold til kontrollene ble fordoblet. According to the definition, the effective compound concentration was presented over a dose-response curve where the thrombin time compared to the controls was doubled.

Tabellene nedenfor inneholder de oppnådde verdiene: The tables below contain the values obtained:

Eksempelvis var det ikke mulig i rotter å observere akutte toksiske bivirkninger ved applikasjon av forbindelsene A, D, E og G opp til en dose på 1 mg/kg i.v. Disse forbindelsene er følgelig godt tålbare. For example, it was not possible to observe acute toxic side effects in rats when applying the compounds A, D, E and G up to a dose of 1 mg/kg i.v. These compounds are therefore well tolerated.

Foreliggende oppfinnelse vedrører følgelig legemiddel, kjennetegnet ved at det inneholder en forbindelse ifølge minst ett av kravene 1 til 9, idet E er en RbNH-C(=NH)-gruppe, eller et salt ifølge krav 10 ved siden av en eventuelt flere inerte bærestoffer og/eller fortynningsmidler. The present invention therefore relates to a medicinal product, characterized in that it contains a compound according to at least one of claims 1 to 9, where E is an RbNH-C(=NH) group, or a salt according to claim 10 next to an optional several inert carriers and/or diluents.

Det er videre beskrevet anvendelse av en forbindelse ifølge minst ett av kravene 1 til 9, hvor E er en RbNH-C(=NH)-gruppe eller et salt ifølge krav 10 for fremstilling av et legemiddel med en virkning som forlenger trombintiden, en trombinhemmende virkning og en hemmende virkning på kjente serinproteaser. It is further described the use of a compound according to at least one of claims 1 to 9, where E is a RbNH-C(=NH) group or a salt according to claim 10 for the production of a drug with an effect that prolongs thrombin time, a thrombin inhibitor effect and an inhibitory effect on known serine proteases.

Foreliggednde oppfinnelse beskriver videre fremgangsmåte for fremstilling av et legemiddel ifølge krav 11, kjennetegnet ved at det ved ikke-kjemisk vei blir innarbeidet en forbindelse ifølge minst ett av kravene 1 til 9, hvor E er en RbNH-C(=NH)-gruppe, eller et salt ifølge krav 9 i en eller flere inerte bærestoffer og/eller fortynningsmidler. The present invention further describes a method for producing a drug according to claim 11, characterized in that a compound according to at least one of claims 1 to 9 is incorporated by non-chemical means, where E is an RbNH-C(=NH) group, or a salt according to claim 9 in one or more inert carriers and/or diluents.

De for oppnåelse av en tilsvarende virkning nødvendig dosering utgjør hensiktsmessig ved intravenøs tilførsel 0,1 til 30 mg/kg, fortrinnsvis 0,3 til 10 mg/kg og ved oral tilførsel 0,1 til 50 mg/kg, fortrinnsvis 0,3 til 30 mg/kg, hver 1 til 4 ganger daglig. Her er det mulig å tilføre eventuelt i kombinasjon med andre virkestoffer, sammen med en eller flere inerte vanlige bærestoffer og/eller fortynningsmidler, f.eks med maisstivelse, melke-sukker, rørsukker, mikrokrystallinsk cellulose, magnesiumstearat, polyvinylpyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/glyserin, vann/sorbitin, vann/polyetylenglykol, propylenglykol, cetylstearylalkohol, karboksymetylcellulose eller fettholdige forbindelser som hjertefett eller egnede blandinger derav, i vanlige galeniske tilberedninger som The dosages necessary to achieve a similar effect are suitably for intravenous administration 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg and for oral administration 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg, each 1 to 4 times daily. Here it is possible to add possibly in combination with other active ingredients, together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water , water/ethanol, water/glycerin, water/sorbitin, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty compounds such as heart fat or suitable mixtures thereof, in common galenic preparations such as

tabletter, drageer, kapsler, pulvere, suspensjoner eller safter. tablets, dragees, capsules, powders, suspensions or juices.

De følgende eksempler forklarer oppfinnelsen nærmere: The following examples explain the invention in more detail:

Forbemerkning Preliminary remark

Ved bestemmelse av Rf-verdiene ble det dersom ikke annet er angitt alltid anvendt polygram-kiselgelplater fra firmaet E. Merck, Darmstadt. When determining the Rf values, unless otherwise stated, polygram silica gel plates from the company E. Merck, Darmstadt, were always used.

EKA-massespektrene (elektrospray-massespektrene av kationer) ble eksempelvis beskrevet i Chemie unserer Zeit 6, 308-316 (1991). The EKA mass spectra (electrospray mass spectra of cations) were for example described in Chemie unserer Zeit 6, 308-316 (1991).

Eksempel 1 Example 1

3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[4,5-b]pyri^ etoksykarbonyletyl)-amid 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyri^ethoxycarbonylethyl)-amide

a) 6-metylarnino-5-nitro-nikotinsyremetylester a) 6-methylarnino-5-nitro-nicotinic acid methyl ester

1,6 g (7,4 mMol) 6-klor-5-nitronikotinsyremetylester (se Bernie et al. i J. Chem. 1.6 g (7.4 mmol) 6-chloro-5-nitronicotinic acid methyl ester (see Bernie et al. in J. Chem.

Soc. 1951, 2590) ble omrørt i 20 ml vandig 40% metylaminløsning i 30 min ved romtemperatur. Reaksjonsblandingen ble deretter fortynnet med isvann, utfelt gult bunnfall filtrert av og tørket. Soc. 1951, 2590) was stirred in 20 ml of aqueous 40% methylamine solution for 30 min at room temperature. The reaction mixture was then diluted with ice water, precipitated yellow precipitate filtered off and dried.

Utbytte: 1,2 g (80% av teoretisk) Yield: 1.2 g (80% of theoretical)

Rf-verdi: 0,66 (kiselgel; eddikester/etanol/iseddik = 90:5:5) Rf value: 0.66 (silica gel; acetic ester/ethanol/glacial vinegar = 90:5:5)

b) 5 -amino-6-metylamino-nikotinsyremetylester b) 5-amino-6-methylamino-nicotinic acid methyl ester

Til en løsning av 3,1 g (15 mMol) 6-metylamino-5-nitronikotinsyremetylester i 100 To a solution of 3.1 g (15 mmol) 6-methylamino-5-nitronicotinic acid methyl ester in 100

ml etanol/diklormetan (3:1) ble det tilsatt 1 g palladium på kull (10%) og resulterende suspensjon ble hydrert ved 5 bar hydrogentrykk i 1,5 t ved romtemperatur. Til slutt ble katalysatoren filtrert av og løsningsmiddelet destillert av i vakuum. Det oppnådde oljeholdige råproduktet ble deretter direkte videre omsatt. ml of ethanol/dichloromethane (3:1) 1 g palladium on charcoal (10%) was added and the resulting suspension was hydrated at 5 bar hydrogen pressure for 1.5 h at room temperature. Finally, the catalyst was filtered off and the solvent distilled off in vacuo. The oil-containing crude product obtained was then directly sold on.

Utbytte: 2,4 g (92% av teoretisk) Yield: 2.4 g (92% of theoretical)

Rrverdi: 0,44 (kiselgel; eddikester/etanol/ammoniakk = 90:10:1) Rr value: 0.44 (silica gel; acetate/ethanol/ammonia = 90:10:1)

c) 5-[2-(4-cyanofenyl)etylkarbonylamino]-6-metylaminonikotinsyremetylester c) 5-[2-(4-cyanophenyl)ethylcarbonylamino]-6-methylaminonicotinic acid methyl ester

En løsning av 2,6 g (15 mMol) 3-(4-cyanofenyl)propionsyre i 25 ml absolutt tetrahydrofuran ble omsatt med 2,4 g (15 mMol) N,N'-karbonyldimidazol og omrørt i 20 min ved romtemperatur. Til slutt ble imidazolid omsatt med en løsning av 2,3 g (13 mMol) 5-amino-6-metylaminonikotinsyremetylester i 25 ml dimetylformamid og oppvarmet i 3 t til 100°C. Etter fjerning av oppløsningsmiddelet i vakuum ble oppnådd råprodukt tatt opp i eddikester, organisk fase vasket med vann og etter tørking over natriumsalt på ny befridd for løsningsmiddel. Den oppnådde resten ble renset ved flammekromatografi (kiselgel; A solution of 2.6 g (15 mmol) of 3-(4-cyanophenyl)propionic acid in 25 ml of absolute tetrahydrofuran was reacted with 2.4 g (15 mmol) of N,N'-carbonyldimidazole and stirred for 20 min at room temperature. Finally, imidazolide was reacted with a solution of 2.3 g (13 mmol) of 5-amino-6-methylaminonicotinic acid methyl ester in 25 ml of dimethylformamide and heated for 3 h at 100°C. After removing the solvent in vacuo, the crude product obtained was taken up in ethyl acetate, the organic phase washed with water and, after drying over sodium salt, again freed from solvent. The residue obtained was purified by flame chromatography (silica gel;

gradient: Diklormetan til diklormetan/etanol =19:1). gradient: Dichloromethane to dichloromethane/ethanol =19:1).

Utbytte: 2,1 g beigefarvet fast stoff (50% av teoretisk), Yield: 2.1 g beige solid (50% of theoretical),

Rrverdi: 0,54 (kiselgel; eddikester/etanol/ammoniakk = 90:10:1) Rr value: 0.54 (silica gel; acetic acid/ethanol/ammonia = 90:10:1)

d) 3-metyl-2-[2-(4-cyanofenyl)e1yl]-imidazo[4,5-b]pyridin-6-karboksylsyr^ d) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid

En løsning av 2,0 g (5,9 mMol) 5-[2-(4-cyanofenyl)etylkarbonylamino]-6-metyl-aminonikotinsyremetylester ble oppvarmet i 50 ml iseddik i 11 til 100°C. Etter fjerning av oppløsningsmiddelet ble det tatt opp i diklormetan, vasket med natriumhydrogenkarbonat-løsning, tørket med natriumsulfat og på ny ble løsningsmiddelet destillert av. A solution of 2.0 g (5.9 mmol) of 5-[2-(4-cyanophenyl)ethylcarbonylamino]-6-methyl-aminonicotinic acid methyl ester was heated in 50 ml of glacial acetic acid at 11 to 100°C. After removal of the solvent, it was taken up in dichloromethane, washed with sodium bicarbonate solution, dried with sodium sulfate and the solvent was again distilled off.

Utbytte: 1,7 g brunt fast stoff (89% av teoretisk), Yield: 1.7 g brown solid (89% of theoretical),

Rrverdi: 0,50 (kiselgel; eddikester/etanol/ammoniakk = 90:10:1) Rr value: 0.50 (silica gel; acetic acid/ethanol/ammonia = 90:10:1)

e) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]pyridin-6-karboksylsyre e) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid

En løsning av 3,2 g (10 mMol) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]-pyridin-6-karboksylsyresyremetylester ble oppvarmet i 150 ml metanol ble omsatt med en løsning av 1,5 g litiumhydroksid i 20 ml vann og omrørt i 241 ved romtemperatur. Til slutt ble dette fortynnet med 50 ml vann, alkohol ble destillert av og den vandige fasen ble vasket med eddikester. Etter surgj øring med fortynnet saltsyre ble det flere ganger ekstrahert med diklormetan/metanol (9:1), den organiske fasen ble tørket med natriumsulfat og løsningsmiddelet destillert av. A solution of 3.2 g (10 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid methyl ester was heated in 150 ml of methanol was reacted with a solution of 1.5 g of lithium hydroxide in 20 ml of water and stirred for 241 at room temperature. Finally, this was diluted with 50 ml of water, alcohol was distilled off and the aqueous phase was washed with acetic acid. After acidification with dilute hydrochloric acid, it was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulfate and the solvent distilled off.

Utbytte: 2,1 g beigefarvet fast stoff (70% av teoretisk), Yield: 2.1 g beige solid (70% of theoretical),

Rf-verdi: 0,38 (kiselgel; eddikester/etanoVammoniakk = 50:45:5) Rf value: 0.38 (silica gel; acetic acid/ethanoammonia = 50:45:5)

f) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]pyridin-6-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid f) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

En løsning av 2,0 g (6,5 mMol) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]-pyridin-6-karboksylsyresyre ble omsatt med 20 ml tionylklorid og kokt i 2 t med tilbakeløp. Etter avdestillering av de flytende komponentene ble råproduktet tatt opp 2 ganger i diklormetan og løsningsmiddelet ble destillert av. Det på denne måten oppnådde rå syreklorid (2 A solution of 2.0 g (6.5 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid was reacted with 20 ml of thionyl chloride and boiled for 2 hours under reflux. After distilling off the liquid components, the crude product was taken up twice in dichloromethane and the solvent was distilled off. The crude acid chloride thus obtained (2

g) ble suspendert i 100 ml tetrahydrofuran og omsatt med 1,2 g (6,5 mMol) N-(2-etoksy-karbonyletyl)anilin. Til slutt ble det i løpet av 5 min dråpevis tilsatt 0,73 g (7,2 mMol) g) was suspended in 100 ml tetrahydrofuran and reacted with 1.2 g (6.5 mmol) N-(2-ethoxy-carbonylethyl)aniline. Finally, within 5 min, 0.73 g (7.2 mmol) was added dropwise

trietylamin. Etter omrøring i 11 ble løsningsmiddelet destillert av i vakuum, resten tatt opp i eddikester, organiske fase vasket med vann og tørket med natriumsulfat. Etter avdestillering av oppløsningsmiddelet og flammekromatografi (kiselgel; diklormetan til diklormetan/etanol = 49:1) ble det isolert den ønskede forbindelse som brunaktig olje. triethylamine. After stirring for 11 minutes, the solvent was distilled off in vacuo, the residue taken up in ethyl acetate, the organic phase washed with water and dried with sodium sulfate. After distilling off the solvent and flame chromatography (silica gel; dichloromethane to dichloromethane/ethanol = 49:1), the desired compound was isolated as a brownish oil.

Utbytte: 1,9 g (65% av teoretisk), Yield: 1.9 g (65% of theoretical),

Rf-verdi: 0,44 (kiselgel; eddikester/etanol/ammoniakk = 92:10:1) Rf value: 0.44 (silica gel; acetic ester/ethanol/ammonia = 92:10:1)

g) 3-metyl-2-[2-(4-amidinfenyl)et^ N-(2-etoksykarbonyletyl)-amid g) 3-methyl-2-[2-(4-amidinephenyl)eth^N-(2-ethoxycarbonylethyl)-amide

1,8 g (3,75 mMol) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]pyridin-6-karboksylsyresyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble ble omrørt i 100 1 med klorhydrogenmettet etanol il6 t først ved 0°C og deretter ved romtemperatur helt til tynnsjiktskromatografi ikke viste utgangsmaterialet. Til slutt løsningsmiddelet destillert av, den oljeholdige resten tatt opp i 50 ml absolutt etanol og omsatt med 3,6 g (37 mMol) ammoniumkarbonat. Etter 41 ble løsningsmiddelet destillert av i vakuum, oppnådde råprodukt renset ved flammekromatografi (kiselgel; gradient: diklormetan/etanol = 19:1 til 4:1) og på nytt redusert. 1.8 g (3.75 mmol) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2- ethoxycarbonylethyl)-amide was stirred in 100 1 of chlorohydrogen-saturated ethanol for 16 h first at 0°C and then at room temperature until thin-layer chromatography did not show the starting material. Finally, the solvent distilled off, the oily residue taken up in 50 ml of absolute ethanol and reacted with 3.6 g (37 mmol) of ammonium carbonate. After 41, the solvent was distilled off in vacuo, obtaining crude product purified by flame chromatography (silica gel; gradient: dichloromethane/ethanol = 19:1 to 4:1) and reduced again.

Utbytte: 1,6 g beigefarvet fast stoff (80% av teoretisk), Yield: 1.6 g beige solid (80% of theoretical),

Rf-verdi: 0,30 (kiselgel; eddikester/etanol/ammoniakk = 90:5:5) Rf value: 0.30 (silica gel; acetic ester/ethanol/ammonia = 90:5:5)

Eksempel 2 Example 2

3 -metyl-2- [2-(4-amidinfenyl)etyl] -imidazo [4,5 -b]pyridin-6-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid 3-methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide

En løsning av 535 mg (1,0 mMol) 3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[4,5-b]pyridin-6-karboksylsyresyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ilO ml etanol ble omsatt med 5 ml 2N natronlut og omrørt i 2 t ved romtemperatur. Deretter ble det fortynnet med 10 ml vann, alkohol ble destillert av, den vandige fasen ble vaskett med 20 ml eddikester og forsuret med konsentrert saltsyre idet den ønskede forbindelsen falt ut som hvite krystaller. A solution of 535 mg (1.0 mmol) of 3-methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2 -ethoxycarbonylethyl)-amide 110 ml of ethanol was reacted with 5 ml of 2N caustic soda and stirred for 2 h at room temperature. It was then diluted with 10 ml of water, alcohol was distilled off, the aqueous phase was washed with 20 ml of ethyl acetate and acidified with concentrated hydrochloric acid, the desired compound falling out as white crystals.

Utbytte: 375 mg (74% av teoretisk), Yield: 375 mg (74% of theoretical),

Rrverdi: 0,23 (kiselgel; eddikester/etanol/ammoniakk = 90:5:5) Rr value: 0.23 (silica gel; acetate/ethanol/ammonia = 90:5:5)

C26H26N603 (470,54) C26H26N603 (470.54)

Massespekter: (M+H)<+> = 471 Mass spectrum: (M+H)<+> = 471

Eksempel 3 Example 3

3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[4,5-b]pyridin-6-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amidhydroklorid 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 1 fra 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]pyridin-6-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-metoksykarbonyletyl)-amid, metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2 -methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 75% av teoretisk, Yield: 75% of theoretical,

C26H27N703 (485,55) C26H27N703 (485.55)

R^verdi: 0,31 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) R^value: 0.31 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 486 EKA mass spectrum: (M+H)<+> = 486

Eksempel 4 Example 4

3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[4,5-b]pyridin-6-yl-karboksylsyre-N-fenyl-N-etoksykarbonylmetyl-amidhydroklorid 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride

Fremstilt analogt i eksempel 1 fra 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[4,5-b]pyridin-6-yl-karboksylsyresyre-N-fenyl-N-etoksykarbonylmetyl-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously in example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 84% av teoretisk, Yield: 84% of theoretical,

C27H28N603 (484,56) C27H28N603 (484.56)

Rrverdi: 0,44 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rr value: 0.44 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 485 EKA mass spectrum: (M+H)<+> = 485

Eksempel 5 Example 5

3 -metyl-2- [2-(4-amidinfenyl)etyl] -imidazo [4,5 -b]pyridin-6-yl-karboksylsyre-N-fenyl-N-hydroksykarbonylmetyl-amidhydroklorid 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-hydroxycarbonylmethyl-amide hydrochloride

Fremstilt analogt i eksempel 2 fra 3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[4,5-b]pyridin-6-yl-karboksylsyresyre-N-fenyl-N-etoksykarbonylmetyl-amidhydroklorid og natronlut. Prepared analogously in example 2 from 3-methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride and caustic soda .

Utbytte: 85% av teoretisk, Yield: 85% of theoretical,

C25H24N603 (456,51) C25H24N603 (456.51)

Rrverdi: 0,19 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rr value: 0.19 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 457 EKA mass spectrum: (M+H)<+> = 457

Eksempel 6 Example 6

2-[2-(4-amidinfenyl)etyl]-3-metyl-6-(2-metoksykarbonyl-2,3-dihydroindol-l-yl-karbonyl)-imidazo[4,5-b]pyirdinhydroklorid 2-[2-(4-amidinephenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine hydrochloride

Fremstilt analogt i eksempel 1 fra 2-[2-(4-cyanofenyl)etyl]-3-metyl-6-(2-metoksy-karbonyl-2,3-dihydroindol-l -yl-karbonyl)-imidazo[4,5-b]pyridin, metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogously in example 1 from 2-[2-(4-cyanophenyl)ethyl]-3-methyl-6-(2-methoxy-carbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5 -b]pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 20% av teoretisk, Yield: 20% of theoretical,

C27H26N503 (482,54) C27H26N503 (482.54)

Rf-verdi: 0,30 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.30 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 483 EKA mass spectrum: (M+H)<+> = 483

Eksempel 7 Example 7

2-[2-(4-amidinfenyl)etyl]-3-metyl-6-(2-karboksy-2,3-dihydroindol-l-yl-karbonyl)-imidazo[4,5-b]pyridinhydroklorid 2-[2-(4-amidinephenyl)ethyl]-3-methyl-6-(2-carboxy-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine hydrochloride

Fremstilt analogt i eksempel 2 fra 2-[2-(4-amidinfenyl)etyl]-3-metyl-6-(2-metoksy-karbonyl-2,3-dihydroindol-l-yl-karbonyl)-imidazo[4,5-b]pyridin-hydroklorid og natronlut. Utbytte: 90% av teoretisk, Prepared analogously in example 2 from 2-[2-(4-amidinephenyl)ethyl]-3-methyl-6-(2-methoxy-carbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5 -b]pyridine hydrochloride and caustic soda. Yield: 90% of theoretical,

C26H24N603 (468,52) C26H24N603 (468.52)

Rf-verdi: 0,24 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.24 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 469 EKA mass spectrum: (M+H)<+> = 469

(M+Na)<+> = 491 (M+Na)<+> = 491

Eksempel 8 Example 8

l-me1yl-2-[(4-amidinfenyl)oksymetyl]-imidazo[4,5-b]pyridin-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[(4-amidinephenyl)oxymethyl]-imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

a) 2-amino-3-metylamino-6-metylpyridin a) 2-amino-3-methylamino-6-methylpyridine

8,35 g (50 mMol) 2-metyl-5-metylamino-6-nitropyridin (Heterocycles 38, 529, 8.35 g (50 mmol) 2-methyl-5-methylamino-6-nitropyridine (Heterocycles 38, 529,

(1994)) ble oppløst i 3001 eddikester og hydrert med 1,5 g Raney-nikkel i 3,5 t ved romtemperatur. Til slutt ble katalysatoren filtrert av og filtratet inndampet. Etter krystallisering av oppnådde rest fra petroleter oppnådde man 5,75 g (84% av teoretisk) som olivengrønne krystaller. (1994)) was dissolved in 3001 acetic acid and hydrated with 1.5 g of Raney nickel for 3.5 h at room temperature. Finally, the catalyst was filtered off and the filtrate evaporated. After crystallization of the obtained residue from petroleum ether, 5.75 g (84% of theoretical) were obtained as olive green crystals.

C7H11N3 (137,20) C7H11N3 (137.20)

Smeltepunkt: 112-113°C Melting point: 112-113°C

b) 1,5-dimetyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]-pyridin b) 1,5-dimethyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridine

11,4 g (63 mMol) 4-cyano-fenoksyeddiksyre ble oppløst i 200 ml absolutt 11.4 g (63 mmol) of 4-cyano-phenoxyacetic acid was dissolved in 200 ml of absolute

tetrahydrofuran og omsatt ved romtemperatur med 10,2 g (63 mMol) N,N'-karbonyldiimidazol. Etter 15 min ved 60°C ble det tilsatt 5,70 g (41,5 mMol) 2-amino-3- tetrahydrofuran and reacted at room temperature with 10.2 g (63 mmol) of N,N'-carbonyldiimidazole. After 15 min at 60°C, 5.70 g (41.5 mmol) of 2-amino-3-

metylamino-6-metylpyridin. Etter 2 t ved 60°C ble løsningsmiddelet destillert av, den krystallinske resten omsatt med vann, vasket med vann og tørket. Etter krystallisering fra etanol oppnådde man 9,95 g (91% av teoretisk) som hvite krystaller. methylamino-6-methylpyridine. After 2 h at 60°C, the solvent was distilled off, the crystalline residue reacted with water, washed with water and dried. After crystallization from ethanol, 9.95 g (91% of theory) were obtained as white crystals.

C16H14N40 (278,32) C16H14N40 (278.32)

Massespekter: M<+> = 278 Mass spectrum: M<+> = 278

c) l,5-dimetyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]-pyridin-4-N-oksid c) 1,5-dimethyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridine-4-N-oxide

2,62 g (10 mMol) l,5-dimetyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]pyridin 2.62 g (10 mmol) 1,5-dimethyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridine

ble suspendert i 125 ml diklormetan og omsatt med 2,62 g (12,7 mMol) m-klorperbenzosyre idet det ble oppnådd en klar løsning. Etter 2 t ved romtemperatur ble løsningsmiddelet destillert av og den oppnådde resten omsatt med en natriumhydrogenkarbonatløsning. Etter 30 min ble det oppnådde hvite krystallinske produktet sugd av, vasket med vann og tørket ved 40°C. was suspended in 125 ml of dichloromethane and reacted with 2.62 g (12.7 mmol) of m-chloroperbenzoic acid, obtaining a clear solution. After 2 h at room temperature, the solvent was distilled off and the residue obtained reacted with a sodium bicarbonate solution. After 30 min, the white crystalline product obtained was suctioned off, washed with water and dried at 40°C.

Utbytte: 2,45 (83% av teoretisk) Yield: 2.45 (83% of theoretical)

C16H14N402 (294,30) C16H14N402 (294.30)

Massespekter: M<+> = 294 Mass spectrum: M<+> = 294

d) 1 -metyl-2-[(4-cyanofenyl)oksymetyl] -5 -hydroksymetyl-imidazo [4,5-b] -pyridin 2,40 g (8,2 mMol) l,5-dimetyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]pyridin-4-N-oksid ble suspendert i 75 ml diklormetan og omsatt med 2,4 ml trifluoreddiksyre-anhydrid (16,9 mMol), idet det ble oppstod en klar løsning. Etter 161 ved romtemperatur ble løsningsmiddelet destillert ut, den oppnådde viskøse resten tatt opp i 50 ml diklormetan og belagt med 50 ml 2M natriumhydrogenkarbonatløsning. Etter 3 t med kraftig omrøring ble det dannede bunnfullet sugd av, vasket med vann og tørket ved 40°C. d) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]-pyridine 2.40 g (8.2 mmol) 1,5-dimethyl-2-[ (4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridine-4-N-oxide was suspended in 75 ml of dichloromethane and reacted with 2.4 ml of trifluoroacetic anhydride (16.9 mmol), giving a clear solution. After 161 at room temperature, the solvent was distilled off, the viscous residue obtained was taken up in 50 ml of dichloromethane and coated with 50 ml of 2M sodium bicarbonate solution. After 3 h of vigorous stirring, the resulting sediment was sucked off, washed with water and dried at 40°C.

Utbytte: 1,85 hvitt pulver (78% av teoretisk) Yield: 1.85 white powder (78% of theory)

C16H14N402 (294,30) C16H14N402 (294.30)

Smeltepunkt: 172°C Melting point: 172°C

e) l-metyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]-pyirdin-5-karbaldehyd e) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridine-5-carbaldehyde

3,65 g(12,5 mMol) l-metyl-2-[(4-cyanofenyl)oksymetyl]-5-hydroksymetyl-imidazo[4,5-b]pyridin ble oppløst i 500 ml diklormetan og omsatt med 15,0 g mangandioksid. Etter 961 ved romtemperatur ble det filtrert over kiselgur og oppløsningsmiddelet 3.65 g (12.5 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine was dissolved in 500 ml of dichloromethane and reacted with 15.0 g manganese dioxide. After 961 at room temperature, it was filtered over diatomaceous earth and the solvent

destillert av. Det oppnådde filtratet ble redusert, det krystallinske bunnfallet polert med eter, sugd av og tørket. distilled from. The filtrate obtained was reduced, the crystalline precipitate polished with ether, sucked off and dried.

Utbytte: 3,05 g hvitt pulver (84% av teoretisk) Yield: 3.05 g white powder (84% of theoretical)

C16H,2N402 (292,30) C16H,2N4O2 (292.30)

Smeltepunkt: 231-234°C Melting point: 231-234°C

f) 1 -metyl-2- [(4-cyanofenyl)oksymetyl] -5 -karboksy-imidazo [4,5 -b] -pyridin f) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxyimidazo[4,5-b]-pyridine

1,25 g (4,3 mMol) l-metyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]pyridin-5-karbaldehyd ble løst i 10 ml maursyre og omsatt ved 0°C med 1,0 ml hydrogenperoksid (33%o). Etter 12 t ved 4°C ble det dannede hvite bunnfallet sugd av, vasket med vann og tørket ved 40°C. 1.25 g (4.3 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridine-5-carbaldehyde was dissolved in 10 ml of formic acid and reacted at 0°C with 1.0 ml of hydrogen peroxide (33%o). After 12 h at 4°C, the white precipitate formed was suctioned off, washed with water and dried at 40°C.

Utbytte: 0,81 (61% av teoretisk) Yield: 0.81 (61% of theoretical)

C16H12N403 (308,7) C16H12N403 (308.7)

g) l-metyl-2-[(4-cyanofenyl)oksymetyl]-imidazo[4,5-b]-pyridin-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid g) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

308 mg (1,0 mMol) l-metyl-2-[(4-cyanofenyl)oksymetyl]-5-karboksy-imidazo[4,5-b]pyridin ble suspendert i 5 ml dimetylformamid og omsatt med 303 mg (3,0 mMol) N-metylmorfohn og 321 mg (1,0 mmol) 0-(benzotriazol-l-yl)-N,N,N',N'-tetrametyluronium-tetrafluorborat. Etter 10 min ved romtemperatur ble en løsning av 215 mg (1,2 mMol) N-(2-pyridyl)-3-aminopropionsyremetylester i 2 ml dimetylformamid tilsatt, idet det ble dannet en klar løsning. Etter 121 ved romtemperatur ble reaksjonsløsningen rørt i isvann. Etter 3 ganger ekstrahering med eddikester ble de rensede organiske ekstraktene vasket med koksaltløsning, tørket over natriumsulfat og inndampet. Den oppnådde resten ble kromatografert på kiselgel med diklormetan/etanol (90:1 til 25:1). 308 mg (1.0 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxy-imidazo[4,5-b]pyridine was suspended in 5 ml of dimethylformamide and reacted with 303 mg (3, 0 mmol) of N-methylmorphone and 321 mg (1.0 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate. After 10 min at room temperature, a solution of 215 mg (1.2 mmol) of N-(2-pyridyl)-3-aminopropionic acid methyl ester in 2 ml of dimethylformamide was added, forming a clear solution. After 121 at room temperature, the reaction solution was stirred in ice water. After 3 times extraction with acetic acid, the purified organic extracts were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1).

Utbytte: 165 mg hvitt pulver (35% av teoretisk) Yield: 165 mg white powder (35% of theoretical)

C25H12N604 (407,50) C25H12N604 (407.50)

Smeltepunkt: 139-140°C Melting point: 139-140°C

h) 1 -metyl-2- [(4-amidinfenyl)oksymetyl] -imidazo[4,5 -b] -pyridin-5 -yl-karboksylsyreN-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid h) 1-methyl-2-[(4-amidinephenyl)oxymethyl]-imidazo[4,5-b]-pyridin-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt ved omsetning av 140 mg (0,3 mMol) l-metyl-2-[(4-cyanofenyl)-oksymetyl]-imidazo[4,5-b]pyridin-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-metoksy-karbonyletyl)-amid med etanol mettet med klorhydrogen og med ammoniumkarbonat/ etanol analogt eksempel lg. Det oppnådde produktet ble renset ved kromatografi over kiselgel med diklormetan/etanol (19:1 til 4:1). Prepared by reacting 140 mg (0.3 mmol) of 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl )-N-(2-methoxy-carbonylethyl)-amide with ethanol saturated with hydrogen chloride and with ammonium carbonate/ethanol analogously to example lg. The product obtained was purified by chromatography over silica gel with dichloromethane/ethanol (19:1 to 4:1).

Utbytte: 48 mg hvitt pulver (36% av teoretisk) Yield: 48 mg white powder (36% of theoretical)

C26H27N7O4 (501,57) C26H27N7O4 (501.57)

Massespektrum: (M+H)+ = 502 Mass spectrum: (M+H)+ = 502

Eksempel 9 Example 9

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-etoksy-karbonyletyl)-amid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide

a) 4-fluor-3-metoksyacetamidobenzosyreetylester a) 4-fluoro-3-methoxyacetamidobenzoic acid ethyl ester

En løsning av 2,8 g (15,3 mMol) 3-amino-4-fluor-benzosyreetylester (se L. S. A solution of 2.8 g (15.3 mmol) 3-amino-4-fluoro-benzoic acid ethyl ester (see L. S.

Fosdick, A. F. Dodds i J. Amer. Chem. Soc. 65, 2305 (1943)) og 1,56 ml (1,85 g = 17,0 mMol) metoksyacetylklorid i 50 ml klorbenzen ble omrørt i 11 ved 50°C og til slutt i 15 min ved tilbakeløp. Deretter ble løsningsmiddelet destillert av i vakuum og det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; diklormetan/etanol = 100:1). Den først fremkommende ønskede oljeholdige forbindelsen stivnet i løpet av noen dager. Fosdick, A.F. Dodds in J. Amer. Chem. Soc. 65, 2305 (1943)) and 1.56 ml (1.85 g = 17.0 mmol) of methoxyacetyl chloride in 50 ml of chlorobenzene were stirred for 11 at 50°C and finally for 15 min at reflux. The solvent was then distilled off in vacuo and the crude product obtained was purified by flame chromatography (silica gel; dichloromethane/ethanol = 100:1). The first appearing desired oily compound solidified within a few days.

Utbytte: 3,8 g (98% av teoretisk) Yield: 3.8 g (98% of theoretical)

Rrverdi: 0,38 (kiselgel; diklormetan/etanol = 19:1) Rr value: 0.38 (silica gel; dichloromethane/ethanol = 19:1)

b) 2-metoksymetylbenztiazol-5 -karboksylsyreetylester b) 2-methoxymethylbenzthiazole-5-carboxylic acid ethyl ester

En blanding av 3,0 g (11,7 mMol) 4-fluor-3-metoksyacetamidobenzosyre og 2,1 g A mixture of 3.0 g (11.7 mmol) of 4-fluoro-3-methoxyacetamidobenzoic acid and 2.1 g

(5,2 mMol) Lawessons reagens ble varmet i 61 i 90 ml toluen under tilbakeløp, omsatt på ny med 1,0 g Lawessons reagens og ytterligere oppvarmet i 61 ved 120°C. Etter erstatning av løsningsmiddelet med xylen ble det oppvarmet i ytterligere 8 t i en trykkbeholder ved 180°C. Til slutt ble løsningsmiddelet destillert av i vakuum, det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; eddiksester/petroleter = 5:95) og på ny inndampet. (5.2 mmol) of Lawesson's reagent was heated in 61 in 90 ml of toluene under reflux, reacted again with 1.0 g of Lawesson's reagent and further heated in 61 at 120°C. After replacing the solvent with xylene, it was heated for a further 8 h in a pressure vessel at 180°C. Finally, the solvent was distilled off in vacuo, the crude product obtained was purified by flame chromatography (silica gel; ethyl acetate/petroleum ether = 5:95) and re-evaporated.

Utbytte: 2,1 g gule krystaller (72% av teoretisk) Yield: 2.1 g of yellow crystals (72% of theory)

Rf-verdi: 0,55 (kiselgel; eddikester/petroleter = 3:7) Rf value: 0.55 (silica gel; acetic acid/petroleum ether = 3:7)

c) 2-metoksymetylbenztiazol-5-karboksylsyre c) 2-methoxymethylbenzthiazole-5-carboxylic acid

En blanding av 2,1 g (8,36 mMol) 2-metoksymetylbenztiazol-5-karboksylsyreetylester og 16 ml 2N natronlut ble rørt i 60 ml etanol i 1 time ved romtemperatur. Deretter ble alkoholen avdestillert, råproduktet tatt opp i 20 ml vann, vasket med 50 ml dietyleter og den vandige fasen forsuret med konsentrert saltsyre under isavkjøling. Den utfelte beige-rosa farvede forbindelsen ble sugd av, vasket med vann og tørket. A mixture of 2.1 g (8.36 mmol) of 2-methoxymethylbenzthiazole-5-carboxylic acid ethyl ester and 16 ml of 2N caustic soda was stirred in 60 ml of ethanol for 1 hour at room temperature. The alcohol was then distilled off, the crude product was taken up in 20 ml of water, washed with 50 ml of diethyl ether and the aqueous phase acidified with concentrated hydrochloric acid under ice cooling. The precipitated beige-pink colored compound was sucked off, washed with water and dried.

Utbytte: 1,6 g (86% av teoretisk) Yield: 1.6 g (86% of theoretical)

Rf-verdi: 0,12 (kiselgel; diklormetan/etanol = 29:1) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 29:1)

d) 2-metoksymetylbenztiazol-5-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid d) 2-methoxymethylbenzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

En suspensjon av 1,6 g (7,2 mMol) 2-metoksymetylbenztiazol-5-karboksylsyre i 60 A suspension of 1.6 g (7.2 mmol) of 2-methoxymethylbenzthiazole-5-carboxylic acid in 60

ml diklormetan ble omsatt med 1,6 ml (22 mMol) tionylklorid og kokt i 11 under tilbakeløp. Derved ble faststoffet oppløst etter 20 min. Etter avdestillering av de flytende komponentene ble råproduktet tatt opp ytterligere 2 ganger i diklormetan og løsnings-middelet ble destillert av. Det på denne måten oppnådde rå syreklorid ble tatt opp i 50 ml tetrahydrofuran, dråpevis tilsatt til en blanding av 1,4 g (7,2 mMol) N-(2-etoksykarbonyl-etyl)anilin og 3,0 ml (21 mMol) trietylamin i 50 ml tetrahydrofuran og rørt over natten ved romtemperatur. Til slutt ble løsningsmiddelet destillert av i vakuum, resten tatt opp i 30 ml diklormetan, denne løsningen ble vasket med vann og tørket med natriumsulfat. Etter avdestillering av løsningsmiddelet og flammekromatografi (kiselgel; gradient: Diklormetan/etanol 98,5:1,5 til 80:20) isolerte man den ønskede forbindelsen som brunaktig olje. ml of dichloromethane was reacted with 1.6 ml (22 mmol) of thionyl chloride and boiled for 11 under reflux. Thereby, the solid was dissolved after 20 min. After distilling off the liquid components, the crude product was taken up a further 2 times in dichloromethane and the solvent was distilled off. The crude acid chloride thus obtained was taken up in 50 ml tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2 mmol) N-(2-ethoxycarbonyl-ethyl)aniline and 3.0 ml (21 mmol) triethylamine in 50 ml of tetrahydrofuran and stirred overnight at room temperature. Finally, the solvent was distilled off in vacuo, the residue was taken up in 30 ml of dichloromethane, this solution was washed with water and dried with sodium sulfate. After distilling off the solvent and flame chromatography (silica gel; gradient: dichloromethane/ethanol 98.5:1.5 to 80:20) the desired compound was isolated as a brownish oil.

Utbytte: 2,05 (72% av teoretisk) Yield: 2.05 (72% of theoretical)

verdi: 0,40 (kiselgel; eddikester/petroleter =1:1) value: 0.40 (silica gel; vinegar/petroleum ether = 1:1)

e) 2-[N-(4-cyanofenyl)-aminometyl]-benztiazol-5-karoksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid e) 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

En blanding av 2,05 g (5,14 mMol) 2-metoksymetylbenztiazol-5-karboksylsyreN-fenyl-N-(etoksykarbonyletyl)-amid og 5,7 ml (5,7 mMol) av en IM løsning av bortribromid i diklormetan ble løst i ytterligere 60 ml diklormetan og rørt i 161 ved romtemperatur. Til slutt ble det vasket med 40 ml mettet natriumhydrogenkarbonatløsning, den organiske fasen ble tørket med natriumsulfat og løsningsmiddelet destillert av. Det på denne måten oppnådde rå 2-brommetylbenztiazol-5-karboksylsyre-N-fenyl-N-(2-etoksy-karbonyletyl)-amid (2,4 g) ble tatt opp i 5,0 ml N,N-diisopropyletylamin og omsatt med 0,64 g (5,4 mMol) 4-ammobenzonitril. Etter 11 oppvarming ved 130°C ble løsnings-middelet destillert av i vakuum og det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; gradient: Eddikester/petroleter =1:3 til 1:1), idet det ble oppnådd ved redusering av eluatet et oransjefarvet skum. A mixture of 2.05 g (5.14 mmol) of 2-methoxymethylbenzthiazole-5-carboxylic acid N-phenyl-N-(ethoxycarbonylethyl)-amide and 5.7 ml (5.7 mmol) of a 1M solution of boron tribromide in dichloromethane was dissolved in a further 60 ml of dichloromethane and stirred for 161 at room temperature. Finally, it was washed with 40 ml of saturated sodium bicarbonate solution, the organic phase was dried with sodium sulphate and the solvent distilled off. The crude 2-bromomethylbenzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide (2.4 g) thus obtained was taken up in 5.0 ml of N,N-diisopropylethylamine and reacted with 0.64 g (5.4 mmol) of 4-ammobenzonitrile. After 11 hours of heating at 130°C, the solvent was distilled off in vacuo and the crude product obtained was purified by flame chromatography (silica gel; gradient: Acetic acid/petroleum ether = 1:3 to 1:1), being obtained by reducing the eluate an orange colored foam.

Utbytte: 1,1 g (44% av teoretisk) Yield: 1.1 g (44% of theoretical)

Rf-verdi: 0,35 (kiselgel; eddikester/petroleter = 7:3) Rf value: 0.35 (silica gel; acetic acid/petroleum ether = 7:3)

f) 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid f) 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1,1 g (2,27 mMol) 2-[N-(4-cyanofenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble rørt i 100 ml med klorhydrogenmettet etanol i 5 t først ved 0°C og deretter ved romtemperatur helt til det ved tynnsjiktskromatografi ikke var synlig ytterligere utgangsmaterialer. Til slutt ble løsningsmiddelet destillert av ved 1.1 g (2.27 mmol) of 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 100 ml with hydrogen chloride saturated ethanol for 5 h first at 0°C and then at room temperature until no further starting materials were visible by thin-layer chromatography. Finally, the solvent was distilled from wood

maksimalt 30°C badtemperatur, den oljeholdige resten tatt opp i 100 ml absolutt etanol og omsatt med 1,6 g (22 mMol) ammoniumkarbonat. Etter 18 t omrøring ved romtemperatur ble løsningsmiddelet destillert av i vakuum og råproduktet renset ved flamme-kromatografi (kiselgel; gradient: Vann/metanol = 19:1 til 4:1). Ved redusering av eluatet oppnår man den ønskede forbindelsen som hvitt skum. maximum 30°C bath temperature, the oily residue taken up in 100 ml of absolute ethanol and reacted with 1.6 g (22 mmol) of ammonium carbonate. After 18 h of stirring at room temperature, the solvent was distilled off in vacuo and the crude product was purified by flame chromatography (silica gel; gradient: Water/methanol = 19:1 to 4:1). By reducing the eluate, the desired compound is obtained as a white foam.

Utbytte: 0,77 g (63% av teoretisk) Yield: 0.77 g (63% of theoretical)

Rf-verdi: 0,19 (kiselgel; diklormetan/etanol = 3:7) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 3:7)

C27H27N503S (501,60) C27H27N503S (501.60)

Massespekter: (M+H)+ = 502 Mass spectrum: (M+H)+ = 502

Eksempel 10 Example 10

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-karboksy-etyl)-amid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxy-ethyl)-amide

0,45 g (0,84 mMol) 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyreN-fenyl-N-(2-etoksykarbonyletyl)-amid ble løst i 15 ml etanol, omsatt med 2 ml 2N natronlut og rørt i 41 ved romtemperatur. Til slutt ble dette surgjort med 3 ml 2N saltsyre og løsningsmiddelet destillert av. Det oppnådde råproduktet ble tatt opp i 5 ml diklormetan/etanol (2:1) og destillert fra uløselig natriumklorid. Etter avdestillering av løsningsmiddelet oppnår man den ønskede forbindelse som gult skum. 0.45 g (0.84 mmol) of 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid N-phenyl-N-(2-ethoxycarbonylethyl)-amide was dissolved in 15 ml of ethanol, reacted with 2 ml of 2N caustic soda and stirred for 41 at room temperature. Finally, this was acidified with 3 ml of 2N hydrochloric acid and the solvent distilled off. The crude product obtained was taken up in 5 ml of dichloromethane/ethanol (2:1) and distilled from insoluble sodium chloride. After distilling off the solvent, the desired compound is obtained as a yellow foam.

Utbytte: 0,26 g (67% av teoretisk) Yield: 0.26 g (67% of theoretical)

Rrverdi: 0,47 (kiselgel; metanol/5% vandig natriumklorid = 6:4) Rr value: 0.47 (silica gel; methanol/5% aqueous sodium chloride = 6:4)

C25H23N503S (473,55) C25H23N503S (473.55)

Massespekter: (M+H)<+> = 474 Mass spectrum: (M+H)<+> = 474

Eksempel 11 Example 11

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-metoksykarbonyletyl)-amid-dihydroklorid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide dihydrochloride

Fremstilt analogt eksempel 9 fra 2-[N-(4-cyanofenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid, metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogous Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 68% av teoretisk Yield: 68% of theoretical

C25H24N603S (488,57) C25H24N603S (488.57)

Rf-verdi: 0,13 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 489 Rf value: 0.13 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 489

Eksempel 12 Example 12

2-[2-(4-amidinfenyl)etyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksy-karbonylmetyl)-amid-dihydroklorid 2-[2-(4-Amidinephenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxy-carbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 9 fra 2-[2-(4-cyanofenyl)-etyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)-ethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 95% av teoretisk Yield: 95% of theoretical

C26H25N503S (487,58) C26H25N503S (487.58)

Rrverdi: 0,20 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 488 Rr value: 0.20 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 488

Eksempel 13 Example 13

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksy-karbonylmetyl)-amid-dihydroklorid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxy-carbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 9 fra 2-[N-(4-cyanofenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyhnetyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 68% av teoretisk Yield: 68% of theoretical

C25H24N603S (488,57) C25H24N603S (488.57)

Rf-verdi: 0,14 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 489 Rf value: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 489

Eksempel 14 Example 14

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(hydroksykarbonylmetyl)-amid-dihydroklorid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 10 fra 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid,-dihydroklorid og natronlut. Prepared analogously to Example 10 from 2-[N-(4-amidinphenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, dihydrochloride and caustic soda.

Utbytte: 90% av teoretisk Yield: 90% of theoretical

C23H2oN603S (460,52) C23H2oN603S (460.52)

Rf-verdi: Rf value:

EKA-massespekter: (M+H)<+> = 461 EKA mass spectrum: (M+H)<+> = 461

(M+Na)<+> = 483 (M+Na)<+> = 483

(M+2Na)<++> = 253 (M+2Na)<++> = 253

Eksempel 15 Example 15

2-psf-(4-amidinfenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-dihydroklorid 2-psf-(4-amidinephenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide dihydrochloride

a) 2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid a) 2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 9e fra 4-cyano-N-metylanilin og 2-metoksymetylbenztiazol-5-karboksylsyre-N-fenyl-N-(2-etyoksykarbonyletyl)-amid. Prepared analogous example 9e from 4-cyano-N-methylaniline and 2-methoxymethylbenzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.

Utbytte: 57% av teoretisk Yield: 57% of theoretical

C25H24N603S (488,57) C25H24N603S (488.57)

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

b) 2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-dihydroklorid b) 2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide dihydrochloride

Fremstilt analogt eksempel 9 fra 2-[N-(4-cyanofenyl)-N-metylaminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-N-methylaminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 73% av teoretisk Yield: 73% of theoretical

C28H29N5O3S (515,64) C28H29N5O3S (515.64)

Rf-verdi: 0,29 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: M(+H)<+> = 516 Rf value: 0.29 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: M(+H)<+> = 516

Eksempel 16 Example 16

2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 10 fra 2-[N-(4-amidinfenyl)-N-metylaminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 10 from 2-[N-(4-amidinephenyl)-N-methylaminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 96% av teoretisk Yield: 96% of theoretical

C26H25N503S (487,58) C26H25N503S (487.58)

Rf-verdi: 0,48 (Merck RP-8, metanol/5%> NaCl-løsning = 6:4) Rf value: 0.48 (Merck RP-8, methanol/5%> NaCl solution = 6:4)

EKA-massespekter: (M+H)<+> = 488 EKA mass spectrum: (M+H)<+> = 488

(M+2Na)<++> = 266,5 (M+2Na)<++> = 266.5

Eksempel 17 Example 17

2-[(4-amidinfenyl)tiometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 2-[(4-amidinephenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 9 fra 2-[(4-cyanofenyl)tiometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 9 from 2-[(4-cyanophenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 61% av teoretisk Yield: 61% of theoretical

C27H26N4O3S2 (518,66) C27H26N4O3S2 (518.66)

Rf-verdi: 0,27 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: M(+H)<+> = 519 Rf value: 0.27 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: M(+H)<+> = 519

Eksempel 18 Example 18

2-[(4-amidinfenyl)tiometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksy-karbonyletyl)-amid-hydroklorid 2-[(4-amidinephenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-carbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 10 fra2-[(4-amidinfenyl)tiometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 10 from 2-[(4-amidinephenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 95% av teoretisk Yield: 95% of theoretical

C25H22N403S2 (490,61) C25H22N403S2 (490.61)

Rf-verdi: 0,25 (Merck RP-8, metanol/5% NaCl-løsning = 6:4) Rf value: 0.25 (Merck RP-8, methanol/5% NaCl solution = 6:4)

EKA-massespekter: (M+H)<+> = 491 EKA mass spectrum: (M+H)<+> = 491

(M+Na)<++> = 513 (M+Na)<++> = 513

Eksempel 19 Example 19

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(etoksy-karbonylmetyl)-amid-hydroklorid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxy-carbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 9 fra 2-[N-(4-cyanofenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 82% av teoretisk Yield: 82% of theoretical

C26H25N503S (487,58) C26H25N503S (487.58)

Rf-verdi: 0,21 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 488 Rf value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 488

Eksempel 20 Example 20

2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(hydroksykarbonylmetyl)-amid-hydroklorid 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 10 fra 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 10 from 2-[N-(4-amidinphenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride and caustic soda.

Utbytte: 75% av teoretisk Yield: 75% of theoretical

C24H21N503S (459,53) C24H21N503S (459.53)

Rf-verdi: 0,14 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 460 Rf value: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 460

(M+Na)<+> = 482 (M+Na)<+> = 482

Eksempel 21 Example 21

2-[2-(4-amidinfenyl)etyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 2-[2-(4-amidinephenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 9 fra 2-[2-(4-cyanofenyl)etyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 80% av teoretisk Yield: 80% of theoretical

C28H28N403S (500,62) C28H28N403S (500.62)

Rrverdi: 0,30 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 501 Rr value: 0.30 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 501

Eksempel 22 Example 22

2-[2-(4-amidinfenyl)etyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyl-etyl)-amid-hydroklorid 2-[2-(4-amidinephenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide hydrochloride

Fremstilt analogt eksempel 10 fra 2-[2-(4-amidinfenyl)etyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 10 from 2-[2-(4-amidinephenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 77% av teoretisk Yield: 77% of theoretical

C26H24N403S (472,57) C26H24N403S (472.57)

Rf-verdi: 0,18 (kiselgel; metylenkloird/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 473 Rf value: 0.18 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 473

(M+Na)<+> = 495 (M+Na)<+> = 495

(M+H+Na)^ = 259 (M+H+Na)^ = 259

Eksempel 23 Example 23

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 4-metylamino-3-nitro-benzosyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid a) 4-methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

Til en løsning av 24,7 g (0,115 Mol) 4-metylamino-3-nitro-benzosyreklorid og 22,3 To a solution of 24.7 g (0.115 Mol) 4-methylamino-3-nitro-benzoic acid chloride and 22.3

g (0,115 Mol) N-(2-etoksykarbonyletyl)-anilin i 300 ml tetrahydrofuran ble det under omrøring ved romtemperatur i løpet av 15 min dråpevis tilsatt 13,1 g (0,13 Mol) trietylamin. Etter 21 omrøring ble løsningsmiddelet destillert av i vannstrålevakuum og resten omsatt under røring med 700 ml vann. Blandingen ble ekstrahert tre ganger hver med 200 ml diklormetan, det organiske ekstraktet ble vasket med 200 ml 2N saltsyre og to ganger hver med 300 ml vann og tørket over natriumsulfat. Løsningsmiddelet ble deretter destillert av og det på denne måten oppnådde oljeholdige produktet ble renset ved kolonne-kromatografi (1 kg kiselgel; løpemiddel: Petroleter/eddikester = 2:1). g (0.115 mol) of N-(2-ethoxycarbonylethyl)-aniline in 300 ml of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise during 15 minutes with stirring at room temperature. After 21 minutes of stirring, the solvent was distilled off in a water jet vacuum and the residue reacted with stirring with 700 ml of water. The mixture was extracted three times each with 200 ml of dichloromethane, the organic extract was washed with 200 ml of 2N hydrochloric acid and twice each with 300 ml of water and dried over sodium sulfate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluent: petroleum ether/acetic ester = 2:1).

Utbytte: 35,0 g (82% av teoretisk) Yield: 35.0 g (82% of theoretical)

Rf-verdi: 0,28 (kiselgel; diklormetan/etanol = 50:1) Rf value: 0.28 (silica gel; dichloromethane/ethanol = 50:1)

b) 3-amino-4-metylamino-benzosyre-N-fenyl-N-(2-eto^ b) 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-eto^

12,1 g (0,0326 Mol) 4-metylamino-3-nitrobenzosyre-N-fenyl-N-(2-etoksykarbonyl-etyl)-amid ble hydrert i 300 ml etanol og 150 ml diklormetan etter tilførsel av ca 4 g palladium/kull (10%) ved romtemperatur og et hydrogentrykk på 5 bar. Deretter ble det filtrert fra katalysatoren og filtratet inndampet. Det på denne måten oppnådde råproduktet ble uten ytterligere rensning omsatt. 12.1 g (0.0326 Mol) of 4-methylamino-3-nitrobenzoic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide was hydrogenated in 300 ml of ethanol and 150 ml of dichloromethane after the addition of approx. 4 g of palladium /coal (10%) at room temperature and a hydrogen pressure of 5 bar. It was then filtered from the catalyst and the filtrate evaporated. The crude product obtained in this way was marketed without further purification.

Utbytte: 10,6 g (95% av teoretisk) Yield: 10.6 g (95% of theoretical)

Rrverdi: 0,19 (kiselgel; diklormetan/etanol = 50:1) Rr value: 0.19 (silica gel; dichloromethane/ethanol = 50:1)

c) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid c) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

6,17 g (0,035 Mol) N-(4-cyanofenyl)glysin og 5,68 g (0,035 Mol) N,N'-karbonyldiimidazol ble oppvarmet i 300 ml tetrahydrofuran i 30 min til tilbakeløp, og deretter ble 10,6 g (0,032 Mol) 3-amino-4-metylamino-benzosyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid tilført og det ble ytterligere oppvarmet i 5 t til tilbakeløp. Deretter ble løsnings-middelet destillert fra i vakuum, resten oppløst i 150 ml iseddik og oppvarmet 11 til tilbakeløp. Deretter ble iseddik avdestillert i vakuum, resten løst i ca 300 ml diklormetan, løsningen vasket to ganger hver med ca 150 ml vann og til slutt tørket over natriumsulfat. Etter avdampning av løsningsmiddelet ble det på denne måten oppnådde råproduktet renset ved kolonnekromatografi (800 g kiselgel; løpemiddel: Diklormetan med 1-2% etanol). 6.17 g (0.035 Mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 Mol) of N,N'-carbonyldiimidazole were heated in 300 ml of tetrahydrofuran for 30 min to reflux, and then 10.6 g (0.032 Mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was added and it was further heated for 5 h to reflux. The solvent was then distilled off in vacuo, the residue dissolved in 150 ml of glacial acetic acid and heated to reflux. Glacial acetic acid was then distilled off in vacuo, the residue dissolved in about 300 ml of dichloromethane, the solution washed twice each with about 150 ml of water and finally dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g silica gel; eluent: dichloromethane with 1-2% ethanol).

Utbytte: 8,5 g (57% av teoretisk) Yield: 8.5 g (57% of theoretical)

Rrverdi: 0,51 (kiselgel; diklormetan/etanol =19:1) Rr value: 0.51 (silica gel; dichloromethane/ethanol = 19:1)

d) l-metyl-2-fN-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid d) 1-methyl-2-n-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

1,2 g (2,49 mMol) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble rørt i 100 ml mettet etanolisk saltsyre i 61 ved romtemperatur. Til slutt ble det redusert i vakuum til tørrhet, resten løst i 100 ml etanol, omsatt med 2,5 g (26 mMol) ammoniumkarbonat og rørt over natt ved romtemperatur. Etter avdestillering av løsningsmiddelet ble det på denne måten oppnådde råproduktet renset ved kolonnekromatografi (100 g kiselgel; løpemiddel: Diklormetan/ etanol = 4:1). Ved redusering av eluatet oppnådde man den ønskede forbindelsen som hvitt, amorf fast stoff. 1.2 g (2.49 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 100 ml of saturated ethanolic hydrochloric acid for 61 at room temperature. Finally, it was reduced in vacuo to dryness, the residue dissolved in 100 ml of ethanol, reacted with 2.5 g (26 mmol) of ammonium carbonate and stirred overnight at room temperature. After distilling off the solvent, the crude product thus obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane/ethanol = 4:1). By reducing the eluate, the desired compound was obtained as a white, amorphous solid.

Utbytte: 1,10 g (83% av teoretisk) Yield: 1.10 g (83% of theoretical)

Rf-verdi: 0,18 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.18 (silica gel; dichloromethane/ethanol = 4:1)

C28H3oN603 x HC1 (498,6) C28H3oN603 x HC1 (498.6)

Rf-verdi: 0,14 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 499 Rf value: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 499

(M+2H)<++> = 250 (M+2H)<++> = 250

(M+H+Na)^ = 261 (M+H+Na)^ = 261

Eksempel 24 Example 24

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide

En blanding av 300 mg (0,56 mMol) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid, 15 ml etanol, 4 ml vann og 120 mg (3,0 mMol) natriumhydroksid ble omrørt i 21 ved romtemperatur. Til slutt ble dette fortynnet med ca 20 ml vann og gjort svakt sur med iseddik. Det derved utkrystalliserte produktet ble sugd av, vasket med vann og tørket ved 60°C i vakuum. A mixture of 300 mg (0.56 mmol) of 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide -hydrochloride, 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mmol) of sodium hydroxide were stirred for 21 at room temperature. Finally, this was diluted with about 20 ml of water and made slightly acidic with glacial acetic acid. The thus crystallized product was sucked off, washed with water and dried at 60°C in a vacuum.

Utbytte: 250 mg (95% av teoretisk) Yield: 250 mg (95% of theoretical)

C26H26N603 (470,5) C26H26N603 (470.5)

EKA-massespekter: (M+H)<+> = 471 EKA mass spectrum: (M+H)<+> = 471

(M+H+Na)^ = 247 (M+H+Na)^ = 247

(M+2Na)<++> = 258 (M+2Na)<++> = 258

Eksempel 25 Example 25

l-metyl-2-[(4-amidinfenyl)tiometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt fra 1 -metyl-2-[(4-cyanofenyl)tiometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 90% av teoretisk Yield: 90% of theoretical

C28H29N503S (515,64) C28H29N503S (515.64)

Rf-verdi: 0,24 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.24 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 496 EKA mass spectrum: (M+H)<+> = 496

(M+H+Na)^ = 269,7 (M+H+Na)^ = 269.7

Eksempel 26 Example 26

1-metyl-2-[(4-amidinfenyl)tio hydroksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[(4-amidinephenyl)thio hydroxycarbonylethyl)-amide hydrochloride

Fremstilt fra 1 -metyl-2-[(4-amidinfenyl)tiometyl]-benzimidazol-5-yl-karboksylsyreN-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared from 1-methyl-2-[(4-amidinephenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 76% av teoretisk Yield: 76% of theoretical

C26H25N5O3S (487,58) C26H25N5O3S (487.58)

Rf-verdi: 0,31 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.31 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 488 EKA mass spectrum: (M+H)<+> = 488

(M+Na)<+> = 510 (M+Na)<+> = 510

Eksempel 27 Example 27

l-metyl-2-[(4-amidinfenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-N-(l-metylpiperidin-4-yl)-N-metyl-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpiperidin-4-yl)-N-methyl-amide hydrochloride

a) 4-klor-3 -nitrobenzensulfonsyre-N-( 1 -metyl-piperidin-4-yl)-N-metyl-amid a) 4-chloro-3-nitrobenzenesulfonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide

Til en løsning av 2,2 ml (15 mMol) l-metyl-4-metylamino-piperidin i 60 ml pyridin To a solution of 2.2 ml (15 mmol) of 1-methyl-4-methylamino-piperidine in 60 ml of pyridine

ble det under isavkjøling porsjonsvis tilsatt 3,8 g (15 mMol) 4-klor-3-nitrobenzensulfon-syreklorid. Deretter ble det under avkjøling ytterligere omrørt i 21, til slutt inndampet til tørrhet, resten ble omsatt med ca 50 ml vann og under kraftig omrøring med konsentrert ammoniakk innstilt alkalisk. Det utfelte råproduktet ble sugd av og renset ved kolonne-kromatografi (250 g kiselgel, løpemiddel: Diklormetan med 1,5% etanol). 3.8 g (15 mmol) of 4-chloro-3-nitrobenzenesulfonic acid chloride were added in portions under ice-cooling. Then, while cooling, it was further stirred for 21, finally evaporated to dryness, the residue was reacted with about 50 ml of water and, with vigorous stirring, concentrated ammonia adjusted alkaline. The precipitated crude product was sucked off and purified by column chromatography (250 g silica gel, eluent: dichloromethane with 1.5% ethanol).

Utbytte: 1,6 g (31 % av teoretisk) Yield: 1.6 g (31% of theoretical)

C13H,8C1N304S (347,8) C13H,8C1N304S (347.8)

Rf-verdi: 0,19 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1)

b) 4-metylamino-3-nitrobenzensulfonsyre-N-metyl-N-( 1 -metyl-piperidin-4-yl)-amid 1,6 g (4,6 mMol) 4-klor-3-nitrobenzensulfonsyre-N-metyl-N-(l-metyl-piperidin-4-yl)-amid ble omsatt med 30 ml 40% metylaminløsning og omrørt i lukket kolbe 41 ved romtemperatur. Deretter ble det fortynnet med ca 40 ml vann, det utfelte produktet ble sugd av, vasket med vann og tørket. b) 4-methylamino-3-nitrobenzenesulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide 1.6 g (4.6 mmol) 4-chloro-3-nitrobenzenesulfonic acid-N-methyl -N-(1-methyl-piperidin-4-yl)-amide was reacted with 30 ml of 40% methylamine solution and stirred in closed flask 41 at room temperature. It was then diluted with about 40 ml of water, the precipitated product was sucked off, washed with water and dried.

Utbytte: 1,5 g (95% av teoretisk) Yield: 1.5 g (95% of theoretical)

C14H22N4O4S (343,4) C14H22N4O4S (343.4)

Rf-verdi: 0,45 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.45 (silica gel; dichloromethane/ethanol = 4:1)

c) 3-amino-4-metylaminobenzensulfonsyre-N-metyl-N-(l-metyl-piperidin-4-yl)-amid 1,5 g (4,4 mMol) 4-metylamino-3-nitrobenzensulfonsyre-N-metyl-N-(l-metyl-piperidin-4-yl)-amid ble løst i 100 ml metanol og ved romtemperatur og 5 bar hydrogentrykk katalytisk hydrert (10% palladium på kull). Deretter ble katalysatoren avfiltrert og filtratet redusert. Det på denne måten oppnådde oljeholdige produktet ble uten rensning ytterligere omsatt. c) 3-amino-4-methylaminobenzenesulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide 1.5 g (4.4 mmol) 4-methylamino-3-nitrobenzenesulfonic acid-N-methyl -N-(1-methyl-piperidin-4-yl)-amide was dissolved in 100 ml of methanol and catalytically hydrogenated (10% palladium on charcoal) at room temperature and 5 bar hydrogen pressure. The catalyst was then filtered off and the filtrate reduced. The oily product obtained in this way was further processed without purification.

Utbytte: 1,4 g (100% av teoretisk) Yield: 1.4 g (100% of theoretical)

C4H24N4O2S (312,4) C4H24N4O2S (312.4)

Rf-verdi: 0,33 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.33 (silica gel; dichloromethane/ethanol = 4:1)

d) l-metyl-2-[(4-cyanofenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-N-metyl-N-(l-metyl-piperidin-4-yl)-amid d) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide

532 mg (3,0 mMol) 4-cyanofenyloksyeddiksyre og 486 mg (3,0 mMol) 1,1'-karbonyldiimidazol ble løst i 40 ml tetrahydrofuran og oppvarmet i 15 min til tilbakeløp. Deretter ble 700 mg (2,24 mMol) 3-amino-4-metylaminobenzensulfonsyre-N-metyl-N-(l-metyl-piperidin-4-yl)-amid tilført og ytterligere kokt i 8 t. Deretter ble det inndampet og det på denne måten oppnådde oljeholdige resten ble varmet i 30 ml iseddik i 11 til tilbakeløp. Iseddik ble destillert av, resten omsatt med ca 30 ml vann og innstilt alkalisk med konsentrert ammoniakk, og løsningen ble ekstrahert tre ganger hver med ca 20 ml diklormetan. Den organiske fasen ble tørket og inndampet. Det på denne måten oppnådde produktet ble uten ytterligere rensning videre omsatt. 532 mg (3.0 mmol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran and heated for 15 min to reflux. Then 700 mg (2.24 mmol) of 3-amino-4-methylaminobenzenesulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide was added and further boiled for 8 h. It was then evaporated and the oily residue obtained in this way was heated in 30 ml of glacial acetic acid for 11 to reflux. Glacial acetic acid was distilled off, the residue reacted with about 30 ml of water and made alkaline with concentrated ammonia, and the solution was extracted three times each with about 20 ml of dichloromethane. The organic phase was dried and evaporated. The product obtained in this way was sold on without further purification.

C23H27N503S (453,6) C23H27N503S (453.6)

Rf-verdi: 0,37 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.37 (silica gel; dichloromethane/ethanol = 4:1)

e) 1 -metyl-2- [(4-amidinfenyl)oksymetyl] -benzimidazol-5 -yl-sulfonsyre-N-metyl-N-( 1 - metylpiperidin-4-yl)-amid-hydroklorid e) 1-methyl-2-[(4-amidinephenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide hydrochloride

Fremstilt analogt eksempel 23 fra 400 mg l-metyl-2-[(4-cyanofenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-N-metyl-N-(l-metylpiperidin-4-yl)-amid med etanolisk saltsyre og ammoniumkarbonat. Prepared analogously to Example 23 from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide with ethanolic hydrochloric acid and ammonium carbonate.

Utbytte: 370 mg (83% av teoretisk) Yield: 370 mg (83% of theoretical)

C23H3oN603S (470,6) C23H3oN603S (470.6)

EKA-massespekter: (M+H)<+> = 471 EKA mass spectrum: (M+H)<+> = 471

(M+2H)<++> = 236 (M+2H)<++> = 236

Eksempel 28 Example 28

l-metyl-2-[(4-amidinfenyl)oksymetyl]-benzimi^ amid-hydroklorid 1-Methyl-2-[(4-amidinephenyl)oxymethyl]-benzimi^ amide hydrochloride

Fremstilt analogt eksempel 27 fra l-metyl-2-[(4-cyanofenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-N-metyl-N-fenyl-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-phenyl-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 46% av teoretisk Yield: 46% of theoretical

C23H23N503S (449,5) C23H23N503S (449.5)

EKA-massespekter: (M+H)<+> = 450 EKA mass spectrum: (M+H)<+> = 450

(M+H+metanol)<+> = 482 (M+H+methanol)<+> = 482

(M+2H)<++> = 223 (M+2H)<++> = 223

Eksempel 29 Example 29

1 -metyl-2- [(4-amidinfenyl)oksymetyl] -benzimidazol-5 -yl-sulfonsyre-N-(3 -etoksykarbonyl-n-propyl)-N-fenyl-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenylamide hydrochloride

Fremstilt analogt eksempel 27 fra l-metyl-2-[(4-cyanofenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-N-(3-etoksykarbonyl-n-propyl)-N-fenyl-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 57% av teoretisk Yield: 57% of theoretical

C28H31N505S (549,7) C28H31N505S (549.7)

EKA-massespekter: (M+H)<+> = 550 EKA mass spectrum: (M+H)<+> = 550

Eksempel 30 Example 30

l-metyl-2-[(3-amidinfenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-pyrrolidid-hydroklorid 1-methyl-2-[(3-amidinephenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid pyrrolidide hydrochloride

Fremstilt analogt eksempel 27 fra l-metyl-2-[(3-cyanofenyl)oksymetyl]-benzimidazol-5-yl-sulfonsyre-pyrrolidid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 27 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 71% av teoretisk Yield: 71% of theoretical

C20H23N5O3S (413,5) C20H23N5O3S (413.5)

EKA-massespekter: (M+H)<+> = 414 EKA mass spectrum: (M+H)<+> = 414

Eksempel 31 Example 31

l-metyl-2-[2-(4-amidinfenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N metoksykarbonylpropyl)-amid-dihydroklorid 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-methoxycarbonylpropyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-tert.butyloksykarbonylpropyl)-amid og metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 83,5% av teoretisk Yield: 83.5% of theoretical

Rf-verdi: 0,17 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C29H3iN503 (497,6) C29H3iN503 (497.6)

EKA-massespekter: (M+H)<+> = 498 EKA mass spectrum: (M+H)<+> = 498

(M+H+Na)^ = 260,7 (M+H+Na)^ = 260.7

Eksempel 32 Example 32

l-metyl-2-[2-(4-amidinfenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-hydroksykarbonylpropyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[(4-amidinfenyl)aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-metoksykarbonylpropyl)-amid-dihydro-klorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[(4-amidinephenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonylpropyl)-amide dihydrochloride and caustic soda.

Utbytte: 92% av teoretisk Yield: 92% of theoretical

Rf-verdi: 0,09 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1)

C28H29N503 (483,6) C28H29N503 (483.6)

EKA-massespekter: (M+H)<+> = 484 EKA mass spectrum: (M+H)<+> = 484

(M+Na)<+> = 506 (M+Na)<+> = 506

(M+H+Naf" = 253,7 (M+H+Naf" = 253.7

Eksempel 33 Example 33

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-etoksykarbonylpropyl)-amid-dihydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide dihydrochloride

a) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-tert.butyloksykarbonylpropyl)-amid a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)-amide

Fremstilt analogt eksempel 23c fra N-(4-cyanofenyl)-glysin og 3-amino-4-metyl-mino-benzosyre-N-fenyl-N-(3-tert.butyloksykarbonylpropyl)-amid. Prepared analogous example 23c from N-(4-cyanophenyl)-glycine and 3-amino-4-methyl-mino-benzoic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)-amide.

Utbytte: 65% av teoretisk Yield: 65% of theoretical

Rf-verdi: 0,17 (kiselgel; diklormetan/metanol =19:1) Rf value: 0.17 (silica gel; dichloromethane/methanol = 19:1)

b) l-metyl-2-[N-(4-amidinfenyl)-aminomet fenyl-N-(3-etoksykarbonylpropyl)-amid-dihydroklorid b) 1-methyl-2-[N-(4-amidinephenyl)-aminometh phenyl-N-(3-ethoxycarbonylpropyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-tert.butyloksykarbonylpropyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 68% av teoretisk Yield: 68% of theoretical

Rf-verdi: 0,12 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)

C29H32N603 (512,6) C29H32N603 (512.6)

EKA-massespekter: (M+H)<+> =513 EKA mass spectrum: (M+H)<+> =513

(M+H+Na)4^ =268 (M+H+Na)4^ =268

Eksempel 34 Example 34

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-hydroksykarbonylpropyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-etoksykarbonylpropyl)-amid-dihydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide dihydrochloride and caustic soda.

Utbytte: 73,5% av teoretisk Yield: 73.5% of theoretical

C27H28N603 (484,6) C27H28N603 (484.6)

EKA-massespekter: (M+H)<+> = 485 EKA mass spectrum: (M+H)<+> = 485

(M+2H)<++> = 243 (M+2H)<++> = 243

(M+H+Na)^ =254 (M+H+Na)^ =254

Eksempel 35 Example 35

l-metyl-2-[2-(4-amidinfenyl)-etyl]-ben2imidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksy-karbonylpropyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-ben2imidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxy-carbonylpropyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyI)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarboant. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 73% av teoretisk Yield: 73% of theoretical

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)

C28H29N503 (483,6) C28H29N503 (483.6)

EKA-massespekter: (M+H)<+> = 484 EKA mass spectrum: (M+H)<+> = 484

(M+H+Na)^ = 253,7 (M+H+Na)^ = 253.7

Eksempel 36 Example 36

l-metyl-2-[2-(4-amidinfenyl)-etyl]-b^ karbonylpropyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)ethyl]-b carbonylpropyl)amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5 -yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid-hydroklorid og natronlut Utbytte: 97% av teoretisk Prepared analogously to example 24 from 1-methyl-2-[2-(4-amidinphenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride and caustic soda Yield: 97% of theoretical

C26H25N503 (455,5) C26H25N503 (455.5)

EKA-massespekter: (M+H)<+> =456 EKA mass spectrum: (M+H)<+> =456

(M+Na)<+> = 478 (M+Na)<+> = 478

(M+2Na)<++> = 250,6 (M+2Na)<++> = 250.6

Eksempel 37 Example 37

1 -metyl-2- [(4-amidinfenyl)-oksymetyl] -benzimidazol-5 -yl-karboksylsyre-N-fenyl-N-(etoksykarbonylpropyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylpropyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[(4-cyanofenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 76% av teoretisk Yield: 76% of theoretical

Rf-verdi: 0,17 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C27H27N504 (485,6) C27H27N504 (485.6)

EKA-massespekter: (M+H)<+> =486 EKA mass spectrum: (M+H)<+> =486

(M+H+Na)^ = 254,7 (M+H+Na)^ = 254.7

Eksempel 38 Example 38

l-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(hydroksykarbonylmetyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra 1-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid-hydroklorid og natronlut. Utbytte: 58% av teoretisk Prepared analogously to Example 24 from 1-methyl-2-[(4-amidinphenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride and caustic soda. Yield: 58% of theoretical

C25H23N504 (457,5) C25H23N504 (457.5)

EKA-massespekter: (M+H)<+> =458 EKA mass spectrum: (M+H)<+> =458

(M+Na)<+> = 480 (M+Na)<+> = 480

(M+2Na)<++> =251,6 (M+2Na)<++> =251.6

Eksempel 39 Example 39

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Utbytte: 74% av teoretisk Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% of theoretical

Rf-verdi: 0,12 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)

C27H28N503 (484,6) C27H28N503 (484.6)

EKA-massespekter: (M+H)<+> = 485 EKA mass spectrum: (M+H)<+> = 485

(M+H+Na)<++> = 254 (M+H+Na)<++> = 254

Eksempel 40 Example 40

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(hydroksykarbonylmetyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(etoksykarbonylmetyl)-amid-hydroklorid og natronlut. Utbytte: 84% av teoretisk Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride and caustic soda. Yield: 84% of theoretical

C25H24N603 (456,5) C25H24N603 (456.5)

EKA-massespekter: (M+H)<+> = 457 EKA mass spectrum: (M+H)<+> = 457

(M+Na)<+> = 479 (M+Na)<+> = 479

(M+2Na)<++> =251 (M+2Na)<++> =251

Eksempel 41 Example 41

l-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-(4-pyrimidyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[(4-cyanofenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-(4-pyrimidyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 14% av teoretisk Yield: 14% of theoretical

C26H27N7O4 (501,6) C26H27N7O4 (501.6)

EKA-massespekter: (M+H)<+> =502 EKA mass spectrum: (M+H)<+> =502

Eksempel 42 Example 42

1-metyl-2-[(4-amidinfenyl)-oksymet^ 1-methyl-2-[(4-amidinephenyl)-oxymeth^

(etoksykarbonylmetyl)-amid-hydroklorid (ethoxycarbonylmethyl)amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[(4-cyanofenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 44% av teoretisk Yield: 44% of theoretical

C26H26N604 (486,5) C26H26N604 (486.5)

EKA-massespekter: (M+H)<+> =487 EKA mass spectrum: (M+H)<+> =487

(M+2H)^ = 244 (M+2H)^ = 244

(M+H+Na)<++> =255 (M+H+Na)<++> =255

Eksempel 43 Example 43

1-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(hydroksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-dihydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[(4-amidinphenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride and caustic soda.

Utbytte: 85% av teoretisk Yield: 85% of theoretical

C24H22N604 (458,5) C24H22N604 (458.5)

EKA-massespekter: (M+H)<+> =459 EKA mass spectrum: (M+H)<+> =459

(M+Na)<+> =481 (M+Na)<+> =481

(M+2Na)<++> = 252 (M+2Na)<++> = 252

Eksempel 44 Example 44

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-dihydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride

a) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-etoksykarbonylmetyl-amid a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide

Fremstilt analogt eksempel 23c fra N-(4-cyanofenyl)-glysin og 3-amino-4-metyl-amino-benzosyre-N-(pyridyl)-N-etoksykarbonylmetyl-amid. Prepared analogous example 23c from N-(4-cyanophenyl)-glycine and 3-amino-4-methyl-amino-benzoic acid-N-(pyridyl)-N-ethoxycarbonylmethyl-amide.

Utbytte: 24% av teoretisk Yield: 24% of theoretical

Rf-verdi: 0,56 (kiselgel; diklormetan/metanol = 4:1) Rf value: 0.56 (silica gel; dichloromethane/methanol = 4:1)

b) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-etoksykarbonylmetyl)-amid-dihydroklorid b) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 70% av teoretisk Yield: 70% of theoretical

Rrverdi: 0,16 (kiselgel; diklormetan/etanol = 4:1) Rr value: 0.16 (silica gel; dichloromethane/ethanol = 4:1)

C26H27N703(485,6) C26H27N703(485.6)

EKA-massespekter: (M+H)<+> = 486 EKA mass spectrum: (M+H)<+> = 486

(M+2H)<++> = 243,7 (M+2H)<++> = 243.7

(M+H-Na)^ =254,6 (M+H-Na)^ =254.6

Eksempel 45 Example 45

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(hydroksykarbonylmetyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-dihydro-klorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride and baking soda.

Utbytte: 91% av teoretisk Yield: 91% of theoretical

C24H23N703 (457,5) C24H23N703 (457.5)

EKA-massespekter: (M+H)<+> = 458 EKA mass spectrum: (M+H)<+> = 458

(M+Na)<+> = 480 (M+Na)<+> = 480

(M+2Na)<++> =251,7 (M+2Na)<++> =251.7

Eksempel 46 Example 46

l-metyl-2-[2-(4-amidinfenyl)-e1yl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-dihydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 90% av teoretisk Yield: 90% of theoretical

Rf-verdi: 0,17 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C27H28N603 (484,6) C27H28N603 (484.6)

EKA-massespekter: (M+H)<+> = 485 EKA mass spectrum: (M+H)<+> = 485

(M+2H)<++> = 243 (M+2H)<++> = 243

(M+H+Na)<++> =254 (M+H+Na)<++> =254

Eksempel 47 Example 47

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(hydroksykarbonylmetyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-dihydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride and caustic soda .

Utbytte: 89% av teoretisk Yield: 89% of theoretical

C25H24N603 (456,5) C25H24N603 (456.5)

EKA-massespekter: (M+H)<+> =457 EKA mass spectrum: (M+H)<+> =457

(M+Na)<+> = 479 (M+Na)<+> = 479

Eksempel 48 Example 48

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benz-imida2ol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benz-imid-2ol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 87% av teoretisk Yield: 87% of theoretical

Rf-verdi: 0,11 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1)

C27H28N603 (484,6) C27H28N603 (484.6)

EKA-massespekter: (M+H)<+> = 485 EKA mass spectrum: (M+H)<+> = 485

(M+2H)<++> = 243 (M+2H)<++> = 243

(M+H+Na)^ =254 (M+H+Na)^ =254

Eksempel 49 Example 49

l-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimidaz etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimidaz ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[(4-cyanofenyl)-oksymetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 79,5% av teoretisk Yield: 79.5% of theoretical

C28H29N504 (499,6) C28H29N504 (499.6)

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =500,0 EKA mass spectrum: (M+H)<+> =500.0

(M+H+Na)^ =261,7 (M+H+Na)^ =261.7

Eksempel 50 Example 50

l-metyl-2-[(4-amidinfenyl)-oksymetyl]-benzimida2ol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-oxymethyl]-benzimida-2ol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra 1 -metyl-2-[(4-amidinfenyl)-oksymetyl] -benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[(4-amidinphenyl)-oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 82% av teoretisk Yield: 82% of theoretical

C26H25N504(471,5) C26H25N504(471.5)

Rf-verdi: 0,11 (kiselgel; diklormetan/etanol =4:1) Rf value: 0.11 (silica gel; dichloromethane/ethanol =4:1)

EKA-massespekter: (M+H)<+> =472 EKA mass spectrum: (M+H)<+> =472

(M+H+Na)^ = 247,6 (M+H+Na)^ = 247.6

(M+Na)<+> =494 (M+Na)<+> =494

(M+2Na)<++> =258,6 (M+2Na)<++> =258.6

Eksempel 51 Example 51

l-metyl-2-[2-(2-amidintiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[2-(2-amidinthiofen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-2-[2-(2-cyanotiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid a) 1-methyl-2-[2-(2-cyanothiophen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 23c fra 3-(2-cyanotiofen-5-yl)-propionsyre og 3-amino-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid. Prepared analogous example 23c from 3-(2-cyanothiophen-5-yl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Utbytte: 18% av teoretisk Yield: 18% of theoretical

Rf-verdi: 0,66 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.66 (silica gel; dichloromethane/methanol = 9:1)

b) l-metyI-2-[2-(2-amidintiofen-5-yl)-etyl]-berizimidazoI-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-2-[2-(2-amidinthiopen-5-yl)-ethyl]-berizimidazoI-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(2-cyanotiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(2-cyanothiophen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 53% av teoretisk Yield: 53% of theoretical

C26H28N603S (504,6) C26H28N603S (504.6)

Rf-verdi: 0,22 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.22 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =505 EKA mass spectrum: (M+H)<+> =505

(M+H+Na)^ =264 (M+H+Na)^ =264

Eksempel 52 Example 52

l-metyl-2-[2-(2-amidintiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[2-(2-amidinthiofen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(2-amidintiofen-5-yl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[2-(2-amidinthiopen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 98% av teoretisk Yield: 98% of theoretical

C24H24N603S (476,6) C24H24N603S (476.6)

EKA-massespekter: (M+H)<+> =477 EKA mass spectrum: (M+H)<+> =477

(M+Na)<+> = 499 (M+Na)<+> = 499

(M+2H)<++> = 239 (M+2H)<++> = 239

Eksempel 53 Example 53

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 23c fra N-(4-cyanofenyl)-glysin og 3-amino-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid. Prepared analogous example 23c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Utbytte: 61% av teoretisk Yield: 61% of theoretical

Rf-verdi: 0,62 (kiselgel; diklormetan/metanol =19:1) Rf value: 0.62 (silica gel; dichloromethane/methanol = 19:1)

b) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yI-karboksyIsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 71% av teoretisk Yield: 71% of theoretical

C27H29N703 (499,6) C27H29N703 (499.6)

Rf-verdi: 0,28 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.28 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =500 EKA mass spectrum: (M+H)<+> =500

(M+H+Na)^ =261,8 (M+H+Na)^ =261.8

(M+2H)^ = 250,8 (M+2H)^ = 250.8

Eksempel 54 Example 54

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 91% av teoretisk Yield: 91% of theoretical

C25H25N703 (471,5) C25H25N703 (471.5)

EKA-massespekter: (M+H)<+> =472 EKA mass spectrum: (M+H)<+> =472

(M+H+Na)^ = 247,6 (M+H+Na)^ = 247.6

( M+ m)* = 236,7 ( M + m)* = 236.7

(M+2Na)<++> = 258,6 (M+2Na)<++> = 258.6

Eksempel 55 Example 55

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyIetyl)-amid a) 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 142a fra 3-(4-cyanofenyl)-propionsyre og 3-amino-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid. Prepared analogous example 142a from 3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Utbytte: 22% av teoretisk Yield: 22% of theoretical

Rf-verdi: 0,68 (kiselgel; diklormetan/metanol = 19:1) Rf value: 0.68 (silica gel; dichloromethane/methanol = 19:1)

b) l-metyl-2-[2-(4-amidmfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-2-[2-(4-amidimphenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 85% av teoretisk Yield: 85% of theoretical

C28H3oN603 (498,6) C28H3oN6O3 (498.6)

Rf-verdi: 0,30 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.30 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =499 EKA mass spectrum: (M+H)<+> =499

(M+H+Na)^ = 261 (M+H+Na)^ = 261

Eksempel 56 Example 56

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 97% av teoretisk Yield: 97% of theoretical

C26H26N603 (470,5) C26H26N603 (470.5)

EKA-massespekter: (M+H)<+> =471 EKA mass spectrum: (M+H)<+> =471

(M+H+Na)^ = 247 (M+H+Na)^ = 247

(M+Na)<+> = 493 (M+Na)<+> = 493

Eksempel 57 Example 57

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 86% av teoretisk Yield: 86% of theoretical

C29H3iN503 (497,6) C29H3iN503 (497.6)

Rf-verdi: 0,11 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =498 EKA mass spectrum: (M+H)<+> =498

(M+2H)<++> = 249,8 (M+2H)<++> = 249.8

Eksempel 58 Example 58

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 71% av teoretisk Yield: 71% of theoretical

C27H27N503 (469,6) C27H27N503 (469.6)

EKA-massespekter: (M+H)<+> =470 EKA mass spectrum: (M+H)<+> =470

(M+H+Na)^ = 246,6 (M+H+Na)^ = 246.6

(M+Na)<+> = 492 (M+Na)<+> = 492

( M+ 2<WT> =235,6 (M+ 2<WT> =235.6

Eksempel 59 Example 59

l-metyl-2-rN-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(metoksykarbonylmetyl)-amid-dihydroklorid 1-methyl-2-n-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(metoksykarbonylmetyl)-amid og metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 73% av teoretisk Yield: 73% of theoretical

C25H25N7Q3 (471,5) C25H25N7Q3 (471.5)

Rf-verdi: 0,12 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =472 EKA mass spectrum: (M+H)<+> =472

(M+H+Na)^ = 247,8 (M+H+Na)^ = 247.8

Eksempel 60 Example 60

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-dihydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(metoksykarbonyletyl)-amid og metanolisk saltsyre, metanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utbytte: 78% av teoretisk Yield: 78% of theoretical

C26H27N703 (485,6) C26H27N703 (485.6)

Rf-verdi: 0,31 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =486 EKA mass spectrum: (M+H)<+> =486

(M+H+Na)^ = 254,8 (M+H+Na)^ = 254.8

Eksempel 61 Example 61

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide hydrochloride

a) l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(1 H-tetrazol-5 -yl)etyl] -amid a) 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl] - amide

Fremstilt analogt eksempel 23c fra 3-(4-cyanofenyl)-propionsyre og 3-amino-4-metylaminobenzosyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid. Prepared analogous example 23c from 3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide.

Utbytte: 67% av teoretisk Yield: 67% of theoretical

IR-massespekter (KBr): Karakteristisk bånd ved IR mass spectrum (KBr): Characteristic band at

3439.5 cm"<1>(N-H); 2235,5 cm"<1> (C=N); 3439.5 cm"<1>(N-H); 2235.5 cm"<1> (C=N);

1631.6 cm"<1>(C=0) 1631.6 cm"<1>(C=0)

b) l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(1 H-tetrazol-5-yl)etyl]-amid-hydroklorid b) 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]- amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl ]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 92% av teoretisk Yield: 92% of theoretical

C27H27N90 (493,6) C27H27N90 (493.6)

EKA-massespekter: (M+H)<+> =494 EKA mass spectrum: (M+H)<+> =494

(M+Na)<+> =516 (M+Na)<+> =516

(M+2H)^ = 258,7 (M+2H)^ = 258.7

Eksempel 62 Example 62

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzim^ 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzim^

[2-(lH-tetrazol-5-yl)etyl]-amid-hydroklorid [2-(1H-tetrazol-5-yl)ethyl]-amide hydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl)-aminornetyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl ]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 29% av teoretisk Yield: 29% of theoretical

C26H26N10O (494,6) C26H26N10O (494.6)

EKA-massespekter: (M+H)<+> =495 EKA mass spectrum: (M+H)<+> =495

Eksempel 63 Example 63

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-n-heksyloksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-n-hexyloxycarbonylethyl)-amide hydrochloride

I ca 30 ml med klorhydrogenmettet n-heksanol ble 0,60 g (1,1 mMol) l-metyl-2-[N-(4-amidinfenyl)-arninometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid tilsatt og i 191 omrørt ved romtemperatur. Deretter ble heksanol avdestillert i vakuum, resten omsatt med 5 ml IN ammoniakkoppløsning under omrøring og på ny inndampet. Det på denne måten oppnådde råprodukt ble deretter renset ved kolonnekromatografi (kiselgel, diklormetan/metanol = 5:1). In about 30 ml of chlorohydrogen-saturated n-hexanol, 0.60 g (1.1 mmol) of 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2 -pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride added and stirred for 191 at room temperature. Hexanol was then distilled off in vacuum, the residue reacted with 5 ml of 1N ammonia solution while stirring and re-evaporated. The crude product thus obtained was then purified by column chromatography (silica gel, dichloromethane/methanol = 5:1).

Utbytte: 53% av teoretisk Yield: 53% of theoretical

C3,H37N703 (555,7) C3,H37N703 (555.7)

Rf-verdi: 0,36 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.36 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =556 EKA mass spectrum: (M+H)<+> =556

Eksempel 649 Example 649

l-metyI-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 1 -metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid a) 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- hydrochloride

Fremstilt analogt eksempel 23c fra N-(4-cyanofenyl)-N-metyl-glysin og 3-amino-4-metylaminobenzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid. Utbytte: 71% av teoretisk Rf-verdi: 0,66 (kiselgel; diklormetan/metanol = 19:1) Prepared analogous example 23c from N-(4-cyanophenyl)-N-methyl-glycine and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 71% of theoretical Rf value: 0.66 (silica gel; dichloromethane/methanol = 19:1)

b) l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimid karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyle1yl)-amid-hydroklorid b) 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimide carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-1yl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 77% av teoretisk Yield: 77% of theoretical

C28H31N703 (513,6) C28H31N703 (513.6)

EKA-massespekter: (M+H)<+> =514 EKA mass spectrum: (M+H)<+> =514

(M+H+Na)^ = 268,7 (M+H+Na)^ = 268.7

Eksempel 65 Example 65

l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra 1-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogous Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 66% av teoretisk Yield: 66% of theoretical

C26H27N703 (485,6) C26H27N703 (485.6)

EKA-massespekter: (M+H)<+> =486 EKA mass spectrum: (M+H)<+> =486

(M+Na)<+> = 508 (M+Na)<+> = 508

(M+2Na)<++> = 265,6 (M+2Na)<++> = 265.6

Eksempel 66 Example 66

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-syklopentyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 24d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-syklopentyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 24d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 65% av teoretisk Yield: 65% of theoretical

C28H35N503 (489,6) C28H35N503 (489.6)

EKA-massespekter: (M+H)<+> 490 EKA mass spectrum: (M+H)<+> 490

Eksempel 67 Example 67

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-^ hydroksykarbonyletyl)-amid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-^hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-cyklopentyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 89% av teoretisk Yield: 89% of theoretical

C26H31N5O3 (461,6) C26H31N5O3 (461.6)

EKA-massespekter: (M+H)<+> =462 EKA mass spectrum: (M+H)<+> =462

(M+H-Na)^ =242,6 (M+H-Na)^ =242.6

(M+Na)<+> = 484 (M+Na)<+> = 484

(M+2H)^ =231,6 (M+2H)^ =231.6

Eksempel 68 Example 68

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-cyklopentyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-cyklopentyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 60% av teoretisk Yield: 60% of theoretical

C27H34N6O3 (490,6) C27H34N6O3 (490.6)

EKA-massespekter: (M+H)<+> =491 EKA mass spectrum: (M+H)<+> =491

Eksempel 69 Example 69

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-cyklopentyl-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-cyklopentyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Utbytte: 45% av teoretisk C25H3oN304 (462,6) Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda. Yield: 45% of theoretical C25H3oN304 (462.6)

EKA-massespekter: (M+H)<+> =463 EKA mass spectrum: (M+H)<+> =463

(M+H+Na)^ = 243 (M+H+Na)^ = 243

(M+Na)<+> =485 (M+Na)<+> =485

(M+2Na)<++> = 254 (M+2Na)<++> = 254

Eksempel 70 Example 70

l-metyl-2-[N-(4-amidinfenyl)-N-m (2-pyridyl)-N-(etoksykarbonylmetyl)-arnid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-N-m(2-pyridyl)-N-(ethoxycarbonylmethyl)-arnide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 54% av teoretisk Yield: 54% of theoretical

C27H29N703 (499,6) C27H29N703 (499.6)

EKA-massespekter: (M+H)<+> =500 EKA mass spectrum: (M+H)<+> =500

(M+2H)<++> = 250,7 (M+2H)<++> = 250.7

Eksempel 71 Example 71

l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(etoksykarbonylmetyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide -hydrochloride and caustic soda.

Utbytte: 68% av teoretisk Yield: 68% of theoretical

C25H25N7O3 (471,5) C25H25N7O3 (471.5)

EKA-massespekter: (M+H)<+> =472 EKA mass spectrum: (M+H)<+> =472

(M+Na)<+> = 494 (M+Na)<+> = 494

(M+2Na)<++> = 258,6 (M+2Na)<++> = 258.6

Eksempel 72 Example 72

l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[2-(4-cyanofenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 91% av teoretisk Yield: 91% of theoretical

C28H3oN603 (498,6) C28H3oN6O3 (498.6)

Rf-verdi: 0,19 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =499 EKA mass spectrum: (M+H)<+> =499

Eksempel 73 Example 73

1-metyl-2-[N-(4-amidinfen^ pyridyl)-N-(2-etoksykarbonyletyl)-amid-dihydroklorid 1-Methyl-2-[N-(4-amidinphen^pyridyl)-N-(2-ethoxycarbonylethyl)-amide dihydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 86% av teoretisk Yield: 86% of theoretical

C27H29N7O3 (499,6) C27H29N7O3 (499.6)

Rrverdi: 0,09 (kiselgel; diklormetan/etanol = 4:1) Rr value: 0.09 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =500 EKA mass spectrum: (M+H)<+> =500

Eksempel 74 Example 74

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid-dihydroklorid og natronlut. Prepared analogous Example 24 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide dihydrochloride and baking soda.

Utbytte: 85% av teoretisk Yield: 85% of theoretical

C25H25N7O3 (471,5) C25H25N7O3 (471.5)

EKA-massespekter: (M+H)<+> =472 EKA mass spectrum: (M+H)<+> =472

(M+2H)^ =236,6 (M+2H)^ =236.6

(M+2Na)<++> = 258,6 (M+2Na)<++> = 258.6

Eksempel 75 Example 75

l-metyl-2-pSf-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-pSf-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 64% av teoretisk Yield: 64% of theoretical

C28H31N703 (513,6) C28H31N703 (513.6)

EKA-massespekter: (M+H)<+> =514 EKA mass spectrum: (M+H)<+> =514

Eksempel 76 Example 76

l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimid (3-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimide (3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 70% av teoretisk Yield: 70% of theoretical

C26H27N703 (485,6) C26H27N703 (485.6)

EKA-massespekter: (M+H)<+> =486 EKA mass spectrum: (M+H)<+> =486

(M+Na)<+> = 508 (M+Na)<+> = 508

(M+2Na)<++> = 265,6 (M+2Na)<++> = 265.6

Eksempel 77 Example 77

l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 1 -metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-pyridyl) -N-(2-etoksykarbonyletyl)-amid a) 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) )-amide

Fremstilt analogt eksempel 23c fra N-(4-cyanofenyl)-N-metylglysin og 3-amino-4-metylamino-benzosyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid. Prepared analogous example 23c from N-(4-cyanophenyl)-N-methylglycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.

Utbytte: 71% av teoretisk Yield: 71% of theoretical

Rf-verdi: 0,38 (kiselgel, diklormetan/metanol = 19:1) Rf value: 0.38 (silica gel, dichloromethane/methanol = 19:1)

b) 1 -metyl-2-[^-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-2-[^-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 74% av teoretisk Yield: 74% of theoretical

C29H32N603 (512,6) C29H32N603 (512.6)

EKA-massespekter: (M+H)<+> =513 EKA mass spectrum: (M+H)<+> =513

(M+H+Na)^ = 268 (M+H+Na)^ = 268

(M+2H)<++> = 257 (M+2H)<++> = 257

Eksempel 78 Example 78

l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzim fenyl-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzim phenyl-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 80% av teoretisk Yield: 80% of theoretical

C27H28N603 (484,6) C27H28N603 (484.6)

EKA-massespekter: (M+H)<+> =485 EKA mass spectrum: (M+H)<+> =485

(M+H+Na)^ = 254 (M+H+Na)^ = 254

(M+Na)<+> = 507 (M+Na)<+> = 507

(M+2Na)<+> 265 (M+2Na)<+> 265

Eksempel 79 Example 79

l-etyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-ethyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-etyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5 -yl-karboksylsyre-N-(2-pyirdyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 85% av teoretisk Yield: 85% of theoretical

C28H3iN703 (513,6) C28H3iN703 (513.6)

Rrverdi: 0,21 (kiselgel; diklormetan/metanol = 5:1) Rr value: 0.21 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =514 EKA mass spectrum: (M+H)<+> =514

(M+H+Na)^ = 268,6 (M+H+Na)^ = 268.6

(M+2H)<++> = 257,7 (M+2H)<++> = 257.7

Eksempel 80 Example 80

l-etyl-2-[N-(4-amidmfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-ethyl-2-[N-(4-amidemphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-etyl-2-rN-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og 2N natronlut. Prepared analogously to Example 24 from 1-ethyl-2-n-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and 2N caustic soda.

Utbytte: 49% av teoretisk Yield: 49% of theoretical

C26H27N703 (485,6) C26H27N703 (485.6)

EKA-massespekter: (M+H)<+> =486 EKA mass spectrum: (M+H)<+> =486

(M+H+Na)^ = 254,6 (M+H+Na)^ = 254.6

(M+2H)<++> =243,6 (M+2H)<++> =243.6

(M+2Na)<+> = 265,7 (M+2Na)<+> = 265.7

Eksempel 81 Example 81

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-fluorfenyl))-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 88% av teoretisk Yield: 88% of theoretical

C28H29FN6O3 (516,6) C28H29FN6O3 (516.6)

Rf-verdi: 0,08 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.08 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> 517 EKA mass spectrum: (M+H)<+> 517

(M+H+Na)"^ = 270 (M+H+Na)"^ = 270

(M+2H)<++> = 259 (M+2H)<++> = 259

Eksempel 82 Example 82

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-fluorfenyl))-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl))-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and soda ash.

Utbytte: 45% av teoretisk Yield: 45% of theoretical

C26H25FN603 (488,5) C26H25FN603 (488.5)

Rf-verdi: 0,05 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.05 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =489 EKA mass spectrum: (M+H)<+> =489

(M+H+Na)^ = 267 (M+H+Na)^ = 267

(M+2H)<++> = 256 (M+2H)<++> = 256

Eksempel 83 Example 83

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimi^ metylfenyl))-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimi^methylphenyl))-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-metylfenyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 79% av teoretisk Yield: 79% of theoretical

C29H32N603 (512,6) C29H32N603 (512.6)

Rf-verdi: 0,10 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.10 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =513 EKA mass spectrum: (M+H)<+> =513

(M+H+Na)4"*' = 268 (M+H+Na)4"*' = 268

Eksempel 84 Example 84

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-metylfenyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-metylfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C27H28N603 (484,6) C27H28N603 (484.6)

EKA-massespekter: (M+H)<+> =485 EKA mass spectrum: (M+H)<+> =485

(M+H+Na)"* = 254 (M+H+Na)"* = 254

(M+Na)<+> = 507 (M+Na)<+> = 507

(M+2Na)<++> = 265 (M+2Na)<++> = 265

Eksempel 85 Example 85

l-metyl-2-[N-(4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-(4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1,1 g (2,06 mMol) l-metyl-2-|Tsr-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid ble løst i en blanding av 40 ml tetrahydrofuran og 10 ml vann, til slutt ble 570 mg (4,12 mMol) kaliumkarbonat og 362 mg (2,2 mMol) klormaursyre-n-heksylester tilsatt og omrørt i 2 t ved romtemperatur. Løsningsmiddelet ble deretter destillert fra, resten omsatt med ca 50 ml mettet koksalt- 1.1 g (2.06 mmol) 1-methyl-2-|Tsr-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide- hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, finally 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of chloroformic acid n-hexyl ester were added and stirred for 2 h at room temperature. The solvent was then distilled from, the residue reacted with approx. 50 ml saturated sodium chloride

øsning og den på denne måten oppnådde løsningen ble ekstrahert tre ganger hver med 20 ml diklormetan. Ekstraktene ble tørket over natriumsulfat og inndampet. Det på denne måten oppnådde råprodukt ble renset ved kolonnekromatografi (100 g kiselgel; diklormetan + 5% etanol). ladle and the solution thus obtained was extracted three times each with 20 ml of dichloromethane. The extracts were dried over sodium sulfate and evaporated. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane + 5% ethanol).

Utbytte: 78% av teoretisk Yield: 78% of theoretical

C35H42N6O5 (626,8) C35H42N6O5 (626.8)

Rf-verdi: 0,49 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.49 (silica gel; dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> 627 EKA mass spectrum: (M+H)<+> 627

(M+H+Na)^ = 325 (M+H+Na)^ = 325

(M+2H)<++> =314 (M+2H)<++> =314

Eksempel 86 Example 86

l-metyl-2-[N-[4-(N-metoksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-methoxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyremetylester. Utbytte: 41% av teoretisk Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid methyl ester. Yield: 41% of theoretical

C3oH32N605 (556,6) C3oH32N6O5 (556.6)

Rf-verdi: 0,85 (kiselgel, diklormetan/etanol = 4:1) Rf value: 0.85 (silica gel, dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =557 EKA mass spectrum: (M+H)<+> =557

(M+H+Na)^ = 290 (M+H+Na)^ = 290

(M+Na)<+> 579 (M+Na)<+> 579

Eksempel 87 Example 87

l-metyl-2-[N-[4-(N-etoksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-ethoxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-arnid-hydroklorid og klormaursyreetylester. Utbytte: 62% av teoretisk C3oH32N60s (556,6) Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-arnide hydrochloride and chloroformate ethyl ester. Yield: 62% of theoretical C3oH32N60s (556.6)

Rf-verdi: 0,51 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.51 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> = 557 EKA mass spectrum: (M+H)<+> = 557

(M+H+Na)^ = 290 (M+H+Na)^ = 290

(M+2H)<+> = 279 (M+2H)<+> = 279

Eksempel 88 Example 88

l-metyl-2-[N-[4-(T^-sykloheksyloksykarbonylamidin)fenyl]-aminom yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(T^-cyclohexyloxycarbonylamidine)phenyl]-aminomylcarboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyresykloheksylester. Prepared analogous example 85 from 1-methyl-2-[N-(4-amidinphenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformate cyclohexyl ester.

Utbytte: 25% av teoretisk Yield: 25% of theoretical

C34H38N6O5 (610,7) C34H38N6O5 (610.7)

Rf-verdi: 0,44 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.44 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =611 EKA mass spectrum: (M+H)<+> =611

(M+2H)<++> = 306 (M+2H)<++> = 306

Eksempel 89 Example 89

1 -metyl-2- [N-[4- [N-[2-(metylsulfonyl)etyloksykarbonyl] -amidin)fenyl] -aminometyl] - benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1 -methyl-2- [N-[4- [N-[2-(methylsulfonyl)ethyloxycarbonyl]-amidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl )-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-2-(metylsulfonyl)-etylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-2 -(methylsulfonyl)-ethyl ester.

Utbytte: 66% av teoretisk Yield: 66% of theoretical

C32H36N607S (648,8) C32H36N607S (648.8)

Rf-verdi: 0,44 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.44 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =649 EKA mass spectrum: (M+H)<+> =649

(M+H+Na)^ = 336 (M+H+Na)^ = 336

( M+ 2WT =325 ( M+ 2WT =325

Eksempel 90 Example 90

l-metyl-2-[N-[4-(N-n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyI-2-[N-(4-amidinfenyl)-aminometyI]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n -octyl ester.

Utbytte: 41% av teoretisk Yield: 41% of theoretical

C36H44N605 (640,8) C36H44N605 (640.8)

Rf-verdi: 0,43 (kiselgel, diklormetan/etanol =19:1) Rf value: 0.43 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =641 EKA mass spectrum: (M+H)<+> =641

(M+Na)<+> = 663 (M+Na)<+> = 663

Eksempel 91 Example 91

l-metyl-2-[N-[4-(N-hydroksylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-hydroxylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1,44 g (3,0 mMol) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, 0,625 g (9,0 mMol) hydroksyl-aminhydroklorid og 0,425 g (4,0 mMol) natriumkarbonat ble løst i 80 ml etanol og oppvarmet i 7 t til tilbakeløp. Det ble deretter tilsatt ytterligere 210 mg hydroksyl-aminhydroklorid og 170 mg natriumkarbonat, ytterligere tørket i 5 t og til slutt inndampet i vakuum. Resten ble løst i ca 30 ml diklormetan, den oppnådde løsningen ble vasket med 20 ml vann, den organiske fasen tørket og inndampet. Det på denne måten oppnådde råproduktet ble renset søylekromatografisk (200 g kiselgel; diklormetan + 4% etanol). 1.44 g (3.0 mmol) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.625 g (9.0 mmol) of hydroxylamine hydrochloride and 0.425 g (4.0 mmol) of sodium carbonate were dissolved in 80 ml of ethanol and heated for 7 h to reflux. A further 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate were then added, further dried for 5 h and finally evaporated in vacuo. The residue was dissolved in about 30 ml of dichloromethane, the solution obtained was washed with 20 ml of water, the organic phase dried and evaporated. The crude product thus obtained was purified by column chromatography (200 g silica gel; dichloromethane + 4% ethanol).

Utbytte: 39% av teoretisk Yield: 39% of theoretical

C28H3oN604 (514,6) C28H3oN6O4 (514.6)

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =515 EKA mass spectrum: (M+H)<+> =515

(M+Na)<+> = 537 (M+Na)<+> = 537

(2M+H)<+> = 1029 (2M+H)<+> = 1029

(2M+Na)<+> =1051 (2M+Na)<+> =1051

Eksempel 92 Example 92

l-metyl-2-[N-[4-(N-heptyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-heptyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heptylester. Utbytte: 43% av teoretisk C35H42N6O5 (626,8) Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n -heptyl ester. Yield: 43% of theoretical C35H42N6O5 (626.8)

Rf-verdi: 0,40 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.40 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =627 EKA mass spectrum: (M+H)<+> =627

(M+H+Na)^ = 325 (M+H+Na)^ = 325

(M+Na)<+> = 649 (M+Na)<+> = 649

Eksempel 93 Example 93

1 -metyl-2- [N- [4-(N-benzoylamidin)fenyl] -aminometyl]-benzimidazol-5 -yl-karboksylsyreN-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-benzoylamidin)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid og benzoylklorid. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and benzoyl chloride.

Utbytte: 88% av teoretisk C34H32N604 (588,7) Yield: 88% of theory C34H32N604 (588.7)

Rf-verdi: 0,37 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.37 (silica gel, dichloromethane/ethanol = 19:1)

tø-NMR-spekter (D6-DMSO): 2,61 (t, 2H), 3,54 (s, 3H), 3,76 (s, 3H), 4,10 (t, 2H), 4,61 (d, 2H), 6,83 (d, 2H), 7,05 til 7,55 (m, 12H), 8,03 (d, 2H), 8,25 (dd, 2H), 8,98 (s, 1H), 10,48 (s, 1H). melt NMR spectrum (D6-DMSO): 2.61 (t, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 4.10 (t, 2H), 4.61 (d, 2H), 6.83 (d, 2H), 7.05 to 7.55 (m, 12H), 8.03 (d, 2H), 8.25 (dd, 2H), 8.98 ( p, 1H), 10.48 (p, 1H).

Eksempel 94 Example 94

l-metyl-2-|^-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-|^-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n -hexyl ester.

Utbytte: 54% av teoretisk C34H40N6O5 (612,7) Yield: 54% of theory C34H40N6O5 (612.7)

Rf-verdi: 0,45 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.45 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =613 EKA mass spectrum: (M+H)<+> =613

Eksempel 95 Example 95

l-metyl-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-n-propyloksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-meryl-2-[N-(4-amidmfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-n-propyloksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogous Example 85 from 1-meryl-2-[N-(4-amidmphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide hydrochloride and chloroformic acid -n-hexyl ester.

Utbytte: 31% av teoretisk C36H44N6O5 (640,8) Yield: 31% of theory C36H44N6O5 (640.8)

Rf-verdi: 0,42 (kiselgel, diklormetan/etanol =19:1) Rf value: 0.42 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =641 EKA mass spectrum: (M+H)<+> =641

(M+H+Na)^ = 332 (M+H+Na)^ = 332

(M+Na)<+> = 663 (M+Na)<+> = 663

Eksempel 96 Example 96

1 -metyl-2- [N- [4-(N-etoksykarbonylamidin)fenyl] -aminometyl] -benzimidazol-5 -yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2- [N-[4-(N-ethoxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra 1 -metyl-2-[N-(4-amidmfenyl)-aminometyl] - benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyreetylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidmphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformate ethyl ester.

Utbytte: 72% av teoretisk Yield: 72% of theoretical

C29H31N705 (557,6) C29H31N705 (557.6)

Rf-verdi: 0,58 (kiselgel, diklormetan/etanol = 9:1) Rf value: 0.58 (silica gel, dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> =558 EKA mass spectrum: (M+H)<+> =558

(M+H+Na)^ = 290,8 (M+H+Na)^ = 290.8

(M+Na)<+> = 580 (M+Na)<+> = 580

Eksempel 97 Example 97

l-metyl-2-[N-[4-(N-n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-octyl ester.

Utbytte: 57% av teoretisk Yield: 57% of theoretical

C35H43N7O5 (641,8) C35H43N7O5 (641.8)

Rf-verdi: 0,60 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.60 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =642 EKA mass spectrum: (M+H)<+> =642

(M+H+Na)^ = 332,8 (M+H+Na)^ = 332.8

(M+Na)<+> = 664 (M+Na)<+> = 664

Eksempel 98 Example 98

l-metyl-2-[N-[4-(N-metoksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-methoxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyremetylester. Utbytte: 48%> av teoretisk Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid methyl ester. Yield: 48%> of theoretical

C29H3,N705 (557,6) C29H3,N705 (557.6)

Rf-verdi: 0,62 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.62 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =558 EKA mass spectrum: (M+H)<+> =558

(M+H+Na)^ = 290,7 (M+H+Na)^ = 290.7

(M+Na)<+> = 580 (M+Na)<+> = 580

Eksempel 99 Example 99

l-metyl-2-[N-[4-(N-n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

0,7 g (1,1 mMol) l-metyl-2-[N-n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid omrørt i en blanding av 0,12 g (3,0 mMol) natriumhydroksid, 5 ml vann og 10 ml metanol i en time ved romtemperatur. Deretter ble det fortynnet med 20 ml vann og innstilt med eddiksyre til pH 6. Dette ble deretter tilført ca 5 ml dietyleter og dette ble omrørt omfattende i en time. Det derved utfelte produktet ble sugd fra, vasket med noe vann og deretter med dietyleter og tørket. Utbytte: 80% av teoretisk 0.7 g (1.1 mmol) 1-methyl-2-[N-n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl) -amide stirred in a mixture of 0.12 g (3.0 mmol) sodium hydroxide, 5 ml water and 10 ml methanol for one hour at room temperature. It was then diluted with 20 ml of water and adjusted with acetic acid to pH 6. This was then added with approx. 5 ml of diethyl ether and this was stirred extensively for an hour. The thus precipitated product was suctioned off, washed with some water and then with diethyl ether and dried. Yield: 80% of theoretical

C34H4iN705 (627,8) C34H4iN705 (627.8)

EKA-massespekter: (M+H)<+> =628 EKA mass spectrum: (M+H)<+> =628

(M+H+Na)^ = 325,7 (M+H+Na)^ = 325.7

(M+Na)<+> = 650 (M+Na)<+> = 650

(M+2Na)<++> = 337,7 (M+2Na)<++> = 337.7

Eksempel 100 Example 100

l-metyl-2-|^-[4-psf-(2-metylsulfonyletyloksy benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-|^-[4-psf-(2-methylsulfonylethyloxy benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-2-(metylsulfonyl)-etylester. Utbytte: 65% av teoretisk C3,H35N707S (649,7) Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid 2-(methylsulfonyl)-ethyl ester. Yield: 65% of theoretical C3,H35N707S (649.7)

Rr-verdi: 0,54 (kiselgel, diklormetan/metanol = 9:1) Rr value: 0.54 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =650 EKA mass spectrum: (M+H)<+> =650

(M+H+Na)^ = 336,6 (M+H+Na)^ = 336.6

(M+Na)<+> = 672 (M+Na)<+> = 672

(M+2Na)<++> = 347,6 (M+2Na)<++> = 347.6

Eksempel 101 Example 101

1 -metyl-2-[N- [4-(N-n-butyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-butyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-butylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-butyl ester.

Utbytte: 30% av teoretisk Yield: 30% of theoretical

C3,H35N705 (585,7) C3,H35N705 (585.7)

Rf-verdi: 0,62 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.62 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =586 EKA mass spectrum: (M+H)<+> =586

(M+H+Na)^ = 304,7 (M+H+Na)^ = 304.7

(M+2H)<++> = 293,7 (M+2H)<++> = 293.7

Eksempel 102 Example 102

l-metyl-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-hexyl ester.

Utbytte: 51% av teoretisk Yield: 51% of theoretical

C33H39N7O5 (613,7) C33H39N7O5 (613.7)

Rf-verdi: 0,56 (kiselgel, diklormetan/metanol =9:1) Rf value: 0.56 (silica gel, dichloromethane/methanol =9:1)

EKA-massespekter: (M+H)<+> =614 EKA mass spectrum: (M+H)<+> =614

(M+H+Na)^ =318,7 (M+H+Na)^ =318.7

(M+2H)<++> = 307,6 (M+2H)<++> = 307.6

Eksempel 103 Example 103

l-metyl-2-[N-[4-(N-n-heptyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-heptyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heptylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-heptyl ester.

Utbytte: 21% av teoretisk Yield: 21% of theoretical

C34H4iN705 (627,8) C34H4iN705 (627.8)

Rf-verdi: 0,60 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.60 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =628 EKA mass spectrum: (M+H)<+> =628

(M+H+Na)^ = 325,7 (M+H+Na)^ = 325.7

(M+2H)^ =314,7 (M+2H)^ =314.7

Eksempel 104 Example 104

l-metyl-2-|^-[4-(N-n-pentyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-|^-[4-(N-n-pentyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-pentylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-pentyl ester.

Utbytte: 66% av teoretisk Yield: 66% of theoretical

C32H37N705 (599,7) C32H37N705 (599.7)

Rf-verdi: 0,58 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.58 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =600 EKA mass spectrum: (M+H)<+> =600

(M+H+Na)<++>=311,7 (M+H+Na)<++>=311.7

(M+Na)<+> = 622 (M+Na)<+> = 622

Eksempel 105 Example 105

l-metyl-2-[N-[4-(N-n-nonyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-nonyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-nonylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-nonyl ester.

Utbytte: 60% av teoretisk Yield: 60% of theoretical

C36H45N705 (655,8) C36H45N705 (655.8)

Rf-verdi: 0,48 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.48 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =656 EKA mass spectrum: (M+H)<+> =656

(M+H+Na)^ = 339,8 (M+H+Na)^ = 339.8

(M+Na)<+> = 678 (M+Na)<+> = 678

Eksempel 106 Example 106

l-metyl-2-[N-[4-(N-benzoylamidin)fenyl]-aminometyl]-be N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-benzoylamidin)phenyl]-aminomethyl]-be N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og benzoylklorid. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and benzoyl chloride.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C33H3,N704 (589,7) C33H3,N7O4 (589.7)

Rf-verdi: 0,50 (kiselgel, diklormetan/metanol =9:1) Rf value: 0.50 (silica gel, dichloromethane/methanol =9:1)

EKA-massespekter: (M+H)<+> =590 EKA mass spectrum: (M+H)<+> =590

(M+Na)<+> = 612 (M+Na)<+> = 612

Eksempel 107 Example 107

l-metyl-2-[N-[4-(N-nikotinoylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-nicotinoylamidin)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og nikotinsyreklorid. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide hydrochloride and nicotinic acid chloride.

Utbytte: 40% av teoretisk Yield: 40% of theoretical

C32H3oN804 (590,7) C32H3oN8O4 (590.7)

Rf-verdi: 0,47 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.47 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =591 EKA mass spectrum: (M+H)<+> =591

(M+H+Na)^ = 307 (M+H+Na)^ = 307

(M+Na)<+> =613 (M+Na)<+> =613

Eksempel 108 Example 108

l-metyl-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-hexyl ester.

Utbytte: 51% av teoretisk Yield: 51% of theoretical

C34H4,N705 (627,8) C34H4,N705 (627.8)

Rf-verdi: 0,53 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.53 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =628 EKA mass spectrum: (M+H)<+> =628

(M+H+Na)<++> = 325,7 (M+H+Na)<++> = 325.7

(M+2H)<++> =314,7 (M+2H)<++> =314.7

Eksempel 109 Example 109

l-metyl-2-[N-[4-(N-n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-octyl ester.

Utbytte: 57% av teoretisk Yield: 57% of theoretical

C36H45N705 (655,8) C36H45N705 (655.8)

Rf-verdi: 0,46 (kiselgel, diklormetan/metanol = 9:1) Rf value: 0.46 (silica gel, dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =656 EKA mass spectrum: (M+H)<+> =656

(M+H+Na)^ = 339,7 (M+H+Na)^ = 339.7

(M+2H)<**> = 328,7 (M+2H)<**> = 328.7

Eksempel 110 Example 110

l-metyl-2-[N-[4-(N-(2-metylsulfonyletyloksykarbonyl)amidin]-fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonylmetyl)-amid 1-methyl-2-[N-[4-(N-(2-methylsulfonylethyloxycarbonyl)amidine]-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylmethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-etoksykarbonylmetyl)-amid-hydroklorid ogklormaursyre-2-(metylsulfonyl)-etylester. Prepared analogous example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl)-amide hydrochloride and chloroformic acid-2 -(methylsulfonyl)-ethyl ester.

Utbytte: 72% av teoretisk Yield: 72% of theoretical

C3oH33N707S (635,7) C3oH33N707S (635.7)

Rf-verdi: 0,23 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.23 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =636 EKA mass spectrum: (M+H)<+> =636

(M+H+Na)^ = 329,8 (M+H+Na)^ = 329.8

Eksempel 111 Example 111

1-metyl-2-[N-[4-(N-sykloheksyloksy^^ yl-karboksylsyre-N-(2-pyridyl)-N-metoksykarbonylmetyl)-amid 1-methyl-2-[N-[4-(N-cyclohexyloxy^^yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl)-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-metoksykarbonylmetyl-amid-hydroklorid og klormaursyre-sykloheksylester. Prepared analogous example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide hydrochloride and chloroformate cyclohexyl ester .

Utbytte: 40% av teoretisk Yield: 40% of theoretical

C32H35N705 (597,7) C32H35N705 (597.7)

Rf-verdi: 0,26 (kiselgel, diklormetan/etanol =19:1) Rf value: 0.26 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =598 EKA mass spectrum: (M+H)<+> =598

(M+Na)<+> = 620 (M+Na)<+> = 620

Eksempel 112 Example 112

l-metyl-2-[N-[4-(N-metoksykarbonylamidin)-fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-etoksykarbonylmetyl)-amid 1-methyl-2-[N-[4-(N-methoxycarbonylamidine)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl)-amide

Fremstilt analogt eksempel 85 fra 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-etoksykarbonylmetyl-amid-hydroklorid og klormaursyremetylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide hydrochloride and chloroformic acid methyl ester.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C28H29N705 (543,6) C28H29N705 (543.6)

Rf-verdi: 0,19 (kiselgel, diklormetan/etanol =19:1) Rf value: 0.19 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =544 EKA mass spectrum: (M+H)<+> =544

(M+H+Na)^ = 283,8 (M+H+Na)^ = 283.8

(M+Na)<+> = 566 (M+Na)<+> = 566

Eksempel 113 Example 113

l-metyl-2-[N-[4-(N-etoksykarbonylamidin)-fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-metoksykarbonylmetyl)-amid 1-methyl-2-[N-[4-(N-ethoxycarbonylamidine)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-metoksykarbonylmetyl-amid-hydroklorid og klormaursyreetylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide hydrochloride and chloroformate ethyl ester.

Utbytte: 42% av teoretisk Yield: 42% of theoretical

C28H29N705 (543,6) C28H29N705 (543.6)

Rf-verdi: 0,20 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.20 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> = 544 EKA mass spectrum: (M+H)<+> = 544

Eksempel 114 Example 114

1 -metyl-2- [N- [4-(N-n-oktyloksykarbonylamidin)-fenyl] -aminometyl] -benzimidazol-5 -yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-octyl ester.

Utbytte: 35% av teoretisk Yield: 35% of theoretical

C36H45N705 (655,8) C36H45N705 (655.8)

Rf-verdi: 0,28 (kiselgel, diklormetan/etanol = 19:1) Rf value: 0.28 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =656 EKA mass spectrum: (M+H)<+> =656

(M+2H)<++> = 328,7 (M+2H)<++> = 328.7

Eksempel 115 Example 115

l-metyl-2-[^-[4-(N-n-heksyloksykarbonylamidin)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[^-[4-(N-n-hexyloxycarbonylamidine)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl )-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and chloroformic acid n-hexyl ester.

Utbytte: 58% av teoretisk Yield: 58% of theoretical

C35H43N705 (641,2) C35H43N705 (641.2)

Rf-verdi: 0,42 (kiselgel, diklormetan/etanol =19:1) Rf value: 0.42 (silica gel, dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =642 EKA mass spectrum: (M+H)<+> =642

(M+H+Na)^ = 332,7 (M+H+Na)^ = 332.7

Eksempel 116 Example 116

l-metyl-2-[N-[4-(N-n-oktyloksykarbonylamidin)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidine)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl )-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and chloroformic acid n-octyl ester.

Utbytte: 36% av teoretisk Yield: 36% of theoretical

C37H47N705 (669,8) C37H47N705 (669.8)

EKA-massespekter: (M+H)<+> =670 EKA mass spectrum: (M+H)<+> =670

(M+H+Na)^ = 346,8 (M+H+Na)^ = 346.8

(M+2H)^ = 335,6 (M+2H)^ = 335.6

Eksempel 117 Example 117

l-metyl-2-[N-[4-(N-n-butyloksykarbonylamidin)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-butyloxycarbonylamidine)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl )-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-butylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and chloroformic acid n-butyl ester.

Utbytte: 34% av teoretisk Yield: 34% of theoretical

C33H39N7O5 (613,7) C33H39N7O5 (613.7)

EKA-massespekter: (M+H)<+> =614 EKA mass spectrum: (M+H)<+> =614

(M+H+Na)<++> =318,7 (M+H+Na)<++> =318.7

(M+Na)<+> 636 (M+Na)<+> 636

Eksempel 118 Example 118

l-metyl-2-[N-[4-(N-benzoylamidin)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-benzoylamidin)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl )-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og benzoylklorid. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and benzoyl chloride.

Utbytte: 63% av teoretisk Yield: 63% of theoretical

C35H35N704 (617,7) C35H35N704 (617.7)

EKA-massespekter: (M+H)<+> =618 EKA mass spectrum: (M+H)<+> =618

(M+H+Na)<++> = 320,7 (M+H+Na)<++> = 320.7

(M+Na)<+> = 640 (M+Na)<+> = 640

Eksempel 119 Example 119

1-metyl-2-[(4-amidinfenyl)oksy^ sykloheks-1 -yl)-keton-hydroklorid 1-Methyl-2-[(4-amidinephenyl)oxy^cyclohex-1-yl)-ketone hydrochloride

a) 4-klorfenyl-( 1 -hydroksykarbonylmetyl-sykloheks-1 -yl)-keton a) 4-chlorophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone

8,4 g (40 mMol) 3-(4-klorbenzoyl)-propionsyre ble oppløst i 300 ml tetrahydrofuran 8.4 g (40 mmol) of 3-(4-chlorobenzoyl)-propionic acid were dissolved in 300 ml of tetrahydrofuran

og porsjonsvis ble det tilsatt 5,8 g (120 mMol) natriumhydrid (50-60% suspensjon i parafinolje). Deretter ble det oppvarmet i 1,5 t under omrøring til tilbakeløp og 8,9 ml (60 mMol) 1,5-dijodpentan ble tilsatt og ytterligere kokt i tre timer. Etter avkjølingen ble løsningen innrørt i 200 ml isvann og deretter ble tetrahydrofuran avdestillert i vakuum, den på denne måten oppnådde vandige løsningen ble surgjort med 2N saltsyre og tre ganger hver med 150 ml diklormetan ektrahert. Den organiske fasen ble tørket og inndampet og det på denne måten oppnådde råproduktet ble renset ved kolonnekromatografi (500 g kiselgel; løpemiddel: Diklormetan med 1-2% etanol). and 5.8 g (120 mmol) of sodium hydride (50-60% suspension in paraffin oil) was added in portions. It was then heated for 1.5 h with stirring to reflux and 8.9 ml (60 mmol) of 1,5-diiodopentane was added and further boiled for three hours. After cooling, the solution was stirred into 200 ml of ice water and then tetrahydrofuran was distilled off in vacuo, the aqueous solution thus obtained was acidified with 2N hydrochloric acid and extracted three times each with 150 ml of dichloromethane. The organic phase was dried and evaporated and the crude product thus obtained was purified by column chromatography (500 g silica gel; eluent: dichloromethane with 1-2% ethanol).

Utbytte: 6,2 g (55% av teoretisk) oljeholdig produkt, Yield: 6.2 g (55% of theoretical) oily product,

C15H17C103 (280,8) C15H17C103 (280.8)

Rf-verdi: 0,56 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.56 (silica gel; dichloromethane/ethanol = 19:1)

b) 4-klor-3-nitrofenyl-(l-hydroksykarbonylmetyl-sykloheks-l-yl)-keton b) 4-chloro-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone

7,0 g (25 mMol) 4-klorfenyl-(l-hydroksykarbonylmetyl-sykloheks-l-yl)-ketonble 7.0 g (25 mmol) 4-chlorophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketoneble

under røring ved -5 til -10°C porsjonsvis innført i 80 ml røket saltpetersyre. Til slutt ble det etterrørt i ytterligere 10 min og deretter ble løsningen innrørt i 200 ml isvann, det utfelte produktet ble vasket med vann og tørket. with stirring at -5 to -10°C introduced in portions into 80 ml of fumed nitric acid. Finally, it was stirred for a further 10 min and then the solution was stirred into 200 ml of ice water, the precipitated product was washed with water and dried.

Utbytte: 7,8 g (96% av teoretisk) Yield: 7.8 g (96% of theoretical)

Ci5H16ClN05 (325,8) Ci5H16ClN05 (325.8)

Rf-verdi: 0,41 (kiselgel; petroleter/eddikester = 4:6) Rf value: 0.41 (silica gel; petroleum ether/acetic ester = 4:6)

c) 4-metylamino-3-nitrofenyl-(l-hydroksykarbonylmetyl-sykloheks-l-yl)-keton c) 4-methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone

7,8 g (23,9 mMol) 4-klorfenyl-(l-hydroksykarbonylmetyl-sykloheks-l-yl)-ketonble 7.8 g (23.9 mmol) of 4-chlorophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketoneble

omrørt i 100 ml 40% vandig metylaminløsning ved romtemperatur i 141 og deretter med ca 150 ml vann fortynnet og innstilt med iseddik til svak surhet. Det utfelte produktet ble sugd fra, vasket med vann og tørket. stirred in 100 ml of 40% aqueous methylamine solution at room temperature for 141 and then diluted with approx. 150 ml of water and adjusted with glacial acetic acid to weak acidity. The precipitated product was sucked off, washed with water and dried.

Utbytte: 7,1 g (93% av teoretisk) Yield: 7.1 g (93% of theoretical)

C16H2oN205 (320,4) C16H2oN2O5 (320.4)

Rf-verdi: 0,34 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1)

d) 4-metylamino-3-nitrofenyl-(l-metoksykarbonylmetyl-sykloheks-l-yl)-keton d) 4-methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

4,9 g (15 mMol) 4-metylamino-3-nitrofenyl-(l-hydroksykarbonylmetyl-sykloheks-l-yl)-keton ble løst i 100 ml tetrahydrofuran, 2,4 g (15 mMol) 1,1 '-karbonyldiimidazol ble tilsatt og i 15 min oppvarmet til tilbakeløp. Deretter ble løsningsmiddelet avdampet, 30 ml metanol ble tilført og dette ble under omrøring kokt i tre timer. Etter avdestillering av metanol ble det på denne måten oppnådde råproduktet renset ved kolonnekromatografi (250 g kiselgel, løpemiddel: Diklormetan med 1 til 5% etanol). 4.9 g (15 mmol) of 4-methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone was dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mmol) of 1,1'-carbonyldiimidazole was added and heated to reflux for 15 min. Then the solvent was evaporated, 30 ml of methanol was added and this was boiled for three hours with stirring. After distillation of methanol, the crude product thus obtained was purified by column chromatography (250 g silica gel, eluent: dichloromethane with 1 to 5% ethanol).

Utbytte: 2,4 g (48% av teoretisk) Yield: 2.4 g (48% of theoretical)

C17H22N205 (334,4) C17H22N2O5 (334.4)

Rf-verdi: 0,76 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.76 (silica gel; dichloromethane/ethanol = 19:1)

e) 3-amino-4-metylaminofenyl-(l -metoksykarbonylmetyl-sykloheks-1 -yl)-keton e) 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

2,4 g (7,2 mMol) 4-metylamino-3-nitrofenyl-(l-metoksykarbonylmetyl-sykloheks-l-yl)-keton ble katalytisk hydrert i 100 ml metanol ved romtemperatur og 5 bar hydrogentrykk (10% palladium på kull). Det på denne måten oppnådde råproduktet ble uten rensning videre omsatt. 2.4 g (7.2 mmol) of 4-methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone was catalytically hydrogenated in 100 ml methanol at room temperature and 5 bar hydrogen pressure (10% palladium on carbon ). The crude product obtained in this way was sold further without purification.

Utbytte: 2,1 g (96% av teoretisk) Yield: 2.1 g (96% of theoretical)

Rf-verdi: 0,34 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1)

f) 3 -(4-cyanofenyloksyacetylamino)-4-metylaminofenyl-( 1 -metoksykarbonylmetyl-sykloheks-1 -yl)-keton f) 3-(4-cyanophenyloxyacetylamino)-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

620 mg (3,5 mMol) 4-cyanofenyloksyeddiksyre og 570 mg (3,5 mMol) 1,1'-karbonyl-diimidazol ble oppvarmet i 50 ml tetrahydrofuran i 15 min til tilbakeløp. Da ble 1,0 g (3,28 mMol) 3-amino-4-metylaminofenyl-(l-metoksykarbonylmetyl-sykloheks-l-yl)-keton tilført og ytterligere kokt i 41. Til slutt ble løsningsmiddelet avdampet og det på denne måten oppnådde råproduktet ble renset ved kolonnekromatografi (150 g kiselgel; løpemiddel: Diklormetan med 0 til 2% etanol). 620 mg (3.5 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1'-carbonyldiimidazole were heated in 50 ml of tetrahydrofuran for 15 min to reflux. Then 1.0 g (3.28 mmol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone was added and further boiled for 41. Finally, the solvent was evaporated and in this way the crude product obtained was purified by column chromatography (150 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Utbytte: 1,4 g (93% av teoretisk) Yield: 1.4 g (93% of theoretical)

C26H29N305 (463,5) C26H29N305 (463.5)

Rf-verdi: 0,44 (kiselgel; diklormetan/etanol =19:1) Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1)

g) 1 -metyl-2-[(4-cyanofenyI)oksymetyl]-benzimidazol-5-yl-(l -metoksykarbonylmetyl-sykloheks-1 -yl)-keton g) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

1,4 g (3,02 mMol) 3-(4-cyanofenyloksyacetylamino)-4-metyl-aminofenyl-(l-metoksykarbonylmetyl-sykloheks-l-yl)-keton ble oppvarmet i 50 ml.iseddik i en time til tilbakeløp. Deretter ble iseddik destillert fra, resten omsatt med 20 ml vann og innstilt alkalisk med konsentrert ammoniakk. Denne løsningen ble ekstrahert tre ganger hver med 20 ml diklormetan, det organiske ekstraktet ble tørket og inndampet. Det på denne måten oppnådde råproduktet ble renset ved kolonnekromatografi (100 g kiselgel; løpemiddel: diklormetan med 0 til 2% etanol). 1.4 g (3.02 mmol) of 3-(4-cyanophenyloxyacetylamino)-4-methyl-aminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone was heated in 50 ml of glacial acetic acid for one hour to reflux. Then glacial acetic acid was distilled from, the residue reacted with 20 ml of water and made alkaline with concentrated ammonia. This solution was extracted three times each with 20 ml of dichloromethane, the organic extract was dried and evaporated. The crude product thus obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Utbytte: 700 mg (52% av teoretisk) Yield: 700 mg (52% of theoretical)

C26H27N304 (445,5) C26H27N304 (445.5)

h) l-metyl-2-[(4-amidinfenyl)oksymetyl]-benzimidazol-5-yl-(l-etoksykarbonylmetyl-sykloheks-1 -yI)-keton-hydroklorid h) 1-methyl-2-[(4-amidinephenyl)oxymethyl]-benzimidazol-5-yl-(1-ethoxycarbonylmethyl-cyclohex-1-yl)-ketone hydrochloride

Fremstilt analogt eksempel 23d fra 700 mg (1,57 mMol) l-metyl-2-(4-cyano-fenyloksymetyl)-benzimidazol-5-yl-(l-metoksykarbonylmetyl-sykloheks-l-yl)-ketonmed etanolisk saltsyre og ammoniumkarbonat. Prepared analogous example 23d from 700 mg (1.57 mmol) of 1-methyl-2-(4-cyano-phenyloxymethyl)-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone with ethanolic hydrochloric acid and ammonium carbonate .

Utbytte: 390 mg (50% av teoretisk) Yield: 390 mg (50% of theoretical)

C27H32N404 (476,6) C27H32N404 (476.6)

EKA-massespekter: (M+H)<+> = 477 EKA mass spectrum: (M+H)<+> = 477

'H-NMR-spekter (d6-DMSO): 1,10 (t, 3H); 1,0-2,15 (m, 10H); 3,36 (s, 3H); 3,90 (s, 2H); 3,94 (q, 2H); 5,60 (s, 2H); 7,25-7,40 (m, 3H); 7,56-7,75 (m, 2H); 7,90 (d, 2H); 9,20 (bredde s, 4H) ppm 1 H-NMR spectrum (d 6 -DMSO): 1.10 (t, 3H); 1.0-2.15 (m, 10H); 3.36 (s, 3H); 3.90 (s, 2H); 3.94 (q, 2H); 5.60 (s, 2H); 7.25-7.40 (m, 3H); 7.56-7.75 (m, 2H); 7.90 (d, 2H); 9.20 (width s, 4H) ppm

Eksempel 120 Example 120

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-tert.butyl-keton-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-tert-butyl ketone hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-(N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-tert.butyl-keton, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-(N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert-butyl ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 59% av teoretisk Yield: 59% of theoretical

C21H25N50 (363,5) C21H25N50 (363.5)

EKA-massespekter: (M+H)<+> = 364 EKA mass spectrum: (M+H)<+> = 364

Eksempel 121 Example 121

1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-( 1 -metylsyklopent-1 -yl)-keton-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-(1-methylcyclopent-1-yl)-ketone hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-(N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-(l-metylsyklopent-l-yl)-keton, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-(N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-(1-methylcyclopent-1-yl)-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 63,5% av teoretisk Yield: 63.5% of theoretical

C23H27N50 (389,5) C23H27N50 (389.5)

EKA-massespekter: (M+H)<+> = 390 EKA mass spectrum: (M+H)<+> = 390

Eksempel 122 Example 122

2-[(4-amidinfenyl)sulfinylmetyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksy-karbonyletyl)-amid-hydroklorid 2-[(4-amidinephenyl)sulfinylmethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide hydrochloride

En løsning av 0,15 g (0,27 mMol) 2-[(4-amidinfenyl)tiometyl]-benztiazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydrokloirdklorid i 10 ml eddiksyre ble omsatt med 0,09 ml (ca 0,81 mMol) 30% hydrogenperoksidløsning og rørt ved romtemperatur. Etter 4 dager ble det tilsatt ytterligere 0,18 ml hydrogenperoksidløsning og ytterligere omrørt i to dager. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flammekromatografi (kiselgel; metylenklorid/etanol = 10:1 til 4:1). A solution of 0.15 g (0.27 mmol) of 2-[(4-amidinphenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride in 10 ml acetic acid was reacted with 0.09 ml (approx. 0.81 mmol) of 30% hydrogen peroxide solution and stirred at room temperature. After 4 days, a further 0.18 ml of hydrogen peroxide solution was added and further stirred for two days. After removal of the solvent in vacuo, the obtained crude product was purified by flame chromatography (silica gel; methylene chloride/ethanol = 10:1 to 4:1).

Utbytte: 58% av teoretisk Yield: 58% of theoretical

C27H26N404S2 (534,66) C27H26N404S2 (534.66)

Rf-verdi: 0,24 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 535 Rf value: 0.24 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 535

Eksempel 123 Example 123

2-[N-(4-amidinfenyl)aminmetyl]-tiazol[5,4-b]pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 2-[N-(4-amidinephenyl)aminomethyl]-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 5-amino-6-klor-nikotinsyremetylester a) 5-amino-6-chloro-nicotinic acid methyl ester

En løsning av 1,08 g (5,00 mMol) 6-klor-5-mtro-nikotinsyremetylester (se A. H. A solution of 1.08 g (5.00 mmol) 6-chloro-5-mtro-nicotinic acid methyl ester (see A. H.

Berrie, G. T. Newbold, F. S. Spring i J. Chem. Soc, 2590,1951) i 25 ml absolutt etanol ble suksessivt omsatt med 0,53 ml (29 mMol) vann, 3,2 g (57 mMol) jernpulver og 0,030 ml konsentert saltsyre og oppvarmet i en time til kokepunkt. Til slutt ble det tilsatt ytterligere like mengder vann, jernpulver og saltsyre og i 30 min oppvarmet til koking. Bunnfallet som fremkom ved avkjøling ble filtrert fra, vasket med metanol og løsningsmiddelet ble avdestillert i vakuum. Berrie, G.T. Newbold, F.S. Spring in J. Chem. Soc, 2590,1951) in 25 ml of absolute ethanol was successively reacted with 0.53 ml (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated for one hour to the boiling point. Finally, further equal amounts of water, iron powder and hydrochloric acid were added and heated to boiling for 30 minutes. The precipitate that appeared on cooling was filtered off, washed with methanol and the solvent was distilled off in vacuo.

Utbytte: 0,75 g (81% av teoretisk) gulgrønt fast stoff, Yield: 0.75 g (81% of theory) yellow-green solid,

Rf-verdi: 0,31 (kiselgel; eddikester/petroleter = 1:4) Rf value: 0.31 (silica gel; acetic acid/petroleum ether = 1:4)

C7H7CIN2O2 (186,60) C7H7CIN2O2 (186.60)

YEF-massespekter: M<++>= 186 og 188 (klorisotop) YEF mass spectrum: M<++>= 186 and 188 (chlorine isotope)

b) 6-klor-5-metoksyacetamido-nikotinsyremetylester b) 6-chloro-5-methoxyacetamido-nicotinic acid methyl ester

En løsning av 0,75 g (4,02 mMol) 5-amino-6-klor-nikotinsyremetylester og 0,43 g = A solution of 0.75 g (4.02 mmol) 5-amino-6-chloro-nicotinic acid methyl ester and 0.43 g =

0,35 ml (4,5 mMol) metoksyacetylklorid i 20 ml klorbenzen ble omrørt i en time ved 110°C. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; metylenklorid/etanol = 100:1) på ny inndampet i vakuum og til slutt digerert med petroleter. 0.35 ml (4.5 mmol) of methoxyacetyl chloride in 20 ml of chlorobenzene was stirred for one hour at 110°C. After removal of the solvent in vacuo, the crude product obtained was purified by flame chromatography (silica gel; methylene chloride/ethanol = 100:1), re-evaporated in vacuo and finally digested with petroleum ether.

Utbytte: 0,55 g (53% av teoretisk) halvgult amorf fast stoff, Yield: 0.55 g (53% of theory) semi-yellow amorphous solid,

Rf-verdi: 0,33 (kiselgel; eddikester/petroleter = 1:4) Rf value: 0.33 (silica gel; acetic acid/petroleum ether = 1:4)

c) 2-metoksymetyl-tiazol[5,4-b]pyridin-6-yl-karboksylsyre-metylester En blanding av 0,53 g (2,05 mMol) 6-klor-5-metoksyacetamidonikotinsyremetylester og c) 2-Methoxymethyl-thiazol[5,4-b]pyridin-6-yl-carboxylic acid methyl ester A mixture of 0.53 g (2.05 mmol) 6-chloro-5-methoxyacetamidonicotinic acid methyl ester and

0,42 g (1,0 mMol) Lawessons reagens ble oppvarmet i 161 i 25 ml xylen under tilbakeløp. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; metylenklorid/etanol = 100:1) og på ny inndampet i vakuum. 0.42 g (1.0 mmol) of Lawesson's reagent was heated at 161 in 25 ml xylene under reflux. After removal of the solvent in vacuo, the crude product obtained was purified by flame chromatography (silica gel; methylene chloride/ethanol = 100:1) and re-evaporated in vacuo.

Utbytte: 0,33 g (67% av teoretisk) gult amorf fast stoff, Yield: 0.33 g (67% of theory) yellow amorphous solid,

Rr-verdi: 0,52 (kiselgel; eddikester/petroleter = 1:4) Rr value: 0.52 (silica gel; acetic acid/petroleum ether = 1:4)

d) 2-metoksymetyl-tiazol[5,4-b]pyridin-6-yl-karboksylsyre d) 2-methoxymethyl-thiazol[5,4-b]pyridin-6-yl carboxylic acid

En blanding av 1,1 g (4,62 mMol) 2-metoksymetyl-tiazol[5,4-b]pyridin-6-karboksylsyremetylester og 9,2 ml 2N natronlut ble omrørt i 50 ml etanol i en time ved romtemperatur. Deretter ble det tilsatt 9,2 ml 2N saltsyre, alkoholen ble destillert av og fortynnet med 20 ml vann. Den vandige fasen ble surgjort med konsentrert saltsyre under isavkjøling, den beigefarvete utfellingen ble frafiltrert, til slutt vasket med vann og tørket. A mixture of 1.1 g (4.62 mmol) of 2-methoxymethylthiazol[5,4-b]pyridine-6-carboxylic acid methyl ester and 9.2 ml of 2N caustic soda was stirred in 50 ml of ethanol for one hour at room temperature. Then 9.2 ml of 2N hydrochloric acid was added, the alcohol was distilled off and diluted with 20 ml of water. The aqueous phase was acidified with concentrated hydrochloric acid under ice-cooling, the beige precipitate was filtered off, finally washed with water and dried.

Utbytte: 1,03 g (100% av teoretisk) Yield: 1.03 g (100% of theoretical)

Rf-verdi: 0,10 (kiselgel; eddikester/petroleter = 3:7) Rf value: 0.10 (silica gel; acetic acid/petroleum ether = 3:7)

e) 2-metoksymetyl-tiazol[5,4-b]pyridm-6-yl-karboksylsyre-N-fenyl-N-(2-e karbonyletyl)-amid e) 2-Methoxymethyl-thiazol[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-e carbonylethyl)-amide

En suspensjon av 1,03 g (4,62 mMol) 2-metoksymetyl-tiazol[5,4-b]pyirdin-6-yl-karboksylsyre i 40 ml metylenklorid ble omsatt med 1,6 g = 1,0 ml (13,5 mMol) tionylklorid og kokt i 90 min ved tilbakeløp, dermed løste faststoffet seg opp. Etter avdestillering av den flytende komponenten ble råproduktet ytterligere to ganger tatt opp i metylenklorid og enda en gang konsentrert. Rå syreklorid (1,2 g) oppnådd på denne måten ble tatt opp i 40 ml tetrahydrofuran til en blanding av 0,94 g (4,86 mMol) N-(2-etoksykarbonyletyl)anilin og 2,1 ml (13,8 mMol) trietylamin i 30 ml tetrahydrofuran ble dråpevis tilsatt og omrørt i 2 t ved romtemperatur. Til slutt ble det fortynnet med 200 ml eddikester, vasket med 100 ml 14% koksalt-løsning og den organiske fasen tørket med natriumsulfat. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; metylenkloird/etanol = 100:1). A suspension of 1.03 g (4.62 mmol) of 2-methoxymethyl-thiazol[5,4-b]pyridin-6-ylcarboxylic acid in 40 ml of methylene chloride was reacted with 1.6 g = 1.0 ml (13 .5 mmol) of thionyl chloride and boiled for 90 min at reflux, thus the solid dissolved. After distilling off the liquid component, the crude product was taken up twice more in methylene chloride and concentrated once more. Crude acid chloride (1.2 g) thus obtained was taken up in 40 ml of tetrahydrofuran to a mixture of 0.94 g (4.86 mmol) N-(2-ethoxycarbonylethyl)aniline and 2.1 ml (13.8 mmol) of triethylamine in 30 ml of tetrahydrofuran was added dropwise and stirred for 2 h at room temperature. Finally, it was diluted with 200 ml of acetic acid, washed with 100 ml of 14% sodium chloride solution and the organic phase dried with sodium sulphate. After removal of the solvent in vacuo, the crude product obtained was purified by flame chromatography (silica gel; methylene chloride/ethanol = 100:1).

Utbytte: 1,57 g (87% av teoretisk) gul olje Yield: 1.57 g (87% of theory) yellow oil

Rf-verdi: 0,55 (kiselgel; metylenkloird/etanol =19:1) Rf value: 0.55 (silica gel; methylene chloride/ethanol = 19:1)

f) 2-[N-(4-cyanofenyl)-aminometyl]-tiazol[5,4-b]pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid f) 2-[N-(4-cyanophenyl)-aminomethyl]-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

En blanding av 1,54 g (3,85 mMol) 2-metoksymetyl-tiazol[5,4-b]pyirdin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og 4,3 ml (4,3 mMol) av en 1 molar løsning av bortribromid i metylenklorid ble løst i ytterligere 30 ml metylenklorid og omrørt i 5 t ved romtemperatur. Til slutt ble det vasket med 40 ml mettet natriumhydrogen-karbonatløsning, den organiske fasen tørket med natriumsulfat og løsningsmiddelet destillert av. Råproduktet (1,9 g) ble tatt opp i 15,0 ml N,N-diisopropyl-etylamin, omsatt med 0,50 g (4,2 mMol) 4-aminobenzonitril og oppvarmet i en time til kokepunkt. Til slutt ble løsningsmiddelet destillert av i vakuum, råproduktet tatt opp i 100 ml metylenklorid, organiske fasen vasket med 100 ml vann og tørket med natriumsulfat. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flammekromatografi (kiselgel; eddikester/petroleter = 35:65 til 1:1) og på ny inndampet i vakuum. A mixture of 1.54 g (3.85 mmol) of 2-methoxymethyl-thiazol[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mmol) of a 1 molar solution of boron tribromide in methylene chloride was dissolved in an additional 30 ml of methylene chloride and stirred for 5 h at room temperature. Finally, it was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase dried with sodium sulphate and the solvent distilled off. The crude product (1.9 g) was taken up in 15.0 ml of N,N-diisopropylethylamine, reacted with 0.50 g (4.2 mmol) of 4-aminobenzonitrile and heated for one hour to the boiling point. Finally, the solvent was distilled off in vacuo, the crude product was taken up in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried with sodium sulphate. After removal of the solvent in vacuo, the crude product obtained was purified by flame chromatography (silica gel; acetic acid/petroleum ether = 35:65 to 1:1) and re-evaporated in vacuo.

Utbytte: 0,45 g (24% av teoretisk) gult amorf faststoff, Yield: 0.45 g (24% of theory) yellow amorphous solid,

Rf-verdi: 0,34 (kiselgel; eddikester/petroleter = 1:1) Rf value: 0.34 (silica gel; acetic acid/petroleum ether = 1:1)

g) 2-[N-(4-amidinfenyl)-aminometyl]-tiazol[5,4-b]pyridin-6-yl-karb N-(2-etoksykarbonyletyl)-amid-hydroklorid g) 2-[N-(4-amidinephenyl)-aminomethyl]-thiazol[5,4-b]pyridin-6-yl-carb N-(2-ethoxycarbonylethyl)-amide hydrochloride

0,39 g (0,803 mMol) 2-[N-(4-cyanofenyl)-aminometyl]-tiazol[5,4-b]pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble i 40 ml med klorhydrogen mettet etanol i 5 t først ved 0°C og deretter ved romtemperatur, helt til tynnsjiktskromatografi viste at utgangsmaterialet ikke mer var påviselig. Til slutt ble løsningsmiddelet avdestillert ved max 30°C badtemperatur, den oljeholdige resen tatt opp i 40 ml absolutt etanol og omsatt med 0,5 g ammoniumkarbonat. Etter 18 t ble løsningsmiddelet fjernet i vakuum og det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; metylenklorid/etanol = 9:1 til 4:1). 0.39 g (0.803 mmol) 2-[N-(4-cyanophenyl)-aminomethyl]-thiazol[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- amide was in 40 ml of hydrogen chloride saturated ethanol for 5 h first at 0°C and then at room temperature, until thin layer chromatography showed that the starting material was no longer detectable. Finally, the solvent was distilled off at max. 30°C bath temperature, the oily residue was taken up in 40 ml of absolute ethanol and reacted with 0.5 g of ammonium carbonate. After 18 h, the solvent was removed in vacuo and the crude product obtained was purified by flame chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1).

Utbytte: 78% av teoretisk gult skum Yield: 78% of theoretical yellow foam

C26H26N603S (502,60) C26H26N603S (502.60)

Rf-verdi: 0,19 (kiselgel; metylenkloird/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 503 Rf value: 0.19 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 503

Eksempel 124 Example 124

l-metyl-2-[4-amidinfenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[4-amidinephenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-2-merkapto-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksy-karbonyletyl)-amid a) 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide

En løsning av 6,5 g (19 mMol) 3-amino-4-metylamino-benzosyre-n-fenyl-N-(2-etoksykarbonyletyl)-amid og 4,5 g (22,8 mMol) N,N'-tiokarbonyldiimidazol ble løst under nitrogenatmosfære i 100 ml tetrahydrofuran, oppvarmet i 41 ved 90°C og latt stå i 161 ved romtemperatur. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; petroleter/eddikester = 100:0 til 65:35). A solution of 6.5 g (19 mmol) of 3-amino-4-methylamino-benzoic acid-n-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.5 g (22.8 mmol) of N,N'- thiocarbonyldiimidazole was dissolved under a nitrogen atmosphere in 100 ml of tetrahydrofuran, heated for 41 at 90°C and left for 161 at room temperature. After removal of the solvent in vacuo, the obtained crude product was purified by flame chromatography (silica gel; petroleum ether/acetic ester = 100:0 to 65:35).

Utbytte: 6,8 g (93% av teoretisk) beigefarvet, krystallinsk faststoff, Yield: 6.8 g (93% of theory) beige crystalline solid,

Rf-verdi: 0,55 (kiselgel; eddikester) Rf value: 0.55 (silica gel; acetic acid)

b) l-metyl-2-[(4-cyanofenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid b) 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

En løsning av 1,30 g (3,4 mMol) l-metyl-2-merkapto-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, 0,52 g (3,74 mMol) kaliumkarbonat og 0,66 g (3,4 mMol) 4-brommetylbenzonitril ble løst i 40 ml absolutt etanol, rørt i 41 ved 60°C og 16 t ved romtemperatur. Til slutt ble løsningsmiddelet destillert av i vakuum, råproduktet tatt opp i 30 ml metylenklorid, vasket med 40 ml vann og tørket med natriumsulfat. Etter filtrering og avdestillering av løsningsmiddelet ble det oppnådd ønsket forbindelse som beige-hvitt faststoff. A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.52 g (3, 74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromomethylbenzonitrile were dissolved in 40 ml of absolute ethanol, stirred for 41 at 60°C and 16 h at room temperature. Finally, the solvent was distilled off in vacuo, the crude product was taken up in 30 ml of methylene chloride, washed with 40 ml of water and dried with sodium sulfate. After filtering and distilling off the solvent, the desired compound was obtained as a beige-white solid.

Utbytte: 1,8 g (100% av teoretisk) Yield: 1.8 g (100% of theoretical)

Rf-verdi: 0,64 (kiselgel; eddikester) Rf value: 0.64 (silica gel; acetic acid)

c) l-metyl-2-[(4-amidinfenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid c) 1-methyl-2-[(4-amidinephenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

1,5 g (3,0 mMol) l-metyl-2-[(4-cyanofenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble rørt i 80 ml med klorhydrogenmettet etanol i 6,5 t først ved 0°C og deretter ved romtemperatur helt til tynnsjiktskromatografi ikke viste ytterligere utgangsmaterialer. Til slutt ble løsnings-middelet avdestillert ved max 30°C badtemperatur, den oljeholdige resten tatt opp i 90 ml absolutt etanol og omsatt med 1,0 g (10,5 mMol) ammoniumkarbonat. Etter 18 t ble løsningsmiddelet avdestillert i vakuum og det oppnådde råproduktet renset ved flamme-kromatografi (kiselgel; metylenklorid/etanol = 19.1 til 10:1). 1.5 g (3.0 mmol) of 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 80 ml with chlorohydrogen-saturated ethanol for 6.5 h first at 0°C and then at room temperature until thin-layer chromatography showed no further starting materials. Finally, the solvent was distilled off at max. 30°C bath temperature, the oily residue was taken up in 90 ml of absolute ethanol and reacted with 1.0 g (10.5 mmol) of ammonium carbonate. After 18 h, the solvent was distilled off in vacuo and the crude product obtained was purified by flame chromatography (silica gel; methylene chloride/ethanol = 19.1 to 10:1).

Utbytte: 78% av teoretisk, lysbeigefarvet faststoff, Yield: 78% of theoretical, light beige colored solid,

C28H29N503S (515,63) C28H29N503S (515.63)

Rf-verdi: 0,19 (kiselgel; metylenkloird/etanol = 4:1) Rf value: 0.19 (silica gel; methylene chloride/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =516 EKA mass spectrum: (M+H)<+> =516

(M+H.Na)** =269,7 (M+H.Na)** =269.7

(M+2H)<++> = 258,7 (M+2H)<++> = 258.7

Eksempel 125 Example 125

l-metyl-2-[(4-amidinfenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 10 fra l-metyl-2-[(4-amidinfenyl)metyltio]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 10 from 1-methyl-2-[(4-amidinphenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 57% av teoretisk Yield: 57% of theoretical

C26H25N503S (487,58) C26H25N503S (487.58)

Rf-verdi: 0,23 (revers fase kiselgel RP-8; metanol/5% koksaltløsning = 6:4) Rf value: 0.23 (reverse phase silica gel RP-8; methanol/5% sodium bicarbonate solution = 6:4)

EKA-massespekter: (M+H)<+> = 488 EKA mass spectrum: (M+H)<+> = 488

(M+Na)<+> =510 (M+Na)<+> =510

(M+Na+H)"^ = 255,6 (M+Na+H)"^ = 255.6

Eksempel 126 Example 126

l-metyl-2-[(4-amidinfenyl)-aminome1yl]-benzimidazol-5-yl-karboksylsyre-N-propargyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 232 fra l-metyl-2-[(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-propargyI-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarboant. Prepared analogous Example 232 from 1-methyl-2-[(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 81% av teoretisk Yield: 81% of theoretical

C25H28N603 (460,6) C25H28N603 (460.6)

Rf-verdi: 0,094 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.094 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> =461 EKA mass spectrum: (M+H)<+> =461

(M+H+Na)^ = 242 (M+H+Na)^ = 242

(M+2H)<++> =231 (M+2H)<++> =231

Eksempel 127 Example 127

l-metyl-2-[2-(4-(N-n-heksyloksykarbonylamidin)fenyl]etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[2-(4-(N-n-hexyloxycarbonylamidine)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[2-(4-amidinfenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyI)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogous Example 85 from 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-hexyl ester.

Utbytte: 72% av teoretisk Yield: 72% of theoretical

C35H42N605 (626,8) C35H42N605 (626.8)

Rf-verdi: 0,54 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 627 EKA mass spectrum: (M+H)<+> = 627

(M+Na)<+> = 649 (M+Na)<+> = 649

Eksempel 128 Example 128

l-metyl-2-[2-[4-(N-benzoylamidin)fenyl]etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[2-[4-(N-benzoylamidin)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[2-(4-amidinfenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og benzoylklorid. Prepared analogous Example 85 from 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and benzoyl chloride.

Utbytte: 79% av teoretisk Yield: 79% of theoretical

C35H34N6O4 (602,7) C35H34N6O4 (602.7)

Rf-verdi: 0,52 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 603 EKA mass spectrum: (M+H)<+> = 603

(M+Na)<+> = 625 (M+Na)<+> = 625

Eksempel 129 Example 129

l-metyl-2-[2-[4-(K-nikotinoylamidin)fenyl]etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[2-[4-(N-nicotinoylamidin)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[2-(4-amidinfenyl)etyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid ognikotin-syreklorid. Prepared analogous Example 85 from 1-methyl-2-[2-(4-amidinephenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride ognicotin - acid chloride.

Utbytte: 56% av teoretisk Yield: 56% of theoretical

C34H33N704 (603,7) C34H33N704 (603.7)

Rf-verdi: 0,52 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 604 EKA mass spectrum: (M+H)<+> = 604

(M+Na)<+> = 626 (M+Na)<+> = 626

Eksempel 130 Example 130

l-syklopropyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-cyclopropyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-syklopropyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-cyclopropyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 31% av teoretisk Yield: 31% of theoretical

C30H33N6O3 (524,6) C30H33N6O3 (524.6)

Rf-verdi: 0,40 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.40 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =525 EKA mass spectrum: (M+H)<+> =525

(M+H+Na)"1^ = 274 (M+H+Na)"1^ = 274

(M+2H)<++> = 263 (M+2H)<++> = 263

Eksempel 131 Example 131

l-syklopropyl-2-[N-(4-amidinfenyl)-aminometyl]-beira fenyl-N-(2-hydroksykarbonyletyl)-amid 1-cyclopropyl-2-[N-(4-amidinephenyl)-aminomethyl]-beiraphenyl-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-syklopropyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-cyclopropyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 64% av teoretisk Yield: 64% of theoretical

C28H28N603 (496,6) C28H28N603 (496.6)

Rf-verdi: 0,40 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.40 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> = 497 EKA mass spectrum: (M+H)<+> = 497

(M+H+Na)^ = 260 (M+H+Na)^ = 260

(M+Na)<+> =519 (M+Na)<+> =519

(M+2Na)<++> = 271 (M+2Na)<++> = 271

Eksempel 132 Example 132

l-metyl-2-[N-(4-amidinfenyl)-N-(n-butyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-N-(n-butyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C32H38N603 (554,7) C32H38N603 (554.7)

EKA-massespekter: (M+H)<+> = 555 EKA mass spectrum: (M+H)<+> = 555

(M+H+Na)^ = 289 (M+H+Na)^ = 289

(M+2H)<**> = 278 (M+2H)<**> = 278

Eksempel 133 Example 133

l-metyl-2-[N-(4-amidin-2-klorfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidin-2-chlorophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyano-2-klorfenyl)-aminometyl]-benzimidazol-5-yI-karboksylsyre-N-fenyl-N-(2-etoksykarbonyIetyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyano-2-chlorophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 82% av teoretisk Yield: 82% of theoretical

C28H29C1N603 (533,1) C28H29C1N603 (533.1)

EKA-massespekter: (M+H)<+> = 533/5 EKA mass spectrum: (M+H)<+> = 533/5

(M+H+Na)^ = 278/9 (M+H+Na)^ = 278/9

Eksempel 134 Example 134

l-metyl-2-[N-[4-(n-oktyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-[4-(n-octyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-oktylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n -octyl ester.

Utbytte: 34% av teoretisk Yield: 34% of theoretical

C37H46N6O5 (654,8) C37H46N6O5 (654.8)

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 19:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1)

EKA-massespekter: (M+H)<+> =655 EKA mass spectrum: (M+H)<+> =655

(M+H+Na)^ = 339 (M+H+Na)^ = 339

(M+Na)<+> = 677 (M+Na)<+> = 677

Eksempel 135 Example 135

1 -metyl-2- [N-(4-amidin-2-etylfenyl] -aminometyl] -benzimidazol-5 -yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidin-2-ethylphenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyano-2-etylfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyano-2-ethylphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 61% av teoretisk Yield: 61% of theoretical

C3oH34N603 (526,6) C3oH34N6O3 (526.6)

EKA-massespekter: (M+H)<+> = 527 EKA mass spectrum: (M+H)<+> = 527

(M+H+Na)4"* = 275 (M+H+Na)4"* = 275

(M+2H)<++> = 264 (M+2H)<++> = 264

Eksempel 136 Example 136

1 -metyl-2- [N- [4-(N-(2-(2-etoksyetoksy)etyloksy)-karbonylamidin)fenyl] -aminometyl] - benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(l-etoksykarbonyletyl)-amid 1 -methyl-2- [N- [4-(N-(2-(2-ethoxyethoxy)ethyloxy)-carbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)- N-(1-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyreester av dietylenglykolmonoetyleter. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid ester of diethylene glycol monoethyl ether.

Utbytte: 43% av teoretisk Yield: 43% of theoretical

CsaH^NvO? (659,8) CsaH^NvO? (659.8)

Rf-verdi: 0,56 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.56 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 660 EKA mass spectrum: (M+H)<+> = 660

(M+H+Na)^ =341,7 (M+H+Na)^ =341.7

Eksempel 137 Example 137

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(l-metylpyrazol-4-yl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 60% av teoretisk Yield: 60% of theoretical

C26H3oN803 (502,6) C26H3oN8O3 (502.6)

Rf-verdi: 0,13 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 503 EKA mass spectrum: (M+H)<+> = 503

(M+H+Na)^ = 263 (M+H+Na)^ = 263

(M+2H)<++> = 252 (M+2H)<++> = 252

Eksempel 138 Example 138

3-metyl-2-[(4-amidinfenyl]-tiometyl]-imidazo[4,5-b]-pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 3-Methyl-2-[(4-amidinephenyl]-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 1 fra 3-metyl-2-[(4-cyanofenyl]-tiometyl]-imidazo[4,5-b] -pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 1 from 3-methyl-2-[(4-cyanophenyl]-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)- amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 88% av teoretisk Yield: 88% of theoretical

C27H28N603S (516,63) C27H28N603S (516.63)

Rf-verdi: 0,23 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.23 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> =517 EKA mass spectrum: (M+H)<+> =517

(M+H+Na)^ = 270 (M+H+Na)^ = 270

Eksempel 139 Example 139

3-metyl-2-[N-(4-amidinfenyl]-aminometyl]-imidazo[4,5-b]-pyri fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 3-Methyl-2-[N-(4-amidinephenyl]-aminomethyl]-imidazo[4,5-b]-pyriphenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 1 fra 3-metyl-2-[N-(4-cyanofenyl)-aminometyl]-imidazo[4,5-b]-pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 1 from 3-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl )-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 82% av teoretisk Yield: 82% of theoretical

C27H29N703 (499,58) C27H29N703 (499.58)

Rf-verdi: 0,20 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.20 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 500 EKA mass spectrum: (M+H)<+> = 500

(M+H+Na)^ =261,7 (M+H+Na)^ =261.7

Eksempel 140 Example 140

3 -metyl-2- [(4-amidinfenyl] -tiometyl] -imidazo [4,5 -b] -pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 3-methyl-2-[(4-amidinephenyl]-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 2 fra 3-meryl-2-[(4-amidinfenyl)-tiometyl]-imidazo[4,5-b]-pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 2 from 3-meryl-2-[(4-amidinephenyl)-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- amide hydrochloride and caustic soda.

Utbytte: 88% av teoretisk Yield: 88% of theoretical

C25H24N603S (488,56) C25H24N603S (488.56)

Rf-verdi: 0,21 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.21 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 489 EKA mass spectrum: (M+H)<+> = 489

(M+Na)<+> =511 (M+Na)<+> =511

Eksempel 141 Example 141

3-metyl-2-[N-(4-amidinfenyl]-aminometyl]-imidazo[4,5-b]-pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 3-Methyl-2-[N-(4-amidinephenyl]-aminomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 2 fra 3-metyl-2-[N-(4-amidinfenyl)-aminometyl]-imidazo[4,5-b]-pyridin-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 2 from 3-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl )-amide hydrochloride and caustic soda.

Utbytte: 80% av teoretisk Yield: 80% of theoretical

C25H25N703 (471,52) C25H25N703 (471.52)

Rf-verdi: 0,19 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 472 EKA mass spectrum: (M+H)<+> = 472

(M+Na)<+> = 494 (M+Na)<+> = 494

(M+2Na)<++> = 258,6 (M+2Na)<++> = 258.6

Eksempel 142 Example 142

l-metyl-2-[N-(4-amidinfenyl]-aminomeryl]-benzimidazol-5-yl-sulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl]-aminomeryl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-2-(^-(4-cyanofenyl]-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid a) 1-methyl-2-(^-(4-cyanophenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

2,54 g (6,2 mMol) 3-nitro-4-metylamino-benzensulfonsyre-N-fenyl-N-(2-etoksy-karbonyletyl)-amid ble hydrert ved romtemperatur og 5 bar hydrogentrykk over palladium/kull (10%) i en blanding av 75 ml etanol og 75 ml diklormetan. Det på denne måten oppnådde rå 3-amino-4-metylamino-benzensulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid ble uten rensning tatt opp i 30 ml fosforoksyklorid, og deretter ble 1,1 g (6,2 mMol) N-(4-cyanofenyl)-glysin tilført og blandingen kokt i to timer under tilbakeløp. Etter avkjøling til romtemperatur ble reaksjonsblandingen ført inn i ca 70 ml vann under avkjøling og på denne måten ble fosforoksyklorid i overskudd nedbrutt. Den på denne måten oppnådde løsningen ble nøytralisert med fast natriumkarbonat og ekstrahert tre ganger hver med 30 ml eddikester. Etter inndampning av løsningsmiddelet ble råproduktet renset ved kolonne-kromatografi (100 g kiselgel; løpemiddel: Sykloheksan/eddikester = 2:3). 2.54 g (6.2 mmol) of 3-nitro-4-methylamino-benzenesulfonic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide was hydrogenated at room temperature and 5 bar hydrogen pressure over palladium/charcoal (10% ) in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. The crude 3-amino-4-methylamino-benzenesulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide thus obtained was taken up without purification in 30 ml of phosphorus oxychloride, and then 1.1 g (6.2 mMol) of N-(4-cyanophenyl)-glycine added and the mixture boiled for two hours under reflux. After cooling to room temperature, the reaction mixture was introduced into approximately 70 ml of water while cooling and in this way excess phosphorus oxychloride was decomposed. The solution thus obtained was neutralized with solid sodium carbonate and extracted three times each with 30 ml of acetic acid. After evaporation of the solvent, the crude product was purified by column chromatography (100 g silica gel; eluent: Cyclohexane/acetic ester = 2:3).

Utbytte: 860 mg (26,8% av teoretisk) Yield: 860 mg (26.8% of theoretical)

Smeltepunkt: 188-19FC Melting point: 188-19FC

C27H27N503S (517,6) C27H27N503S (517.6)

Rf-verdi: 0,52 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> =518 EKA mass spectrum: (M+H)<+> =518

(M+Na)<+> = 540 (M+Na)<+> = 540

b) l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 25d fra l-metyl-2-[N-(4-cyanofenyl]-aminometyl]-benzimidazol-5 -yl-sulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 25d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 87% av teoretisk Yield: 87% of theoretical

C27H30N6O4S (534,6) C27H30N6O4S (534.6)

Rrverdi: 0,13 (kiselgel; diklormetan/etanol = 9:1) Rr value: 0.13 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> =535 EKA mass spectrum: (M+H)<+> =535

(M+H+Na)"^ = 279 (M+H+Na)"^ = 279

Eksempel 143 Example 143

1 -metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-( 1 - metylpyrazol-4-yl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra 1-metyl-2-[N-(4-cyanofenyl]-aminometyl] - benzimidazol-5-yl-sulfonsyre-N-(l-metylpyrazol-4-yl)-N-(2-etoksykarbonyletyl)-amid, etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 38% av teoretisk Yield: 38% of theoretical

C25H3oN804S (538,6) C25H3oN804S (538.6)

Rr verdi: 0,09 (kiselgel; diklormetan/etanol = 9:1) Rr value: 0.09 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> = 539 EKA mass spectrum: (M+H)<+> = 539

Eksempel 144 Example 144

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-5-(2,3-dihydroindol-l-yl-sulfonyl)-benzimidazol-hydroklorid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-5-(2,3-dihydroindol-1-yl-sulfonyl)-benzimidazole hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl]-aminometyl]-5-(2,3-dihydroindol-l-yl-sulfonyl)-benzimidazol-hydroklorid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-5-(2,3-dihydroindol-1-yl-sulfonyl)-benzimidazole hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 15% av teoretisk Yield: 15% of theoretical

Rf-verdi: 0,36 (kiselgel; diklormetan/metanol = 4:1) Rf value: 0.36 (silica gel; dichloromethane/methanol = 4:1)

C24H24N602S (460,6) C24H24N602S (460.6)

EKA-massespekter: (M+H)<+> =461 EKA mass spectrum: (M+H)<+> =461

Eksempel 145 Example 145

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinphenyl]-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda.

Utbytte: 24% av teoretisk Yield: 24% of theoretical

Rf-verdi: 0,55 (revers fase RP-18 kiselgel; metanol/5% koksaltløsning = 3:2) C25H26N604S (506,6) Rf value: 0.55 (reverse phase RP-18 silica gel; methanol/5% sodium bicarbonate solution = 3:2) C25H26N604S (506.6)

EKA-massespekter: (M+H)<+> = 507 EKA mass spectrum: (M+H)<+> = 507

(M+Na)^ = 529 (M+Na)^ = 529

(M+2Na)<++> =276 (M+2Na)<++> =276

Eksempel 146 Example 146

1- metyl-2-[N-(4-amidinfenyl]-aminometyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazol-hydroklorid 1- methyl-2-[N-(4-amidinephenyl]-aminomethyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazole hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl]-aminometyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazol og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 33% av teoretisk Yield: 33% of theoretical

Rf-verdi: 0,32 (kiselgel; diklormetan/metanol = 4:1) Rf value: 0.32 (silica gel; dichloromethane/methanol = 4:1)

C24H24N602S (460,6) C24H24N602S (460.6)

EKA-massespekter: (M+H)<+> =461 EKA mass spectrum: (M+H)<+> =461

Eksempel 147 Example 147

2- [2-(4-amidinfenyl]-etyl]-kinazolin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyl-etyl)amid-hydroklorid 2- [2-(4-Amidinephenyl]-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)amide hydrochloride

a) 4-metyl-3-nitro-benzosyreetylester a) 4-methyl-3-nitro-benzoic acid ethyl ester

Til en løsning av 3 ml konsentrert saltsyre og 4 ml konsentrert svovelsyre ble det To a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid it was

under omrøring ved 5°C dråpevis tilsatt 4,9 g (0,03 Mol) p-tolylsyreetylester og 11 under avkjøling etterrørt i isbad. Etter oppvarming til romtemperatur ble isvann tilført og ekstrahert med eddikester. De organiske ekstraktene ble vasket med natriumhydrogenkarbonatløsning, tørket og inndampet. while stirring at 5°C, 4.9 g (0.03 mol) of p-tolylic acid ethyl ester and 11, while cooling, were added dropwise in an ice bath. After warming to room temperature, ice water was added and extracted with vinegar. The organic extracts were washed with sodium bicarbonate solution, dried and evaporated.

Utbytte: 5,7 g (90% av teoretisk) Yield: 5.7 g (90% of theoretical)

Rf-verdi: 0,81 (kiselgel; eddikester/sykloheksan = 1:1) Rf value: 0.81 (silica gel; acetate/cyclohexane = 1:1)

b) 4-(2-dimetylaminovinyl)-3-nitro-benzosyremetylester b) 4-(2-dimethylaminovinyl)-3-nitro-benzoic acid methyl ester

1,0 g (4,8 mMol) 4-metyl-3-nitro-benzosyreetylester, 0,74 g (6,2 mMol) 1.0 g (4.8 mmol) 4-methyl-3-nitro-benzoic acid ethyl ester, 0.74 g (6.2 mmol)

dimetylformamiddimetylacetal og 2 ml dimetylformamid ble under omrøring oppvarmet i 3 t til 140°C. Til slutt ble løsningsmiddelet destillert av og det på denne måten oppnådde råproduktet ble omsatt uten ytterligere rensning. dimethylformamide dimethylacetal and 2 ml of dimethylformamide were heated to 140°C for 3 hours with stirring. Finally, the solvent was distilled off and the crude product thus obtained was reacted without further purification.

Utbytte: 1,2 g (100% av teoretisk) Yield: 1.2 g (100% of theoretical)

Rf-verdi: 0,54 (kiselgel; eddikester/sykloheksan = 1:1) Rf value: 0.54 (silica gel; acetate/cyclohexane = 1:1)

c) 4-formyl-3-nitro-benzosyremetylester c) 4-formyl-3-nitro-benzoic acid methyl ester

1,2 g (4,8 mMol) 4-(2-dimetylaminovinyl)-3-nitro-benzosyremetylester ble oppløst i 1.2 g (4.8 mmol) of 4-(2-dimethylaminovinyl)-3-nitro-benzoic acid methyl ester was dissolved in

120 ml tetrahydrofuran/vann (1:1) og etter tilførsel av 3,0 g (14,3 mMol) natrium-metaperiodat ble det omrørt i 201 ved romtemperatur. Suspensjonen ble til slutt fortynnet med vann og metylenklorid og ekstrahert med metylenklorid. De forente organiske ekstraktene ble med natriumhydrogenkarbonatløsning vasket, tørket og inndampet. Resten ble kromatografert på kiselgel og eluert med eddikester/sykloheksan (1:3). 120 ml of tetrahydrofuran/water (1:1) and after adding 3.0 g (14.3 mmol) of sodium metaperiodate, it was stirred for 20 minutes at room temperature. The suspension was finally diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3).

Utbytte: 0,6 g (63% av teoretisk) Yield: 0.6 g (63% of theoretical)

Rf-verdi: 0,63 (kiselgel; eddikester/sykloheksan = 1:1) Rf value: 0.63 (silica gel; acetate/cyclohexane = 1:1)

d) 3 -amino-4-formyl-benzosyremetylester d) 3-amino-4-formyl-benzoic acid methyl ester

Til en løsning av 25 ml etanol/iseddik/vann (2:2:1) ble det tilsatt 0,6 g (2,9 mMol) To a solution of 25 ml of ethanol/glacial vinegar/water (2:2:1) was added 0.6 g (2.9 mmol)

4-formyl-3-nitrobenzosyremetylester, 1,2 g (21,4 mMol) jernpulver og 0,01 ml konsentrert saltsyre og under omrøring i 15 min oppvarmet til tilbakeløp. Til slutt ble jernet separert fra, løsningen fortynnet med vann og ekstrahert med metylenklorid. De forente organiske ekstrakter ble vasket med vann, tørket og inndampet. 4-formyl-3-nitrobenzoic acid methyl ester, 1.2 g (21.4 mmol) of iron powder and 0.01 ml of concentrated hydrochloric acid and heated to reflux with stirring for 15 min. Finally, the iron was separated from, the solution diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and evaporated.

Utbytte: 0,3 g (58% av teoretisk) Yield: 0.3 g (58% of theoretical)

Rf-verdi: 0,74 (kiselgel; metylenkloird/metanol = 9,5:0,5) Rf value: 0.74 (silica gel; methylene chloride/methanol = 9.5:0.5)

e) 3-[3-(4-cyanofenyl)-propionylamino]-4-formylbenzosyremetylester e) 3-[3-(4-cyanophenyl)-propionylamino]-4-formylbenzoic acid methyl ester

1,0 g (5,6 mMol) 3-amino-4-formyl-benzosyremetylester og 1,1 g (5,6 mMol) 4-cyanofenylpropionsyreklorid ble løst i 50 ml metylenklorid og etter tilførsel av 0,7 g (5,6 mMol) N-etyl-diisopropylamin omrørt i 241 ved romtemperatur. Til slutt ble det ekstrahert med natriumhydrogenkarbonatløsning, de forente organiske ekstraktene ble tørket og 1.0 g (5.6 mmol) of 3-amino-4-formyl-benzoic acid methyl ester and 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride were dissolved in 50 ml of methylene chloride and after adding 0.7 g (5, 6 mmol) N-ethyl-diisopropylamine stirred in 241 at room temperature. Finally, it was extracted with sodium bicarbonate solution, the combined organic extracts were dried and

inndampet. Resten ble kromatografert på kiselgel og eluert med eddikester/sykloheksan (1:3). evaporated. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3).

Utbytte: 0,6 g (32% av teoretisk) Yield: 0.6 g (32% of theoretical)

Rf-verdi: 0,60 (kiselgel; eddikester/sykloheksan = 1:1) Rf value: 0.60 (silica gel; acetate/cyclohexane = 1:1)

f) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-karboksylsyremetylester f) 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid methyl ester

0,6 g (1,8 mMol) 3-[3-(4-cyanofenyl)-propionylamino]-4-formylbenzosyreetylester 0.6 g (1.8 mmol) 3-[3-(4-cyanophenyl)-propionylamino]-4-formylbenzoic acid ethyl ester

og 10 ml metanolisk ammoniakkløsning ble rørt i en trykkinnretning i 361. Til slutt ble løsningsmiddelet destillert av, resten kromatografert på kiselgel og eluert med metylenklorid, som ga 0 til 1% metanol. and 10 ml of methanolic ammonia solution was stirred in a pressure device at 361. Finally, the solvent was distilled off, the residue chromatographed on silica gel and eluted with methylene chloride, which gave 0 to 1% methanol.

Utbytte: 0,35 g (62% av teoretisk) Yield: 0.35 g (62% of theoretical)

Rf-verdi: 0,38 (kiselgel; eddikester/sykloheksan = 1:1) Rf value: 0.38 (silica gel; acetate/cyclohexane = 1:1)

g) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-karboksylsyre g) 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid

0,3 g (0,94 mMol) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-karboksylsyremetylester 0.3 g (0.94 mmol) 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid methyl ester

ble løst i 4,7 ml IN litiumhydroksidløsning og 4 ml tetrahydrofuran og omrørt i 3 t ved romtemperatur. Til slutt ble det tilsatt 4,7 ml IN saltsyre og omrørt i 30 min. Det utfelte produktet ble sugd av, vasket med vann og tørket. was dissolved in 4.7 ml of 1N lithium hydroxide solution and 4 ml of tetrahydrofuran and stirred for 3 h at room temperature. Finally, 4.7 ml of IN hydrochloric acid was added and stirred for 30 min. The precipitated product was sucked off, washed with water and dried.

Utbytte: 0,30 g (100% av teoretisk) Yield: 0.30 g (100% of theoretical)

Rr verdi: 0,1 (kiselgel; eddikester/sykloheksan = 1:1) Rr value: 0.1 (silica gel; acetate/cyclohexane = 1:1)

h) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-yl-karboksylsyre-N-fenyl-N-(2-metoksy-karbonyletyl)-amid h) 2-[2-(4-cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide

0,4 g 81,3 mMol) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-karboksylsyre og 5 ml tionylklorid ble rørt i 60 min ved 50°C. Til slutt ble tionylklorid destillert av, resten løst i metylenklorid, omsatt med 0,24 g (1,3 mMol) 3-(N-fenylamino)-propionsyremetylester og 0,22 ml (1,3 mMol) N-etyldiisopropylamin og omrørt ved romtemperatur i 18 t. Etter avdampning av løsningsmiddelet i vakuum ble det kromatografert på kiselgel og med metylenklorid, som inneholdt 1% metanol. 0.4 g (81.3 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred for 60 min at 50°C. Finally, thionyl chloride was distilled off, the residue dissolved in methylene chloride, reacted with 0.24 g (1.3 mmol) 3-(N-phenylamino)-propionic acid methyl ester and 0.22 ml (1.3 mmol) N-ethyldiisopropylamine and stirred at room temperature for 18 h. After evaporation of the solvent in vacuo, it was chromatographed on silica gel and with methylene chloride, which contained 1% methanol.

Utbytte: 230 mg (37% av teoretisk) Yield: 230 mg (37% of theoretical)

Rrverdi: 0,64 (kiselgel; metylenklorid/metanol = 9:1) Rr value: 0.64 (silica gel; methylene chloride/methanol = 9:1)

i) 2-[2-(4-amidinfenyl)-etyl]-kinazolin-7-yl-karboksylsyre-N-fenyl-N-(2-etoks karbonyletyl)-amid-hydroklorid i) 2-[2-(4-amidinphenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxy carbonylethyl)-amide hydrochloride

230 mg (0,5 mMol) 2-[2-(4-cyanofenyl)-etyl]-kinazolin-7-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble omrørt i 30 ml mettet etanolisk saltsyre i 8 t ved romtemperatur. Til slutt ble det inndampet i vakuum til tørrhet, resten tatt opp i 20 ml etanol, omsatt med 0,5 g (5,0 mMol) ammoniumkarbonat og over natt omrørt ved romtemperatur. Etter avdampning av løsningsmiddelet ble råproduktet kromatografert på kiselgel og eluert med metylenklorid(etanol (4:1). 230 mg (0.5 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide was stirred in 30 ml of saturated ethanolic hydrochloric acid for 8 h at room temperature. Finally, it was evaporated in vacuo to dryness, the residue taken up in 20 ml of ethanol, reacted with 0.5 g (5.0 mmol) of ammonium carbonate and stirred overnight at room temperature. After evaporation of the solvent, the crude product was chromatographed on silica gel and eluted with methylene chloride (ethanol (4:1).

Utbytte: 100 mg (39% av teoretisk) Yield: 100 mg (39% of theoretical)

Rf-verdi: 0,5 (kiselgel; metylenklorid/metanol = 4:1) Rf value: 0.5 (silica gel; methylene chloride/methanol = 4:1)

C29H29N503 (495,59) C29H29N503 (495.59)

Massespekter: (M+H)<+> =496 Mass spectrum: (M+H)<+> =496

Eksempel 148 Example 148

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-(l-metyl-pyrazol-4-yl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methyl-pyrazol-4-yl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-sulfonsyre-N-(l-metylpyrazol-4-yl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 95% av teoretisk Yield: 95% of theoretical

C23H26N8O4S (510,6) C23H26N8O4S (510.6)

Rf-verdi: 0,53 (revers fase kiselgel RP-18; metanol + 5% koksaltløsning) Rf value: 0.53 (reverse phase silica gel RP-18; methanol + 5% sodium bicarbonate solution)

Massespekter: (M+H)<+> =511 Mass spectrum: (M+H)<+> =511

(M+Na)<+> = 533 (M+Na)<+> = 533

(M+2Na)<++> =278 (M+2Na)<++> =278

Eksempel 149 Example 149

l-mety]-2-[N-(3-amidinpyridin-6-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-arnid-hydroklorid 1-Methyl-2-[N-(3-amidinepyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aramide hydrochloride

a) 3-[(N-tert.butoksykarbonyl-amino)acetylamino]-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid a) 3-[(N-tert.butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

19,2 g (0,11 Mol) N-tert.butyloksykarbonylglysin ble løst i 175 ml dimetylformamid omsatt med 35,2 g (0,11 Mol) 0-benzotriazol-l-yl)-N,N,N',N'-tetrametyluronium- 19.2 g (0.11 Mol) of N-tert.butyloxycarbonylglycine was dissolved in 175 ml of dimethylformamide reacted with 35.2 g (0.11 Mol) of O-benzotriazol-1-yl)-N,N,N',N '-tetramethyluronium-

tetrafluorborat, 11,0 g trietylamin og 34,2 g (0,10 Mol) 3-amino-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og omrørt i 2,5 t ved romtemperatur. Til slutt ble reaksjonsløsningen omsatt med 5 1 isvann og omrørt i 2 t. Det dannede grå bunnfall ble filtrert fra, vasket med vann, tørket og under tilsetning av aktivt kull omkrystallisert fra eddikester. tetrafluoroborate, 11.0 g triethylamine and 34.2 g (0.10 Mol) 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and stirred in 2, 5 h at room temperature. Finally, the reaction solution was reacted with 5 1 of ice water and stirred for 2 h. The gray precipitate formed was filtered off, washed with water, dried and, with the addition of activated carbon, recrystallized from ethyl acetate.

Utbytte: 39,85 g (80% av teoretisk) Yield: 39.85 g (80% of theoretical)

C25H33N506 (499,6) C25H33N506 (499.6)

Rr verdi: 0,55 (kiselgel; metylenkloird/etanol = 19:1) Rr value: 0.55 (silica gel; methylene chloride/ethanol = 19:1)

b) l-metyl-2-(N-tert.butoksykarbonyl-aminometyl)-benzimidazol-5-yl-karboksylsyreN-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid b) 1-methyl-2-(N-tert-butoxycarbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

10,0 g (0,02 mol) 3-[(N- tert.butoksykarbonyl-amino)acetylamino]-4-metylamino-benzosyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid ble løst i 50 ml iseddik og oppvarmet i en time under tilbakeløp. Til slutt ble løsningsmiddelet destillert fra, resten omsatt med isvann og innstilt ved tilsetning av 2N ammoniakk på pH 8. Etter ekstrahering tre ganger med eddikester ble de forente organiske fasene vasket med koksaltløsning og tørket over natriumsulfat. Etter avdampning av løsningsmiddelet ble råproduktet kromatografert på kiselgel, begynnende med metylenklorid, senere med metylenklorid/etanol (50:1) og (25:1). De ønskede fraksjonene ble forent og inndampet. 10.0 g (0.02 mol) of 3-[(N-tert.butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide was dissolved in 50 ml of glacial acetic acid and heated for one hour under reflux. Finally, the solvent was distilled off, the residue reacted with ice water and adjusted by the addition of 2N ammonia to pH 8. After extraction three times with ethyl acetate, the combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on silica gel, starting with methylene chloride, later with methylene chloride/ethanol (50:1) and (25:1). The desired fractions were combined and evaporated.

Utbytte: 5,85 g (61% av teoretisk) Yield: 5.85 g (61% of theoretical)

C25H3iN505 (481,6) C25H3iN505 (481.6)

Rrverdi: 0,70 (kiselgel; metylenkloird/etanol = 9:1) Rr value: 0.70 (silica gel; methylene chloride/ethanol = 9:1)

c) l-metyl-2-aminometyl-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-trifluoracetat c) 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide trifluoroacetate

4,81 g (0,10 mol) l-metyl-2-(N-tert.butoksykarbonyl-aminometyl)-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid ble løst i 25 ml metylenklorid, omsatt med 5 ml trifluoreddiksyre og omrørt i 51 ved romtemperatur. Til slutt ble løsningsmiddelet avdampet og resten rørt med eter. De derved dannede krystallene ble filtrert fra, vasket med eter og tørket. 4.81 g (0.10 mol) 1-methyl-2-(N-tert-butoxycarbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide was dissolved in 25 ml of methylene chloride, reacted with 5 ml of trifluoroacetic acid and stirred for 51 at room temperature. Finally, the solvent was evaporated and the residue stirred with ether. The crystals thus formed were filtered off, washed with ether and dried.

Utbytte: 3,15 g (68% av teoretisk) Yield: 3.15 g (68% of theoretical)

C2oH23N503 (381,4) C2oH23N5O3 (381.4)

Rr verdi: 0,18 (kiselgel; metylenklorid/etanol = 9:1) Rr value: 0.18 (silica gel; methylene chloride/ethanol = 9:1)

d) l-metyl-2-[N-(3-cyanopyridin-6-yty^ N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid d) 1-methyl-2-[N-(3-cyanopyridin-6-yl)-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

1,5 g (3,25 mMol) l-metyl-2-aminometyl-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-trifluoracetat ble omrørt i 10 ml N-etyl-diisopropylamin og oppvarmet i 15 min ved 100°C. Etter tilførsel av 720 mg (5,25 mMol) 2-klor-5-cyanopyridin ble reaksjonsblandingen oppvarmet i 21 ved 125°C. Etter avkjøling til romtemperatur og omrøring med ca 20 ml vann ble det ved tilførsel av IN saltsyre innstilt til pH 4 og ekstrahert 3 ganger med eddikester. De forente organiske fasene ble vasket med koksaltløsning og tørket over natriumsulfat. Etter avdampning av løsningsmiddelet ble råproduktet kromatografert på kiselgel, begynnende med metylenklorid, senere med metylenkloird/etanol (25:1) og (19:1). De ønskede fraksjonene ble blandet sammen og inndampet. 1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide trifluoroacetate was stirred in 10 ml N-ethyl-diisopropylamine and heated for 15 min at 100°C. After adding 720 mg (5.25 mmol) of 2-chloro-5-cyanopyridine, the reaction mixture was heated for 21 at 125°C. After cooling to room temperature and stirring with approx. 20 ml of water, pH was adjusted to 4 by adding 1N hydrochloric acid and extracted 3 times with acetic acid. The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on silica gel, starting with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated.

Utbytte: 1,05 g (67% av teoretisk) Yield: 1.05 g (67% of theoretical)

C26H25N70 (483,6) C26H25N70 (483.6)

Massespekter: (M+H)<+> = 484 Mass spectrum: (M+H)<+> = 484

e) l-metyl-2-[N-(3-amidinpyridin-6-yl)-aminometyl]benzimidazol-5-yl-karboksylsyreN-(2-pyiridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid e) 1-methyl-2-[N-(3-amidinepyridin-6-yl)-aminomethyl]benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 25d fra l-metyl-2-[N-(3-cyanopyridin-6-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 25d from 1-methyl-2-[N-(3-cyanopyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 38% av teoretisk Yield: 38% of theoretical

C28H28N803 (500,6) C28H28N803 (500.6)

Massespekter: (M+H)<+> = 501 Mass spectrum: (M+H)<+> = 501

Eksempel 150 Example 150

l-mety].-2-[^-(4-amidmfenyl)aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydrojodid 1-methyl]-2-[^-(4-amidmphenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydroiodide

a) 4-nitro-benzosyre-N-fenyl-N-(2-metoksykarbonyletyl)amid a) 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide

16,7 g (0,1 mol) 4-nitrobenzosyre ble ved tilbakeløp kokt i 1 t i 50 ml tionylklorid 16.7 g (0.1 mol) of 4-nitrobenzoic acid was refluxed for 1 h in 50 ml of thionyl chloride

og 3 dråper dimetylformamid. Etter avdestillering av løsningsmiddelet i vakuum ble råproduktet løst i 150 ml tetrahydrofuran og til en løsning av 18 g (0,1 mol) N-(2- and 3 drops of dimethylformamide. After distilling off the solvent in vacuo, the crude product was dissolved in 150 ml of tetrahydrofuran and into a solution of 18 g (0.1 mol) N-(2-

metoksykarbonyletyl)anilin i 250 ml tetrahydrofuran og 42 ml (0,3 mol) trietylamin dråpevis tilsatt. Etter røring i en time ved romtemperatur ble det fortynnet med 250 ml etylacetat og vasket 2x med 200 ml 14% koksaltløsning. Etter avdestillering av løsningsmiddelet og kromatografi (kiselgel; metylenklorid) isolerte man en gul olje som langsomt stivnet. methoxycarbonylethyl)aniline in 250 ml tetrahydrofuran and 42 ml (0.3 mol) triethylamine added dropwise. After stirring for one hour at room temperature, it was diluted with 250 ml of ethyl acetate and washed twice with 200 ml of 14% sodium chloride solution. After distilling off the solvent and chromatography (silica gel; methylene chloride), a yellow oil was isolated which slowly solidified.

Utbytte: 32,6 g (100% av teoretisk) Yield: 32.6 g (100% of theoretical)

Rf-verdi: 0,37 (kiselgel; metylenklorid/metanol = 50:1) Rf value: 0.37 (silica gel; methylene chloride/methanol = 50:1)

b) 4-amino-benzosyre-N-fenyl-N-(2-metoksykarbonyletyl)amid b) 4-amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide

22 g (67 mMol) 4-nitro-benzosyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble 22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide was

hydrert i 500 ml metanol med 2 g 10% palladium på kull ved 3 bar vannstofftrykk i 3 t. Etter filtrering og avdestillering av løsningsmiddelet ble det vasket med 100 ml eter og det hvite krystallinske produktet ble direkte videre omsatt. hydrated in 500 ml of methanol with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 h. After filtering and distilling off the solvent, it was washed with 100 ml of ether and the white crystalline product was directly further reacted.

Utbytte: 18,6 g (94% av teoretisk) Yield: 18.6 g (94% of theoretical)

Rf-verdi: 0,70 (kiselgel; metylenkloird/etanol = 19:1) Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1)

c) 2-metyl-3-tiometyl-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid c) 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

26,8 g (91 mMol) 4-amino-benzosyre-N-fenyl-N-(2-metoksykarbonyletyl)amid ble løst i 500 ml metylenklorid, avkjølt til -70°C og i løpet av 30 min omsatt med frisk fremstilt tert.butylhypokloritt (M. J. Mintz et al., Organic Synthesis, Coll. Vol. 5, side 184). Dette ble omrørt i 21 ved -70°C, deretter ble 9,46 g (91 mMol) metyltioaceton i 40 ml metylenklorid i løpet av 10 min dråpevis tilsatt og ytterligere omrørt i 1,5 t. Til slutt ble 12,7 ml (9,1 g, 91 mMol) trietylamin i 25 ml metylenklorid tilsatt. Dette ble holdt i 30 min ved -78°C og deretter oppvarmet langsomt til romtemperatur. Etter 2 x vaskinger hver med 50 ml vann ble den organiske fasen separert fra og tørket med natriumsulfat. Etter fjerning av løsningsmiddelet i vakuum oppnår man etter rensning ved kromatografi (kiselgel; eddikester/petroleter = 2:8 til 3:7) en hvit amorf forbindelse. 26.8 g (91 mmol) of 4-amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide was dissolved in 500 ml of methylene chloride, cooled to -70°C and reacted with freshly prepared tert within 30 min .butyl hypochlorite (M. J. Mintz et al., Organic Synthesis, Coll. Vol. 5, page 184). This was stirred for 21 at -70°C, then 9.46 g (91 mmol) of methylthioacetone in 40 ml of methylene chloride were added dropwise over 10 min and further stirred for 1.5 h. Finally, 12.7 ml ( 9.1 g, 91 mmol) of triethylamine in 25 ml of methylene chloride added. This was held for 30 min at -78°C and then slowly warmed to room temperature. After 2 x washings each with 50 ml of water, the organic phase was separated from and dried with sodium sulfate. After removal of the solvent in vacuo, a white amorphous compound is obtained after purification by chromatography (silica gel; acetic acid/petroleum ether = 2:8 to 3:7).

Utbytte: 24,1 g (69% av teoretisk) Yield: 24.1 g (69% of theoretical)

Rf-verdi: 0,58 (kiselgel; eddikester/petroleter = 1:1) Rf value: 0.58 (silica gel; acetic acid/petroleum ether = 1:1)

C2iH22N203S (382,49) C2iH22N203S (382.49)

Massespekter: (M)<+> =382 Mass spectrum: (M)<+> =382

d) l-tert-butoksykarbonyl-2-metyl-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metok karbonyletyl)-amid d) 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy carbonylethyl)-amide

8,9 g (23 mMol) 2-metyl-3-tiometyl-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble løst i 600 ml etanol, omsatt med ca 150 mg Raney-nikkel og omrørt i 2 t ved romtemperatur (analogt P. G. Gassman et al., Organic Synthesis Coll. Vol. 6, side 601). Til slutt ble det filtrert og løsningsmiddelet fjernet i vakuum. Det på denne måten oppnådde råproduktet (8 g) ble løst i 200 ml absolutt tetrahydrofuran, omsatt med 150 mg dimetylaminopyridin og 6,84 g (32 mMol) pyrokullsyre-di-tert.butylester og omrørt i 2,5 t ved 50°C. Til slutt ble løsningsmiddelet destillert fra i vakuum og råproduktet renset ved kromatografi (kiselgel, eddikester/petroleter = 1:4). 8.9 g (23 mmol) of 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide was dissolved in 600 ml of ethanol, reacted with about 150 mg of Raney -nickel and stirred for 2 h at room temperature (analogous to P. G. Gassman et al., Organic Synthesis Coll. Vol. 6, page 601). Finally, it was filtered and the solvent removed in vacuo. The crude product thus obtained (8 g) was dissolved in 200 ml of absolute tetrahydrofuran, reacted with 150 mg of dimethylaminopyridine and 6.84 g (32 mmol) of pyrocarbonic acid di-tert-butyl ester and stirred for 2.5 h at 50°C . Finally, the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel, acetic acid/petroleum ether = 1:4).

Utbytte: 10,0 g (98% av teoretisk) Yield: 10.0 g (98% of theoretical)

Rf-verdi: 0,40 (kiselgel; eddikester/petroleter = 3:7) Rf value: 0.40 (silica gel; acetic acid/petroleum ether = 3:7)

e) 2-[N-(4-cyanofenyl)aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksy-karbonyletyl)-amid e) 2-[N-(4-cyanophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide

3,5 g (8 mMol) l-tert.butoksykarbonyl-2-metyl-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble løst i 80 ml tetraklorkarbon med 1,5 g (8,4 mMol) N-brom-suksinimid og omsatt med 20 mg azobisisobutyronitril og kokt i 2,51 med tilbakeløp. Deretter ble den fortsatt varme løsningen filtrert, det oppnådde filtratet vasket med mettet natriumhydrogenkarbonatløsning og tørket med natriumsulfat. Etter avdestillering av løsningsmiddelet ble råproduktet løst i 30 ml N-etyl-diisopropylamin, omsatt med 1,0 g (8 mMol) 4-aminobenzonitril og oppvarmet i 2,5 t ved tilbakeløp. Løsningsmiddelet ble destillert, av i vakuum og den oppnådde resten ble renset ved kromatografi (kiselgel; eddikester/petroleter = 1:4 til 1:1). 3.5 g (8 mmol) of 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide was dissolved in 80 ml of carbon tetrachloride with 1.5 g (8.4 mmol) of N-bromosuccinimide and reacted with 20 mg of azobisisobutyronitrile and boiled for 2.51 under reflux. Then the still warm solution was filtered, the filtrate obtained washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After distilling off the solvent, the crude product was dissolved in 30 ml of N-ethyl-diisopropylamine, reacted with 1.0 g (8 mmol) of 4-aminobenzonitrile and heated for 2.5 h at reflux. The solvent was distilled off in vacuo and the residue obtained was purified by chromatography (silica gel; acetic acid/petroleum ether = 1:4 to 1:1).

Utbytte: 1,1 g (30% av teoretisk) Yield: 1.1 g (30% of theoretical)

Rf-verdi: 0,21 (kiselgel; eddikester/petroleter = 1:1) Rf value: 0.21 (silica gel; acetic acid/petroleum ether = 1:1)

f) l-metyl-2-[N-(4-tiokarbamoylfenyl)aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid f) 1-methyl-2-[N-(4-thiocarbamoylphenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

1,5 g (3,3 mMol) 2-[N-(4-cyanofenyl)aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble løst i 60 ml xylen, omsatt med 0,45 g (3,3 mMol) kaliumkarbonat og 0,5 ml (3,3 mMol) p-toluensulfonsyremetylester og oppvarmet ved tilbakeløp i 41. Til slutt ble det tilsatt ytterligere mengder kaliumkarbonat og 1.5 g (3.3 mmol) of 2-[N-(4-cyanophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide was dissolved in 60 ml of xylene , reacted with 0.45 g (3.3 mmol) potassium carbonate and 0.5 ml (3.3 mmol) p-toluenesulfonic acid methyl ester and heated at reflux for 41. Finally, further amounts of potassium carbonate were added and

toluensulfonsyremetylester og dette ble oppvarmet over natt ved tilbakeløp. Det ble filtrert og vasket med aceton. Etter inndamping av det på denne måten oppnådde filtratet ble den oppnådde resten renset ved kromatografi (kiselgel; eddikester/petroleter =1:4 til 2:3). Oppnådd N-metylert indol (utbytte: 0,64 g, 41% av teoretisk) ble løst i 20 ml pyridin og omsatt med 0,67 ml (1,37 mMol) trietylamin. Til slutt ble det i denne oppnådde løsningen ledet inn svovelhydrogengass. Etter 4,5 dager ble det i løpet av 30 min ledet nitrogen gjennom reaksjonsløsningen, løsningsmiddelet ble filtrert ut og oppnådde rest renset ved kromatografi (kiselgel; metylenklorid/etanol 99:1 til 98:2). toluenesulfonic acid methyl ester and this was heated overnight at reflux. It was filtered and washed with acetone. After evaporation of the filtrate thus obtained, the obtained residue was purified by chromatography (silica gel; acetic acid/petroleum ether = 1:4 to 2:3). The obtained N-methylated indole (yield: 0.64 g, 41% of theoretical) was dissolved in 20 ml of pyridine and reacted with 0.67 ml (1.37 mmol) of triethylamine. Finally, hydrogen sulphide gas was introduced into this obtained solution. After 4.5 days, nitrogen was passed through the reaction solution for 30 min, the solvent was filtered out and the residue obtained was purified by chromatography (silica gel; methylene chloride/ethanol 99:1 to 98:2).

Utbytte: 0,30 g (43% av teoretisk) Yield: 0.30 g (43% of theoretical)

C28H28N403S (500,62) C28H28N403S (500.62)

EKA-massespekter: (M+H)<+> = 501 EKA mass spectrum: (M+H)<+> = 501

(M+Na)<+> = 523 (M+Na)<+> = 523

g) l-metyl-2-[N-(4-amidinfenyl)aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid-hydrojodid g) 1-methyl-2-[N-(4-amidinephenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydroiodide

0,30 g (0,60 mMol) l-metyl-2-[N-(4-tiokarbamoyl)-fenyl)-aminometyl]-indol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble sammen med 0,75 ml (12 mMol) metyljodid løst i 20 ml aceton og omrørt i 21 ved romtemperatur. Til slutt ble løsningsmiddelet destillert av og råproduktet ble rørt sammen med 1,0 g ammoniumacetat i 12 ml etanol og 5 ml metylenklorid i 201 ved 40°C. Løsningsmiddelet ble destillert av i vakuum og den oppnådde resten renset ved hjelp av kromatografi (kiselgel; metylenkloird/etanol = 9:1 til 4:1). 0.30 g (0.60 mmol) 1-methyl-2-[N-(4-thiocarbamoyl)-phenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) -amide was dissolved together with 0.75 ml (12 mmol) methyl iodide in 20 ml of acetone and stirred for 21 at room temperature. Finally, the solvent was distilled off and the crude product was stirred with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride in 201 at 40°C. The solvent was distilled off in vacuo and the residue obtained was purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1).

Utbytte: 55% av teoretisk Yield: 55% of theoretical

C28H29N503 (483,58) C28H29N503 (483.58)

Rf-verdi: 0,20 (kiselgel; metylenkloird/etanol = 4:1 + 1 dråpe eddiksyre) Rf value: 0.20 (silica gel; methylene chloride/ethanol = 4:1 + 1 drop of acetic acid)

Massespekter: (M+H)<+> = 484 Mass spectrum: (M+H)<+> = 484

Eksempel 151 Example 151

l-metyl-2-[N-(4-amidinfenyl)aminometyl]-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) Metoksyeddiksyreiminoetylester-hydroklorid a) Methoxyacetic acid iminoethyl ester hydrochloride

En løsning av 35,5 g (0,50 mol) metoksyacetonitril i 29 ml (23 g, 0,50 mol) etanol A solution of 35.5 g (0.50 mol) methoxyacetonitrile in 29 mL (23 g, 0.50 mol) ethanol

og 30 ml absolutt dietyleter ble kjølt til 0°C og i løpet av en 11 ble 22,5 g (0,62 mol) klorhydrogengass ledet inn, idet det mot slutten av gassinnledningen ble utkrystallisert reaksjonsprodukt. For fullføring av fellingen ble det omsatt med 130 ml dietyleter og de farveløse nålene ble filtrert ut. and 30 ml of absolute diethyl ether were cooled to 0°C and in the course of 11 22.5 g (0.62 mol) of chlorine hydrogen gas were introduced, with the reaction product crystallized towards the end of the gas introduction. To complete the precipitation, it was reacted with 130 ml of diethyl ether and the colorless needles were filtered out.

Utbytte: 66,4 g (86% av teoretisk) Yield: 66.4 g (86% of theoretical)

Smeltepunkt: 117-118°C. Melting point: 117-118°C.

b) 4-hydroksymetyl-2-metoksymetyl-imidazol b) 4-hydroxymethyl-2-methoxymethyl-imidazole

En blanding av 30,6 g (0,20 mol) metoksyeddiksyreiminoetylesterhydroklorid, 18 g A mixture of 30.6 g (0.20 mol) methoxyacetic acid iminoethyl ester hydrochloride, 18 g

(0,20 mol) 1,3-dihydroksyaceton og 200 ml flytende ammoniakk ble oppvarmet i 3 t i rørautoklaven ved et trykke på 27 bar ved 68°C (analogt: P. Dziuron et al. Arch. Pharm. 307,1974, s. 470). Deretter ble ammoniakk fjernet og omsatt med 200 ml metylenklorid. Det utfelte hvite presipitatet ble filtrert fra og vasket med metylenklorid. Filtratet ble inndampet og den oppnådde resten ble renset kromatografisk (aluminiumoksid; metylenklorid/etanol = 90:10 til 85:15). (0.20 mol) of 1,3-dihydroxyacetone and 200 ml of liquid ammonia were heated for 3 h in the tube autoclave at a pressure of 27 bar at 68°C (analogous: P. Dziuron et al. Arch. Pharm. 307, 1974, p . 470). Ammonia was then removed and reacted with 200 ml of methylene chloride. The precipitated white precipitate was filtered off and washed with methylene chloride. The filtrate was evaporated and the residue obtained was purified chromatographically (alumina; methylene chloride/ethanol = 90:10 to 85:15).

Utbytte: 26,7 g (94% av teoretisk) Yield: 26.7 g (94% of theoretical)

Rr-verdi: 0,43 (kiselgel; metylenklorid/etanol = 9:1) Rr value: 0.43 (silica gel; methylene chloride/ethanol = 9:1)

C6H10N2O2 (142,20) C6H10N2O2 (142.20)

Massespekter: (M+)<+> = 142 Mass spectrum: (M+)<+> = 142

c) 4-hydroksymetyl-2-metoksymetyl-l-metyl-imidazol som 1:1 blanding med 5-hydroksymetyl-2-metoksymetyl-1 -metyl-imidazol c) 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole as a 1:1 mixture with 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

En blanding av 7,1 g (50 mMol) 4-hydroksymetyl-2-metoksymetylimidazol, 3,0 g (53 mMol) pulverisert kaliumhydroksid og 3,4 ml (0,55 mMol) metyljodid ble oppvarmet i 100 ml dimetylformamid i 41 ved 50°C (analogt I. Sinclair et al., J. Med. Chem., 29,1986, 261). Deretter ble løsningsmiddelet destillert av i vakuum og råproduktet ble renset kolonne-kromatografisk (aluminiumoksid; metylenklorid/etanol = 99.1 til 95:5). A mixture of 7.1 g (50 mmol) 4-hydroxymethyl-2-methoxymethylimidazole, 3.0 g (53 mmol) powdered potassium hydroxide and 3.4 ml (0.55 mmol) methyl iodide was heated in 100 ml dimethylformamide for 41 50°C (analogous to I. Sinclair et al., J. Med. Chem., 29, 1986, 261). Then the solvent was distilled off in vacuo and the crude product was purified by column chromatography (alumina; methylene chloride/ethanol = 99.1 to 95:5).

Utbytte: 6,1 g (78% av teoretisk; 1:1 blanding av begge regioisomerer) Yield: 6.1 g (78% of theory; 1:1 mixture of both regioisomers)

Rf-verdi: 0,32 (kiselgel; metylenkloird/etanol =19:1) Rf value: 0.32 (silica gel; methylene chloride/ethanol = 19:1)

d) 5-klor-4-hydroksymetyl-2-metokysmetyl-l-metyl-imidazol d) 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

En l:l-blanding av 7,7 g (49 mMol) 4-hydroksymetyl-2-metoksy-metyl-l-metyl-imidazol og 5-hydroksyrnetyl-2-metoksymetyl-l-metyl-imidazol samt 7,3 g (55 mMol) N-klorsuksinimid ble oppvarmet i 48 ml etylenglykolmonoetyleter og 70 ml dioksan i 101 ved 50°C. Deretter ble løsningsmiddelet destillert av i vakuum og råproduktet ble renset ved kromatografi (kiselgel; metylenklorid/etanol = 99:1 til 90:10) til isomer-ren tittelforbindelse. A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole as well as 7.3 g ( 55 mmol) of N-chlorosuccinimide was heated in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane in 101 at 50°C. Then the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride/ethanol = 99:1 to 90:10) to the isomerically pure title compound.

Utbytte: 3,4 g (36% av teoretisk) Yield: 3.4 g (36% of theoretical)

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

e) 5-kIor-4-formyl-2-metoksymetyl-1 -metyl-imidazol e) 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole

3,4 g (18 mMol) 5-klor-4-hydroksymetyl-2-metoksymetyl-l-metyl-imidazol ble løst 3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole was dissolved

i 100 ml metylenklorid og omsatt med 2 timers mellomrom med mangandioksid (2 x 6,0 g, totalt 0,14 mol). Etter 41 ble de uorganiske komponentene filtrert fra, løsningsmiddelet fjernet og det oppnådde råproduktet omsatt uten ytterligere rensning. in 100 ml of methylene chloride and reacted at 2 hour intervals with manganese dioxide (2 x 6.0 g, total 0.14 mol). After 41, the inorganic components were filtered off, the solvent removed and the obtained crude product reacted without further purification.

Utbytte: 3,0 g (89% av teoretisk) Yield: 3.0 g (89% of theoretical)

Rf-verdi: 0,44 (kiselgel; metylenklorid/etanol = 50:1) Rf value: 0.44 (silica gel; methylene chloride/ethanol = 50:1)

f) l-metyl-2-metoksymetyl-tieno[2,3-d]imidazol-5-yl-karboksylsyreetylester f) 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid ethyl ester

Til en frisk fremstilt natriumetanol-løsning (av 391 mg, 17 mMol natrium) i 15 ml To a freshly prepared sodium ethanol solution (of 391 mg, 17 mmol sodium) in 15 ml

etanol ble det dråpevis tilsatt 1,9 ml (2,1 g, 17 mMol) tioglykolsyreetylester. Etter omrøring i 11 ved romtemperatur ble det tilsatt 1,6 g (8,5 g mMol) 5-klor-4-formyl-2-metoksymetyl-1-metyl-imidazol i 20 ml absolutt etanol og oppvarmet ved 80°C (analogt B. Iddon et al., J. Chem. Soc. Perkin Trans. 1,1987,1457). Etter 5 t ble løsningsmiddelet destillert ut, resten ble tatt opp i 50 ml metylenklorid og vasket med 20 ml vann. Den vandige fasen ble vasket enda en gang med 20 ml metylenklorid og til slutt ble de forente organiske fasene tørket med natriumsulfat. Etter fjerning av løsningsmiddelet i vakuum ble det oppnådde råproduktet renset ved kolonnekromatografi (aluminiumoksid; metylenklorid). Utbytte: 1,0 g (46% av teoretisk) ethanol, 1.9 ml (2.1 g, 17 mmol) thioglycolic acid ethyl ester was added dropwise. After stirring for 11 at room temperature, 1.6 g (8.5 g mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole was added in 20 ml of absolute ethanol and heated at 80°C (analogously B. Iddon et al., J. Chem. Soc. Perkin Trans. 1, 1987, 1457). After 5 h, the solvent was distilled off, the residue was taken up in 50 ml of methylene chloride and washed with 20 ml of water. The aqueous phase was washed once more with 20 ml of methylene chloride and finally the combined organic phases were dried with sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by column chromatography (alumina; methylene chloride). Yield: 1.0 g (46% of theoretical)

Rf-verdi: 0,48 (kiselgel; metylenklorid/etanol = 50:1) Rf value: 0.48 (silica gel; methylene chloride/ethanol = 50:1)

C11HHN2O3S (254,31) C11HHN2O3S (254.31)

EKA-massespekter: (M+H)<+> = 255 EKA mass spectrum: (M+H)<+> = 255

(M+Na)<+> 0 277 (M+Na)<+> 0 277

g) 1 -metyl-2-metoksymetyl-tieno[2,3-d]imidazol-5-yl-karboksylsyre g) 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid

Til en løsning av 0,90 g (3,54 mMol) 1-metyl-2-metoksymetyl-tieno[2,3-d]imidazoI-5-yI-karboksylsyreetylester i 30 ml etanol blir dråpevis tilsatt 5 ml 2N natronlut og omrørt i 21 ved romtemperatur. Til slutt ble løsningsmiddelet destillert av i vakuum, resten tatt opp i 5 ml vann og vasket med 10 ml dietyleter. Den vandige fasen ble surgjort med 6 ml 2N saltsyre, avkjølt til 0°C og utfelte krystaller filtrert fra. To a solution of 0.90 g (3.54 mmol) of 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazoI-5-yl-carboxylic acid ethyl ester in 30 ml of ethanol, 5 ml of 2N caustic soda is added dropwise and stirred for 21 at room temperature. Finally, the solvent was distilled off in vacuo, the residue taken up in 5 ml of water and washed with 10 ml of diethyl ether. The aqueous phase was acidified with 6 ml of 2N hydrochloric acid, cooled to 0°C and precipitated crystals were filtered off.

Utbytte: 0,50 g (63% av teoretisk) Yield: 0.50 g (63% of theoretical)

Rf-verdi: 0,21 (kiselgel; metylenklorid/etanol = 9:1 + noen dråper eddiksyre) C9H,oN203S (226,26) Rf value: 0.21 (silica gel; methylene chloride/ethanol = 9:1 + a few drops of acetic acid) C9H,oN2O3S (226.26)

EKA-massespekter: (M)<+> = 226 EKA mass spectrum: (M)<+> = 226

h) 1 -metyl-2 -metoksymetyl-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid h) 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

En suspensjon av 0,50 g (2,2 mMol) 1-metyl-2-metoksymetyI-tieno[2,3-d]imidazol-5-yl-karboksylsyre i 20 ml metylenklorid ble omsatt med 2,0 ml (3,2 g, 27 mMol) tionylklorid og kokt i 60 min med tilbakeløp og dermed ble faststoffet oppløst. Etter avdestillering av de flytende komponentene ble råproduktet tatt opp ytterligere 2x i metylenklorid. Etter fornyet fjerning av oppløsningsmiddelet ble rå syreklorid tatt opp i 20 ml tetrahydrofuran og dråpevis tilsatt til en blanding av 0,42 g (2,3 mMol) N-(2-metoksykarbonyletyl)anilin og 0,92 ml (6,6 mMol) trietylamin i 30 ml tetrahydrofuran. Etter omrøring i 161 ved 50°C ble løsningsmiddelet fjernet og det oppnådde råproduktet renset ved kromatografi (kiselgel; metylenkloird/etanol = 100:1). A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid in 20 ml of methylene chloride was reacted with 2.0 ml (3, 2 g, 27 mmol) of thionyl chloride and boiled for 60 min with reflux and thus the solid was dissolved. After distilling off the liquid components, the crude product was taken up a further 2x in methylene chloride. After repeated removal of the solvent, the crude acid chloride was taken up in 20 ml of tetrahydrofuran and added dropwise to a mixture of 0.42 g (2.3 mmol) N-(2-methoxycarbonylethyl)aniline and 0.92 ml (6.6 mmol) triethylamine in 30 ml of tetrahydrofuran. After stirring for 161 at 50°C, the solvent was removed and the crude product obtained was purified by chromatography (silica gel; methylene chloride/ethanol = 100:1).

Utbytte: 0,66 g (77% av teoretisk) Yield: 0.66 g (77% of theoretical)

Rf-verdi: 0,47 (kiselgel; metylenkloird/etanol = 19:1) Rf value: 0.47 (silica gel; methylene chloride/ethanol = 19:1)

i) l-metyl-2-(N-4-cyanofenylaminometyl)-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid i) 1-methyl-2-(N-4-cyanophenylaminomethyl)-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

Til en løsning av 0,73 g (1,88 mMol) l-metyl-2-metoksymetyl-tieno[2,3-d]-imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid i 30 ml metylenklorid ble det dråpevis tilsatt ved 5°C 2,9 ml (2,9 mMol) en 1-molar løsning av bortribromid i metylenklorid. Etter omrøring i 161 ved romtemperatur ble det vasket med 20 ml mettet natriumhydrogenkarbonatløsning, den organiske fasen ble separert, tørket med natriumsulfat og filtrert. Filtratet ble omsatt med 14 ml N-etyl-diisopropylamin og 0,43 g To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethyl-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) -amide in 30 ml of methylene chloride, 2.9 ml (2.9 mmol) of a 1-molar solution of boron tribromide in methylene chloride was added dropwise at 5°C. After stirring for 161 at room temperature, it was washed with 20 ml of saturated sodium bicarbonate solution, the organic phase was separated, dried with sodium sulfate and filtered. The filtrate was reacted with 14 ml of N-ethyl-diisopropylamine and 0.43 g

(3,64 mMol) 4-aminobenzonitril. Til slutt ble metylenklorid filtrert fra i vakuum, den oppnådde resten ble oppvarmet i 11 ved 50°C og deretter ble gjenværende løsningsmiddel destillert av i vakuum. Man oppnår etter kromatografi (kiselgel; metylenklorid/etanol = 99:1 til 97:3) en gul langsomtstivnende olje. (3.64 mmol) 4-aminobenzonitrile. Finally, methylene chloride was filtered off in vacuo, the residue obtained was heated for 11 at 50°C and then the remaining solvent was distilled off in vacuo. After chromatography (silica gel; methylene chloride/ethanol = 99:1 to 97:3) a yellow slow-solidifying oil is obtained.

Utbytte: 0,37 g (42% av teoretisk) Yield: 0.37 g (42% of theoretical)

Rf-verdi: 0,29 (kiselgel; metylenklorid/etanol = 50:1 + noen dråper ammoniakk) Rf value: 0.29 (silica gel; methylene chloride/ethanol = 50:1 + a few drops of ammonia)

j) l-metyl-2-(N-(4-amidinfenyl)aminometyl]-tieno[2,3-d]imidazol-5-yl-karboksylsyreN-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid j) 1-methyl-2-(N-(4-amidinephenyl)aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

0,38 g (0,80 mMol) l-metyl-2-(N-4-cyanofenylaminometyl)-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid ble rørt i 40 ml med klorhydrogen mettet etanol i 5 t først ved 0°C og senere ved romtemperatur helt til det ikke var påviselig ved tynnsjiktskromatografi mer utgangsmateriale. Til slutt ble løsnings-middelet destillert av ved maksimalt 28°C badtemperatur, den oljeholdige resten ble tatt opp i 40 ml absolutt etanol og omsatt med 1,1 g ammoniumkarbonat. Etter 18 t ble løsningsmiddelet destillert av i vakuum og råproduktet renset ved kromatografi (kiselgel; metylenklorid/etanol = 9:1 til 4:1). Utbytte: 57% av teoretisk 0.38 g (0.80 mmol) 1-methyl-2-(N-4-cyanophenylaminomethyl)-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) )-amide was stirred in 40 ml of hydrogen chloride saturated ethanol for 5 h first at 0°C and later at room temperature until no more starting material was detectable by thin layer chromatography. Finally, the solvent was distilled off at a maximum 28°C bath temperature, the oily residue was taken up in 40 ml of absolute ethanol and reacted with 1.1 g of ammonium carbonate. After 18 h, the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1). Yield: 57% of theoretical

C26H28N603S (504,62) C26H28N603S (504.62)

Rf-verdi: 0,21 (kiselgel; metylenklorid/etanol = 4:1 + noen dråper eddiksyre) EKA-massespekter: (M+H)<+> = 505 Rf value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)<+> = 505

(M+H+Na)^ =264 (M+H+Na)^ =264

Eksempel 152 Example 152

l-metyl-2-|^-(4-amidinfenyl)aminometyl]-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 1-methyl-2-|^-(4-amidinephenyl)aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 2 fra l-metyl-2-(N-(4-amidinfenyl)aminometyl]-tieno[2,3-d]imidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Utbytte: 85% av teoretisk Prepared analogously to Example 2 from 1-methyl-2-(N-(4-amidinephenyl)aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- amide hydrochloride and caustic soda Yield: 85% of theory

C24H24N603S (476,56) C24H24N603S (476.56)

Rf-verdi: 0,36 (revers fase kiselgel RP-8; metanol + 5% koksaltløsning) EKA-massespekter: (M+H)<+> = 477 Rf value: 0.36 (reverse phase silica gel RP-8; methanol + 5% sodium bicarbonate solution) EKA mass spectrum: (M+H)<+> = 477

(M+Na)<+> = 499 (M+Na)<+> = 499

(M+2Na)<++> = 250 (M+2Na)<++> = 250

Eksempel 153 Example 153

1 -metyl-3 -(N-(4-amidinfenyl)tiometyl] -kinoksalin-2-on-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-3-(N-(4-amidinephenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) l-metyl-3-[N-(4-cyanofenyl)tiometyl]-kinoksalin-2-on-6-yl-karboksylsyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid a) 1-methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

En løsning av 2,5 g (7,6 mMol) 3-amino-4-metylamino-benzosyre-N-fenyl-N-(2-metoksykarbonyletyl)-amid og 2,4 g (9,6 mMol) 3-(4-cyanofenyl)tio-2-okso-propion-syreetylester ble oppvarmet i 50 ml etanol i 30 min til kokepunkt. Etter fjerning av løsningsmiddelet ble det oppnådde råproduktet renset kromatografisk (kiselgel; metylenklorid). A solution of 2.5 g (7.6 mmol) 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and 2.4 g (9.6 mmol) 3-( 4-Cyanophenyl)thio-2-oxo-propionic acid ethyl ester was heated in 50 ml of ethanol for 30 min to boiling point. After removal of the solvent, the crude product obtained was purified chromatographically (silica gel; methylene chloride).

Utbytte: 1,6 g (40% av teoretisk) Yield: 1.6 g (40% of theoretical)

Rf-verdi: 0,63 (kiselgel; eddikester/etanol/ammomakk = 90:10:1) Rf value: 0.63 (silica gel; acetate/ethanol/ammonia = 90:10:1)

b) l-metyl-3-[N-(4-amidinfenyl)tiometyl]-kinoksalin-2-on-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 1-methyl-3-[N-(4-amidinephenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 1 fra l-metyl-3-[N-(4-cyanofenyl)tiometyl]-kinoksalin-2- on-6-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 1 from 1-methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin-2-one-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utbytte: 23% av teoretisk Yield: 23% of theoretical

C28H27N5O4S (543,6) C28H27N5O4S (543.6)

Rf-verdi: 0,25 (kiselgel; eddikester/etanol/ammomakk = 50:45:5) Rf value: 0.25 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 544 EKA mass spectrum: (M+H)<+> = 544

(M+Na)<+> = 566 (M+Na)<+> = 566

Eksempel 154 Example 154

3- metyl-2-[2-(4-amidirifenyl)etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 3- methyl-2-[2-(4-amidiriphenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[ 1,2-a]pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid a) 3-Methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1,4 g (4,6 mMol) 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre (fremstilt fra 4-brom-l-(4-cyanofenyl)-l-penten-3-on og 2-aminopyridin-4-karboksylsyremetylester analogt Y. Katsura et al. Chem. Pharm. Bull. 1992, 40, 1424-1438) ble suspendert i 15 ml tionylklorid og oppvarmet til kokepunkt i 11 helt til fullstendig løsning. Etter avdestillering av tionylklorid ble syrekloridet løst uten videre rensning i 15 ml pyridin og omsatt ved 0°C med 1,0 g (5,2 mMol) N-(2-etoksykarbonyl-tyl)anilin. Etter 11 ble løsningsmiddelet destillert av, resten tatt opp i 30 ml metylenklorid, vasket med 15 ml IN saltsyre og tørket med natriumsulfat. Etter avdestillering av løsningsmiddelet og kromatografi (kiselgel; metylenkloird/etanol = 0 til 2%) oppnår man en brun olje. 1.4 g (4.6 mmol) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid (prepared from 4-bromo-1 -(4-cyanophenyl)-1-penten-3-one and 2-aminopyridin-4-carboxylic acid methyl ester analogous to Y. Katsura et al. Chem. Pharm. Bull. 1992, 40, 1424-1438) was suspended in 15 ml of thionyl chloride and heated to boiling point for 11 until complete solution. After distilling off thionyl chloride, the acid chloride was dissolved without further purification in 15 ml of pyridine and reacted at 0°C with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonyl-tyl)aniline. After 11, the solvent was distilled off, the residue taken up in 30 ml of methylene chloride, washed with 15 ml of 1N hydrochloric acid and dried with sodium sulphate. After distilling off the solvent and chromatography (silica gel; methylene chloride/ethanol = 0 to 2%), a brown oil is obtained.

Utbytte: 1,48 g (64% av teoretisk) Yield: 1.48 g (64% of theoretical)

Rf-verdi: 0,73 (kiselgel; eddikester/etanol/ammoniakk = 90:10:1) Rf value: 0.73 (silica gel; acetic ester/ethanol/ammonia = 90:10:1)

b) 3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid b) 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 1 fra 3-metyl-2-[2-(4-cyanofenyl)etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C29H3,N503 (497,6) C29H3,N503 (497.6)

Rf-verdi: 0,23 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.23 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 498 EKA mass spectrum: (M+H)<+> = 498

Eksempel 155 Example 155

3-metyl-2-[2-(4-amidinfenyI)etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid-hydroklorid 3-Methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 2 fra 3-metyl-2-[2-(4-amidinfenyl)etyl]-imidazo[l,2-a]-pyridin-7-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinephenyl)ethyl]-imidazo[1,2-a]-pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 92% av teoretisk Yield: 92% of theoretical

C27H27N5O3 (469,55) C27H27N5O3 (469.55)

Rf-verdi: 0,19 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> = 470 EKA mass spectrum: (M+H)<+> = 470

(M+Na)<+> =492 (M+Na)<+> =492

(M+2H)<++> = 235,7 (M+2H)<++> = 235.7

(M+H+Na)^ = 246,7 (M+H+Na)^ = 246.7

(M+2Na)<+> = 257,7 (M+2Na)<+> = 257.7

Eksempel 156 Example 156

l-metyl-2-[N-(4-amidinfenyl)-amin^ 1-methyl-2-[N-(4-amidinephenyl)-amine^

[(N-etoksykarbonyletyl-N-metyl)-2-aminoetyl]-amid-hydroklorid [(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[(N-etoksykarbonyletyl-N-metyl)-2-aminoetyl]-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2- aminoethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 80% av teoretisk Yield: 80% of theoretical

C31H37N7O3 (555,7) C31H37N7O3 (555.7)

Rf-verdi: 0,24 (kiselgel; diklormetan/metanol = 4:1) Rf value: 0.24 (silica gel; dichloromethane/methanol = 4:1)

EKA-massespekter: (M+H)<+> =556 EKA mass spectrum: (M+H)<+> =556

(M+H+Na)44" = 289,8 (M+H+Na)44" = 289.8

(M+2H)<++> = 278,8 (M+2H)<++> = 278.8

Eksempel 157 Example 157

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[(N-hyckoksykarbonyletyl-N-metyl)-2-aminoe1yl]-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide- hydrochloride

Fremstilt analogt eksempel 24 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyI-N-[(N-etoksykarbonyletyl-N-metyl)-2-amino-etyl]-amid-dihydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2- amino-ethyl]-amide dihydrochloride and caustic soda.

Utbytte: 79% av teoretisk Yield: 79% of theoretical

C29H33N703 (527,6) C29H33N703 (527.6)

Rf-verdi: 0,43 (revers fase kiselgel RP-18; metanol/5% vandig koksaltløsning = 4:1) EKA-massespekter: (M+H)<+> = 528 Rf value: 0.43 (reverse phase silica gel RP-18; methanol/5% aqueous sodium bicarbonate solution = 4:1) EKA mass spectrum: (M+H)<+> = 528

(M+H+Na)<+> =275,6 (M+H+Na)<+> =275.6

(M+2H)<++> = 264,6 (M+2H)<++> = 264.6

Eksempel 158 Example 158

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzim^ 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzim^

(3-hydroksy-n-propyl)-amid-hydroklorid (3-hydroxy-n-propyl)-amide hydrochloride

Fremstilt fra 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid-hydroklorid ved hydrering over palladium/kull (10%) ved 5 bar hydrogentrykk og romtemperatur. Prepared from 1-methyl-2-[N-(4-amidinphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide hydrochloride by hydrogenation over palladium/coal (10%) at 5 bar hydrogen pressure and room temperature.

Utbytte: 61% av teoretisk Yield: 61% of theoretical

C26H28N602 (456,6) C26H28N602 (456.6)

Rf-verdi: 0,70 (revers fase kiselgel RP-18; metanol/5% vandig koksaltløsning = 9:1) EKA-massespekter: (M+H)<+> = 457 Rf value: 0.70 (reverse phase silica gel RP-18; methanol/5% aqueous sodium bicarbonate solution = 9:1) EKA mass spectrum: (M+H)<+> = 457

(M+H+Na)^ = 240 (M+H+Na)^ = 240

Eksempel 159 Example 159

l-metyl-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-[4-(N-n-heksyloksykarbonyl-amidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksy-karbonyletyl)-amid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonyl-amidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2 -ethoxycarbonylethyl)amide and caustic soda.

Utbytte: 97% av teoretisk Yield: 97% of theoretical

C32H37N705 (599,7) C32H37N705 (599.7)

Rf-verdi: 0,22 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.22 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 600 EKA mass spectrum: (M+H)<+> = 600

(M+H+Na)^ =311,7 (M+H+Na)^ =311.7

( M+ 2WT = 300,8 (M+ 2WT = 300.8

(M+2N3)44" = 322,8 (M+2N3)44" = 322.8

Eksempel 160 Example 160

l-metyl-2-[N-[4-(N-n-heksyIoksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-hydroksy-n-propyl)-amid 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide

Fremstilt analogt eksempel 158 fra l-metyl-2-[N-[4-(N-n-heksyloksykarbonyl-amidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid ved katalytisk debenzylering. Prepared analogous example 158 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonyl-amidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n -propyl)-amide by catalytic debenzylation.

Utbytte: 26% av teoretisk Yield: 26% of theoretical

C33H4oN604 (584,7) C33H4oN6O4 (584.7)

Rf-verdi: 0,39 (kiselgel; diklormetan/etanol = 9:1) Rf value: 0.39 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> = 585 EKA mass spectrum: (M+H)<+> = 585

(M+H+Na)44" = 304 (M+H+Na)44" = 304

(M+Na)<+> = 607 (M+Na)<+> = 607

Eksempel 161 Example 161

l-metyl-2-[N-(4-amidmfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-Methyl-2-[N-(4-amidemphenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltysyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 42% av teoretisk Yield: 42% of theoretical

C28H29FN603 (516,6) C28H29FN603 (516.6)

Rf-verdi: 0,31 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =517 EKA mass spectrum: (M+H)<+> =517

(M+H+Na)44" = 270 (M+H+Na)44" = 270

Eksempel 162 Example 162

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(4-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyanofenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(4-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltysyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyanophenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 90% av teoretisk Yield: 90% of theoretical

C28H29FN603 (516,6) C28H29FN603 (516.6)

Rf-verdi: 0,29 (kiselgel; diklormetan/metanol = 5:1) Rf value: 0.29 (silica gel; dichloromethane/methanol = 5:1)

EKA-massespekter: (M+H)<+> =517 EKA mass spectrum: (M+H)<+> =517

(M+H+Na)<4>^ = 270 (M+H+Na)<4>^ = 270

Eksempel 163 Example 163

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-fluorfenyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(3-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 97% av teoretisk Yield: 97% of theoretical

C26H25FN603 (488,5) C26H25FN603 (488.5)

Rf-verdi: 0,13 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 489 EKA mass spectrum: (M+H)<+> = 489

(M+Na)<+> =511 (M+Na)<+> =511

(M+2Na)"H" = 267 (M+2Na)"H" = 267

Eksempel 164 Example 164

l-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(4-fluorfenyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra 1-metyl-2-[N-(4-amidinfenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(4-fluorfenyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Utbytte: 89% av teoretisk Prepared analogous Example 24 from 1-methyl-2-[N-(4-amidinephenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and caustic soda Yield: 89% of theoretical

C26H25FN603 (488,5) C26H25FN603 (488.5)

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 489 EKA mass spectrum: (M+H)<+> = 489

(M+Na)<+> =511 (M+Na)<+> =511

(M+2Na)<++> = 267 (M+2Na)<++> = 267

Eksempel 165 Example 165

l-metyl-2-pSf-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-pS-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyano-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Utbytte: 89% av teoretisk C29H32N604 (528,6) Prepared analogous example 23d from 1-methyl-2-[N-(4-cyano-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 89% of theory C29H32N604 (528.6)

Rf-verdi: 0,13 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 529 EKA mass spectrum: (M+H)<+> = 529

(M+H+Na)<++=>276 (M+H+Na)<++=>276

(M+2H)^ = 265 (M+2H)^ = 265

Eksempel 166 Example 166

1 -metyl-2- [N- [4-(N-4-etylbenzoylamidino)fenyl-aminometyl] -benzimidazol-5 -yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-4-ethylbenzoylamidino)phenyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og 4-etylbenzoylklorid. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and 4-ethylbenzoyl chloride.

Utbytte: 64% av teoretisk Yield: 64% of theoretical

C36H37N7O4 (631,7) C36H37N7O4 (631.7)

Rf-verdi: 0,78 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.78 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 632 EKA mass spectrum: (M+H)<+> = 632

(M+H+Na)^ = 327,8 (M+H+Na)^ = 327.8

(M+Na)<+> = 654 (M+Na)<+> = 654

Eksempel 167 Example 167

1 -metyl-2- [N- [4-(N-benzyloksykarbonylamidin)fenyl] -aminometyl] -benzimidazol-5 -yl-karboks3/lsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyrebenzylester. Prepared analogous Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformate benzyl ester.

Utbytte: 64% av teoretisk Yield: 64% of theoretical

C35H35N7O5 (633,6) C35H35N7O5 (633.6)

Rf-verdi: 0,60 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 634 EKA mass spectrum: (M+H)<+> = 634

(M+H+Na)^ = 328,8 (M+H+Na)^ = 328.8

(M+Na)<+> = 656 (M+Na)<+> = 656

Eksempel 168 Example 168

l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-fenyl-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra 1-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogous Example 24 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and baking soda.

Utbytte: 71% av teoretisk Yield: 71% of theoretical

C27H28N604 (500,6) C27H28N604 (500.6)

Rf-verdi: 0,15 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 501 EKA mass spectrum: (M+H)<+> = 501

(M+Na)<+> = 523 (M+Na)<+> = 523

(M+2Na)<++> = 273 (M+2Na)<++> = 273

Eksempel 169 Example 169

l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(4-cyano-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(4-cyano-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 67% av teoretisk Yield: 67% of theoretical

C28H31N704 (529,6) C28H31N704 (529.6)

Rf-verdi: 0,16 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.16 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 530 EKA mass spectrum: (M+H)<+> = 530

Eksempel 170 Example 170

l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(4-amidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogous example 24 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 78% av teoretisk Yield: 78% of theoretical

C26H27N7O4 (501,6) C26H27N7O4 (501.6)

Rf-verdi: 0,12 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 502 EKA mass spectrum: (M+H)<+> = 502

Eksempel 171 Example 171

l-metyl-2-[N-[4-(N-benzyloksykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 99 fra l-metyl-2-[N-[4-(N-benzyloksykarbonyl-amidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksy-karbonyletyl)-amid og natronlut. Prepared analogous Example 99 from 1-methyl-2-[N-[4-(N-benzyloxycarbonyl-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2 -ethoxycarbonylethyl)amide and caustic soda.

Utbytte: 62% av teoretisk Yield: 62% of theoretical

C33H31N7O5 (605,7) C33H31N7O5 (605.7)

Rf-verdi: 0,26 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1)

EKA-massespekter: (M+H)<+> = 606 EKA mass spectrum: (M+H)<+> = 606

(M+Na)<+> = 628 (M+Na)<+> = 628

(M-H+2Na)<+> = 650 (M-H+2Na)<+> = 650

(M+2H)<++> = 303,8 (M+2H)<++> = 303.8

(M+H+Na)^ =314,8 (M+H+Na)^ =314.8

(M+2Na)<++> = 325,7 (M+2Na)<++> = 325.7

Eksempel 172 Example 172

l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid-hydroklorid 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide hydrochloride

Fremstilt analogt eksempel 23 fra l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 23 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 61% av teoretisk Yield: 61% of theoretical

C33H34N6O2 (546,7) C33H34N6O2 (546.7)

Rf-verdi: 0,19 (kiselgel; diklormetan/etanol = 4:1) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 4:1)

EKA-massespekter: (M+H)<+> = 547 EKA mass spectrum: (M+H)<+> = 547

(M+H+Na)<++>=285 (M+H+Na)<++>=285

Eksempel 173 Example 173

l-mety]-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid 1-methyl]-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide

Fremstilt analogt eksempelt 85 fra l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(3-benzyloksy-n-propyl)-amid-hydroklorid og klormaursyre-n-heksylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide hydrochloride and chloroformic acid n-hexyl ester.

Utbytte: 73% av teoretisk Yield: 73% of theoretical

C40H46N6O4 (674,9) C40H46N6O4 (674.9)

Rf-verdi: 0,46 (kiselgel; diklormetan/etanol = 9:1) Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> = 675 EKA mass spectrum: (M+H)<+> = 675

(M+H+Na)^ = 349 (M+H+Na)^ = 349

(M+Na)<+> = 697 (M+Na)<+> = 697

(M+K)<+> =713 (M+K)<+> =713

Eksempel 174 Example 174

3-me1yl-2-[2-(4-amidinfenyl]etyl]-imidazo[l,2-a]pyridin-7-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 3-Methyl-2-[2-(4-amidinephenyl]ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 1 fra 3-metyl-2-[2-(4-cyanofenyl]etyl]-imidazo[l,2-a]-pyridin-7-yl-karboksylsyre-N-(2-pyridyl)-N-(2-metoksykarbonyletyl)-amid-hydroklorid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl]ethyl]-imidazo[1,2-a]-pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-Methoxycarbonylethyl)-amide hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 53% av teoretisk Yield: 53% of theoretical

C28H3oN603 (498,59) C28H3oN6O3 (498.59)

Rf-verdi: 0,42 (kiselgel; eddikester/etanol/ammoniakk = 50:45:5) Rf value: 0.42 (silica gel; acetate/ethanol/ammonia = 50:45:5)

EKA-massespekter: (M+H)<+> =499 EKA mass spectrum: (M+H)<+> =499

(M+2Na)<++> = 272 (M+2Na)<++> = 272

(M+H+Na)^ = 261 (M+H+Na)^ = 261

(M+2H)<++> = 250 (M+2H)<++> = 250

Eksempel 175 Example 175

l-metyl-2-[N-(3-amidinpyridin-6-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(3-amidinepyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(3-cyanopyridin-6-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid og natronlut. Prepared analogously to Example 24 from 1-methyl-2-[N-(3-cyanopyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl) -amide and caustic soda.

Utbytte: 40% av teoretisk Yield: 40% of theoretical

C24H24N803 (472,9) C24H24N803 (472.9)

Rf-verdi: 0,67 (revers fase kiselgel RP-8; metanol/5%) koksaltløsning = 1:1) EKA-massespekter: (M+H)<+> =473 Rf value: 0.67 (reverse phase silica gel RP-8; methanol/5% sodium chloride solution = 1:1) EKA mass spectrum: (M+H)<+> =473

Eksempel 176 Example 176

l-metyl-2-[N-[4-(N-hydroksylamidin)fenyl]-amin^ syre-N-(2-pyridyl)-N-[2-(metansulfonylaminokarbonyl)-etyI]-arnid 1-methyl-2-[N-[4-(N-hydroxylamidine)phenyl]-amine^ acid-N-(2-pyridyl)-N-[2-(methanesulfonylaminocarbonyl)-ethyl]-anide

a) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-[2-(metansulfonylaminokarbonyl)-etyl]-arriid a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulfonylaminocarbonyl)-ethyl]-aryl

2,0 g (4,5 mMol) l-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid og 0,73 g (4,7 mMol) karbonyldiimidazol ble løst i 80 ml tetrahydrofuran og 5 ml dimetylformamid og omrørt i 30 min ved romtemperatur og 2 t ved 90°C. Parallelt ble 0,55 g (5,8 mMol) metansulfonsyreamid og 0,28 g (5,8 mMol) natriumhydrid suspendert i 15 ml dimetyl-formamid og omrørt i 2 t ved romtemperatur. Til slutt ble denne suspensjonen tilsatt ved romtemperatur til tetrahydrofuran-løsningen. Etter 121 ved romtemperatur ble det tilsatt 50 ml vsinn og pH-verdien innstilt på 6,8. Løsningen ble ekstrahert 4x med metylenklorid, de forente organiske fasene ble tørket over natriumsulfat og inndampet. Råproduktet ble kromatografert på kiselgel (metylenklorid/etanol (40:1). De ønskede fraksjonene ble slått sammen og inndampet. 2.0 g (4.5 mmol) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl) )-amide and 0.73 g (4.7 mmol) of carbonyldiimidazole were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide and stirred for 30 min at room temperature and 2 h at 90°C. In parallel, 0.55 g (5.8 mmol) of methanesulfonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred for 2 h at room temperature. Finally, this suspension was added at room temperature to the tetrahydrofuran solution. After 121 at room temperature, 50 ml of water was added and the pH value was adjusted to 6.8. The solution was extracted 4x with methylene chloride, the combined organic phases were dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1). The desired fractions were combined and evaporated.

Utbytte: 1,05 g (44% av teoretisk) Yield: 1.05 g (44% of theoretical)

C26H25N704S (531,6) C26H25N704S (531.6)

Rf-verdi: 0,72 (kiselgel; diklormetan/metanol = 9:1) Rf value: 0.72 (silica gel; dichloromethane/methanol = 9:1)

b) l-metyl-2-[N-[4-(N-hydroksylamidin)fenyl]-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-[2-(metansulfonylaminokarbonyl)-etyl3-amid b) 1-methyl-2-[N-[4-(N-hydroxylamidine)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulfonylaminocarbonyl)- ethyl 3-amide

Fremstilt analogt eksempelt 91 fra 1-metyl-2-[N-(4-cyanofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-[2-(metansulfonylaminokarbonyl)-etyl]-amid hydroksylamin. Prepared analogously to example 91 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulfonylaminocarbonyl)-ethyl] -amide hydroxylamine.

Utbytte: 27% av teoretisk Yield: 27% of theoretical

C26H28N805S (564,6) C26H28N805S (564.6)

Rf-verdi: 0,75 (kiselgel; diklormetan/etanol = 7:3 + 1% iseddik) Rf value: 0.75 (silica gel; dichloromethane/ethanol = 7:3 + 1% glacial acetic acid)

EKA-massespekter: (M+H)<+> = 565 EKA mass spectrum: (M+H)<+> = 565

(M+Na)<+> = 587 (M+Na)<+> = 587

Eksempel 177 Example 177

l-metyl-2-[N-(5-amidintiazol-2-yl)-aminometyl]-benzimida^ pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-[N-(5-amidinthiazol-2-yl)-aminomethyl]-benzimida^pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(5-cyanotiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(5-cyanothiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Eksempel 178 Example 178

l-metyl-2-[N-(5-amidintiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(5-amidinthiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempelt 24 fra l-metyl-2-[N-(5-amidintiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogously to example 24 from 1-methyl-2-[N-(5-amidinthiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Eksempel 179 Example 179

l-metyl-2-psf-(2-aniidinpyrazin-5-yl)-amino pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid 1-methyl-2-ps-(2-aniidinepyrazin-5-yl)-amino pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Fremstilt analogt eksempel 23d fra l-metyl-2-[N-(2-cyanopyrazin-5-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og etanolisk saltsyre, etanol og ammoniumkarbonat. Prepared analogous example 23d from 1-methyl-2-[N-(2-cyanopyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utbytte: 19% av teoretisk Yield: 19% of theoretical

C25H27N903 (501,6) C25H27N903 (501.6)

Rf-verdi: 0,28 (kiselgel; diklormetan/metanol 4:1+ 1% iseddik) Rf value: 0.28 (silica gel; dichloromethane/methanol 4:1+ 1% glacial acetic acid)

EKA-massespekter: (M+H)<+> = 502 EKA mass spectrum: (M+H)<+> = 502

(M+H+Na)^ = 262,5 (M+H+Na)^ = 262.5

Eksempel 180 Example 180

l-metyl-2-[N-(2-amidinpyrazin-5-yl)-aminomeryl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid 1-methyl-2-[N-(2-amidinepyrazin-5-yl)-aminomeryl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide

Fremstilt analogt eksempel 24 fra l-metyl-2-[N-(2-amidinpyrazin-5-yl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og natronlut. Prepared analogous Example 24 from 1-methyl-2-[N-(2-amidinepyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and caustic soda.

Utbytte: 11 % av teoretisk Yield: 11% of theoretical

C23H23N9O3 (473,5) C23H23N9O3 (473.5)

Rf-verdi: 0,55 (revers fase kiselgel RP-8; 5% koksaltløsning/metanol = 6:4) EKA-massespekter: (M+H)<+> = 474 Rf value: 0.55 (reverse phase silica gel RP-8; 5% sodium chloride solution/methanol = 6:4) EKA mass spectrum: (M+H)<+> = 474

(M+Na)<+> = 496,6 (M+Na)<+> = 496.6

Eksempel 181 Example 181

1 -metyl-2-[2-[4-(N-n-heksyloksykarbonylamidin)fenyl]-etyl] -benzimidazol-5 -yl-karboksylsyre-N-fenyl-N-(lH-tetrazol-5-yl)-etyl]-amid 1-methyl-2-[2-[4-(N-n-hexyloxycarbonylamidine)phenyl]-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(1H-tetrazol-5-yl)-ethyl]- amide

Fremstilt analogt eksempelt 85 fra l-metyl-2-[2-[4-(amidinfenyl)-etyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)-etyl]-amid og klormaursyre-n-heksylester. Prepared analogously to example 85 from 1-methyl-2-[2-[4-(amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl) -ethyl]-amide and chloroformic acid n-hexyl ester.

Eksempel 182 Example 182

l-metyl-2-[N-(2-metoksy-4-n-pentoksykarbonylamidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidin-2-metoksyfenyl)- aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-pentylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid n-pentyl ester.

Utbytte: 53% av teoretisk Yield: 53% of theoretical

C35H42N606 (642,7) C35H42N606 (642.7)

Rf-verdi: 0,54 (kiselgel; diklormetan/etanol = 9:1) Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> = 643 EKA mass spectrum: (M+H)<+> = 643

(M+H+Na)^ = 333,4 (M+H+Na)^ = 333.4

Eksempel 183 Example 183

l-metyl-2-(^-(4-n-heptyloksykarbonylamidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-(^-(4-n-heptyloxycarbonylamidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra 1-metyl-2-[N-(4-amidin-2-metoksyfenyl)- aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl^ hydroklorid og klormaursyre-n-heptylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl^ hydrochloride and chloroformate-n-heptyl ester.

Utbytte: 68%> av teoretisk Yield: 68%> of theoretical

C37H46N606 (670,8) C37H46N606 (670.8)

Rf-verdi: 0,56 (kiselgel; diklormetan/etanol = 9:1) Rf value: 0.56 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> =671 EKA mass spectrum: (M+H)<+> =671

(M+H+Na)^ = 347,4 (M+H+Na)^ = 347.4

Eksempel 184 Example 184

l-metyl-2-[N-(4-etoksykarbonylamidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-(4-ethoxycarbonylamidine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidin-2-metoksyfenyl)- aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyreetylester. Prepared analogous example 85 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and chloroformate ethyl ester.

Utbytte: 43% av teoretisk Yield: 43% of theoretical

C3iH35N706 (601,7) C3iH35N706 (601.7)

Rr verdi: 0,44 (kiselgel; diklormetan/etanol = 9:1) Rr value: 0.44 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> =602 EKA mass spectrum: (M+H)<+> =602

(M+H+Na)^ =312,8 (M+H+Na)^ =312.8

Eksempel 185 Example 185

l-metyl-2-[N-(2-metoksy-4-n-pentoksykarbonylamidinofenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempelt 85 fra l-metyl-2-[N-(4-amidin-2-metoksyfenyl)- aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid-hydroklorid og klormaursyre-n-pentylester. Prepared analogously to example 85 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and chloroformic acid n-pentyl ester.

Utbytte: 72% av teoretisk Yield: 72% of theoretical

C34H4,N706 (643,7) C34H4,N706 (643.7)

Rrverdi: 0,49 (kiselgel; diklormetan/etanol = 9:1) Rr value: 0.49 (silica gel; dichloromethane/ethanol = 9:1)

EKA-massespekter: (M+H)<+> = 644 EKA mass spectrum: (M+H)<+> = 644

(M+H+Na)^ = 333,9 (M+H+Na)^ = 333.9

Eksempel 186 Example 186

l-metyl-2-[N-(2-metoksy-4-n-heptyloksykarbonylamidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid 1-methyl-2-[N-(2-methoxy-4-n-heptyloxycarbonylamidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide

Fremstilt analogt eksempel 85 fra l-metyl-2-[N-(4-amidin-2-metoksyfenyl)- aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyri^ hydroklorid og klormaursyre-n-heptylester. Prepared analogously to Example 85 from 1-methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyri^ hydrochloride and chloroformate-n-heptyl ester).

Utbytte: 55% av teoretisk Yield: 55% of theoretical

C36H45N706 (671,8) C36H45N706 (671.8)

Rf-verdi: 0,54 (kiselgel; diklormetan/etanol = 9:1) EKA-massespekter: (M+H)<+> = 672 Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)<+> = 672

(M+H+Na)<++> = 347,9 (M+H+Na)<++> = 347.9

Eksempel 187 Example 187

Tørrampulle med 75 mg virkestoff pr 10 ml Sammensetning: Dry ampoule with 75 mg active ingredient per 10 ml Composition:

Fremstilling: Manufacturing:

Virkestoff og mannitol blir løst i vann. Etter påfylling blir dette frysetørket. Oppløsningen til brukerferdig løsning foregår med vann for injeksjonsformål. Active ingredient and mannitol are dissolved in water. After filling, this is freeze-dried. The dissolution into a ready-to-use solution takes place with water for injection purposes.

Eksempel 188 Example 188

Tørrampulle med 35 mg virkestoff pr 2 ml Dry ampoule with 35 mg of active ingredient per 2 ml

Sammensetning: Composition:

Fremstilling: Manufacturing:

Virkestoff og mannitol blir løst i vann. Etter påfylling blir dette frysetørket. Oppløsningen til brukerferdig løsning foregår med vann for injeksjonsformål. Active ingredient and mannitol are dissolved in water. After filling, this is freeze-dried. The dissolution into a ready-to-use solution takes place with water for injection purposes.

Eksempel 189 Example 189

Tablett med 50 mg virkestoff Tablet with 50 mg active ingredient

Sammensetning: Composition:

Fremstilling: Manufacturing:

(1), (2) og (3) blir blandet og granulert med vandig løsning av (4). Det tørkede granulatet blir (5) blandet. Av denne blandingen blir det presset tabletter, biplan med bredsidig fasett og ensidig delelinje. Diameter til tabletten: 9 mm. (1), (2) and (3) are mixed and granulated with aqueous solution of (4). The dried granulate is (5) mixed. This mixture is pressed into tablets, biplane with wide-sided facet and one-sided parting line. Diameter of the tablet: 9 mm.

Eksempel 190 Example 190

Tablett med 350 mg virkestoff Tablet with 350 mg active ingredient

Sammensetning: Composition:

Fremstilling: Manufacturing:

(1), (2) og (3) blir blandet og granulert med vandig løsning av (4). Det tørkede granulatet blir (5) blandet. Av denne blandingen blir det presset tabletter, biplan med bredsidig fasett og ensidig delelinje. Diameter til tabletten: 12 mm. (1), (2) and (3) are mixed and granulated with aqueous solution of (4). The dried granulate is (5) mixed. This mixture is pressed into tablets, biplane with wide-sided facet and one-sided parting line. Diameter of the tablet: 12 mm.

Eksempel 191 Example 191

Kapsler med 50 mg virkestoff Capsules with 50 mg active ingredient

Sammensetning: Composition:

Fremstilling: Manufacturing:

(1) blir behandlet med (3). Dette blir tilsatt blandingen ifølge (2) og (4) under omfattende blanding. (1) is treated with (3). This is added to the mixture according to (2) and (4) under extensive mixing.

Denne pulverblandingen blir i en kapsel påfyllingsmaskin fylt inn i harde gelatin-stikk-apsler med størrelse 3. This powder mixture is filled in a capsule filling machine into size 3 hard gelatin capsules.

Eksempel 192 Example 192

Kapsler med 350 mg virkestoff Capsules with 350 mg active ingredient

Sammensetning: Composition:

Fremstilling: Manufacturing:

(1) blir behandlet med (3). Dette blir tilsatt blandingen ifølge (2) og (4) under omfattende blanding. (1) is treated with (3). This is added to the mixture according to (2) and (4) under extensive mixing.

Denne pulverblandingen blir i en kapsel-påfyllingsmaskin fylt inn i harde gelatin-stikk-apsler Gr6Be 0. This powder mixture is filled into hard gelatin capsules Gr6Be 0 in a capsule filling machine.

Eksempel 193 Example 193

Suppositorier med 100 mg virkestoff. Suppositories with 100 mg active ingredient.

1 tapping inneholder: 1 bottling contains:

Claims (14)

1. Disubstituerte bisykliske heterosykler, karakterisert ved at de har den generelle formelen hvor A er en med benzo-, pyrido- eller tienodel av resten Het koplet karbonyl- eller sulfonylgruppe, idet de ovennevnte delene dessuten ikke kan inneholde resten Ri, B er en etylengruppe, hvor en metylengruppe, som enten er koplet med resten Het eller Ar, kan bli erstattet med et oksygen- eller svovelatom, med en sulfinyl-, sulfonyl-, karbonyl-eller-NR]-gruppe, idet Ri er et hydrogenatom eller en Ci^-alkylgruppe, E er en RbNH-C(=NH)-gruppe hvor Rb er et hydrogenatom, en hydroksygruppe, en Ci-3-alkylgruppe eller eventuelt med Ci-Cé-alkylsulfonyl eller Ci-C6-alkoksy-Ci-C6-alkyl substituert Ci-Cg-alkoksykarbonyl, C3-C7-cykloalkoksykarbonyl, fenyl-Ci-C4-alkoksykarbonyl, eventuelt med Ci-C4-alkyl substituert med benzoyl eller pyridinoyl, Ar er fenylengruppe eventuelt substituert med et fluor-, klor- eller bromatom, med en trifluormetyl-, Ci-3-alkyl- eller Ci-3-alkoksygruppe, en eventuelt i karbonskjelettet tienylen-, tiazolylen, pyridinylen-, pyrimidinylen-, pyrazinylen- eller pyridazinylengruppe eventuelt substituert med en Ci-3-alkyl-gruppe, Het er en bisyklisk heterosyklus med formelen hvor X er et nitrogenatom og Y er et oksygen- eller svovelatom eller en eventuelt med en Ci-6-alkyl- eller C3-7-sykloalkylgruppe substituert nitrogenatom, eller X er en eventuelt med resten Ri substituert metingruppe, idet Ri er definert som ovenfor, og Y er et nitrogenatom eventuelt substituert med en Ci-6-alkyl- eller C3_7-syklo-alkylgruppe, eller Het er en gruppe med formlene eller idet Ri er definert som ovenfor og R er et hydrogenatom eller en Ci-6-alkyl, eller C3-7-sykloalkylgruppe, og Ra er en Ci-6-alkylgruppe, en eventuelt med en Ci-3-alkylgruppe substituert C3.7-sykloalkylgruppe, idet Ci-3-alkylgruppen i tillegg kan være substituert med en karboksylgruppe eller Ci-Cé-alkoksykarbonyl, eller en R2NR3-gruppe, hvor R2 er en Ci-4-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, Ci-3-alkylsulfonylaminokarbonyl-, fenyl-sulfonyl-aminokarbonyl-, trifluorsulfonylamino, trifluorsulfonylaminokarbonyl- eller lH-tetra-zolylgruppe, eller med hydroksy-, fenyl-Qo-akoksy, karboksy-Ci.3-alkylamino-, Ci-3-alkoksy-karbonyl-Ci.3alkylamino-, N-(Ci.3-alkyl)-karboksy-Ci-3-alkylamino eller N-(Ci-3-alkyl)-Ci-3-alkoksykarbonyl-Ci.3-alkylaminogruppe substituert C2-4-alkylgruppe, idet i den ovenfor angitte gruppen a-karbonatomet som står ved siden av nitrogen-atomet ikke kan være substituert, eller en eventuelt med en Ci-3-alkylgruppe substituert piperidinylgruppe og R3 er en eventuelt med en Ci-3-alkyl-gruppe substituert C3-7-sykloalkylgruppe, en C3-6-alkenyl- eller alkinylgruppe, idet den umettede delen ikke kan være direkte koplet til nitrogenatomet i R2NR3-gruppen, en fenylgruppe eventuelt substituert med et fluor, klor-eller bromatom, med en Ci-3-alkyl- eller Ci-3-alkoksygruppe, en even-tuelt med en C1.3-alkylgruppe substituert benzyl-, oksazolyl-, isoksazolyl-, tiazolyl, isotiazolyl-, pyrazolyl-, pyrrolyl-, tienyl-, pyrimidinyl-, pyrazinyl-, pyridazinyl-, imidazolyl- eller piperidinylgruppe eller R2 og R3 sammen med nitrogenatomet som ligger derimellom er 5- til 7-leddet sykloalleyleniminogruppe valgt blant dihydroindolyl, isoindolinyl eller pyrrolidinyl eventuelt substituert med en karboksy- eller Ci-4-alkoksykarbonygruppe, tautomerer, stereoisomerer og salter derav.1. Disubstituted bicyclic heterocycles, characterized in that they have the general formula where A is one with a benzo-, pyrido- or thieno part of the residue Het coupled carbonyl or sulfonyl group, the above-mentioned parts also cannot contain the residue Ri, B is an ethylene group, where a methylene group, which is either linked to the residue Het or Ar, may be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl, or NR] group, wherein R 1 is a hydrogen atom or a C 1-4 alkyl group, E is a RbNH-C(=NH) group where Rb is a hydrogen atom, a hydroxy group, a C 1-3 alkyl group or optionally with C 1-C 6 alkylsulfonyl or C 1-C 6 alkoxy-C 1-C 6 alkyl substituted C 1-C 8 -alkyloxycarbonyl, C 3-C 7 -cycloalkoxycarbonyl, phenyl-C 1 -C4-Alkoxycarbonyl, optionally with C1-C4-alkyl substituted with benzoyl or pyridinoyl, Ar is phenylene group optionally substituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, C 1-3 alkyl or C 1-3 alkoxy group, an optional thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton with a C 1-3 alkyl group, Het is a bicyclic heterocycle with the formula where X is a nitrogen atom and Y is an oxygen or sulfur atom or a nitrogen atom optionally substituted with a C1-6 alkyl or C3-7 cycloalkyl group, or X is a methine group optionally substituted with the residue Ri, Ri being defined as above, and Y is a nitrogen atom optionally substituted with a C1-6 alkyl or C3-7 cycloalkyl group, or Het is a group with the formulas or while Ri is defined as above and R is a hydrogen atom or a C 1-6 alkyl, or C 3-7 cycloalkyl group, and Ra is a C1-6 alkyl group, a C3.7-cycloalkyl group optionally substituted with a C1-3 alkyl group, the C1-3 alkyl group can additionally be substituted with a carboxyl group or C1-C6 alkoxycarbonyl, or an R2NR3- group, where R2 is a C1-4 alkyl group, which may be substituted with a carboxy-, C1-6-alkyloxycarbonyl, benzyloxycarbonyl-, C1-3-alkylsulfonylaminocarbonyl-, phenyl-sulfonyl-aminocarbonyl-, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl- or 1H-tetra- zolyl group, or with hydroxy-, phenyl-C1-3-alkylamino-, carboxy-C1-3-alkylamino-, C1-3-carboxy-carbonyl-C1-3-alkylamino-, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(Ci-3-alkyl)-Ci-3-Alkoxycarbonyl-Ci.3-alkylamino group substituted C2-4-alkyl group, in that in the above-mentioned group the α-carbon atom which stands next to the nitrogen atom cannot be substituted, or a piperidinyl group optionally substituted with a C 1-3 alkyl group and R3 is a C3-7 cycloalkyl group optionally substituted with a C1-3 alkyl group, a C3-6 alkenyl or alkynyl group, the unsaturated part cannot be directly linked to the nitrogen atom in the R2NR3 group, a phenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a C 1-3 alkyl or C 1-3 alkoxy group, an optionally with a C 1.3 alkyl group substituted benzyl-, oxazolyl-, isoxazolyl-, thiazolyl, isothiazolyl-, pyrazolyl, pyrrolyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl or piperidinyl group or R2 and R3 together with the nitrogen atom that lies between them is a 5- to 7-membered cycloallylenimino group selected from dihydroindolyl, isoindolinyl or pyrrolidinyl optionally substituted with a carboxy- or C1-4-alkyloxycarbonyl group, tautomers, stereoisomers and salts thereof. 2. Disubstituerte bisykliske heterosykler med generell formel I ifølge krav 1, karakterisert ved at A er en karbonyl- eller sulfonylgruppe koplet med benzo-, pyrido- eller tienodelen av resten Het, B er en etylengruppe, hvor metylengruppen, som er koplet til rest Ar, kan bli erstattet med et oksygen- eller svovelatom eller med en -NR] -gruppe idet Ri er et hydrogenatom eller en Ci^t-alkylgruppe, E er en RbNH-C(=NH)-gruppe idet Rb er et hydrogenatom, en hydroksy-, Ci-9-alkoksykarbonyl-, sykloheksyl-oksykarbonyl-, fenyl-Ci_3-alkoksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller pyridinoylgruppe, idet etoksydelen i 2-stillingen til ovenfor angitte Ci.g-alkoksykarbonyl-gruppe i tillegg kan være substituert med en Ci-3-alkyl-sulfonyl- eller 2-(Ci.3-alkoksy)-etyl-gruppe, Ar er en eventuelt med et kloratom, metyl, etyl eller en metoksygruppe, substituert 1,4-fenylengruppe eller en 2,5-tienylengruppe, Het er en l-(Ci-3-alkyl)-2,5-benzimidazolylen-, l-sykopropyl-2,5-benzimida-zolylen-, 2,5-benztiazolylen-, l-(Ci_3-alkyl)-2,5-indolylen-, l-(Ci-3-alkyl)-2,5-imidazo[4,5-bjpyridinylen-, 3-(Ci-3-alkyl)-2,7-imidazo[l,2-a]pyridinylen- eller l-(Ci-3-alkyl)-2,5-tieno-[2,3-d]imidazolylengruppe og Ra er en R2NR3-gruppe, hvor R2 er en Ci-4-alkylgruppe, som kan være substituert med en karboksy-, Ci-6-alkyloksykarbonyl, benzyloksykarbonyl-, Ci-3-alkylsulfonylamino-karbonyl- eller 1H-tetrazol-5-ylgruppe, en C2-4-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci.3-alkylamino-, Ci-3-alkoksykarbonyl-Ci-3-alkylamino-, N-(Ci-3-alkyl)-karboksy-Ci-3-alkylamino eller N-(Ci.3-alkyl)-Ci.3-alkoksykarbonyl-Ci-3-alkylaminogruppe, idet i den ovennevnte gruppen a-karbonatomet som står ved siden av nitrogenatomet ikke være substituert, R3 er en C3-7-sykloalkylgruppe, en propargylgruppe, idet den innettede delen ikke direkte kan være koplet med nitrogenatomet til R2NR3-gruppen, en fenylgruppe eventuelt substituert med et fluor- eller kloratom, med en metyl- eller metoksygruppe, en eventuelt med en metylgruppe substituert pyrazolyl-, pyridazolyl- eller pyridinylgruppe, eller R2 og R3 sammen med det mellomliggende nitrogenatomet er 5- til 7-leddet sykloalkyleniminogruppe eventuelt substituert med en karboksy- eller Ci-4-alkoksy-karbonylgruppe, hvortil i tillegg en fenylring kan være påkondensert, tautomerer, stereoisomerer og salter derav.2. Disubstituted bicyclic heterocycles of general formula I according to claim 1, characterized in that A is a carbonyl or sulfonyl group linked to the benzo, pyrido or thieno part of the residue Het, B is an ethylene group, where the methylene group, which is connected to the residue Ar, can be replaced by an oxygen or sulfur atom or by a -NR] group as R 1 is a hydrogen atom or a C 1-6 alkyl group, E is a RbNH-C(=NH) group in that Rb is a hydrogen atom, a hydroxy-, C1-9-alkyloxycarbonyl-, cyclohexyloxycarbonyl-, phenyl-C1-3-alkoxycarbonyl-, benzoyl-, p-C1-3-alkylbenzoyl or pyridinoyl group, the ethoxy part in the 2-position to above indicated C 1-6 -Alkoxycarbonyl group can additionally be substituted with a C 1-3 -alkyl-sulfonyl- or 2-(C 1-3-Alkoxy)-ethyl group, Ar is a substituted 1,4-phenylene group or a 2,5-thienylene group, optionally with a chlorine atom, methyl, ethyl or a methoxy group, Het is a l-(Ci-3-alkyl)-2,5-benzimidazolylene-, l-cyclopropyl-2,5-benzimidazolylene-, 2,5-benzthiazolylene-, l-(Ci_3-alkyl)-2, 5-indolylene-, 1-(Ci-3-alkyl)-2,5-imidazo[4,5-bjpyridinylene-, 3-(Ci-3-alkyl)-2,7-imidazo[1,2-a] pyridinylene or 1-(Ci-3-alkyl)-2,5-thieno-[2,3-d]imidazolylene group and R a is an R 2 NR 3 group, where R 2 is a C 1-4 alkyl group, which may be substituted with a carboxy-, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, C 1-3 alkylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, a C 2-4 alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C 1-3 alkylamino-, C 1-3 carboxycarbonyl-C 1-3 alkylamino-, N-(C 1-3 alkyl)-carboxy-C 1- 3-alkylamino or N-(Ci-3-alkyl)-Ci-3-alkoxycarbonyl-Ci-3-alkylamino group, in that in the above-mentioned group the α-carbon atom standing next to the nitrogen atom is not substituted, R3 is a C3-7 cycloalkyl group, a propargyl group, the interlinked part cannot be directly linked to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with a fluorine or chlorine atom, with a methyl or methoxy group, an optionally with a methyl group substituted pyrazolyl, pyridazolyl or pyridinyl group, or R2 and R3 together with the intervening nitrogen atom is a 5- to 7-membered cycloalkylenimino group optionally substituted with a carboxy- or C1-4-alkyloxy-carbonyl group, to which a phenyl ring can additionally be condensed, tautomers, stereoisomers and salts thereof. 3. Disubstituerte bisykliske heterosykler med generell formel I ifølge krav 1, karakterisert ved at A er karbonyl- eller sulfonylgruppe koplet med benzo-, pyrido- eller tienodel av resten Het, B er en etylengruppe, hvor metylengruppen som er koplet med rest Ar, kan være erstattet med et oksygen- eller svovelatom eller med en -NR) -gruppe idet Ri er et hydrogenatom eller en metylgruppe, E er en RbNH-C(=NH)-gruppe, hvor Rb er et hydrogenatom, en hydroksy-, Ci-9-alkoksykarbonyl-, sykloheksyl-oksykarbonyl-, benzyloksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller nikotino-yl-gruppe, idet etoksydelen i 2-stillingen av ovennevnte Ci-9-alkoksykarbonylgruppe i tillegg kan være substituert med en Ci-3-alkylsulfonyl- eller 2-(Ci-3-alkoksy)-etylgruppe, Ar er en eventuelt med et kloratom med en metyl-, etyl- eller metoksygruppe substituert 1,4-fenylengruppe eller en 2,5-tienylengruppe, Het er en l-metyl-2,5-benzimidazolylen, l-syklopropyl-2,5-benzimida-zolylen-, 2,5-benztiazolylen-, l-metyl-2,5-indolylen-, l-metyl-2,5-imidazo[4,5-b]-pyridinylen-, 3-metyl-2,7-imidazo[l,2-a]pyirdinylen- eller l-metyl-2,5-tieno[2,3-d]-imidazolylengruppe og Ra er en R2NR3-gruppe, hvor R2 er en Ci-3-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, metylsulfonylaminokarbonyl- eller lH-tetrazol-5-ylgruppe, C2-3-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci-3-alkylamino-, C1.3-alkoksykarbonyl-C 1.3-alkylamino-, N-(C 1.3-alkyl)-karboksy-C 1.3-alkylamino eller N-(Ci-3-alkyl)-Ci.3-alkoksykarbonyl-Ci.3-alkylaminogruppe, idet i de ovennevnte gruppene a-karbonatomet som står ved siden av nitrogen-atomet ikke kan være substituert, og R3 er en propargylgruppe, idet den umettede delen ikke kan være direkte koplet med nitrogenatomet til R2NR3-gruppen, en eventuelt med et fluor- eller kloratom med en metyl- eller metoksygruppe substituert fenylgruppe eller en pyridinylgruppe, tautomerer, stereoisomerer og salter derav.3. Disubstituted bicyclic heterocycles of general formula I according to claim 1, characterized in that A is a carbonyl or sulfonyl group linked with a benzo-, pyrido- or thieno part of the residue Het, B is an ethylene group, where the methylene group which is connected to the residue Ar may be replaced by an oxygen or sulfur atom or by an -NR) group as R 1 is a hydrogen atom or a methyl group, E is a RbNH-C(=NH) group, where R b is a hydrogen atom, a hydroxy, C 1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C 1-3 -alkylbenzoyl or nicotinoyl group, the ethoxy part in the 2-position of the above C 1-9 -Alkoxycarbonyl group can additionally be substituted with a C 1-3 -alkylsulfonyl or 2-(C 1-3 -Alkoxy)-ethyl group, Ar is a 1,4-phenylene group optionally substituted by a chlorine atom with a methyl, ethyl or methoxy group or a 2,5-thienylene group, Het is a l-methyl-2,5-benzimidazolylene, l-cyclopropyl-2,5-benzimidazolylene-, 2,5-benzthiazolylene-, l-methyl-2,5-indolylene-, l-methyl-2, 5-imidazo[4,5-b]-pyridinylene-, 3-methyl-2,7-imidazo[l,2-a]pyridinylene- or l-methyl-2,5-thieno[2,3-d]- imidazolylene group and R a is an R 2 NR 3 group, where R 2 is a C 1-3 alkyl group, which may be substituted with a carboxy, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, C2-3-alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C1-3-alkylamino-, C1-3-carboxycarbonyl-C1-3-alkylamino-, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(Ci-3-alkyl)-Ci-3-Alkoxycarbonyl-Ci-3-alkylamino group, in that in the above-mentioned groups the α-carbon atom standing next to the nitrogen atom cannot be substituted, and R3 is a propargyl group, in that the unsaturated part cannot be directly linked to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with a fluorine or chlorine atom with a methyl or methoxy group or a pyridinyl group, tautomers, stereoisomers and salts thereof. 4. Disubstituerte bisykliske heterosykler med generell formel 1 ifølge krav 1, karakterisert ved at A er en karbonylgruppe koplet med benzo- eller tienodelen av resten Het, B er en etylengruppe, idet metylengruppen, som er koplet med resten Ar, kan bli erstattet med en -NR] -gruppe, idet Ri er et hydrogenatom eller en metylgruppe, E er en RbNH-C(=NH)-gruppe, idet Rb er et hydrogenatom, en hydroksy-, Ci-9-alkoksykarbonyl-, sykloheksyl-oksykarbonyl-, benzyloksykarbonyl-, benzoyl-, p-Ci-3-alkylbenzoyl- eller nikotino-yl-gruppe hvor etoksydelen i 2-stillingen til ovennevnte Ci-9-alkoksy-karbonylgruppe i tillegg kan være substituert med en metylsulfonyl- eller 2-etoksyetylgruppe, Ar er en eventuelt med en metoksygruppe substituert 1,4-fenylengruppe eller en 2,5 -tienylengruppe, Het er en l-metyl-2,5-benzimidazolylen, 2,5-benztiazolylen-, l-metyl-2,5-indolylen- eller l-metyl-2,5-tieno[2,3-d]-imidazolylengruppe og Ra er en R2NR3-gruppe, idet R2 er en Ci_3-alkylgruppe, som kan være substituert med en karboksy-, C1-6-alkyloksykarbonyl, benzyloksykarbonyl-, metylsulfonylaminokarbonyl- eller lH-tetrazol-5-ylgruppe, en C2-3-alkylgruppe substituert med en hydroksy-, benzyloksy, karboksy-Ci-3-alkylamino-, C1.3-alkoksykarbonyl-C 1.3-alkylamino-, N-(C 1.3-alkyl)-karboksy-Ci .3-alkylamino eller N-(Ci-3-alkyl)-Ci.3-alkoksykarbonyl-Ci.3-alkylaminogruppe, idet i de ovennevnte gruppene kan a-karbonatomet som står ved siden av nitrogen-atomet ikke være substituert, og R3 er en eventuelt med et fluoratom substituert fenylgruppe eller en 2-pyridinylgruppe, tautomerer, stereoisomerer og salter derav.4. Disubstituted bicyclic heterocycles of general formula 1 according to claim 1, characterized in that A is a carbonyl group linked to the benzo or thieno part of the residue Het, B is an ethylene group, the methylene group, which is linked to the residue Ar, can be replaced by a -NR] group, R 1 is a hydrogen atom or a methyl group, E is a RbNH-C(=NH) group, wherein Rb is a hydrogen atom, a hydroxy-, C1-9-alkoxycarbonyl-, cyclohexyl-oxycarbonyl-, benzyloxycarbonyl-, benzoyl-, p-C1-3-alkylbenzoyl or nicotinoyl group where the ethoxy part in the 2-position of the above Ci -9-Alkoxycarbonyl group can additionally be substituted with a methylsulfonyl or 2-ethoxyethyl group, Ar is a 1,4-phenylene group optionally substituted with a methoxy group or a 2,5-thienylene group, Het is a 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]-imidazolylene group and R a is an R 2 NR 3 group, wherein R 2 is a C 1-3 alkyl group, which may be substituted with a carboxy, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, a C 2-3 alkyl group substituted with a hydroxy-, benzyloxy, carboxy-C 1-3 alkylamino-, C 1.3-carboxycarbonyl-C 1.3-alkylamino-, N-(C 1.3-alkyl)-carboxy-C 1.3- alkylamino or N-(Ci-3-alkyl)-Ci-3-alkoxycarbonyl-Ci-3-alkylamino group, in that in the above-mentioned groups the α-carbon atom standing next to the nitrogen atom cannot be substituted, and R3 is a phenyl group optionally substituted with a fluorine atom or a 2-pyridinyl group, tautomers, stereoisomers and salts thereof. 5. Forbindelser, karakterisert ved at de har generell formel I: (a) 2-[N-(4-amidinfenyl)-aminometyl]-benztiazol-5-karboksylsyre-N-fenyl-N-(2-karboksy-etyl)-amid, (b) 2-pSf-(4-amidinfenyl)-N-metylaminometyl]-benztiazol-5-yl- karboksylsyre -N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (c) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyreN-fenyl-N-(2-hydroksykarbonyletyl)-amid, (d) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyreN-fenyl-N-(3-hydroksykarbonylpropyl)-amid, (e) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksyls pyridyl)-N-(hydroksykarbonylmetyl)-arnid, (f) l-metyl-2-[2-(2-amidintiofen-5-yl)-etyl]-b^ pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (g) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-berizirnidazol-5-yl- karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (h) 1 -metyl-2-[2-(4-amidinfenyl)-etyl]-benzirnidazol-5-yl- karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (i) l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimid hydroksykarbonyletyl)-amid, (j) l-metyl-2-[2-(4-amidinfenyl)-etyl]-benzimidazol-5-yl- karboksylsyre-N-fenyl-N-[2-(lH-tetrazol-5-yl)etyl]-amid, (k) l-metyl-2-[N-(4-amidinfenyl)-aminometyl^^ N-[2-(lH-tetrazol-5-yl)etyl]-amid, (1) 1 -metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-berizim karboksylsyreN-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (m) l-metyl-2-[N-(4-amidinfenyl)-N-metyl-aminometyl]-benzimida^ karboksylsyre-N-(3-pyridyl)-N-(2-hydroksykarbonyletyl)-arnid, (n) 1-metyl-2-[N-(4-amidinfenyl)-N-m karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (o) l-metyl-2-[N-(4-amimnfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-fenyl-N-[(N-hydroksykarbonyletyl-N-mety])-2-aminoetyl]amid, (p) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl- karboksylsyreN-(3-fluorfenyl)-N-(2-hydroksykarbonyleryl)-amid, (q) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyreN-(4-fluorfenyl)-N-(2-hydroksykarbonyIetyl)-amid, (r) l-metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid, (s) l-metyl-2-pST-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, (t) l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-indol-5-yl-karboks (2-metoksykarbonyletyl)-amid og (u) 1 -metyl-2-[N-(4-amidinfenyl)-aminometyl]-tieno[23-d]-imidazol-5-yl- karboksylsyre-N-fenyl-N-(2-hydroksykarbonyletyl)-amid, tautomerer, promedikamenter, dobbeltpromedikamenter, stereoisomerer og salter derav.5. Compounds, characterized in that they have general formula I: (a) 2-[N-(4-amidinephenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxy-ethyl)- amide, (b) 2-pSf-(4-amidinephenyl)-N-methylaminomethyl]-benzthiazol-5-yl- carboxylic acid -N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (c) 1 -methyl-2 -[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (d) 1 -methyl-2-[N-(4-amidinephenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, (e) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl -carboxyl pyridyl)-N-(hydroxycarbonylmethyl)-arnide, (f) 1-methyl-2-[2-(2-amidinthiofen-5-yl)-ethyl]-b^ pyridyl)-N-(2-hydroxycarbonylethyl) -amide, (g) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-berizirnidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (h) 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benznidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (i) 1-methyl-2-[2-(4-amide). nphenyl)-ethyl]-benzimide hydroxycarbonylethyl)-amide, (j) 1-methyl-2-[2-(4-amidinephenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2- (1H-tetrazol-5-yl)ethyl]-amide, (k) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl^^ N-[2-(1H-tetrazol-5-yl)ethyl ]-amide, (1) 1 -methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-berizim carboxylic acid N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (m ) 1-methyl-2-[N-(4-amidinephenyl)-N-methyl-aminomethyl]-benzimida^ carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-arnide, (n) 1- methyl-2-[N-(4-amidinephenyl)-N-m carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (o)l-methyl-2-[N-(4-aminophenyl)-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl])-2-aminoethyl]amide, (p) 1 -methyl-2-[N-(4-amidinephenyl)-aminomethyl ]-benzimidazol-5-yl-carboxylic acid N-(3-fluorophenyl)-N-(2-hydroxycarbonylaryl)-amide, (q) 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5 -yl-carboxylic acid N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (r) 1-methyl-2-[N-(4-am idine-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (s) 1-methyl-2-pST-(4-amidin-2- methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (t) l-methyl-2-[N-(4-amidinephenyl)- aminomethyl]-indol-5-yl-carbox (2-methoxycarbonylethyl)-amide and (u) 1 -methyl-2-[N-(4-amidinephenyl)-aminomethyl]-thieno[23-d]-imidazole-5- howl- carboxylic acid N-phenyl-N-(2-hydroxycarbonylethyl)-amide, tautomers, prodrugs, double prodrugs, stereoisomers and salts thereof. 6. Forbindelse, karakterisert ved at den er l-metyl-2-[N-(4-amidinfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-fenyl-N-(2-hydroksy-karbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav.6. Compound, characterized in that it is 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-carbonylethyl)-amide , prodrugs, double prodrugs and salts thereof. 7. Forbindelse, karakterisert ved at den er 1 -metyl-2-[N-(4-amidinfenyl)-aminome1yl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyirdyl)-N-(2-hydroksykarbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav.7. Compound, characterized in that it is 1-methyl-2-[N-(4-amidinephenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl) -amide, prodrugs, double prodrugs and salts thereof. 8. Forbindelse, karakterisert ved at den er 1 -metyl-2-[N-(4-amidin-2-metoksyfenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-hydroksykarbonyletyl)-amid, promedikamenter, dobbeltpromedikamenter og salter derav.8. Compound, characterized in that it is 1 -methyl-2-[N-(4-amidin-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-hydroxycarbonylethyl)-amide, prodrugs, double prodrugs and salts thereof. 9. Forbindelse, karakterisert ved at den er l-metyl-2-[N-[4-(N-n-heksyloksykarbonylamidin)fenyl)-aminometyl]-benzimidazol-5-yl-karboksylsyre-N-(2-pyridyl)-N-(2-etoksykarbonyletyl)-amid og salter derav.9. Compound, characterized in that it is 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidine)phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- (2-ethoxycarbonylethyl)-amide and salts thereof. 10. Fysiologisk tålbare salter av forbindelser ifølge krav 1 til 9, karakterisert ved at E er en R*NH-C(=NH)-gruppe.10. Physiologically tolerable salts of compounds according to claims 1 to 9, characterized in that E is an R*NH-C(=NH) group. 11. Legemiddel, karakterisert ved at det inneholder en forbindelse ifølge minst ett av kravene 1 til 9, idet E er en RbNH-C(=NH)-gruppe, eller et salt ifølge krav 10 ved siden av en eventuelt flere inerte bærestoffer og/eller fortynningsmidler.11. Medicinal product, characterized in that it contains a compound according to at least one of claims 1 to 9, where E is an RbNH-C(=NH) group, or a salt according to claim 10 next to an optional several inert carriers and/ or diluents. 12. Anvendelse av en forbindelse ifølge minst ett av kravene 1 til 9, hvor E er en RbNH-C(=NH)-gruppe eller et salt ifølge krav 10 for fremstilling av et legemiddel med en virkning som forlenger trombintiden, en trombinhemmende virkning og en hemmende virkning på kjente serinproteaser.12. Use of a compound according to at least one of claims 1 to 9, where E is a RbNH-C(=NH) group or a salt according to claim 10 for the preparation of a drug with an effect that prolongs thrombin time, a thrombin-inhibiting effect and an inhibitory effect on known serine proteases. 13. Fremgangsmåte for fremstilling av et legemiddel ifølge krav 11, karakterisert ved at det ved ikke-kjemisk vei blir innarbeidet en forbindelse ifølge minst ett av kravene 1 til 9, hvor E er en RbNH-C(=NH)-gruppe, eller et salt ifølge krav 9 i en eller flere inerte bærestoffer og/eller fortynningsmidler.13. Method for producing a medicinal product according to claim 11, characterized in that a compound according to at least one of claims 1 to 9 is incorporated by non-chemical means, where E is an RbNH-C(=NH) group, or a salt according to claim 9 in one or more inert carriers and/or diluents. 14. Fremgangsmåte for fremstilling av forbindelser ifølge kravene 1 til 10, karakterisert ved at a. for fremstilling av en forbindelse med generell formel I, hvor E er en RbNH-C(=NH)-gruppe, hvor Rb er et hydrogenatom, en hydroksy- eller Ci-3-alkyl-gruppe, blir en eventuelt i reaksjonsblandingen dannet forbindelse med generell formel hvor A, B, Ar, Het og Ra er som definert i kravene 1 til 9 og Zi er en alkoksy-, aralkoksy-, alkyltio eller aralkyltiogruppe omsatt med et amin med generell formel hvor Rb' er et hydrogenatom, en hydroksy- eller Ci-3-alkylgruppe, eller b. for fremstilling av en forbindelse med generell formel I, hvor Ra-A-gruppen og E med den forutsetningen som i kravene 1 til 9 er definert, idet Ra-A-gruppen innholder en karboksygruppe og E er som definert i krav 1 til 9 eller Ra-A-gruppen er som definert i kravene 1 til 9 og E er en NH2-C(=NH)-gruppe eller Ra-A-gruppen inneholder en karboksygruppe og E er en NH2-C(=NH)-gruppe, blir en forbindelse med generell formel hvor A, B, Ar og Het er definert som i kravene 1 til 9 og Ra'-A-gruppen og E' har de for Ra-A-gruppen og E i kravene 1 til 9 nevnte betydning med den forutsetningen at Ra'-A-gruppen inneholder en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i en karboksylgruppe overførbar gruppe og E er definert som i kravene 1 til 9 eller E' er en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i NH2-C(=NH)-gruppe overførbar gruppe og Ra'-A-gruppen er de for Ra-A-gruppen i kravene 1 til 9 nevnte betydning eller Ra'-A-gruppen inneholder en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse i en karboksylgruppe overførbar gruppe og E' er en ved hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse til en NH2-C(=NH)-gruppe overførbar gruppe, ved hjelp av hydrolyse, behandling med en syre eller base, termolyse eller hydrogenolyse blir overført til en forbindelse med generell formel I, idet Ra-A-gruppen og E er definert som angitt i kravene 1 til 9, idet Ra-A-gruppen inneholder en karboksygruppe og E er som definert i kravene 1 til 9 eller Ra-A-gruppen oppviser betydningen angitt i kravene 1 til 9 og E er en NH2-C(=NH)-gruppe eller Ra-A-gruppen inneholder en karboksygruppe og E er en NH2-C(=NH)-gruppe, blir overført eller c. for fremstilling av en forbindelse med generell formel I hvor Ra-A-gruppen inneholder en i definisjonen av Ra-A-gruppen i kravene 1 til 9 nevnte estergrupper, blir en forbindelse med generell formel hvor B, E, Ar og Het er som definert i kravene 1 til 9 og Ra"-A-gruppen har betydningen som Ra-A-gruppen i kravene 1 til 9 med den forutsetningen at Ra"-A-gruppen inneholder en karboksylgruppe eller en ved hjelp av en alkohol i en tilsvarende estergruppe ovenførbar gruppe, med en alkohol med generell formel hvor R7 er alkyldelen av en av kravene 1 til 9 nevnte in vivo avspaltbar rest med unntak av R4-CO-0-(R5CR6)-gruppen er en karboksylgruppe, eller med formamidacetaler derav eller med en forbindelse med generell formel hvor R7 er alkyldelen av en i kravene 1 til 9 nevnte in vivo avspaltbare rester med unntakelse av R4-CO-0-(R5CR6)-gruppen med en karboksylgruppe og Z2 er en utgående gruppe eller d. for fremstilling av en forbindelse med generell formel I, hvor Rb utgjør en in vivo avspaltbar rest, blir en forbindelse med generell formel hvor Ra, A, Het, B og Ar er definert som i kravene 1 til 9, omsatt med en forbindelse med generell formel hvor Rg er en in vivo avspaltbar rest og Z2 er en nukleofil utgående gruppe, eller e. fremstilling av en forbindelse med generell formel I hvor B er en etylengruppe, idet en metylengruppe er erstattet med en sulfinyl- eller sulfonyl-gruppe, blir en forbindelse med generell formel hvor A, E, Ar, Het og Ra er definert som i kravene 1 til 9 og B' er en etylengruppe, hvor en metylengruppe er erstattet med en sulfenyl- eller sulfinylgruppe, oksydert eller f. fremstilling av en forbindelse med generell formel I, hvor E er en cyanogruppe og B er en etylengruppe, hvor en metylengruppe, som enten er koplet med resten Het eller Ar er erstattet med et oksygen- eller svovelatom, med en sulfinyl-, sulfonyl-, karbonyl- eller -NRi -gruppe, blir en forbindelse med generell formel omsatt med en forbindelse med generell formel hvor Ra, A, Ar og Het er som definert i kravene 1 til 9, en av restene U eller V er en HO-, HS-, HOSO-, HOSO2- eller HNRi -gruppe og den andre av restene er en Z3CH2-gruppe, idet R] er definert som i kravene 1 til 9 og Z3 er en nukleofil utgangsgruppe, eller For fremstilling av en forbindelse med generell formel I hvor E er en cyanogruppe og Ra er en R2NR3-gruppe blir en forbindelse med generell formel hvor A, B, Het og Ar er definert som angitt i kravene 1 til 10, omsatt med et amin med generell formel hvor R2 og R3 er definert som i kravene 1 til 9, eller omsatt med reaksjonsdyktige derivater derav, eller fremstilling av en benzimidazolyl-, benztiazolyl- eller benzoksazolylforbindelse med generell formel I, hvor B er en etylengruppe, blir en forbindelse med generell formel hvor Ra, A og Y er definert som i kravene 1 til 9 omsatt med en forbindelse med generell formel hvor Ar og E er definert som angitt i kravene 1 til 9, eller blir omsatt med reaksjonsdyktige derivater derav, for fremstilling av en kinoksalin-2-on-forbindelse med generell formel blir en forbindelse med generell formel hvor Ra, Ri og A er definert som angitt i kravene 1 til 9, omsatt med en forbindelse med generell formel hvor Ar og E er definert som angitt i kravene 1 til 9, eller blir omsatt med reaksjonsdyktige derivater derav, eller j. for fremstilling av en forbindelse med generell formel I, idet R2 er en Cm-alkylgruppe, som er substituert med en alkylsulfonylaminokarbonylgruppe, blir en forbindelse med generell formel hvor R3, A, B, E og Het er som definert i kravene 1 til 9 og R2' er en CM-alkylgruppe, som er substituert med en karboksygruppe, eller reaksjonsdyktige derivater derav, omsatt med et salt av en forbindelse med generell formel og dersom en i løpet av omsetningen for beskyttelse av reaktive grupper anvendte beskyttelsesrester blir avspaltet og/eller det deretter er ønskelig å separere en slik oppnådd forbindelse med generell formel I til stereoisomerer derav og/eller blir en på denne måten oppnådd forbindelse med generell formel I overført til salter derav, spesielt for farmasøytisk anvendelse i deres fysiologisk tålbare salter med en uorganisk eller organisk syre eller base.14. Process for the preparation of compounds according to claims 1 to 10, characterized in that a. for the preparation of a compound of general formula I, where E is a RbNH-C(=NH) group, where Rb is a hydrogen atom, a hydroxy - or Ci-3-alkyl group, a compound of general formula is optionally formed in the reaction mixture where A, B, Ar, Het and Ra are as defined in claims 1 to 9 and Zi is an alkoxy, aralkylthio, alkylthio or aralkylthio group reacted with an amine of general formula where Rb' is a hydrogen atom, a hydroxy or C1-3 alkyl group, or b. for the preparation of a compound of general formula I, where the Ra-A group and E with the prerequisite defined in claims 1 to 9, as The Ra-A group contains a carboxy group and E is as defined in claims 1 to 9 or the Ra-A group is as defined in claims 1 to 9 and E is an NH2-C(=NH) group or Ra-A- group contains a carboxy group and E is an NH2-C(=NH) group, becomes a compound of general formula where A, B, Ar and Het are defined as in claims 1 to 9 and The Ra'-A group and E' have the meanings mentioned for the Ra-A group and E in claims 1 to 9, with the proviso that the Ra'-A group contains a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a carboxyl group transferable group and E is defined as in claims 1 to 9 or E' is a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in NH2-C(=NH) group transferable group and Ra'- The A group is the meaning mentioned for the Ra-A group in claims 1 to 9 or the Ra'-A group contains a group transferable by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a carboxyl group and E' is a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis to an NH2-C(=NH) group transferable group, by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis is transferred to a compound of general formula I, in that the Ra-A group and E are defined as stated in claims 1 to 9, in that the Ra-A group contains a carboxy group and E is as defined in claims 1 to 9 or the Ra-A group has the meaning stated in claims 1 to 9 and E is an NH2-C(=NH) group or Ra The -A group contains a carboxy group and E is an NH2-C(=NH) group, is transferred or c. for the preparation of a compound of general formula I where the Ra-A group contains a in the definition of Ra-A- the group in claims 1 to 9 mentioned ester groups, becomes a compound of general formula where B, E, Ar and Het are as defined in claims 1 to 9 and The Ra"-A group has the same meaning as the Ra-A group in claims 1 to 9 with the proviso that the Ra"-A group contains a carboxyl group or a group that can be added using an alcohol in a corresponding ester group, with an alcohol with general formula where R7 is the alkyl part of one of claims 1 to 9 mentioned in vivo cleavable residue with the exception of the R4-CO-0-(R5CR6) group is a carboxyl group, or with formamide acetals thereof or with a compound of general formula where R7 is the alkyl part of an in vivo cleavable residue mentioned in claims 1 to 9 with the exception of the R4-CO-0-(R5CR6) group with a carboxyl group and Z2 is a leaving group or d. for the preparation of a compound of general formula I , where Rb constitutes an in vivo cleavable residue, becomes a compound of general formula where Ra, A, Het, B and Ar are defined as in claims 1 to 9, reacted with a compound of general formula where Rg is an in vivo cleavable residue and Z2 is a nucleophilic leaving group, or e. preparation of a compound of general formula I where B is an ethylene group, a methylene group being replaced by a sulfinyl or sulfonyl group, becomes a compound of general formula where A, E, Ar, Het and Ra are defined as in claims 1 to 9 and B' is an ethylene group, where a methylene group is replaced by a sulfenyl or sulfinyl group, oxidized or f. preparation of a compound of general formula I, where E is a cyano group and B is an ethylene group, where a methylene group, which is either linked to the residue Het or Ar is replaced by an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NRi group, becomes a connection with general formula reacted with a compound of general formula where Ra, A, Ar and Het are as defined in claims 1 to 9, one of the residues U or V is a HO, HS, HOSO, HOSO2 or HNRi group and the other of the residues is a Z3CH2 group, wherein R] is defined as in claims 1 to 9 and Z3 is a nucleophilic leaving group, or For the preparation of a compound of general formula I where E is a cyano group and Ra is an R2NR3 group a compound of general formula becomes where A, B, Het and Ar are defined as stated in claims 1 to 10, reacted with an amine of general formula where R2 and R3 are defined as in claims 1 to 9, or reacted with reactive derivatives thereof, or preparation of a benzimidazolyl, benzthiazolyl or benzoxazolyl compound of general formula I, where B is an ethylene group, becomes a compound of general formula where Ra, A and Y are defined as in claims 1 to 9 reacted with a compound of general formula where Ar and E are defined as stated in claims 1 to 9, or are reacted with reactive derivatives thereof, for the preparation of a quinoxalin-2-one compound of general formula becomes a compound of general formula where Ra, Ri and A are defined as stated in claims 1 to 9, reacted with a compound of general formula where Ar and E are defined as stated in claims 1 to 9, or are reacted with reactive derivatives thereof, or j. for the preparation of a compound of general formula I, wherein R 2 is a C 1 -alkyl group, which is substituted with an alkylsulfonylaminocarbonyl group, becomes a compound of general formula where R3, A, B, E and Het are as defined in claims 1 to 9 and R2' is a C-1-C alkyl group, which is substituted with a carboxy group, or reactive derivatives thereof, reacted with a salt of a compound of general formula and if a protective residue used in the course of the reaction for the protection of reactive groups is cleaved off and/or it is then desired to separate such an obtained compound of general formula I into stereoisomers thereof and/or a compound of general formula I is thus obtained converted into salts thereof, especially for pharmaceutical use in their physiologically tolerable salts with an inorganic or organic acid or base.
NO19993945A 1997-02-18 1999-08-17 Disubstituted bicyclic heterocycles, use and preparation thereof and drug NO313879B1 (en)

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DE19706229A DE19706229A1 (en) 1997-02-18 1997-02-18 New aryl-substituted bi:cyclic heterocyclic compounds
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PCT/EP1998/000865 WO1998037075A1 (en) 1997-02-18 1998-02-16 Disubstituted bicyclic heterocycles, their production and use as medicaments

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Families Citing this family (171)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026933A1 (en) * 1997-11-26 1999-06-03 Axys Pharmaceuticals, Inc. Substituted amidinoaryl derivatives and their use as anticoagulants
AU2720199A (en) * 1998-02-03 1999-08-23 Boehringer Ingelheim Pharma Kg Five-membered, benzo-condensed heterocycles used as antithrombotic agents
US6114532A (en) * 1998-02-03 2000-09-05 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
EP1054886B1 (en) * 1998-02-09 2002-09-04 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines as protease inhibitors, in particular as urokinase inhibitors
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
US6248770B1 (en) 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
EA200100882A1 (en) * 1999-02-09 2002-04-25 3-Дименшенл Фамэсьютикэлс, Инк. AMETHINE, METHYLAMIDINE AND GUANIDA HEAT HYDROARIAL PRODUCTS (OPTIONS) MATERIALS (OPTIONS), PHARMACEUTICAL COMPOSITION (OPTIONS), METHOD FOR INHIBING PROTEASE (OPTIONS) AND SPODA SPEEDS (OPTIONS), SPEED INHIBITION (OPTIONS) AND SPODA PRODUCTS (OPTIONS);
DE19907813A1 (en) * 1999-02-24 2000-08-31 Boehringer Ingelheim Pharma Substituted bicyclic heterocycles, their preparation and their use as pharmaceuticals
AR023510A1 (en) 1999-04-21 2002-09-04 Astrazeneca Ab A TEAM OF PARTS, PHARMACEUTICAL FORMULATION AND USE OF A THROMBIN INHIBITOR.
DE19939463A1 (en) * 1999-08-20 2001-02-22 Boehringer Ingelheim Pharma Tryptase inhibitors useful e.g. for treating inflammatory or allergic disease, arteriosclerosis or neoplasia, comprising new or known 2-phenethyl-benzimidazole-5-carboxamides
US6512000B1 (en) 1999-08-20 2003-01-28 Boehringer Ingelheim Pharma Kg Aminocarbonyl-substituted benzimidazoles having tryptase-inhibitory activity
DE50001742D1 (en) * 1999-09-24 2003-05-15 Boehringer Ingelheim Pharma ARYLSULFONAMIDE SUBSTITUTED BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS TRYPTASE INHIBITORS
DE19945810A1 (en) * 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma Substituted benzimidazole derivatives, process for their preparation and their use as medicaments
US6413990B1 (en) 1999-09-24 2002-07-02 Boehringer Ingelheim Pharma Kg Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
DE19945787A1 (en) 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma New 2-(amidino- or aminomethyl-phenethyl)-5-sulfonylamino-benzimidazoles, are tryptase inhibitors useful e.g. for treating inflammatory or allergic disease such as asthma, urticaria or arthritis
US6407130B1 (en) 1999-11-10 2002-06-18 Boehringer Ingelheim Pharma Kg Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
US6451832B2 (en) 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US20040242627A1 (en) 2001-04-19 2004-12-02 Shuichi Suzuki 2-Iminoimidazole derivatives (1)
DE10133786A1 (en) * 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Use of thrombin inhibitors for the treatment of arthritis
US20030181488A1 (en) 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
EP1485094B2 (en) * 2002-03-07 2020-03-25 Boehringer Ingelheim International GmbH Dosage form for oral administration of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester or its salts
DE10235639A1 (en) * 2002-08-02 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New prodrugs of benzimidazole-5-carboxamide derivative thrombin inhibitor, useful for treating or preventing thrombotic diseases, are well tolerated on subcutaneous injection
AU2003265398A1 (en) 2002-08-09 2004-02-25 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
PE20040804A1 (en) * 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma CARBOXAMID DERIVATIVES AS INHIBITORS OF THE Xa FACTOR
US7429597B2 (en) 2002-12-23 2008-09-30 Boehringer Ingelheim Pharma Gmbh & Co., Kg Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions
DE10260730A1 (en) 2002-12-23 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted nitrogen-containing heterobicyclene, their preparation and their use as pharmaceuticals
AU2004218187C1 (en) 2003-02-19 2011-04-07 Eisai R&D Management Co., Ltd. Methods for producing cyclic benzamidine derivatives
DE10310278A1 (en) * 2003-03-10 2004-09-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg New N-(benzazinyl)-(hetero)aralkylamine derivatives, are inhibitors of factor Xa and/or related serine proteases, useful e.g. as antithrombotic agents and intermediates
AU2004231306A1 (en) 2003-04-24 2004-11-04 Boehringer Ingelheim International Gmbh Use of dipyridamole or mopidamole for treatment and prevention of thrombo-embolic diseases and disorders caused by excessive formation of thrombin and/or by elevated expression of thrombin receptors
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
CA2531796A1 (en) 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
WO2005014534A1 (en) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
DE10337697A1 (en) * 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-iminomethyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionic acid ethyl ester or its salts
DE10339862A1 (en) * 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg New crystalline forms of ethyl 3-(N-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-N-(2-pyridyl)amino)propionate methanesulfonate used for post-operative prophylaxis of deep vein thrombosis
DE10341043A1 (en) * 2003-09-03 2005-03-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg New Oral Dosage Form for 3 - [(2 - {[4-hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] Propionic acid ethyl ester and its salts
EP1609784A1 (en) * 2004-06-25 2005-12-28 Boehringer Ingelheim Pharma GmbH & Co.KG Process for the preparation of 4-(benzimidazolylmethylamino)-benzamidines
US20060222640A1 (en) * 2005-03-29 2006-10-05 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of thrombosis
DE102005020002A1 (en) * 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg New hexyloxycarbonylamino-imino-methyl-phenylamino-methyl-benzimidazole-pyridine-propionic acid-ethyl ester salts such as hydrochloride useful for the prophylaxis of vein thrombosis and stroke
DE102005025728A1 (en) * 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphs of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester
ATE485269T1 (en) 2005-06-27 2010-11-15 Bristol Myers Squibb Co C-LINKED CYCLIC ANTAGONISTS OF THE P2Y1 RECEPTOR USEFUL IN THE TREATMENT OF THROMBOTIC DISORDERS
DE102005061623A1 (en) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Improved process for the preparation of 4- (benzimidazolylmethylamino) -benzamidines and their salts
DE102005061624A1 (en) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Improved process for the preparation of salts of 4- (benzimidazolylmethylamino) -benzamidines
US8044242B2 (en) 2006-03-09 2011-10-25 Bristol-Myers Squibb Company 2-(aryloxy) acetamide factor VIIa inhibitors useful as anticoagulants
WO2007146719A2 (en) 2006-06-08 2007-12-21 Bristol-Myers Squibb Company 2-aminocarbonylphenylamino-2-phenylacetamides as factor viia inhibitors useful as anticoagulants
JP2009543843A (en) * 2006-07-17 2009-12-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New indications for direct thrombin inhibitors
WO2008009638A2 (en) * 2006-07-17 2008-01-24 Boehringer Ingelheim International Gmbh New indications for direct thrombin inhibitors in the cardiovascular field
CA2666396A1 (en) * 2006-10-10 2008-04-17 Boehringer Ingelheim International Gmbh Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
WO2008076805A2 (en) 2006-12-15 2008-06-26 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors
PE20081775A1 (en) 2006-12-20 2008-12-18 Bristol Myers Squibb Co MACROCYCLIC COMPOUNDS AS INHIBITORS OF FACTOR VIIA
EP1956018A1 (en) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Method of preparing a derivative of benzimidazole
MX2009011089A (en) 2007-04-23 2009-10-30 Sanofi Aventis Quinoline-carboxamide derivatives as p2y12 antagonists.
US8350032B2 (en) 2007-07-31 2013-01-08 Medibeacon Development, Llc Integrated photoactive agents for real-time monitoring of hemostasis
EP2238128B1 (en) 2007-12-26 2012-08-22 Sanofi Heterocyclic pyrazole-carboxamides as p2y12 antagonists
CZ305085B6 (en) * 2008-03-14 2015-04-29 Zentiva, K.S. Process for preparing dabigatran
TWI436994B (en) * 2008-07-14 2014-05-11 Boehringer Ingelheim Int New process for preparing medicament compositions containing dabigatran
JP2012500243A (en) * 2008-08-19 2012-01-05 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Use of dabigatran etexilate for the treatment of patients with pulmonary hypertension
CZ2008669A3 (en) * 2008-10-24 2010-05-05 Zentiva, A. S. Process for preparing dabigatran and intermediates thereof
NZ593787A (en) 2009-02-02 2013-09-27 Boehringer Ingelheim Int Lyophilised dabigatran
JP2012526766A (en) 2009-05-14 2012-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング A novel combination therapy in the treatment of neoplastic and fibrotic diseases
ES2436076T3 (en) 2009-08-24 2013-12-26 Boehringer Ingelheim International Gmbh Emergency interventions of active charcoal with overdosing with dabigatran etexilate
CN102050815B (en) * 2009-11-06 2014-04-02 北京美倍他药物研究有限公司 Dabigatran ester derivatives as prodrug
CN102050814B (en) * 2009-11-06 2014-05-28 北京美倍他药物研究有限公司 Ester derivatives of dabigatran
US8399678B2 (en) 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
AR079944A1 (en) * 2010-01-20 2012-02-29 Boehringer Ingelheim Int NEUTRALIZING ANTIBODY OF THE ACTIVITY OF AN ANTICOAGULANT
HUP1000069A2 (en) 2010-02-02 2012-05-02 Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag New salts for the preparation of pharmaceutical composition
CA2789622C (en) 2010-02-11 2018-04-03 Bristol-Myers Squibb Company Macrocycles as factor xia inhibitors
WO2011107427A1 (en) 2010-03-01 2011-09-09 Ratiopharm Gmbh Dabigatran etexilate-containing oral pharmaceutical composition
JP2013521318A (en) 2010-03-08 2013-06-10 ラティオファルム ゲー・エム・ベー・ハー Pharmaceutical composition containing dabigatran etexilate
PL2588090T3 (en) 2010-07-01 2017-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
JP2013532164A (en) 2010-07-09 2013-08-15 エステヴェ キミカ， エス．エー． Methods for preparing thrombin specific inhibitors
JP2013531004A (en) 2010-07-09 2013-08-01 エステヴェ キミカ， エス．エー． Intermediates and methods for the preparation of thrombin specific inhibitors
WO2012027543A1 (en) 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
WO2012077136A2 (en) 2010-12-06 2012-06-14 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
US9000186B2 (en) 2011-02-01 2015-04-07 Kyowa Hakko Kirin Co., Ltd. Ring-fused heterocyclic derivative
AP2013007046A0 (en) 2011-03-30 2013-08-31 Boehringer Ingelheim Int Anticoagulant antidotes
HUP1100244A2 (en) 2011-05-11 2012-11-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Pharmaceutical intermediates and process for their production
CN102250099B (en) * 2011-05-16 2013-10-16 中国药科大学 Non-peptide thrombin inhibitors as well as preparation method and medical application thereof
CN102838588B (en) * 2011-06-24 2014-03-19 中国药科大学 Oral thrombin inhibitors, preparation methods and medical uses thereof
HUE032862T2 (en) * 2011-07-25 2017-11-28 Dritte Patentportfolio Beteili Amidoxime carboxylic acid esters of dabigatran as prodrugs and their use as medicament
TW201311689A (en) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 Novel macrocycles as factor XIa inhibitors
TW201319068A (en) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 Cyclic P1 linkers as factor XIa inhibitors
WO2013024394A1 (en) * 2011-08-12 2013-02-21 Alembic Pharmaceuticals Limited Novel reference markers of dabigatran etexilate
CN102993174A (en) * 2011-09-08 2013-03-27 天津药物研究院 Dabigatran etexilate derivative as a prodrug
CN102993175B (en) * 2011-09-08 2014-08-13 天津药物研究院 Dabigatran derivatives, and preparation method and application thereof
SI2766346T1 (en) 2011-10-14 2017-05-31 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
WO2013055984A1 (en) 2011-10-14 2013-04-18 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
ES2579832T3 (en) 2011-10-14 2016-08-17 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US20130183384A1 (en) 2011-12-22 2013-07-18 Boehringer Ingelheim International Gmbh Immediate release multi unit pellet system
WO2013111163A2 (en) 2012-01-20 2013-08-01 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
JP2015504903A (en) 2012-01-24 2015-02-16 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New dabigatran formulation for oral administration
HRP20211606T1 (en) 2012-02-21 2022-01-21 Towa Pharmaceutical Europe, S.L. Oral pharmaceutical compositions of dabigatran etexilate
EP2631234A1 (en) 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
WO2013144971A1 (en) 2012-03-27 2013-10-03 Cadila Healthcare Limited New solid forms of dabigatran etexilate bisulfate and mesylate and processes to prepare them
US9273030B2 (en) 2012-04-02 2016-03-01 Msn Laboratories Private Limited Process for the preparation of benzimidazole derivatives and salts thereof
CN103387566B (en) * 2012-05-09 2015-09-09 上海医药工业研究院 Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate
CN103420980A (en) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 Dabigatran derivatives
US20130345262A1 (en) 2012-06-25 2013-12-26 Boehringer Ingelheim International Gmbh Method for prevention of stroke
WO2014012880A1 (en) 2012-07-16 2014-01-23 Interquim, S.A. Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates
CN102766134B (en) * 2012-07-19 2014-06-25 北京普禄德医药科技有限公司 Dabigatran etexilate derivative and preparation method and application thereof
WO2014021383A1 (en) * 2012-07-31 2014-02-06 協和発酵キリン株式会社 Condensed ring heterocyclic compound
LT2882734T (en) 2012-08-03 2016-12-12 Bristol-Myers Squibb Company DIHYDROPYRIDONE AS FACTOR XIa INHIBITORS
DK2880026T3 (en) 2012-08-03 2017-06-06 Bristol Myers Squibb Co DIHYDROPYRIDON-P1 AS A FACTOR XIA INHIBITORS
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
EP2722033A1 (en) 2012-10-19 2014-04-23 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical Compositions of Dabigatran Free Base
EP2722034B1 (en) 2012-10-19 2020-09-16 Sanovel Ilac Sanayi ve Ticaret A.S. Oral pharmaceutical formulations comprising dabigatran
US9399616B2 (en) 2012-10-22 2016-07-26 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
WO2014068587A2 (en) * 2012-10-29 2014-05-08 Biophore India Pharmaceuticals Pvt. Ltd. An improved process for the synthesis of dabigatran and its intermediates
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
CN102977077A (en) * 2012-11-28 2013-03-20 浙江燎原药业有限公司 Method for preparing dabigatran etexilate intermediate
EP2740471B1 (en) 2012-12-07 2015-05-27 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
CN103044404A (en) * 2013-01-14 2013-04-17 中国药科大学 Dabigatran derivatives, and preparation method and application thereof in antithrombosis
WO2014160668A1 (en) 2013-03-25 2014-10-02 Bristol-Myers Squibb Company Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors
CN103224469A (en) * 2013-05-16 2013-07-31 上海应用技术学院 Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof
JP2016520110A (en) 2013-06-03 2016-07-11 バイエル ファーマ アクチエンゲゼルシャフト Substituted benzoxazole
UY35592A (en) 2013-06-03 2014-12-31 Bayer Pharma AG BENZOXAZOLES REPLACED
CN103288744A (en) * 2013-06-04 2013-09-11 上海应用技术学院 Fluorine group-containing-modified dabigatran etexilate analogue and synthetic method thereof
EP2853260A1 (en) 2013-09-27 2015-04-01 ratiopharm GmbH Pharmaceutical preparation comprising dabigatran etexilate bismesylate
NO2760821T3 (en) 2014-01-31 2018-03-10
JP6464176B2 (en) 2014-01-31 2019-02-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Macrocycles as factor XIA inhibitors with aromatic P2 'groups
IN2014MU00675A (en) 2014-02-26 2015-10-23 Megafine Pharma P Ltd
WO2015137680A1 (en) * 2014-03-10 2015-09-17 동아에스티 주식회사 Pharmaceutical composition for treating or preventing stroke and systemic embolism
WO2015145462A1 (en) 2014-03-26 2015-10-01 Cadila Healthcare Limited Pharmaceutical compositions of dabigatran
EP2933002A1 (en) 2014-04-11 2015-10-21 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical combinations of dabigatran and proton pump inhibitors
WO2015155297A1 (en) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
CN104230888A (en) * 2014-06-03 2014-12-24 长春工业大学 Preparation method of benzimidazole compound
CN105218519A (en) * 2014-06-04 2016-01-06 天津药物研究院 A kind of preparation method of dabigatran etexilate intermediate
CN104003977B (en) * 2014-06-05 2016-04-13 雅本化学股份有限公司 The preparation method of N-(2-chloromethyl-1-methyl isophthalic acid H-benzoglyoxaline-5-acyl group)-N-(pyridine-2-base)-3-alanine ethyl ester
DE102014108210A1 (en) 2014-06-11 2015-12-17 Dietrich Gulba rodenticide
CN104045628B (en) * 2014-06-13 2019-04-09 深圳翰宇药业股份有限公司 The purification process of benzimidizole derivatives
CN105315257A (en) * 2014-06-24 2016-02-10 华仁药业股份有限公司 Synthetic and purifying method of dabigatran etexilate
CN106536505A (en) * 2014-08-06 2017-03-22 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
WO2016019848A1 (en) * 2014-08-06 2016-02-11 四川海思科制药有限公司 Dabigatran thioester derivative, preparation method therefor, and pharmaceutical use thereof
NO2721243T3 (en) 2014-10-01 2018-10-20
WO2016070696A1 (en) 2014-11-03 2016-05-12 杭州领业医药科技有限公司 Dosing preparation of dabigatran etexilate or a salt thereof and a preparation method thereof
CN104592204B (en) * 2014-12-26 2017-05-17 华润赛科药业有限责任公司 Dabigatran derivatives as well as preparation method and application thereof
CN104650037A (en) * 2014-12-30 2015-05-27 青岛黄海制药有限责任公司 Synthesis method of dabigatran etexilate
TR201502223A2 (en) 2015-02-25 2016-09-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dronedarone and dabigatran
CN104628733A (en) * 2015-03-02 2015-05-20 中国药科大学 Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors
EP3310777B1 (en) 2015-06-19 2019-10-09 Bristol-Myers Squibb Company Diamide macrocycles as factor xia inhibitors
CN104987323B (en) * 2015-07-10 2017-08-22 浙江美诺华药物化学有限公司 A kind of preparation method of dabigatran etcxilate
MA42480A (en) 2015-07-20 2018-05-30 Sanovel Ilac Sanayi Ve Ticaret As DABIGATRAN PHARMACEUTICAL PREPARATIONS IN FREE BASE FORM
CN114874222A (en) 2015-07-29 2022-08-09 百时美施贵宝公司 Carrying non-aromatic P2 , Novel macrocyclic form of factor XIA
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CN105294651A (en) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 Method for synthesizing and preparing pradaxa formamidine intermediates
CN106866626A (en) * 2015-12-14 2017-06-20 天津药物研究院有限公司 A kind of preparation method of dabigatran etexilate intermediate
CN105481831B (en) * 2015-12-16 2018-06-12 开封明仁药业有限公司 A kind of method for preparing dabigatran etexilate intermediate
WO2017111637A1 (en) 2015-12-23 2017-06-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof
CN105566297A (en) * 2015-12-31 2016-05-11 哈药集团技术中心 Preparation method of dabigatran etexilate mesylate
JP2019507167A (en) 2016-03-02 2019-03-14 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Diamide macrocycle with factor XIA inhibitory activity
CN105669651B (en) * 2016-03-07 2018-03-06 山东罗欣药业集团股份有限公司 A kind of preparation technology of dabigatran etexilate methanesulfonate
CN106397400A (en) * 2016-04-14 2017-02-15 江苏康缘药业股份有限公司 Preparation method for dabigatran etexilate
TR201606697A2 (en) 2016-05-20 2017-12-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi NEW ORAL PHARMACEUTICAL FORMULATIONS OF DABIGATRA
CN106349221A (en) * 2016-08-29 2017-01-25 常州市阳光药业有限公司 Preparation method of high-purity dabigatran etexilate
WO2018104387A1 (en) 2016-12-07 2018-06-14 Sanovel Ilac Sanayi Ve Ticaret A.S. Multilayered tablet compositions of dabigatran
TR201617984A2 (en) 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN
JP2018184375A (en) 2017-04-27 2018-11-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method for producing the same
TR201706848A2 (en) 2017-05-10 2018-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE
WO2019004980A2 (en) 2017-05-10 2019-01-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Solid oral pharmaceutical compositions of dabigatran etexilate
CN109010249A (en) * 2017-06-08 2018-12-18 上海美悦生物科技发展有限公司 Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application
KR20190036857A (en) 2017-09-28 2019-04-05 한미약품 주식회사 Composite capsule formulation comprising dabigatran etexilate
TR201722323A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Oral pharmaceutical compositions of dabigatran
TR201722186A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical compositions of dabigatran
TR201722630A2 (en) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
CN111954532A (en) * 2018-04-13 2020-11-17 上海交通大学医学院附属瑞金医院 Anti-tumor multi-drug resistance of heteroaryl amide compounds, application of heteroaryl amide compounds in treating cancer and protein-drug molecular compound
CN108864047A (en) * 2018-07-02 2018-11-23 河南师范大学 A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate
EP3771465A1 (en) 2019-08-01 2021-02-03 Zaklady Farmaceutyczne Polpharma SA Pharmaceutical composition comprising dabigatran etexilate
CN111606885A (en) * 2020-06-18 2020-09-01 安徽鼎旺医药有限公司 Dabigatran etexilate mesylate and preparation method thereof
CN113929661A (en) * 2020-06-29 2022-01-14 石药集团恩必普药业有限公司 Dabigatran etexilate intermediate and preparation method thereof
EP4070658A1 (en) 2021-04-06 2022-10-12 BIORoxx GmbH Use of anticoagulant active compounds as rodenticide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
DE4129603A1 (en) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K CONDENSED 5-LOW HETEROCYCLES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENTS CONTAINING THESE COMPOUNDS
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
ZA928276B (en) * 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
CA2134192A1 (en) * 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists

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