CA2337804C - Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions - Google Patents

Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions Download PDF

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CA2337804C
CA2337804C CA002337804A CA2337804A CA2337804C CA 2337804 C CA2337804 C CA 2337804C CA 002337804 A CA002337804 A CA 002337804A CA 2337804 A CA2337804 A CA 2337804A CA 2337804 C CA2337804 C CA 2337804C
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alkyl
carboxy
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optionally substituted
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CA2337804A1 (en
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Uwe Ries
Iris Kauffmann
Norbert Hauel
Henning Priepke
Herbert Nar
Jean Marie Stassen
Wolfgang Wienen
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE1998129964 external-priority patent/DE19829964A1/en
Priority claimed from DE1998157202 external-priority patent/DE19857202A1/en
Priority claimed from DE1999112690 external-priority patent/DE19912690A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to novel benzimidazoles of general formula (1), wherei n R a to R c, A, Ar and B have the meanings given in Claim 1, to tautomers, stereoisomers, mixtures and pro-drugs thereof, derivatives thereof containing a group which is negatively charged under physiological conditions in place of a carboxy group, and salts thereof, especially their physiologically compatible salts with inorganic or organic acids or bases with useful properties. The compounds of general formula (I) above wherein R c represents a cyano group are useful intermediate products for the production of the other compounds of general formula (I) and the compounds of general formula (I) wherein R c represents one of the amidino groups cited in Claim I have useful pharmacological properties, especially an antithrombotic effect.

Description

Boehringer Ingelheim Pharma KG Case 5/1241-FL
D-55216 INGELHEIM Foreign filing text Benzimidazoles, the preparation thereof and their use! as pharniaceutical compositions The present invention relates to benzimidazoles of general formula N
Ra I \~-A-B -Ar R. ( I ) , N

Rb their tautomers, their stereoisomers, the mixtures thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions in-stead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties.

The compounds of the above general formula I wherein R, denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein RC denotes one of the following amidino groups, as well as their tautomers, their stereoiso-mers, the mixtures thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and their salts, particularly the physiologically acceptable salts there-of with inorganic or organic acids, and the stereoisomers the-reof have valuable pharmacological properties, particularly an antithrombotic activity.

The present application thus relates to the new compounds of the above general formula I as well as the preparation thereof, the pharmaceutical compositions containing the pharmacologi-cally active compounds, the preparation and use thereof.
In the above general formula Ar denotes a phenylene or naphthylene group optionally sub-stituted by a fluorine, chlorine or bromine atom, by a tri-fluoromethyl, Cl-3-alkyl or Cl_,-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyra-zinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1_,-alkyl group, A denotes a C1_3-alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally sub-lri stituted by a C1_3-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, Ra denotes an Rl-Co-C3_5-cycloalkyl group wherein 20 Rl denotes a C1_3-alkoxy, amino, C1_4-alkylamino or di-(C1-4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino 25 group which may be substituted by a hydroxy group or by one or two C1_j-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C1_3-alkoxy, carb-oxy, carboxy-Ci_3-alkoxy, carboxy-C1_3-alkylamino, N- (C1_3-al-kyl) -N- (carboxy-C1_3-alkyl) -amino, carboxy-C1_3-alkylami.nocar-3U bonyl, N-(C1_3-alkyl)-N-(carboxy-C1_3-alkyl)-aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1- (Cl_3-alkyl) -3- (carb-oxy-C1_3-alkyl) -aminocarbonylamino, 3- (C1_3-alkyl) -3- (carboxy-C1_3-alkyl) -aminocarbonylamino or 1, 3-di- (Cl-3-alkyl) -3-- (carb-oxy-C1_3-alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally sub-stituted by a C1_3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C,_,-alkyl)-piperazino, pyr-rolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, an R2-CX-C3_5-cycloalkyl group wherein l t) R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1_3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group con-lE, tains an imino group optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1_,-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned al-kyl substituent may be substituted by a carboxy, carboxy-2C C1_3-alkoxy, carboxy-C;_3-alkylamino or N- (C1_3-alkyl) -carboxy-C1_3-alkylamino group, and X denotes an oxygen atom, a C1_3-alkylimino, C1_3-alkoxyimino, C1_3-alkylhydrazino, di- (C1_3-alkyl) -hydrazino, C2_4-alkanoyl-25 hydrazino, N- (C1_3-alkyl) -C2_4-alkanoylhydrazino or C1_3-a1-kylidene group each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, 30 a C1_3-alkyl or C3_5-cycloalkyl group substituted by an imidazole or imidazolone group wh(=_rein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1_3-alkyl groups or by one, two or 35 three C1_3-alkyl group.s, wherein the substituents may be iden-tical or different and one of the abovementioned alkyl sub-stituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, C1_3-alkylamino, N- (C2_4-alkanoyl) -C1_3-alkylamino or di- (C1_3-alkyl) -amino group, and the imidazolone ring may be substituted by a Ci_3-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2_4-alkanoyl-amino, Cl_3-alkylamino, N- (C2_4-alkanoyl) -Cl_3-alkylamino or di- (C1_3-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two ad-jacent carbon atoms, 1~ an imidazolidine-2,4-di.on-5-yl group which may be substituted by one or two C1_3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C1_4-alkyl group which is substituted by a Cl_3-alkyl-Yl-C1_3-alky1, HOOC-C1_3-alkyl-Y1-C1_3-alkyl, tetrazolyl-C1_3-alkyl-Y2, R3NR9- or R3NR4-Cl_3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by 2~ a C1_3-alkyl group, by a pyrrolino-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-l-yl-carbonvl, carboxy, aminocar-bonyl, C1_3-alkylaminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C1_3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abo-vementioned C1_3-alkylaminocarbonyl, di-(C1_3-alkyl)-aminocar-bonyl or cycloalkylerieiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C1_4-alkyl group may be wholly or partially replaced by fluo-rine atoms wherein R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1_3-alkyl-Y,-C1_3-alkyl-YZ, carboxy-C1_3-alkyl-Y1-Cl_3-alkyl-Y2, Cl_,-alkyl-Y2 or carboxy-C1_3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them de-note an 4- to 7-membered cycloalkyleneimino group optio-nally substituted by a carboxy, C1_3-alkyl or carboxy-Cl_3-alkyl group wherein Yl denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl,, -NH-, -NH-CO- or -NH-CO-NH- group and Y. denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is lin}ced to the nitrogen atom of the R3NR4-group, and the imino groups occurring in the definition of 21) the groups Y1 and Y2 may each additionally be substituted by a C1_3-alkyl or carboxy-C1_3-alkyl group, a C1_3-alkyl or C3_5-cycloalkyl group substituted by a RNR6-group wherein R. denotes a hydrogen atom, a C1_3-alkyl, CS_,-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C1_3-alkyl, carboxy-Cl_3-alkyl or carboxy-C1_3-al-kylcarbonyl group, a C1_3-alkyl group which is substituted by a C2_4-alkanoyl or CS_,-cycloalkanoyl group and by a C1_3-alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a Cl_3-alkyl group and Rr denotes a cyano group or an amidino group optionally sub-stituted by one or two C1_3-alkyl groups.

The carboxy groups mentioned in the definitions of the above-mentioned groups may also be replaced by a group which can be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, or the amino and imino groups mentioned in the definitions of the abovementioned groups may also be substituted by a group which can be cleaved in vivo. Groups of this kind are described, for example, in WO 98/46576 and by N.M. Nielson et al. in Inter-national Journal of Pharmaceutics 33, 75-85 (1987).

A group which can be ccnverted in vivo into a carboxy group may be, for example, a hydroxmethyl group, a carboxy group esteri-fied with an alcohol, wherein the alcoholic moiety is prefe-rably a C1_6-alkanol, a.phenyl-C1_3-alkanol, a C3_9-cycloalkanol, whilst a C5_8-cycloalkanol may additionally be substituted by one or two C1_3-alkyl groups, a C5_e-cycloalkanol wherein a methylene group in the 3- or 4-position is replaced by an oxy-gen atom or by an imino group optionally substituted by a C1_3-alkyl, phenyl-C1_3-alkyl, phenyl-C1_3-alkoxycarbonyl or C2_6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1_3-alkyl groups, a C4_,-cycl.o-alkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3_5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-^1_3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which may additionally be sub-stituted in the bicycloalkyl moiety by one or two C1_3-alkyl groups, a 1,3-dihydro-3-oxo-i-isobenzofuranol or an alcohol of formula Rd-CO-O- (ReCRf) -OH, wherein Rd denotes a C1_8-alkyl, CS_,-cycloalkyl, phenyl or phenyl-C1_3-alkyl group, Re denotes a hydrogen atom, a C1_3-alkyl, CS_,-cycloalkyl or phenyl group and Rf denotes a hydrogen atom or a C1_3-alkyl group, a group which is negati.vely charged under physiological con-ditions may be a tetrazol-5-yl, phenylcarbonylamino-carbonyl, trifluormethylcarbonyla.minocarbonyl, C1_6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethyl-sulphonylamino, C1_6-alkylsulphonylaminocarbonyl, phenylsulpho-nylamino-carbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1_6-alkylsulphonylaminocarbonyl group and a group which can be cleaved in vivo from an imino or amino group may be, for example, a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted by fluo-rine, chlorine, bromine: or iodine atoms, by C1_3-alkyl or C1_3-alkoxy groups, wherein the substituents may be identical or different, a pyridinoyl group or a C1_16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a Cl_16-alkoxycarbonyl or C,_16-alkylcarbonyloxy group whereiri hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such. as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. but-oxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dode-cyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethyl-carbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyl-oxy, isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbo-nyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dode-cylcarbonyloxy or hexad.ecylcarbonyloxy group, a phenyl-Cl_6-alk-oxycarbonyl group such as the benzyloxycarbonyl, phenylethoxy-_.___ carbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C1_6-alkyl or C3_,-cycloalkyl groups and the substituents may be identical or different,. a C1_3-alkylsulphonyl-C2_4-alkoxycarbo-E> nyl, C1-3-alkoxy-CZ_4-alkoxy-Cz_Q-alkoxycarbonyl, Rd-CO-O- (RdCRt) -O-CO-, C1_6-alkyl-CO-NH- (RgCRh) -O-CO- or C1_6-alkyl-CO-O- (RgCR,,) -(RgCRh) -O-CO- group wherein Rd to Rf are as hereinbefore defi-ned, 1U R. and Rh, which may be identical or different, denote hy-drogen atoms or CY_3-alkyl groups.

Moreover, the saturateci alkyl and alkoxy moieties which contain more than 2 carbon atoms mentioned in the above definitions 15 also include the branched isomers thereof, such as, for exam-ple, the isopropyl, tert.butyl, isobutyl group etc.

Preferred compounds are those of general formula N
Ra ~~---p,-B R ( I a ) , N
I
20 Rb wherein A denotes a Cl_3-alkylene group, 25 B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally sub-stituted by a C1_,-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 3C Ra denotes an Rl-CO-C3_5-cycloalkyl group wherein Rl denotes a Cl_,-alkoxy, amino, C_4-alkylamino or di-(C1_4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C1_3-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C1_3-alkoxy, carboxy, carboxy--Cl_3-alkoxy, carboxy-C1_3-alkylamino, N- (C1_3-alkyl) -N- (carboxy-1C) Cl_3-alkyl) -amino, carboxy-C1_3-alkylaminocarbonyl, N-(C1_3-alkyl)-N-(carboxy-C1_3-alkyl)-aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1-(C1_3-alkyl)-3-(carboxy-Cl_3-alkyl) -aminocarbonylamino, 3- (C1__3-alkyl) -3- (carboxy-Cl_,-alkyl) -aminocarbonylamino or 1, 3-di- (C1_3-alkyl) -3- (carb-oxy-C1_3-alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 2C, a 5- to 7-membered cycloalkyleneimino group optionally sub-stituted by a C1_3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1_3-alkyl)-piperazino, pyrro-lino, 3,4-dehydro-piperidino or pyrrol-i-yl group, an R2-CX-C3_5-cycloalkyl group wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered 3C heteroaryl group optionally substituted by a C1-,-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group con-tains an imino group optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1_3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned al-kyl substituent may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino or N- (C1_3-alkyl) -carboxy-C,_3-alkylamino group, and X denotes an oxygen atom, a C1_3-alkylimino, Cl_3-alkoxyi.mino, E C1_3-alkylhydrazino, di- (C1_3-alkyl) -hydrazino, C2_4-alkanoyl-hydrazino, N- (C1_3-alkyl) -Cz_q-alkanoylhydrazino or C1_3-al-kylidene group each cf which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C1_3-alkyl or C3_5-cycloalkyl group substituted by an imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1_3-alkyl groups or by one, two or three C1_3-alkyl groups, wherein the substituents may be iden-tical or different and one of the abovementioned alkyl sub-stituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, C1_3-alkylamino, N- (C2_4-alkanoyl) -C1_3-alkylamino or di- (C1_3-alkyl) -amino group, and the imidazolone ring may be substituted by a C1_3-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2_4-alkanoyl-amino, Cl_3-alkylamino, N- (C2_4-alkanoyl) -C1_3-alkylamino or di-(Cl_3-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adja-cent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C1_3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C1_4-alkyl group which is substituted by a C1_3-alkyl-Yl-C1_3-alkyl, HOOC-Cl-3-alkyl-Yl-C1_3-alkyl, tetrazolyl-C1_3-alkyl-YZ, R3NR4- or R3NRq-C1-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C1-3-alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro--pi-peridinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbo-nyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in iC the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C1_3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovemen-tioned C1_3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a lE carboxy group, and the remaining hydrogen atoms of the C1-4-alkyl group may be wholly or partially replaced by fluo-rine atoms wherein R3 denotes a hydrogen atom or a C1_3-alkyl group optionally 2C substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3-alkyl-Y1-C1_3-alkyl-Y2, carboxy-C:_3-alkyl-Y1-C1_3-alkyl-Y2, Ci_3-alkyl-Y2 or carboxy-C1_3-alkyl-Y2 group or R3 and R4 together v,rith the nitrogen atom between them de-note an 4- to 7-membered cycloalkyleneimino group optio-nally substituted by a carboxy, C1_3-alkyl or carboxy--C1_3-alkyl group wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and Y. denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, 3E imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R3NR4-group, and the imino groups occurring in the definition of the groups Y1 and Y2 may each additionally be substituted by a C,_j-alkyl or carboxy-C1_3-alkyl group, a C1_3-alkyl or C3_5-cyclc>alkyl group substituted by a RSNRf;-group wherein R. denotes a hydrogen atom, a C1_3-alkyl, CS_,-cycloalkyl, phenylcarbonyl, pheny:Lsulphonyl or pyridinyl group and R6 denotes a C1_3-alkyl, carboxy-Cl_3-alkyl or carboxy-Cl_3-al-kylcarbonyl group, a C1_3-alkyl group which is substituted by a C2_4-alkanoyl or CS_,-cycloalkanoyl group and by a C1_3-alkvl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C1_3-alkyl group and R, denotes a cyano group or an amidino group which may be sub-stituted by a hydroxy group, by one or two C1_3-alkyl groups, or by one or two C1_e-alkoxycarbonyl groups, wherein the carboxy, am_Lno and imino groups mentioned in the definition of the abovernentioned groups may also be substituted by a group which can be cleaved in vivo, the tautomers, stereoisomers and salts thereof.

Particularly preferred compounds of the above general formula Ia are those wherein A denotes a Cl_3-alkylene: group, B denotes an oxygen atom, a methylene, imino or N-(C1_3-alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, R. denotes an C3_5-cycloalkyl group substituted by the Rl-CO
group in the 1 position wherein R 1 denotes a C1_3-alkoxy, amino, Cl_4-alkylamino or di-(C1_4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C1_3-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C1_3-alkoxy, carboxy, carboxy-C1_3-alkoxy, carboxy-C.L_3-alkylamino, N- (C,_3-alkyl) -N- (carboxy-C1_3-alkyl) -amino, car:boxy-C1_3-alkylaminocarbonyl, N- (C1_3-alkyl) -N- (carboxy-C1_3-alkyl) -aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1- (C1_3-alkyl) -3- (carboxy-C1_3-alkyl) -aminocarbonylamino, 3- (C1_3-alkyl) -3- (carboxy-C1_3-alkyl) -aminocarbonylamino or 1, 3-di- (C1_3-alkyl) -3-(carboxy-C1_3-alkyl)-aminocarbonylamino group, a 5- to 7-membered cycloalkyleneimino group optionally sub-stituted by a C1_3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1_3-alkyl)-piperazino, pyrro-lino, 3,4-dehydro-piperidino or pyrrol-i-yl group, a C3_5-cycloalkyl group substituted in the 1 position by the R2-CX- group, wherein R2 denotes a phenyl, iiaphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1_3-alkyl group, wherein the 6-membered. heteroaryl group contains one, 'two or three nitrogen atoms and the 5-membered heteroaryl group con-tains an imino group optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1_3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned al-kyl substituent may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-C1..3-alkylamino or N- (Cl_3-alkyl) -carboxy-C1_3-alkylamino group, and X denotes an oxygen atom, a C1_3-alkylimino, Ci_3-alkoxyimino or C1_3-alkylidene group, each of which may be substituted in the alkyl or alkanoyl moiety by a carboxy group, a C1_3-alkyl group substituted in the 1 position by an imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1_3-alkyl groups or by one, two or three C1_3-alkyl groups, wherein the substituents may be iden-lE. tical or different ar.Ld one of the abovementioned alkyl sub-stituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, C1_3-alkylamino, N- (C2_4-alkanoyl) -Cl_3-alkylamino or di- (Cl_3-alkyl) -amino group, and the imidazolone ring may be substituted by a C1_3-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2_4-alkanc>yl-amino, C1_3-alkylamino, N- (Cz_4-alkanoyl) -C1_3-alkylamino or di-(Cl_3-alkyl) -amino group, and additionally a phenyl. or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adja-cent carbon atoms, an imidazolidine-2,4-di.on-5-yl group which may be substituted by one or two C1_3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C1_4-alkyl group which is substituted in the 1 position by an R3NR4- or R3NR4-C;_3-alkyl group and by a pyrrolinocarbony1, 2,3-dehydro-piperidinocarbonyl, imidazol-l-yl-carbony1, carboxy, aminocarbonyl, C1_3-a1--kylaminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl, isoxazolidin-1-yl-carbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkylene-imino moiety may be substituted by one or two C1_3-alkyl.
groups and at the same time each alkyl moiety or alkyl sub-stituent in the abovementioned C1_3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remai-ning hydrogen atoms caf the C1_4-alkyl group may be wholly or partially replaced by fluorine atoms, wherein R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1_3-alkyl-Yz or carboxy-Cl_j-alkyl-YZ group or R3 and R4 together with the nitrogen atom between them de-note a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1 position by a carboxy, C1_3-alkyl or carboxy-C1_j-alkyl g:roup, wherein Y. denotes a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CC)-group is linked to the nitrogen atom of the R3NR4- group, and the imino group occurring in the definition of the groups Y2 may additionally be substituted by a C1_3-alkyl or carboxy-Cl_3-alkyl group, a C1_3-alkyl or C3_5-cycloalkyl group substituted in the 1 po-sition by an RSNR6- group, wherein R. denotes a hydrogen atom, a C1_3-alkyl, CS_,-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a Cl_,-alkyl, carboxy-C1_3-alkyl or carboxy-C1..3-al-kylcarbonyl group, a C1_3-alkyl group which is substituted by a C2_4-alkanoyl or CS_,-cycloalkanoyl group and by a C1_3-alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a C1_3-alkyl group and Rr denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, C1_e-alkoxycarbonyl, acet-oxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1_3-alkyl or C1_3-alkoxy groups and the substituents may be identical or different, the C1_3-alkanol esters, the tautomers, stereoisomers and salts thereof.

Most particularly preferred compounds of general formula I are those wherein A denotes a methylene g-roup, B denotes an oxygen atom or an imino group, Ra denotes a cyclopropy:l group substituted by the R1-CO- group in the 1 position, wherein R 1 denotes a pyrrolidino or piperidino group optionally sub-stituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-CI_3-alkylamino or N- (Cl_j-alkyl) -carboxy-C1_3-alkylamino group, a cyclopropyl group substituted in the 1 position by the R2-CX-group, wherein R2 denotes a phenyl, pyridyl, pyrazolyl group optionally sub-stituted by a C1_3-alk:yl group and X denotes an oxygen atom, a C1_3-alkoxyimino or C1_3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, lU
a C1_z-alkyl group substituted in the 1 position by an imi-dazole group wherein the imidazole ring may be substituted by a phenyl or carboxy qroup and by one or two C1_3-alkyl groups or by one, two or three C1_3-alkyl groups, wherein the sub-stituents may be ideritical or different and one of the above-mentioned alkyl substituents may simultaneously be substitu-ted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, C1_3-alkylamino, N- (C2_4-alkanoyl) -C, -alkylamino or di- (Cl_3-alkyl) -amino group, whilst additionally a phenyl or pyridine ring may be fused to the abovemeritioned imidazole rings via two adjacent carbon atoms, a C1_2-alkyl substituted. in the'l position by a benzimidazolon-2EI 1-yl group, whilst the imidazolone ring may be substituted by a methyl or ethyl group optionally substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position by an R3NR4- or R3NR, - C1_3 - a lkyl group and by a di-(C1_3-alkyl)-aminocarbonyl group, by an isoxazolidin-1-ylcarbonyl group, by a pyrrolidino-carbonyl or piperidino-carbonyl group substituted by a C1_3-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substi-tuent in the abovementioned groups may be substituted by a carboxy group, wherein R3 denotes a hydrogen atom or a C1_3-alkyl group optionally S substituted by a carboxy group and R4 denotes a hydrogen atom, a C1_3-alkyl-Y2 or carboxy--Cl_,-alkyl-Yz group or R3 and R4 together with the nitrogen atom between them de-note a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy group, wherein Y2 denotes a carbon-n:ir-rogen bond, a carbonyl group or an imino group optionally substituted by a C1_3-alkyl group, a C1_2-alkyl group substituted in the 1 position by an R;NR6-group, wherein R. denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and R6 denotes a C1_.3-alkyl. or carboxy-C1_3-alkyl group, 2S an n-propyl group substituted in the 3 position by a chlorine atom, which is substituted in the 1 position by a cyclopentyl-carbonyl group, a cyclopropyl group substituted in the 1 position by a cyclo-3C pentylamino group, which. is substituted at the nitrogen atom by a carboxy-C1_3-alkylcarbonyl group, R. denotes a methyl group and 3E R, denotes an amidino group which may optionally be substituted by a C1_8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-tri-chloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, particularly those compounds of general formula Ia wherein A denotes a methylene group, B denotes an imino group, Ra denotes a cyclopropyl group substituted by the R1-CO- group in the 1 position, wherein R1 denotes a pyrrolidino or piperidino group optionally sub-stituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-Cl_,-alkylamino or N- (C1_3-alkyl) -carboxy-C1_3-alkylamino group, a cyclopropyl group substituted in the 1 position by the R2-CX
group, wherein R2 denotes a phenyl, pyridyl, pyrazolyl group optionally sub-stituted by a C1_3-alkyl group and X denotes an oxygen atom, a C1_3-alkoxyimino or C1_3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy g,-oup, a C1_z-alkyl group substituted in the 1 position by an imi-dazole group wherein the imidazole ring may be substituted by one to three methyl groups or by two methyl groups and an ethyl group, whilst additionally one of the abovementioned methyl or ethyl substituents may simultaneously be substitu-ted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position by an R3NR4 - or R3NR4 - C:Hz - group and by a di-(C1_3-alkyl)-aminocarbonyl, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by a C1_3-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent may be substituted by a D carboxy group, where:in R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted by a carboxy group and l'D R4 denotes a C1_3-alkyl-Yz or carboxy- C1_3-alkyl-Yz group wherein Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C1_3-alkyl group, Rb denotes a methyl group and Rc denotes an amidino group which may optionally be substituted by a C1_e-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-tri-20 chloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the abovementioned compounds in which the group Ra is in the 5 position are particularly preferred, 25) the C1_3-alkanol esters, the tautomers, stereoisomers and salts thereof.

The following are mentioned as examples of particularly pre-ferred compounds:
(a) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(pyrrol.idin-1-yl-carbonyl)-cyclopropyl]-benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-1:(pyri-din-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benz-imidazole, (c) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, (d) 2- (4-amidinophenylaminomethyl) -i-methyl-5- [1- [2- (2-carb-oxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole, (e) 2- (4-amidinophenylaiminomethyl) -i-methyl-5- [2- (2-carb-oxyethyl)-4,5-dimethyl-imidazol-i-yl-methyl]-benzimidazole (f) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrroli(din-1-yl-carbonyl)-ethyl]-benzimidazole and (g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-methyl-l-(pyrrolidin-1-yl-carbonyl)-ethyl]-b(E!nzimidazole and the C1_3-alkanol esters, the N- (Cl_e-alkoxycarbonyl) , N-benzyloxycarbonyl and N-benzoyl-amidines, the tautomers, stereoisomers and salts thereof.

According to the invention, the compounds of general formula I
are prepared by methods known per se, for example by the fol-lowing methods:
a) In order to prepare a compound of general formula I wherein R, denotes a cyano group:

cyclising a compound of general formula Z\ ZZ

NH C -A-B -Ar -CN
Ra NH (II) , I
Rb optionally formed in the reaction mixture, wherein Ra, Rb, Ar, A and B are as hereinbefore defined, Z1 and Z2, which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon atoms or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylendioxy or alkylenedithio group with 2 or 3 carbon atom.s.
The cyclisation is expediently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethylether, diethyleneglycol dimethylether, sul-pholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250 C, but preferably at the boiling temperature of the re-action mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sul-phuryl chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N-di-cyclohexyl-carbodiimide or optionally in the presence of a base such as potassium ethoxide or potassium tert. butoxide. How-ever, the cyclisation may also be carried out without a solvent and/or condensing agent.

It is particularly advantageous to perform the reaction by preparing a compound of general formula II in the reaction mixture by reduction of a corresponding o-nitro compound optionally in the presence of a carboxylic acid of general f ormul a HO-CO-A--B-Ar-CN (III), wherein Ar, A and B are as hereinbefore defined, by acylation of a corresponding amino conipound optionally formed in the reaction mixture.
b) In order to prepare a compound of general formula I wherein Ra denotes a R2-CX' -C3_5-cycloalkylene group, wherein R2 is as hereinbefore defined and X' denotes one of the imino groups mentioned for X hereinbefore:
reacting a compound of general formula Ra ' ~ } - - A - B -Ar Rc ( I V ) , N
I
Rb wherein Rb, R,, Ar, A and B are as hereinbefore defined and Ra' denotes an R2-CO-C3_5-cycloalkylene group, where R2 is as hereinbefore defined, with an amine of general formula H2X' (V) , wherein X' denotes one of the imino groups mentioned for X herein-before.

The reaction is preferably carried out in a solvent such as methanol/toluene, ethanol, isopropanol or xylene and expedient-ly in the presence of a. dehydrating agent such as molecular sieve, sodium sulphate or calcium chloride optionally in the presence of a base such. as triethylamine at temperatures bet-ween 50 and 100 C, preferably at the boiling temperature of the reaction mixture.

c) In order to prepare a compound of general formula I wherein Ra denotes a R2-CX" -C3_5-cycloalkylene group, wherein R2 is as hereinbefore defined and X" denotes one of the alkylidene groups mentioned for X hereinbefore:

reacting a compound of general formula N
R ~ I \>--A-B -Ar R. ( I V), N
I
Rb wherein Rb, R,, Ar, A and B are as hereinbefore defined and Ra' denotes an R2-CO-Cs_5-cycloalkylene group, where R2 is as hereinbefore defined, with a phosphone of general formula 2;3-HX" (VI), wherein X" denotes one of the alkylidene groups mentioned for X
hereinbefore and Z3 denotes a triphenylphosphono or di-(C1_3-alkoxy)phosphono group such as the triethoxyphosphono group.

The reaction is preferably carried out under protective gas in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, diethylether or dimethyl sulphoxide in the presence of a base such as potassium tert. butoxide, sodium ethoxide or sodium hydride at temperatures between -25 and 50 C, preferably at temperatures between -15 and ambient temperature.
d) In order to prepare a compound of general formula I wherein R,, denotes an amidino group which may be substituted by one or two C1_3-alkyl groups :

reacting a compound of general formula / N
R. \>A-B-Ar C= (NH) Z4 (VII) N

I
Rb optionally formed in the reaction mixture wherein Ra, Rb, Ar, A and B are as hereinbefore defined and Z4 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkyl-thio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula H - R,NRB , (VIII) wherein R, and Re, which may be identical or different, each denote a hydrogen atom or a C,._,-alkyl group, or with the salts thereof.
The reaction is expediently carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 1500C, preferably at temperatures between 0 and 80 C, with an amine of general formula VIII or with a corresponding acid addition salt such as for example ammonium carbonate or ammonium acetate.

3C, A compound of general formula VII is obtained for example by reacting a corresponding cyano compound 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 a corresponding amide with a trialkyloxo-nium salt such as triethyloxonium-tetrafluoroborate in a sol-vent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 C, but preferably at 20 C, or a corresponding nitrile with hydrogen sulphide expediently in a solvent such as pyridine or dimethylformamide and in the pre-sence of a base such as triethylamine and subsequently alkyla-ting the thioamide formed with a corresponding alkyl or aralkyl halide.

e) In order to prepare a compound of general formula I wherein Ra denotes an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C1_3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or C1_3-alkoxycarbonyl group:
cyclising a compound of: general formula / N\
Ran --_A-B-Ar CN (IX), N/
I
Rb optionally formed in the reaction mixture wherein Rb, Ar, A and B are as hereinbefore defined and Ra" denotes an aminocarbonylamino group, substituted in the 3 position by a C1_3-alkoxycarbonyl-C1_3-alkyl group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatu-res between 0 and 50 C, but preferably at 20 C.

3C f) In order to prepare a compound of general formula I wherein Rr denotes a hydroxyamidino group:

reacting a nitrile of general formula / N
R. I ~ -.A-B -Ar CN ( X ) , ~ N
I
Rb wherein Ra, Rb, Ar, A and B are as hereinbefore defined, with hydroxyl-amine or the salts thereof.
The reaction is expediently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetra-hydrofuran, tetrahydrofuran/water, dioxane or dioxane/water at temperatures between 0 and 150 C, preferably at temperatures between 0 and 80 C.

g) In order to prepare a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined or R. is as hereinbefore defined and R, denotes an amidino group optionally substituted by a hydroxy group or by one or two Cl_3-alkyl groups :

converting a compound of general formula N
Ra ~ n I \> A-B -Ar Rc ( XI ) , N

Rb wherein Rb, Ar, A and B are as hereinbefore defined and Ra' " and Rc ' have the meanings given for R. and R, with the proviso that Ra contains a group which may be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Rc is as hereinbefore defined or R, denotes a group which may optionally be converted by hy-drolysis, treatment with an acid or base, thermolysis or hydro-genolysis into an amidino group substituted by a hydroxy group or by one or two C1_3-alkyl groups and Ra is as hereinbefore defined, is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined or Rd is as hereinbefore defined and RC
denotes an amidino grou.p optionally substituted by a hydroxy group or by one or two C1_3-alkyl groups.
A group which may be converted into a carboxy group might be, for example, a carboxyl group protected by a protecting group, such as the functional derivatives thereof, e.g. the unsubsti-tuted or substituted amides, esters, thioesters, trimethyl-1S silylesters, orthoesters or iminoesters thereof which are expediently converted by hydrolysis into a carboxyl group, the esters thereof with. tertiary alcohols, e.g. the tert.butyl ester, which are expediently converted into a carboxyl group by 2Ci treatment with an acid or thermolysis, and the esters thereof with. aralkanols, e.g. the benzylester, which are expediently converted into a carboxyl group by hydrogenoly-sis.

The hydrolysis is expediently carried out either in the pre-sence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoro-acetic acid or the mixtures thereof or in the presence of a 30 base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/te-trahydrofuran or water/dioxane at temperatures between -10 and 120 C, e.g. at temperatures between ambient temperature and the 3EI boiling temperature of the reaction mixture.
If a compound of formula XI for example contains the tert.butyl or tert.butyloxycarbonyl. group, these may also be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric E acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -1.0 and 120 C, e.g. at temperatures bet-ween 0 and 600C, or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, te-trahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, prefe-rably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120 C.

If a compound of formula XI contains, for example, a benzyloxy or benzyloxycarbonyl gr-oup, these may also be cleaved hydroge-nolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a. suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, di-oxane or dimethylformaniide, preferably at temperatures between 0 and 50 C, e.g. at ambient temperature, and at a hydrogen pressure of from 1 to E. bar.
h) In order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by one or two C1_B-alkoxycarbonyl groups or by a group which can be cleaved in vi vo :

reacting a compound of general formula I
/ N
Ra I ~--A-B -Ar RC~~ ( X I I), ~ N
I
Rb wherein Ra, Rb, Ar, A and B are as hereinbefore defined and R," denotes an amidino group, with a compound of general formula Z5 -- R9 (XI I I ) wherein R9 denotes a C1_e-alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned herein-before and ZS denotes a nucleofugic leaving group such as a halogenatom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, to-luene, dioxane, dimethyl sulphoxide or dimethylformamide op-tionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 C and the boiling temperature of the solvent used.

With a compound of general formula XIII wherein Z5 denotes a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, te-trahydrofuran, toluene, acetone/water, dimethylformamide or dimethyl sulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert. butoxi-de or N-ethyl-diisopropylamine at temperatures between 0 and 60 C.

If according to the invention a compound of general formula I
is obtained which contains a(R3NR4) -C1_3-alkyl group wherein at least one of the groups R3 or R, denotes a hydrogen atom, this may subsequently be converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of gene-ral formula I and/or if a compound of general formula I is obtained which contains an NH2-C1_3-alkyl group, this may subsequently be converted with a corresponding acrylic acid ester into a corresponding S 2- (C1_3-alkoxycarbonyl) -ethyl compound of general formula I
and/or if a compound of general formula I is obtained which contains an (R3NR4) -C1_3-alkyl group wherein R3 and R4 each denote a hy-drogen atom, this may subsequently be converted with a corres-ponding dihaloalkane irito a corresponding compound of general formula I wherein R3 and R4 together with the nitrogen atom between them denote a corresponding 4- to 7-membered cycloalky-leneimino group and/or 1C' if a compound of general formula I is obtained wherein R,_ de-notes an amidino group, this may subseauently be converted by reaction with a haloacetic acid derivative and subsequent hy-drolysis and decarboxylation into a corresponding amidino com-2C pound substituted by orie or two methyl groups and/or if a compound of general formula I is obtained wherein R. de-notes a hydroxyamidino group, this may subsequently be conver-ted into a corresponding amidino compound by catalytic hydro-2E genation and/or if a compound of general formula I is obtained wherein R3 con-tains a carboxy group, this may subsequently be converted into a corresponding ester by esterification.

The subsequent preparation of a corresponding urea compound of general formula I is expediently carried out with a correspon-ding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformami_de and optionally in the presence of a 3E tertiary organic base such as triethylamine at temperatures be-tween 0 and 50 C, preferably at ambient temperature, The subsequent preparation of a corresponding 2-(C1_3-alkoxy-carbonyl)-ethyl-compound is carried out with a corresponding acrylic acid ester, preferably in a solvent such as methanol, ethanol or isopropanol at temperatures between 50 and 100 C, preferably at the boiling temperature of the reaction mixture.
The subsequent preparation of a corresponding 4- to 7-membered cycloalkyleneimino compound of general formula I is expediently carried out with a corresponding dihaloalkane, preferably in a solvent such as methanol, ethanol or isopropanol in the presen-ce of a base such as sodium carbonate at temperatures between 50 and 100 C, preferably at the boiling temperature of the reaction mixture.

The subsequent alkylation is expediently carried out in a sol-vent such as methylene chloride, tetrahydrofuran, dioxane, di-methylsulphoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or potas-sium iodide and prefera:bly 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-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously act as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 C, but preferably at temperatures between -10 and 80 C.

The subsequent hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, tri-fluoroacetic 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, methanol, ethanol, water/te-trahydrofuran or water/dioxane and subsequent decarboxylation in the presence of an acid as hereinbefore described at tem-peratures between -10 and 120 C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

The subsequent esterification is carried out with a correspon-ding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, but prefe-rably in an excess of the alcohol used, optionally in the pre-sence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chlo-roformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachlo-ride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N--ethyl-diisopropylamine or N,N-dimethylamino-pyridine expediently at temperatures between 0 and 150 C, preferably at temperatures between 0 and 80 C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or acetone, optionally in the presence of a reaction. accelerator 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 ter-tiary organic base such as N-ethyl-diisopropylamine or N-me-thyl-morpholine, which inay simultaneously act as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 C, but preferably at tem-peratures between -10 and 80 C.

In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, El protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroa.cetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the arnino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahvdrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydro-chloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potas-sium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 C,, pre-ferably at temperatures between 10 and 50 C.

2E, However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a sol-vent such as methanol, ethanol, ethyl acetate, dimethylform-amide, dimethylformamide/acetone or glacial acetic acid, optio-nally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 C, but preferably at ambient tem-perature, and at a hydrogen pressure of 1 to 7 bar, but prefe-rably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidant such as cerium(IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at tem-peratures between 0 and 50 C, but preferably at ambient tempe-rature.

A 2,4-dimethoxybenzyl g:roup, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably clea-ved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hy-drazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopro-panol, toluene/water or dioxan at temperatures between 2C) and 50 C.

An allyloxycarbonyl group is cleaved by treating with a cata-lytic amount of tetrakis-(triphenylphosphine)-palladium(C)), 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 ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I:)chlo-ride 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.

The compounds of general formulae II to XIII used as starting materials, some of which are known from the literature, may be obtained by methods known from the literature and in addition their preparation is described in the Examples.

The chemistry of the cornpounds of general formula III is des-cribed, for example, by Jack Robinson in J. Chem. Soc. 1241, 744, that of the benzimidazoles is described by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, and by Schaumann in Hetarene III, Methoden der organischen Chemie (Houben-Weyl), 4"' edition, Verlag Thi.eme, Stuttgart 1993.

Thus, for example, a compound of general formula II is obtained by acylating a correspc>nding o-diamino compound with a corres-ponding reactive derivative of a compound of general formula III, a compound of general formulae IV, VII, IX, X, XI and XII is obtained by cyclisatior.L of a corresponding substituted compound according to process a) and if necessary subsequent reduction of any nitro group present in the phenyl moiety, followed by acylation, amidation ar.Ld/or halogenation.
1 E, Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.

2C Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereo-chemistry", Vol. 6, Wiley Intersci.ence, 1971) into their op-tical antipodes and compounds of general formula I with at 25 least 2 asymmetric carbon atoms may be resolved into their dia-stereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or frac-tional crystallisation, and, if these compounds are obtained in racemic form, they may subsequenti.y be resolved into the enan-30 tiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically ac-tive solvent or by reacting with an optically active substance 35 which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereo-meric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, as-partic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxy-carbonyl.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, :phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted irito the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexyl-amine, ethanol-amine, diethanolamine and triethanolamine.

As already mentioned hereinbefore, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherein Rc denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I, and the compounds of ge-neral formula I wherein Rc: denotes one of the abovementioned amidino groups, and the tautomers, stereoisomers and the phy-siologically acceptable salts thereof have valuable pharmaco-logical properties, particularly an antithrombotic activity, which is preferably based on an activity which influences thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on an activity which extends the aPTT time and on an inhibiting effect on related serine pro-teases such as, for example, trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the compounds A = 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(pyrrol:idin-1-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride, B = (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyri-din-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benz-imidazole-hydrochloride, C = 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(2-carb(Dxy-ethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride, D = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxy-ethyl)-pyrrolidin-1-y:.-carbonyl]cyclopropyl]-benzimidazole-hy-drochloride, E = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-l-yl-methyl]-benzimidazole-hy-drochloride, F = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride and G = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-methyl-l-(pyrrolidin.-l-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride were investigated for their effect on extending the aPTT time as follows:

Materials:
- Plasma, from hunian citrated blood, - PTT reagent, Boehringer Mannheim (524298), - calcium solution. (0.025 Mol/1), Behring Werke, Marburg (ORH 056/57), - diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), - Biomatic B10 coagulometer, Desaga, Wiesloch.
Method:

The aPTT time was determined using a Biomatic B10-coagulometer made by Messrs. Desaga.

The test substance was added to the test vessels prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 37 C. The clotting reaction was started by the addition of 0.1 ml of calcium solution. Because of the design of the appa-ratus, the time taken for the mixture to clot was measured as the calcium solution was added. Mixtures to which 0.1 ml of DBA
buffer had been added were used as controls.

According to the definition the effective concentration of sub-stance at which the aPTT time was double that of the control was determined by means of a dosage/activity curve.
The following Table contains the values found:
substance APTT time (ED200 in M) A. 0.12 B 0.42 C' 0.31 D 0.29 E 0.29 F 0.20 G 0.17 The compounds prepared according to the invention are well tolerated, since no toxic side effects could be detected at therapeutic doses.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial t:hrom-botic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass ope-rations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated in-travascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic sup-port in thrombolytic tri=_atment, such as for example with rt-PA
or streptokinase, for p:reventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-depen-dent tumours and fibrin-dependent inflammatory processes, e.g.
in the treatment of pulinonary fibrosis.

The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 mg,/kg, preferably 0.3 to 30 mg/kg by oral route, in each case adm:inistered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, mi-crocrystalline cellulose, magnesium stearate, polyvinylpyrro-lidone, citric acid, tartaric acid, water, water/ethanol, wa-ter/glycerol, water/sorbitol, water/polyethyleneglycol, propy-leneglycol, cetylstear.yl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or supposito-ries.

The Examples which follow are intended to illustrate the in-vention:
FxamrDl P ~

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-l-yl-carhonyL) yls o]prnnyl ] -bPnzimi da7.o1P-hydro .hl ori dP
a. 1- (4-chl oro-3-ni t rn-C~h~~l l~~ -~~c'1 0= ro~ anPC-arhox~l i_ a.i d To 350 ml of fuming nitric acid are added, in batches, at -25 C, 50.0 g (0.21 mol) of 1-(4-chlorophenyl)-1-cyclopro-panecarboxylic acid. The solution is stirred for 15 minutes at -25 C and subsequently poured onto ice water. The product pre-cipitated is suction filtered, washed with water and dried.
Yield: 58.5 g (95 0 of theory), R, value: 0.45 (silica gel; methylene chloride/methanol = 9.5:0.5) b. 1-(4-methylamino-3-n:itro-phenyl)-1-cyclopropanecarboxylic aci d 20.0 g(0.083 mol) of 1- (4-chloro-3-nitro-phenyl) -1-cyclopropa-necarboxylic acid and 100 ml of methylamine solution (40u in H20) are heated to 80 C in a pressure vessel for five hours.
The contents are evaporated to dryness, dissolved in water and acidified with glacial acetic acid. The product precipitated is suction filtered, washed with water and dried.
Yield: 16.9 g (93 a of theory), Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) c. 4-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-2-nitro-N-me-t-hy]-ani.line 2.4 g (0.01 mol) of 1-(4--methylamino-3-nitro-phenyl)-i-cyclo-propanecarboxylic acid are dissolved in 50 ml dimethylformamide and after the addition of 3.2 g (0.01 mol) of O-(benzotri.azol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) of pyrrolidine and 1.1 g (0.01 mol) of N-methyl-morpholine stirred for 20 hours at ambient temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired frac-tions are concentrated by evaporation, triturated with ether, suction filtered and dried.
Yield: 1.8 g (61 a of theory), F. value: 0.51 (silica gel; methylene chloride/methanol = 9:1) d. 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-amino-N-me-thyl-an'lin 1.8 g (6.2 mmol) of 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopro-pyl]-2-nitro-N-methyl-aniline are dissolved in 40 ml methanol and 40 ml methylene chloride and after the addition of 0.4 g of palladium on activated charcoal (100) hydrogenated for 4 hours at ambient temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation.
Yield: 1.6 g (100 0 of theory), Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1) e. 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-(4-cyanophe-ny1 ) ami nom -_hyl .sarbnz 1aanino-N-methyl -ani 1 i n.
Prepared analogously to Example ic from 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotria-zol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 66 % of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) f. 2- (4-cyanophenylaminomethyl) -i-methyl-5- [1- (pyrrolidin-1-yl-carbon~rl ) c~rcl o~ ro~~,rl 1-ben7i mi dazol e 1.7 g (0.004 mol) of 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopro-pyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline are refluxed in 7 ml of glacial acetic acid for 2 hours. The solvent is distilled off, the residue dissolved in water and extracted with methylene chloride. The organic phase is dried, concentrated by evaporation and subsequently chroma-tographed on silica gel, eluting with methylene chloride + 2 to 31 methanol.
Yield: 1.0 g (62 0 of theory), Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) g. 2-(4-amidinophenylam.inomethyl)-1-methyl-5-[1-(pyrroli(lin-l-yl-carbonyl ) cycl o~2robyl] -b n.i mi da .ol P-hydro .h1 ori c3 _ 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole are dissolved in 50 ml saturated ethanolic hydrochloric acid and stirred for 5 hours at ambient temperature. The solvent is di-stilled off, the residue dissolved in 50 ml absolute ethanol and mixed with 2.3 g (25 mmol) of ammonium carbonate. After 60 hours at ambient temperature the mixture is evaporated to dryness. The residue is chromatographed on silica gel, eluting with methylene chloride/methanol (7:1).
Yield: 700 mg (62 0 of theory), R. value: 0.61 (silica gel; methylene chloride/methanol = 4:1) C24H28N6O x HCl (416.54/453.0) mass spectrum: (M+H)` = 417 The following compounds are obtained analogously to Example 1:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-methyl-pi-peridin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 45 % of theory, Rf value: 0.25 (silica qel; methylene chloride/methanol = 4:1) Cz6H3zN60 x HC1 (444.59/481.05) mass spectrum: (M+H)' = 445 (2) 2- (4-amidinophenylar.ninomethyl) -i-methyl-5- [1- (piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 57 0 of theory, Rf value: 0.23 (silica qel; methylene chloride/methanol = 4:1) C25H30N6O x HC1 (430.56/467.93) mass spectrum: (M+H)' = 431 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(4-methyl-pi-perazin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 32 of theory, Rf value: 0.26 (silica gel; methylene chloride/methanol/ammonia = 2:1:0.25) C25H31N,0 x HC1 (445 . 58/482 . 04 ) mass spectrum: (M+H)' = 446 (4) 2-(4-amidinophenyla.minomethyl)-1-methyl-5-[1-(2,3-dihydro-indolin-1-yl-carbonyl)cyclopropyll-benzimidazole-hydrochloride Yield: 60 0 of theory, Rf value: 0.34 (silica gel; methylene chloride/methanol = 4:1) C28HZ8N6O x HC1 (464.58/501.04) mass spectrum: (M+H)' = 465 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((2-ethoxy-carbonylethyl)-piperidin-1-yl-carbonyl)cyclopropyl]-benzimi-dazole-hydrochloride Yield: 85 a of theory, Rf value: 0.57 (silica gel; methylene chloride/methanol = 4:1) C30H38N603 x HC1 (530.67/567.13) mass spectrum: (M+H)` = 531 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((2-ethoxy-carbonylethyl)-pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimi-dazole-hydrochloride Yield: 60 0 of theory, C29H36N6O3 x HCl (516.64/553.10) mass spectrum: (M+H)+ = 517 (M+2H) " = 259 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(N-(2-eth-oxycarbonylethyl)-N-methyl-aminomethyl)-pyrrolidin-1-yl-car-bonyl]cyclopropyl]-benz.imidazole-hydrochloride Yield: 65 % of theory, C31H41N703 x HC1 (559.72/ 596.18) mass spectrum: (M+H)' = 560 (M+2H)r' = 280.6 (8) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-[(2-ethoxy-carbonylmethyloxymethyl.)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochlor.ide Yield: 61 % of theory, E Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 o glacial acetic acid) C29H36N6O4 x HCl (532.66/:569.11) mass spectrum: (M+H)' = 533 (M+2H)'' = 267 F,am 1 P 2 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1-cyclopentylcar-bon~rl -3 -r.hl oro-n-proj:~~Tl 1-h -n .i mi dazol P-hydro hl ori dP
a_ 4- [I - (cycrl o ntyl c-arhon~,rl) c~rs1or rojpyl ]-chl orob -nz _n 2.4 g (0.1 mol) of magnesium chips are suspended in 10 ml ether. After the addition of a spatula-tip of iodine, 14.9 g (0.1 mol) of bromocyclopentane are slowly added dropwise to 40 ml of ether, the reaction being started off initially by gentle heating. After the addition has ended the mixture is refluxed for 30 minutes. Then a solution of 14.0 g (0.08 mol) of 1-(4-chlorophenyl)-i-cyclopropanecarbonitrile in 75 ml ether is added and refluxed for a further 3 hours. The reaction so-lution is poured onto ice water, adjusted to pH 3 with hydro-chloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is chroma-tographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1 and 15:1).
Yield: 3.0 g (12 0 of theory), Rf value: 0.58 (silica ciel; petroleum ether/ethyl acetate = 4:1) h_ 4- L~ -(-~r~l,o Pn ~] r r~~nyl )s~rslc~p ro~yl~ -2-ni ro- hlorobPn . nP
Prepared analogously to Example la from 4-[1-(cyclopentylcarbo-nyl)cyclopropyl]-chloro:benzene and fuming nitric acid.
Yield: 87 0 of theory, Rf value: 0.60 (silica qel; petroleum ether/ethyl acetate = 9:1) c. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-N-methyl-ani7 i nP
Prepared analogously to Example lb from 4-[1-(cyclopentylcarbo-nyl)cyclopropyl]-2-nitro-chlorobenzene and aqueous methylamine solution.
Yield: 18 % of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methyl-aniline 2.3 g (7.9 mmol) of 4-[1-(cyclopentylcarbonyl)-cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 125 ml ethyl acetate and 25 ml ethanol and after the addition of 1.0 g Raney nickel hydrogenated for 1.5 hours at ambient temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation.
Yield: 2.0 g (98 0 of theory), Rf value: 0.15 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-(4-cyanophenyl-aminom .t-.hyl crarbonyl amino)-N-mAt-hy - n' l i n.
Prepared analogously to Example ic from 4-[1-(cyclopentylcarbo-nyl)cyclopropyl]-2-amino-N-methyl-aniline, 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 96 % of theory, Rf value: 0.54 (silica ciel; methylene chloride/ethanol = 19:1) f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[l-(cyclopentylcar-bonyl )-c,ysl o~2ropyll -benzi midazol e Prepared analogously to Example if from 4-[1-(cyclopentylcarbo-nyl)cyclopropyl]-2-(4-cyanophenyl-aminomethylcarbonylamino)-N-methyl-aniline in glacial acetic acid.
Yield: 53 0 of theory, Rf value: 0.46 (silica gel; methylene chloride/ethanol = 19:1) g. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1- cyclopentyl-crarbonyl -3-_ l oro-n -pron~rl ) -hPn.i mi da .ol h~rdro .hl ori dP
Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-(1-cyclopentylcarbonyl-3-chloro-n-propyl)-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 61 0 of theory, C25H30C1NSO x HC1 (452.00/488.56) mass spectrum: (M+H) + == 452/4 (Cl)) F=xam~ 1,~- -~

(E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino)-methylene]cyclopropyl]-hen7i mi da .ol P-hy'7rorhl n=ride a. 1- L~~~rri di n-~-yl )-r.arbonyl 1~yc~l o~ rop~rl -hPn . n_ A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether is added dropwise at -40 to -50 C to 100 ml of butyl-lithium (1.6 M in hexane) and then stirred for 20 minutes at -40 C. The mixture is then cooled to -60 C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane-carbonitrile in 125 ml ether is added dropwise. After it has all been added, the reaction mixture is heated to ambient temperature and stirred for 5 hours. The suspension is mixed with 20o hydro-chloric acid and heated to 100 C for 30 minutes. After cooling, the mixture is adjusted to pH 8 with 20o sodium hydroxide solu-tion and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (9:1).
Yield: 14.0 g (46 % of theory), Rf value: 0.27 (aluminium oxide; petroleum ether/ethyl acetate = 9:1) h- 4- j1-((Ipyri cii n--~ -y l 1--arhon~,rl 1 c-ycl o roj:~yl 1-ni rrohPn7enP
Prepared analogously to Example la from 1-[(pyridin-3-yl)-carbonyl]cyclopropyl-be:nzene and fuming nitric acid.
Yield: 53.7 % of theory, Rf value: 0.29 (aluminium oxide; petroleum ether/ethyl acetate = 4:1) c.
4- fl - f(~~rri c3i n-~-~rl Z-carbon~rl ls~rc-1 o ro~~l 1-ani 1 i nP
Prepared analogously to Example 2d from 4-[1-[(pyridin-3=-yl)-carbonyl]cyclopropyl]-n:itrobenzene and Raney nickel in ethyl acetate/ethanol.
Yield: 94 0 of theory, Rf value: 0.51 (silica cfel; methylene chloride/ethanol = 19:1) d. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-trifluoro-acetylanilinP
8.0 g (33.5 mmol) of 4- [1- [(pyridin-3-yl) -carbonyl] cyclopro-pyl]-aniline are dissolved in 100 ml chlorobenzene and after the addition of 15 ml trifluoroacetic anhydride the mixture is stirred for two hours at 110 C. The solvent is distilled off, the residue stirred with petroleum ether/ether (9:1), suction filtered and dried.
Yield: 10.0 g (88 % of theory), Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[1-[(pyridin-3-yl)--carbonyl]cyclopropyl]-2-nitro-tri fl uoroa . yl ani 1 i nP
1.7 g (5 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-trifluoroacetylaniline are added batchwise to 13 ml of conc.
sulphuric acid and 16 m=. of 65o nitric acid at -5 C. Then the mixture is stirred for a further 30 minutes without cooling, poured onto ice water and extracted with ethyl acetate. The organic extracts are dr~_ed and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with me-thylene chloride/ethanol (50:1 and 25:1). The desired fractions are concentrated by evaporation, triturated with ether/petro-leum ether, suction filtered and dried.
Yield: 1.2 g (75 0 of t:heory), Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1) f. 4- [1- [ (pyridin-3-yl) -carbonyl] cyclopropyl] -2-nitro-N-E, t- ri f l voroa Pyl -N-me h~,,] - n i l' n 1.15 g (3.0 mmol) of 4-C1-[(pyridin-3-yl)-carbonyl]cyclopro-pyl]-2-nitro-trifluoroa.cetylaniline are dissolved in 50 ml acetone and after the addition of 2.0 g potassium carbonate and 0.8 ml methyl iodide re:fluxed for two hours. The insoluble matter is filtered off and the solution is evaporated down. The residue is chromatographed on silica gel, eluting with petro-leum ether/ethyl acetate (1:1 and 1:4).
Yield: 0.88 g (75 0 of theory), Rf value: 0.38 (silica gel; petroleum ether/ethyl acetate = 1:1) g. 4- [1- [ (pyridin-3-yl) -carbonyl] cyclopropyl] -2-nitro-N-mel--hyl -anilinP
7.4 g (18.8 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopro-pyl]-2-nitro-N-trifluoroacetyl-N-methyl-aniline are stirred in 200 ml of 20% potassium hydroxide solution for one hour at C. Then the mixture .4-s diluted with isopropanol, the organic phase is separated off, 10.0 g of aluminium oxide are added and the resulting mixture is evaporated to dryness. The residue is 25 chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (4:1 and 1:1).
Yield: 2.6 g (47 0 of theory), R. value: 0.50 (silica gel; petroleum ether/ethyl acetate = 1:1) h. 4- [l- [ (pyridin-3-yl) -,carbonyl] cyclopropyl] -2-amino-N-mel=_hyl -ani line Prepared analogously to Example 2d from 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2--nitro-N-methyl-aniline and Raney nickel in ethyl acetate/ethanol.
Yield: 98 0 of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol =:19:1) i. 4- [1- [ (pyridin-3-yl) -carbonyl] cyclopropyl] -2- (4-cyano--nhenyl )-ami nome hylcarbonyl ami no-N-m hy1 -a i 1 i nP
Prepared analogously to Example ic from 4-[1-[(pyridin-3-y1)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline, O-(benzot:ria-zol-1-yl)-N,N,N1,N'-tet:ramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 97 % of theory, F. value: 0.48 (silica gel; methylene chloride/ethanol = 19:1) k. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-carbonyl 1 oyr.l ~= ro~~,l 1-b=_nzimidazol e Prepared analogously to Example if from 4-(pyridin-3-yl-carb-onyl)cyclopropyl-2-(4-cyanophenyl)-aminomethylcarbonylami.no-N-methyl-aniline in glacial acetic acid.
Yield: 76 0 of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol = 19:1) 1. (E/Z)-2-(4-cyanophenylaminomethyl)-i-methyl-5-[1-[(pyridin-3-yl)-(carboxymethyloxy:imino)methylene]-cyclopropyl]benzimi-KazolP
1.6 g (4.0 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5- [1- [(pyridin-3-yl) -carbonyl] cyclopropyl] -benzimidazole, 3.0 g (12 mmol) of carboxy-methoxylamine-hemihydrate, 0.84 ml of tri-ethylamine, 12 g of molecular sieve 3A and 12 g of molecular sieve 4A are refluxed for 12 hours in 80 ml methanol and 40 ml toluene. Then the molecular sieve is filtered off and the fil-trate is concentrated by evaporation. The residue is stirred with water, suction filtered and dried. The crude product is chromatographed on silica gel, eluting with methylene chlo-ride/ethanol/glacial acetic acid (25:1:0 and 8:2:0.2).
Yield: 0.9 g (48 % of theory), F. value: 0.34 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2) m. (E/Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [ (pyri-din-3-yl)-(ethoxycarbor.iylmethyloxyimino)-methylene]cyclopro-pyl] -b .n .i mi c3azn1 P-hydrochloride Prepared analogously tc> Example ig from (E/Z)-2-(4-cyanophenyl-aminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonyl-methyloxyimino)methyler.Le]cyclopropyl]-benzimidazole and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 60 0 of theory, Rf value: 0.28 (silica gel; methylene chloride/ethanol/gl.acial acetic acid = 8:2:0.2) C2yH31N,O3 x HC1 (525.62/562.09) mass spectrum: (M+H)' = 526 The following compounds are obtained analogously to Example 3:
(1) (E/Z)-2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-[(pyri-dine-2-yl)-(ethoxycarbonylmethyloxyimino)-methylene]cyclopro-pyl]-benzimidazole-hydrochloride Yield: 52 0 of theory, Rf value: 0.21 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2) C29H31N703 x HC1 (525.62/562.09) mass spectrum: (M+H)' = 526 2E, (2) (E/Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl-(ethoxycarbonylmethyloxyimino)-methylene]-cyclopropyl]-benzimidazole-hydrochloride Yield: 18 0 of theory, C30H32N6O3 x HCl (524.63/561.09) mass spectrum: (M+H)' = 525 (M-H+HC1) = 559/61 (Cl) (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1-methyl-pyrazol-5-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 10 % of theory, CZ4H25N,0 x HCl (427.51/ 463.97) mass spectrum: (M+H)' = 428 (M+H+HC1)- = 464/6 (Cl) (4) (E/Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [ (1-me-thyl-pyrazol-5-yl-(ethoxycarbonylmethyloxyimino)-methylene]cyc-lopropyl]-benzimidazole-hydrochloride Yield: 80 0 of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 +
1 a glacial acetic acid) C28H32N803 x HC1 (528.63/565.08) mass spectrum: (M+H)' == 529 (5) (E/Z)-2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-[phenyl-(3-ethoxycarbonyl-n-propyloxyimino)methylene]-cyclopropyl.]-benzimidazole-dihydrochloride Yield: 47 0 of theory, R. value: 0.06 (silica c~el; methylene chloride/methanol = 9:1) C32H36N603 x 2 HC1 (552.69/625.60) mass spectrum: (M+H)' = 553 Rxamz l 4 (E/Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [ (pyri.dine-2-yl)-(carboxymethyloxy_Lmino)methylene]-cyclopropyl]-benzimi-dazol P-hydroc-hl ori dP
150 mg (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(py-ridin-2-yl-(ethoxycarbonvlmethyloxyimino)-methylene]cyclopro-pyl]-benzimidazole-hydrochloride and 2.5 ml of 2N sodium hydro-xide solution are stirred in 10 ml ethanol for 5 hours at am-bient temperature. The alcohol is distilled off and the residue is adjusted to pH 5 with hydrochloric acid. The crystalline product is suction filtered, washed with water and dried.
Yield: 46 0 of theory, Rf value: 0.10 (silica gel; methylene chloride/ethanol/-glacial acetic acid = 8:2:0.1) C27H2.7N703 x HC1 (497.58/534.05) mass spectrum: (M+H)+ = 498 (M+Na) ` = 520 The following compounds are obtained analogously to Example 4:
(1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carb-oxyethyl)-piperidin-l-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 94 0 of theory, Rf value: 0.57 (Reverse(i phase RP 18; methanol/5o sodium chloride solution = 3:2) C28H34N603 x HC1 (502.62/539.08) mass spectrum: (M+H)+ 503 (M+Na)4 == 525 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 98 0 of theory, Rf value: 0.73 (Reversed phase RP 8; methanol/5% sodium chloride solution = 1:2) C26H33N703 x HC1 (491.60/-564.54) mass spectrum: (M+H)+ = 492 (M+2H) ++ = 247 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-carboxy-propionylamino)-1-(ethoxycarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 98 % of theory, R. value: 0.70 (RP 8; methanol/5o sodium chloride solution = 1:2) C25H30N605 x HC1 (494.55/531.05) mass spectrum: (M+H)+ 495 (2M+H)' 989 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxfine-thylamino)-1-(pyrrolidin-1-yl-carbonyl)-methyl]-benzimidazole-hydrochloride Yield: 87 % of theory, C24H29N703 x HC1 (463.54/500.04) mass spectrum: (M+H)' 464 (M+2H)' == 232.6 (5) 2- (4-amidinophenylaminomethyl) -i-methyl-5- [1- [2- (2-carb-oxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 94 0 of theory, C27H32N603 x HC1 (488.59/525.05) mass spectrum: (M+H)' 489 ( M+Na ) ' 511 (6) 2-(4-amidinophenylar.ninomethyl)-1-methyl-5-[1-(carboxyme-thylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-methyl]-benzimidazole-hydrochlo:ride Yield: 49 % of theory, C25H29N701 x HC1 (491.55/528.01) mass spectrum: (M+H)' = 492 ( M+H+Na )"+ = 257.7 (7) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(carboxyme-thylcarbonylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 92 0 of theory, C26H31N7O4 x HC1 (505.58/542.04) mass spectrum: (M+H)+ = 506 ( M+H+Na )'-+ = 264.7 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3-carboxymethyl-imidazolin-2,4-dion-5-yl)-benzimidazole-hy-drochloride Yield: 88 0 of theory, CZ2H23N704 x HC1 (449.47/485.94) mass spectrum: (M+H)` = 450 (M+2Na) " = 247 . 7 (9) (E/Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [ (pyri-din-3-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]--benz-imidazole-hydrochloride Yield: 54 % of theory, C27H27N,03 x HC1 (497.56/534.09) mass spectrum: (M+H)' 498 (M+Na)' 520 (10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (N- (2-carboxyethyl)-N-methyl-aminomethyl)-pyrrolidin-1-yl-carbonyl]-cyclopropyl]-benzimidazole-hydrochlori.de Yield: 100 0 of theory, C29H37N703 x HCl ( 531 . 6 6/ 5 6 8. 12 ) mass spectrum: (M+H)' = 532 (M-H)- = 530 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-carboxy-ethyl)-N-(2-pyridyl)-am:inomethyl]-benzimidazole-hydrochloride Yield: 91 0 of theory, C25H2.,N,02 x HC1 (457. 54; 493 . 96) mass spectrum: (M+H)' = 458 (12) 2-(4-amidinophenylaminomethyl)-i-methyl-5-(N-benzenesul-phonyl-N-carboxymethyl-aminomethyl)-benzimidazole-hydrochloride Yield: 84 0 of theory, C25H26N604S x HC1 (506.59/543.06) mass spectrum: (M+H)` = 507 (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxy-ethyl)-benzimidazole-1-yl-methyl]-benzimidazole-hydrochloride Yield: 760 of theory, C27H27N702 x HC1 ( 4 81 . 5 6/ 5:L B. 0 5) mass spectrum: (M+H)+ = 482 (M+2H) z'` = 242 (M+Na) = 504 (M+H+Na) 253 (M-H+2Na)'= 526 (M+2Na)2" = 264 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(2-methyl-4-carboxy-imidazol-l-yl-methyl)-benzimidazole-hydrochlori.de Yield: 610 of theory, C22H23N.,O2 x HC1 ( 417 . 4 7/ 453.92) mass spectrum: (M+H)' = 418 (15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[3-(3-carboxy-n-propyl)-benzimidazol-:?-on-1-yl-methyl]-benzimidazole-hydro-chloride Yield: 869,5 of theory, Cz8Hz9N703 x HC1 (511.59 /54:8. 04) mass spectrum: (M+H)' = 512 (M+Na)` = 534 (M+H+Na) `' = 267 . 7 (M+2Na)2' = 278.8 (16) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[3-(2-carboxy-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl-methyl]-benzimidazole-hydrochloride Yield: 830 of theory, Cz6Hz6N803 x HC1 (498.55/535) mass spectrum: (M+H)' = 499 (M+Na)' = 521 (M-H)- = 497 (2M-H)-= 995 (17) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-l-yl-methyl]-benzimidazole-hy-drochloride Yield: 680 of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/51i sodium chlo-ride solution = 6:4) CZSH29N,02 x HC1 (459.56/496.01) mass spectrum: (M+H)' = 460 (M+Na)' = 482 (M+H+Na) 2~ = 241 (18) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phe-nyl-(carboxymethyloxyim.ino)methylene]cyclopropyl]-benzimi-dazole-dihydrochloride Yield: 70% of theory, C2BH28N603 x 2HC1 (496.57/569.5) mass spectrum: (M+H)' = 497 (M-H) - = 495 (19) (E/Z)-2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-[(py-ridin-3-yl)-(carboxymethylidene)-methylene]cyclopropyl]-benz-imidazole-hydrochloride Yield: 370 of theory Rf value: 0.45 (Reverse(d phase RP 8; methanol/5% sodium chloride solution = 6:4) C27H26N602 x HC1 (466.55/503.0) mass spectrum: (M+H)` = 467 (20) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(1-me-thyl-pyrazol-5-yl)-(carboxymethyloxyimino)-methylene]cyc:Lopro-pyl]-benzimidazole-hydrochloride Yield: 30% of theory, Rf value: 0.25 (Reversed phase RP 8; (5o saline solution/metha-nol = 1:1) C26HzeNe03 x HCl (500.58/537.03) mass spectrum: (M+H)' = 501 (M-H) - = 499 (M+Cl) + = 535/537 (Cl) (21) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phe-nyl-(3-carboxy-n-propyloxyimino)methylene]-cyclopropyl]-benz-imidazole-dihydrochloride Yield: 37 % of theory, Rf value: 0.35 (Reversed phase RP 8; 5% saline solution/metha-nol = 3:2) C30H32N603 x 2 HC1 (524.64/597.55) mass spectrum: (M+H)' = 525 F'xam= 1 P 1;
2-(4-amidinophenylaminornethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-c-~arbony] ) -ami nomet-hyl l -h .n . ' mi a .ol -hydrochl ori de a. S- (4-r.hlorophenyl ) - irn'dazolidin-2,4-dione 15.0 g (0.11 mol) of 4-chlorobenzaldehyde, 51.3 g (0.53 mol) of ammonium carbonate and 7.6 g(0.12 mol) of potassium cyanate are stirred in 150 ml water and 150 ml methanol for 18 hours at 55 C. The solvent is distilled off, the residue dissolved in water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.
Yield: 8.6 g (38 % of theory), melting point: 215 C
b. 5- (4- _hloro-3-ni ro-~>h~n~rl ) -imida .ol idin- .,4-dion Prepared analogously to Example la from 5-(4-chlorophenyl)-imidazolidin-2,4-dione and fuming nitric acid.
Yield: 52 0 of theory, Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1) e. 4-chloro-3-ni_tro-jLnylalanin.-hydrnchloride 560 mg (2.2 mmol) of 5-(4 -chloro-3-nitro-phenyl)-imidazolidin-2,4-dione are refluxed for 24 hours in 20 ml of semiconc. hy-drochloric acid. The solvent is distilled off, the residue dissolved in water, filtered to remove the insoluble matter and concentrated by evaporation. The residue is dissolved three times in ethanol, evaporated to dryness, triturated with ether, suction filtered and dried.
Yield: 380 mg (65 % of theory), melting point: 186 C
d. 4- hl oro-;-ni tro-N-tf~_rt__but_V1 oxycarhonyl -y)h~-nyl al ani na 5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine-hydro-chloride are dissolved in 50 ml dioxane and 25 ml water and, after the addition of 5.5 ml (39.1 mmol) of triethylamine and 4.8 g (21.3 mmol) of di-tert.butyl-dicarbonate, stirred for 18 hours at ambient temperature. Then the mixture is diluted with 0.5 M potassium hydrogen sulphate solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.
Yield: 6.3 g (100 0 of theory), Rf value: 0.20 (silica gel; methylene chloride/methanol =: 9:1) e. 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylam:ino-1- (IDyrrol i (9 i n-1 -yl ) -Pthanone Prepared analogously to Example 1c from 4-chloro-3-nitro.-N-tert.butyloxycarbonyl-phenylalanine, O-(benzotriazol-l--yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-diisopropylamine in tetrahydrofuran.
Yield: 68 0 of theory, melting point: 203 C

f. 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonyl-amino-l-(Ipyrrolidin-I -yl)-PthanonP
Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin-l-yl)--ethanone and methylamine solution.
Yield: 76 0 of theory, Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate = 1:1) g. 2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-amino-I-T.2yrrolidin-1-yl-ethanone Prepared analogously to Example ld from 2-(4-methylamino=-3-ni-tro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin-1=-yl)-ethanone and palladium on activated charcoal in methylene chloride/ethanol.
Yield: 100 0 of theory, Rf value: 0.12 (silica gel; cyclohexane/ethyl acetate = 1:1) h. 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone Prepared analogously to Example ic from 2-(4-methylamino-3-aminophenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone, O-(berizotriazol-l-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate, 4-cyano-phenylglycine and triethyl-amine in tetrahydrofuran.
Yield: 100 0 of theory, Rf value: 0.50 (silica gel; methylene chloride/methanol =: 9:1) i. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carhon~rl )- mi nom t-hyl 1-bPn .' mi a7ol P
Prepared analogously to Example if from 2-[4-methylamino.-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.bu-tyloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone in glacial acetic acid.
Yield: 30 0 of theory, Rf value: 0.19 (silica gel; methylene chloride/methanol = 9.5:0.5) k. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrroli(ain-l -yl -c-arhonyl ) -ami nomPt-j1y11 -h _n . i mi da .ol -hydrocrhl ori dP
Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-aminomethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 27 % of theory, C22H27N70 x HC1 (405.50/441.96) mass spectrum: (M+H)' = 406 The following compounds are obtained analogously to Example 5:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-acetyl-aminomethyl]-benzimidazole-hydrochlori-de Yield: 29 0 of theory, C24H29N702 x HC1 (447 . 54 /9:84 . 54 ) mass spectrum: (M+H)' = 448 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(2-eth(Dxycarbonylethyl)-N-methyl-aminomethyl]-benzimidazole-hydrochlo:ride Yield: 74 % of theory, C2BH37N7O3 x HC1 (519.65/556.11) mass spectrum: (M+H)' = 520 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(ethoxycarbonylmethyl)-aminomethyl]-benzimida-zole-hydrochloride Yield: 76 0 of theory, C26H33N,03 x HC1 (491.59/528.05) mass spectrum: (M+H)' = 492 (M+2H) " = 246 . 7 (4) 2- (4-amidinophenylarninomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carbonyl)-N,N-di-(e-~hoxycarbonylmethyl)-aminomethyl]-benz-imidazole-hydrochloride Yield: 51 % of theory, C30H39N705 x HC1 (577.68/614.14) mass spectrum: (M+H)' = 578 (M+Na)' = 600 (5) 2- (4-amidinophenylarninomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carbonyl)-N-(ethoxycarbonylmethylcarbonyl)-aminomethyl]-benzimidazole-hydrochloi-:ide Yield: 29 % of theory, C27H33N704 x HC1 (519.60/556.06) mass spectrum: (M+H)+ = 520 (M+2 H)" = 260.7 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimi-dazole-hydrochloride Yield: 84 0 of theory, C27H35N703 x HC1 (505 . 62/542 . 62) mass spectrum: (M+H)' = 506 (M+2H) '" = 253 . 7 ExaII1 1r~P 6 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-(2-ethoxy-carbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-bPn i mi da ol - h~rro .hl ari dA

a . 5- ( 4 - hlnro --~- nit-r - piLap_y_IL- 5 -m h~rl -imida7,nl icain - 4 dionp To 50 ml of fuming nitric acid are added batchwise at -25 C to -35 C 10.0 g (4.45 mmol) of 5-(4-chloro-phenyl)-5-methyl-imi-dazolidin-2,4-dione. After 45 minutes at -25 to -20 C the re-action mixture is poured onto ice water. The crystalline pro-duct is suction filtered, washed with water and dried.
Yield: 10.5 g (100 0 of theory), melting point: 173-178 C:
Rf value: 0.30 (silica qel; cyclohexane/ethyl acetate = 1:1) b. 2-ami no-2- (4-rhl orca-3-nitrs,-= hPnyl )-pro;2i oni r ac=i d 10.5 g (0.044 mol) of 5-(4-chloro-3-ni.tro-phenyl)-5-methyl-imidazolidine-2,4-dione are refluxed in 200 ml dioxane and 700 ml of 6N hydrochloric acid for 5 days. The solution is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The aqueous phase is concen-trated by evaporation, mixed with toluene and evaporated to dryness. The residue is triturated with ether, suction filtered and dried.
Yield: 6.8 g (63 a of theory), Rf value: 0.24 (Reversed phase RPB, 5o saline solution/methanol = 1:1) c. 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phen)7l)-= rnr~i onjc aci d Prepared analogously to Example 5d from 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid, di-tert.butyl pyrocarboriate and triethylamine in dioxane.
Yield: 9.6 g (100 % of theory), Rf value: 0.31 (Reverseci phase RP8, 5% saline solution/methanol = 1:2) d. 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylami_no-1- (~~rrrol i di n-l -yl )-p ro.panone Prepared analogously to Example ic from 2-tert.butyloxycar-bonylamino-2-(4-chloro-.3-nitro-phenyl)-propionic acid, 0-.(ben-zotriazol-i-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-methylmorpholine in dimethylformamide.
Yield: 94 0 of theory, Rf value: 0.11 (silica crel; cyclohexane/ethyl acetate = 1:1) e. 2-(4-methylamino-3-n:itro-phenyl)-2-tert.butyloxycarbonyl-amiIlo-l -(layrrol i di n-~ -y;L) -;~ronanone Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-pro-panone and methylamine solution in dimethylformamide at 160 C.
Rf value: 0.79 (silica crel; ethyl acetate/ethanol = 9:1) f. 2-(4-methylamino-3-arnino-phenyl)-2-tert.butyloxycarbon.yl-ami no-I -~~rrrol i di n-~ -~rl .-nronanone Prepared analogously to Example ld from 2-(4-methylamino-3-ni-tro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin-1_-yl)-propanone and palladium on activated charcoal/hydrogen in methanol.
Yield: 100 % of theory, Rf value: 0.63 (silica gel; ethyl acetate/ethanol = 9:1) g. 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-l-(pyrrolidin-i-yl)--= ror~anone Prepared analogously to Example ic from 2-(4-methylamino--3-amino-phenyl)-2-tert.butyloxycarbonylamino-i-(pyrrolidin-1-yl)-propanone, O-(benzotriazol-i-yl)-N,N,N',N'-tetramet:hyl-uronium tetrafluoroborate, 4-cyano-phenylglycine and N-methyl-morpholine in dimethyl.formamide.
Yield: 37 0 of theory, Rf value: 0.47 (silica gel; ethyl acetate) h. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyl-oxycarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-ber.Lz-i mi a .ol .
Prepared analogously to Example if from 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.bu-tyloxycarbonylamino-l-(pyrrolidin-1-yl)-propanone and glacial acetic acid.
Yield: 60 % of theory, Rf value: 0.37 (silica gel; ethyl acetate) i. 2-(4-cyanophenylamin(Dmethyl)-1-methyl-5-[1-amino-i-(pyrro-lidin-l-yl- arbonyl)-etliyll-bPn7imidazolP
1.3 g (2.3 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzim:idazole are dissolved in 20 ml dioxane and, after the addition of 40 ml of semiconc. hydrochloric acid, stirred for two hours at ambient temperature. The solu-tion is mixed with ice, made alkaline with ammonia and extrac-ted with ethyl acetate. The combined organic extracts are dried and concentra-ted by evaporation.
Yield: 0.9 g (98 % of theory), Rf value: 0.14 (silica gel; ethyl acetate/ethanol = 9:1) k. 2- (4-cyanophenylamin.omethyl) -1-methyl-5- [1- [N- (2-ethoxy-carbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl:J-b -n . i mi da .ol 0.4 g (1.04 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-l-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole are dissolved in 10 ml ethanol and after the addition of 0.3 ml (2.7 mmol) of ethyl acrylate stirred for 24 hours at 95 C. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride/ethanol (20:1 and 4:1).
Yield: 0.16 g (31 0 of theory), R. value: 0.26 (silica gel; ethyl acetate/ethanol = 9:1) 1. 2- (4-amidinophenylaminomethyl) -i-methyl-5- [1-- [N- (2-ethoxy-carbonylethyl)-amino]-l-(pyrrolidin-l-yl-carbonyl)-ethyl]-b.nzi mi da .ol e-hyclro .hl nri_de Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl) -1-methyl-5- [1- [N- (2-ethoxycarbonylethyl) -amino] -1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 96 0 of theory, C26H37N7O3 x HC1 (519.65/556.11) mass spectrum: (M+H)+ 520 (M+Na)' 542 The following compounds are obtained analogously to Example 6:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxycar-bonylpropionylamino)-1-,athoxycarbonyl-ethyl]-benzimidazol.e-hy-drochloride Yield: 69 % of theory, C27H34N605 x HC1 (522.62/555.08) mass spectrum: (M+H)+ = 523 (M+H+Na)"+ = 273 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbo-nylmethylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 95 % of theory, C28H35N704 x HC1 ( 533 . 64 /5'10 . 10 ) mass spectrum: (M+H)+ 534 (M+Na)' 556 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonylpropionylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 20 0 of theory, C29H37N704 x HC1 (547.66/584.12) mass spectrum: (M+H)' = 548 (M+H+Na)" = 285.7 (4) 2-[4-amidinophenyl-]\I-(2-ethoxycarbonylethyl)-aminomet:hyl]-1-methyl-5-[1-dimethylamino-l-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 91 0 of theory, C30H41N703 x HC1 (547.71/584.17) mass spectrum: (M+H)* = 548 (M-H)- = 546 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycar-bonylethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimida-zole-hydrochloride Yield: 40 0 of theory, Rf value: 0.60 (Reversed. phase RP 8; 5o saline solution/metha-nol = 1/1) 026H35N703 x HC1 (493.63/530.08) mass spectrum: (M+H)' = 494 (M-H+2HC]!_) - = 564/566/568 (C12) (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbo-nylmethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimi-dazole-hydrochloride Yield: 77 0 of theory, Rf value: 0.40 (silica cfel; methylene chloride/methanol = 4:1 +
1 o glacial acetic acid) C27H35N703 x HC1 (505.63 /54:2.08) mass spectrum: (M+H)' = 506 (7) 2- (4-amidinophenylarn.inomethyl) -1-methyl-5- [1- (2-ethox:ycar-bonylethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl]-benzimidazole-hydrochlo:r.ide Yield: 85 % of theory, RF value: 0.44 (silica gel; methylene chloride/ethanol = 9:1) C27H37N703 x HC1 (507.64/544.14) mass spectrum: (M+H)` = 508 (M+C1)- = 542/4 (Cl) (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(methoxycar-bonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 99 % of theory, Rf value: 0.21 (silica gel; methylene chloride/methanol = 4:1 +
1 % glacial acetic acid) C26H33N703 x HC1 (491.60/528.05) mass spectrum: (M+H)+ = 492 (M-H+HC1)- = 526/8 (Cl) (M-H+2HC1; - = 562/4/8 (C12) (9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N,N-bis(eth-oxycarbonylmethyl)amino)-1-(pyrrolidinocarbonyl)-ethyl]-benz-imidazole-hydrochloride Yield: 65 0 of theory, Rf value: 0.35 (silica gel; methylene chloride/methanol = 4:1 + 1 % glacial acetic acid) C31H41N705 x HC1 (591.72/628.17) mass spectrum: (M+H)' = 592 (M-H+HC1)- = 626/8 (Cl) (M-H+2HC1.) - = 662/4/6 (C12) (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycar-bonylmethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]-benz-imidazole-hydrochloride Yield: 90 of theory, E Rf value: 0.50 (Reversed phase RP 8; methanol/5o saline solu-tion = 3:2) C26H33N,04 x HC1 (507.60/544.05) mass spectrum: (M+H)' = 508 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-eth(Dxy-carbonyl-ethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochl.oride (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycar-bonylmethylamino)-1-(N-methyl-N-ethylaminocarbonyl)-ethy-~w]-benzimidazole-dihydroch:loride Yield: 58a of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/5o saline solu-tion = 3:2) C26H35N703 x 2 HC1 (493.62/566.52) mass spectrum: (M+H)' = 494 (M+HC1-H)- = 528/30 (Cl) (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((N,N-di-(ethoxycarbonylmethyl)-amino)-1-(N-methyl-N-ethylaminocarbo-nyl)-ethyl]-benzimidazolf_-dihydrochloride Yield: 30% of theory, Rf value: 0.40 (Reversed. phase RP 8; methanol/5% saline solu-tion = 3:2) C30H41N705 x 2 HC1 (579.71/652.62) mass spectrum: (M+H)+ = 580 (M-H)" = 578 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycar-bonylmethylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 820 of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5o saline solu-tion = 3:2) C28H37N703 x 2 HC1 (519.65/592.75) mass spectrum: (M+H)' = 520 (M-H+HC1)- = 534/6 (Cl) (M-H+2HC1)- = 590/2/4 (C12) (15) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(ethoxycar-bonylmethylamino)-1-(diethylaminocarbonyl)-ethyl]-benzimida-zole-dihydrochloride Yield: 88% of theory, Rf value: 0.60 (Reversed Phase RP 8; methanol/5% saline solu-tion = 3:2) C27H37N703 x 2 HC1 (507.64; 580.56) mass spectrum: (M+H)' = 508 (M-H+2HC1) - = 578/580/582 (C12) (16) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycar-bonylmethyl-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 46 0 of theory, Rf value: 0.43 (silica crel; methylene chloride/methanol = 4:1 + lo gla(zial acetic acid) C28H37N703 x 2 HC1 (519. 65/ 592 . 56) mass spectrum: (M+H)' = 520 (M+Cl)- = 554/6 (Cl) (17) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benz-imidazole-dihydrochloride (18) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonyl-propylamino)-1--(pyrrolidin-1-yl-carbonyl)-ethyl]-benz-imidazole-dihydrochloride Yield: 950 of theory, Rf value: 0.50 (Reversed Phase RP 8; methanol/5o saline solu-tion = 1:1) C29H39N703 x 2 HC1 (533.68/606.58) mass spectrum: (M+H)~ = 534 F_ram1~P 7 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino]cyclopropyl]-benzimidazole-hvd o.hlori P

iC, a. 4-((1-tert.butyloxvcarbonylamino)cyclopropyl)-2-nitro.-N-me-thyl- ni 1 i nP
15.0 g (63.5 mmol) of 4-((1-carbox.v)cyclopropyl)-2-nitro--N-me-thyl-aniline and 17.6 ml (127 mmol) of triethylamine are dis-solved in 250 ml of di.chloromethane and 8.3 g (76 mmol) of 15 ethyl chloroformate are added at 0 C. After one hour at ambient temperature 0.75 g tetrabutylammonium bromide are added. Then a solution of 6.3 g (96 mmol) of sodium azide in 20 ml water is added dropwise. After one hour at 0 C the solution is diluted with water and extracted with ethyl acetate. The organic ex-20 tracts are dried and concentrated by evaporation. The residue is dissolved in 200 ml tert.butanol and refluxed for two hours.
The solvent is concentrated by evaporation, the residue chro-matographed on silica gel and eluted with methylene chlor.ide.
Yield: 15.5 g (77 0 of theory), 25 Rf value: 0.83 (silica crel; methylene chloride/methanol = 9.5:0.5) b. 4-((1-amino)cyclopropyl)-2-nitro-N-methyl-aniline-hydro.hlorid 30 15.5 g (0.05 mol) of 4-[(1-tert.butyloxycarbonylamino)-cyclopropyl]-2-nir-ro-N-methyl-aniline are dissolved in 50 ml ethanol and 50 ml ethanolic hydrochloric acid and stirred for 7 hours at ambient temperature. The solvent is distilled off, the residue triturated with ether, suction filtered and dried.
35 Yield: 98 0 of theory, Rf value: 0.44 (silica gel; methylene chloride/methanol = 9.5:0.5) c. 4-[N-(1-cyclopentylarnino)cyclopropyl]-2-nitro-N-methyl-anilinP
12.0 g (0.05 mol) of 4-[(1-amino)cyclopropyl]-2-nitro-N-methyl-aniline-hydrochloride are dissolved in 500 ml of tetrahyciro-furan and after the add:i.tion of 4.1 g (0.05 mol) of cyclopenta-none and 3.2 ml of glacial acetic acid, 13.6 g (0.064 mol) of sodium triacetoxyborohydride are added batchwise under a nitro-gen atmosphere. After 16 hours at ambient temperature, the mix-ture is diluted with sodium hydrogen carbonate solution and ex-tracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:1.) Yield: 10.8 g (80 0 of theory) Rf value: 0.56 (silica gel; methylene chloride/methanol = 9.5:0.5) d. 4-[i-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-cryc,l os ro~y7 1-.-ni ro-N-m~th~rl -ani 1-i ne 1.0 g (3.6 mmol) of 4-[(l-cyclopentylamino)cyclopropyl]-2-ni-tro-N-methyl-aniline are dissolved in 30 ml tetrahydrofuran and after the addition of 0.45 g (4.4 mmol) of triethylamine, 0.65 g (4.4 mmol) of ethyl succinate chloride are added and the resulting mixture is stirred for four hours at ambient tempera-ture. Then it is diluted with ethyl acetate and sodium hydrogen carbonate solution, the organic extracts are dried and concen-trated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1:1).
Yield: 1.3 g (90 a of theory), Rf value: 0.46 (silica gel; ethyl acetate/cyclohexane = 1:1) e. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-cysloj~ro~:)yl 1-.-ami no-N-iethyl -ani 1 i n.
Prepared analogously to Example id 4-[1-(N-(3-ethoxycarbonyl-propionyl)-N-cyclopentyl.-amino)cyclopropyl]-2-nitro-N-methyl-aniline and palladium or.L activated charcoal/hydrogen in methy-lene chloride/ethanol.
Yield: 100 0 of theory, Rf value: 0.18 (silica gel; ethyl acetate/cyclohexane = 1.:1) f. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-me-r_hy1 -ani l inP _ Prepared analogously to Example lc 4-[1-(N-(3-ethoxycarbonyl-propionyl)-N-cyclopentyl-amino)cyclopropyl)-2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluron:ium tetrafluoroborate, 4-cyano-phenylglycine and triethylamiile in dimethylformamide.
Yield: 96 0 of theory, Rf value: 0.54 (silica cTel; methylene chloride/methanol = 9.5:0.5) g. 2-(4-cyanophenylaminomethyl)-i-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino)-cyclopropyl]-benzimidazole Prepared analogously to Example if from 4-[1-(N-(3-ethoxycarbo-nylpropionyl)-N-cyclope:ntyl-amino)cyclopropyl)-2-(4-cyanophe-nyl)-aminomethylcarbonylamino-N-methyl-aniline in glacial ace-tic acid.
Yield: 52 % of theory, Rf value: 0.81 (silica crel; methylene chloride/methanol = 9:1) h. 2-(4-amidinophenylam:inomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylprop:ionyl)-amino]cyclopropyl)-benzimidazol_e-hydrochloride Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpro-pionyl)-amino]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 36 0 of theory, C3DH36N6O3 x HC1 (530.68/567.14) mass spectrum: (M+H)' = 531 Rxamr>1 P 8 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3-ethoxy-carbonylmethyl-imidazolin-2,4-dion-5-yl)benzimidazole-hy--drochloride a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonyl-methylaminocarbonylaminc)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-l-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimida:;ole are dissolved in 10 ml d.imethylformamide and after the addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate stirred for 45 minutes at ambient temperature. The solution is poured onto ice water, the crystalline product is suction filtered and dried. The residue is chromatographed on silica gel, eluting with methylene chloride/ethanol/ammonia (20:1:0.01 and 10:1:0.01).
Rf value: 0.77 (silica gel; methylene chloride/ethanol/ammonia = 9:1:0.01) b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3--eth-oxycarbonylmethyl.-imidazolin-2,4-dion-5-yl)-benzimidazole-h~dro.hloride Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 68 % of theory, C24H27N704 x HC1 ( 4 7 7. 5 2/513 . 9 9) mass spectrum: (M+H)' = 478 Rxam p.lP g 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethy:L)-aminomethyl]-benzimidazole-hodro .hl ori P

a. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nit-r -_hlorohPn Pn 13.4 g (0.053 mol) of 4-chloro-3-nitro-benzylbromide and 11.8 g (0.053 mol) of 2-tert.butyloxycarbonylethylamino-pyridine are stirred in 80 ml of N-ethyl-diisopropylamine for 3 hours at 90 C. The solution is concentrated by evaporation, the residue chromatographed on silica gel, eluting with petroleum ether/-ethyl acetate (8:2 and 7:3).
Yield: 8.2 g (40 0 of theory), Rf value: 0.64 (silica gel; petroleum ether/ethyl acetate = 8:2) b. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-ni tro-N-m .t-hyl -ani l i ne Prepared analogously to Example lb from 4-(2-tert.butyloxycar-bonylethyl)-2-(pyridylaminomethyl)-2-nitro-chlorobenzene and methylamine solution.
Yield: 20 % of theory, Rf value: 0.65 (silica gel; methylene chloride/ethanol = 9:1) c. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-amino-N-m hyl -ani l i ne 1.6 g (4 mmol) of 4-(2-tert.butyloxycarbonylethyl)-2-(pyridyl-aminomethyl)-2-nitro-N-methyl-aniline are dissolved in 200 ml methanol and, after the addition of 2 g of Raney nickel, com-bined with 1 ml of hydrazine hydrate. The solution is stirred for 30 minutes at ambient temperature and concentrated by eva-poration. The residue is chromatographed on silica gel and elu-ted with methylene chloride/ethanol (95:5).
Yield: 1.2 g (82 % of theory), Rf value: 0.33 (silica gel; methylene chloride/ethanol = 9:1) d. 2-(4-cyanophenylaminomethyl)-i-methyl-5-[N-(2-pyridyl)-rJ- (2 -e hoxyc,arbonylethzv,l )-ami nomeYhyl 1-hen .i mi dazol e Prepared analogously to Example ic from 4-(2-tert.butyloxycar-bonylethyl)-2-(pyridy2.aminomethyl)-2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetraf:luo-roborate, 4-cyano-phenylglycine in tetrahydrofuran and glacial acetic acid.
Yield: 72 0 of theory, Rf value: 0.36 (silica gel; methylene chloride/ethanol = 9:1) e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole-hy-drochloride Prepared analogously to Example ig from 4-[(5-(2-tert.butyloxy-carbonylethyl)-2-pyridylaminomethyl-l-methyl-benzimidazole-2-yl)-methylamino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 59 % of theory, C27H31N702 x HC1 (485.59/522.1) mass spectrum: (M+H)' = 486 The following compounds are obtained analogously to Example 9:
(1) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[N-(ethoxycarbo-nylmethyl)-benzenesulphonylaminomethyl]-benzimidazole-hydr.o-chloride Yield: 53 0 of theory, C27H30N604S x HC1 (534.64/571.1) mass spectrum: (M+H)' = 535 (2) 2-(4-amidinophenylam:inomethyl)-1-methyl-5-(N-methyl-phe-nylcarbonylaminomethyl)].-benzimidazole-hydrochloride Yield: 42 0 of theory, C25Hz6N6O x HC1 (426.53/462.96) mass spectrum: (M+H)' = 427 RX~j~I P 1 0 2-(4-amidinophenylaminomethyl)-i-methyl-5-[(2-methyl-h.n .i mi da .ol -1-yl ) met-hz-ll -ben .' mi da .ol P-hydrochl nri d a. 7 - (4- .r7 oro-3-n' r~r~y ) - .-me h~rl -hPn ,imi d ol P
Prepared analogously to Example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide.
Yield: 780 of theory, C15H12C1N302 (301.7) mass spectrum: M+ = 301/303 b. 1- (4-m ryl ami no--~-ni t-rob n73Zl )-2-m .thyl -b _nzi mi dazol , Prepared analogously to Example lb from 1-(4-chloro-3-nit:ro-benzyl)-2-methyl-benzimidazole and methylamine.
Yield: 960 of theory, Rf value: 0.56 (silica qel; methylene chloride/ethanol = 19:1) c. 1-(4-m._rylamino--4-aminobenzy1)-2-methyl-hP imidazole Prepared analogously to Example ic from 1-(4-methylamino-3-ni-trobenzyl)-2-methyl-benzimidazole and hydrogen/Raney nickel.
Yield: 100% of theory, Rf value: 0.34 (silica gel; methylene chloride/ethanol = 19:1) d. 2-(4-cyanophenylaminomethyl)-i-methyl-5-[(2-methyl-b -n .i mi da .o1 -1 -y ) m - _hy;Ll -benz ' mi da .ol _ A mixture of 1.94 g (11.0 mmol) of N-(4-cyanophenyl)-glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole is refluxed in 80 ml of absolute tetra]aydrofuran for 15 minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4-methylamino-3-aminoben-zyl)-2-methyl-benzimida:zole the mixture is refluxed for a further 16 hours. Then the solution is evaporated to dryness, the residue is mixed with 80 ml glacial acetic acid and re-fluxed for 1 hour. It is then evaporated to dryness once more, the residue thus obtained is mixed with 50 ml of water and made alkaline with conc. ammonia (about pH 10). The product which crystallises out is suction filtered, washed with a little water and dried.
Yield: 4.1 g(960 of theory), Rf value: 0.30 (silica gel; methylene chloride/ethanol =:L9:1) C25H22N6 (406.5) mass spectrum: M' = 406 e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-methyl-b.nzi mi da .ol -l-yl ) mP hyl ]-ben .i mi dazol P-rydro _hl ori ciP
Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[(2-methyl-benzimidazol-l-yl)methyl]-benz-imidazole hydrochloric acid/ammonium carbonate.
Yield: 590 of theory, C25H25N., x HC1 (423.5/459.9) mass spectrum: (M+H)' 424 (M+2H) zi == 217 . 7 The following compounds are obtained analogously to Example 10:
(1) 2-(4-amidinophenylo>:ymethyl)-1-methyl-5-[(imidazol-l-yl)-methyl]-benzimidazole-hydrochloride Yield: 30% of theory, C20H20N6O x HCl (360.4/396.9) mass spectrum: (M+H)' 361 (M+2H) 2' == 181 (2) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(imidazol-1-yl)-ethyl]-benzimidazole-hydrochloride Yield: 700 of theory, C21H23N, x HC1 (373.46/410) mass spectrum: (M+H)' 374 (M+2H) z+ 187 . 6 (3) 2- (4-amidinophenylarriinomethyl) -1-methyl-5- [1- (2-ethyl-4-methyl-imidazol-l-yl)-ethyl]-benzimidazole-dihydrochloride Yield: 18% of theory, C24H29N7 x 2HC1 (415.55/488.46) mass spectrum: (M+H)' = 416 (M+2H) -'+ = 208 . 7 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-ethyl-4-me-thyl-imidazol-i-yl)-methyl]-benzimidazole-dihydrochloride Yield: 36% of theory, C23H27N. x 2HC1 (401.52/437.97) mass spectrum: (M+H)' = 402 (M+2H) 2+ = 201 . 7 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(pyridin-2-yl)-N-methyl-aminomethyl]-benzimidazole-dihydrochloride Yield: 780 of theory, C23H25N7 x 2HC1 (399.5/435.95) mass spectrum: (M+H)' = 400 (M+2H) 2+ = 200 . 6 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2-ethoxy-carbonyl-ethyl)-benzimidazol-l-yl)-methyl]-benzimidazole--di-hydrochloride Yield: 61a of theory, C29H31N,02 x HC1 (509.62/546.07) mass spectrum: (M+H)+ = 510 (M+2H) 2' = 255 . 7 (M+H+Na)'+ = 266.7 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(imidazol-i-yl)-methyl]-benzimidazole-hydrochloride Yield: 35% of theory, C20H21N7 x HC1 (359.44/395.89) mass spectrum: (M+H)' = 360 (M+2H)2+ = 180.6 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2-acetyl-amino-ethyl)-4,5-dimethyl-imidazol-l-yl)-methyl]-benzimidazole-dihydrochloride Yield: 42% of theory, C26H32N80 x 2HC1 ( 4 72 . 6/ 5 4 5. 51) mass spectrum: (M+H)+ = 473 (M+2H) = 237 (M+H+Na ) 2+ = 248 c;

(9) 2-(4-amidinophenyla.minomethyl)-1-methyl-5-[(2-(2-aminocar-bonyl-ethyl)-4,5-dimeth.yl-imidazol-i-yl)-methyl]-benzimidazole-dihydrochloride Yield: 680 of theory, 1C C25H30N80 x 2HC1 (458.6/531.51) mass spectrum: (M+H)+ = 459 (M+2H) `` = 230 (10) 2-(4-amidinophenyla.minomethyl)-1-methyl-5-[(2-methyl-15 4-ethoxycarbonyl-imidazol-l-yl)-methyl]-benzimidazole-hy-drochloride Yield: 340 of theory, C24H27N702 x HC1 (445.53/481.98) mass spectrum: (M+H)+ = 446 20 (M+2H)2+ = 223.5 (M+H+Na)2+ = 234.5 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(3-(3-ethoxy-carbonyl-n-propyl)-benzimidazol-2-on-1-yl)-methyl]-benzimi-25 dazole-hydrochloride Yield: 58% of theory, C30H33N703 x HC1 (539.64/576.09) mass spectrum: (M+H)+ = 540 ( M+H+Na ) :Zi = 2 81 . 7 (12) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[(3-(2-ethoxy-carbonyl-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl)-methyl]--benz-imidazole-hydrochloride Yield: 290 of theory, C28H30NB03 x HC1 (526.6/563.05) mass spectrum: (M+H)' = 527 (M+2H) 2` = 264 (M+H+Na) z' = 275 (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-phenyl-imi-dazol-l-yl)-methyl]-ben2:imidazole-hydrochloride Yield: 58% of theory, C26H25N, x HC1 (435.54/472) mass spectrum: (M+H)' = 436 (M+Na)' = 218.6 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(4,5-dimethyl-2-(2-ethoxycarbonylethyl.)-imidazol-l-yl)-methyl]-benzimidazole-dihydrochloride Yield: 52% of theory, C27H33N,02 x 2HC1 (487.61/560.52) mass spectrum: (M+H)' 488 (M+2H) 2, 244 . 6 F,xam3pl1 1 2-(4-amidinophenylaminom,ethyl)-1-methyl-5-[1-(2-ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benz-j mi a.ol -hydro .hl ori dp a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(2-tert.butyl-oxycarbonyl-azetidin-1--yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-hen .i mi da .01 P
0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[l-amino-l-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole and 1.65 g ((5.5 mmol) of tert.butyl 2,4-dibromobutyrate are dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmcl) of sodium carbonate and stirred under nitrogen for 30 hours at 55 C. After cooling, the white precipitate is filtered off and washed with ethanol. The filtrate is concentrated by evapora-tion, the residue is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate/ethanol/ammonia (20:1:0.01). The desired fractions are combined and concen-trated by evaporation.
Yield: 0.44 g(440 of theory) as a mixture of diastereomers, C31H38N6O3 (542 . 69) mass spectrum: (M+H)` = 543 b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycar-bonyl-azetidin-1-yl)-1-(pyrrolidin-l-vl-carbonyl)-ethyl]-ben~imida~ole-hydroc~r'oride (mixture of diasterPnmPrs) Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-i-methyl-5-[1-(2-tert.butyloxycarbonyl-azetidin-l-yl)-1-(pyrrolidin-1-yl-caz.-bonyl)-ethyl]-benzimidazole and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 12 % of theory, C29H3.7NIO3 x HC1 (531.66/568.12) mass spectrum: (M+H)' = 532 (M+H+HC1)2+ = 568/70 (Cl) Rxam~21e_ 12 (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl]-benz-j_mi d zol -hydro .hl or; ciA

a. (E/Z)-2-(4-cyanophenylaminomethyl)-i-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl]-benz-j_m; dazol P
897 mg (4.0 mmol) of triethyl phosphonoacetate are dissolved in ml tetrahydrofuran under argon. At -15 C 449 mg (4.0 mmol) 30 of potassium tert. butoxide are added. After 30 minutes 815 mg (2.0 mmol) of 2- (4-cyan(Dphenylaminomethyl) -i-methyl-5- [1-- (py-ridin-3-yl-carbonyl)cyclopropyl]-benzimidazole are added batch-wise and the mixture is stirred overnight at ambient tempera-ture. Then the solution is refluxed for a further 6 hours and concentrated by evaporation. The residue is mixed with so-dium chloride solution and extracted 3x with ethyl acetate. The com-bined organic phases are dried over sodium sulphate and con-centrated by evaporation. The residue is dissolved in dichloro-methane and chromatographed on silica gel, eluting with dichlo-romethane containing 5o ethanol. The desired fractions are con-centrated by evaporation, the residue is triturated with ether, suction filtered and dried.
Yield: 365 mg (38% of theory).

b. ((E/Z)-2-(4-amidinoph.enylaminomethyl)-i-methyl-5-[1-[(py-ridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl]-b .n .imida .ole-hydroshloride Prepared analogously to Example ig from (E/Z)-2-(4-cyanophenyl-aminomethyl)-i-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethy-lidene)-methylene]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 58 % of theory, C29H30N602 x HC1 (494.60/531.05) mass spectrum: (M+H)' = 495 The following compound is obtained analogously to Example 12:
(1) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(py-ridin-2-yl)-ethoxycarbonylmethylidene)-methylene]-cyclopropyl]-benzimidazole-hydrochlo:ride Yield: 72 0 of theory, C29H30N602 x HC1 (494.60/531.05) mass spectrum: (M+H)' =4:95 Example 13 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(2-carboxy-aze-tidin-1-yl)-1-(pyrrolid:in-1-yl-carbonyl)-ethyl]-benzimidazole-7lydro .hl ori d. (mixture (pf di ast .r .om s) 200 mg (0.35 mmol) of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carb-onyl)-ethyl]-benzimidazole-hydrochloride are dissolved in 30 ml of 6N hydrochloric acid and stirred for 13 hours at ambient temperature. The reaction mixture is concentrated by evapora-tion with the addition of toluene, the residue is triturated with acetone/ether, suction filtered, washed with ether and dried.
Yield: 200 mg (>100 0 of theory, contains ammonium chloride), C27H33N703 x HC1 (503 .62/ 540. 07) mass spectrum: (M+H)' = 504 The following compounds are obtained analogously to Example 13:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimidazol.e-hy-drochloride Yield: 910 of theory, Rf value: 0.75 (Reverseci phase; 5% saline solution/methanol =
1:1) C24H31N703 x HC1 (465.56/502.01) mass spectrum: (M+H)' = 466 (M-H+2HC1) - = 537/539 (C12) (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 70 0 of theory, RF value: 0.51 (Reverseci phase; 5% saline solution/methanol = 3:2) C25H31N703 x 2 HC1 (477 . 5 7/ 550 . 48) mass spectrum: (M+H)+ = 478 (3) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(py-ridin-2-yl)-carboxymethylidene)-methylene]-cyclopropyl]-benz-imidazole-hydrochloride Yield: 65 % of theory, C27H26N602 x HCl (466.55/503.0) mass spectrum: (M+H)' _467 (M+Cl)' _= 501/503 (Cl) (4) 2-(4-amidinophenyl.aminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop--2-yl]-benzimidazole-dihydrochloride Yield: 99 0 of theory, Rf value: 0.55 (Reverseci phase RP 8; methanol/50i saline solu-tion = 1:1) C2eH35N,04 x 2 HC1 (533.64/606.64) mass spectrum: (M+H)' = 534 (M-H)- = 532 (M-H+HCl)- = 568/70 (Cl) (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl]-benz-imidazole-dihydrochloride Yield: 75 0 of theory, Rf value: 0.54 (Reversed phase RP 8; methanol/5o saline solu-tion = 1:1) CZSH33N,03 x 2 HC1 (479 . 59/ 552 . 59 ) mass spectrum: (M+H)` = 480 F',xam= l P 14 2-[4-(N-hexyloxycarbonylamidino)-phenylaminomethyl]-i-met.hyl-5-[1- (2-ethoxycarbonyleth,~rlamino) -1- (dimethylaminocarbonyl) -ethyl ] -bPnz. J mi da7.ol P
1.5 g (2.8 mmol) of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycarbonylethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride are dissolved in 14 ml water and 55 ml tetrahydrofuran, mixed with 2.0 g potassium car=bonate and 1.0 ml (6 mmol) of hexyl chloroformate and stirred for 4 hours at ambient temperature. After removal of the solvent in vacuo the residue is mixed with saline solution and extracted 3 x with methylene chloride. The combined organic phases are washed with a little water, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with methylene chloride plus 2 to 7.50 ethanol. The uniform fractions are combined, concentrated by evaporation, dissolved in a little ethyl acetate and mixed with petroleum ether. The solid form is suction filtered, washed with petroleum ether and dried.
Yield: 0.8 g (43 0 of theory), C33Hq,N,05 (621. 79) Rf value: 0.50 (silica ciel; methylene chloride/ethanol = 19:1) mass spectrum: (M+H)' 622 (M+Na)' 644 ExamplP 1 -9 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycar.bo-nylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-pr-op-2-yl 1-b -n .i mi da .ol P-hydrochl ori d.
a. Methyl 2- (4- . 1 orc~-= h n~rl )-~-hydro~~r-~th~rl -r~ropi nn~ta 35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) are added dropwise to a solution of 8.1 ml of diiso-propylamine (85 mmol) in 20 ml tetrahydrofuran at -78 C. Then a solution of 10.0 g (50 mmol) of methyl 2-(4-chloro-phenyl.)-pro-pionate in 30 ml tetrahydrofuran is added dropwise at -78 C.
Formaldehyde gas is then piped into the reaction mixture at -20 C for 30 minutes. After the addition of 5o citric acid and glacial acetic acid the mixture is extracted with ethyl ace-tate. The organic phases are washed with iN sulphuric acid, wa-ter, saturated sodium bicarbonate solution and saline solution and dried over magnesium sulphate. The crude product is puri-fied on silica gel, eluting with cyclohexane/ethyl acetat.e (19:1; 9:1; 4:1; 1:1 an(i 0:1). The uniform fractions are com-bined and concentrated by evaporation.
Yield: 9.7 g(841 of theory) yellow oil, RF value: 0.25 (silica crel; petroleum ether/ethyl acetate = 4:1) b_ 2 - (4-chl oro-= hPnyl )-3-hydrox_y -2-meth~rl -p rojp i oni c a r i r3 Prepared analogously to Example 4 from methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxide solution in ethanol.
Yield: 830 of theory, R. value: 0.55 (silica gel; ethyl acetate/cyclohexane = 2:1 + glacial acetic acid) c. 2- (4-chloro-3-nitro-phenyl) -2-methyl-3-nitroxy-propioriic acid Prepared analogously to Example la from 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid.
Yield: 900 of theory, melting point: 129-132 C
C10H9C1N20, (304 .64) d. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-hydroxy-propionic acid Prepared analogously to Example 6 from 2-(4-chloro-3-nitro-phenyl)-3-nitrooxy-2-met:hyl-propionic acid and 6N hydrochloric acid in dioxane.
Yield: 980 of theory, C1oH1oC1N05 (259.65) mass spectrum: (M-H)- = 258/60 (Cl) (2M-H) - = 517/9 (C12) e. 2-[4-(N-benzyl-methyl.amino)-3-nitro-phenyl]-2-methyl-3-hy-droxy-nro=ion'. acid Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid and N-methyl-benzyl-amine.
Yield: 810 of theory, C18H2OC1NZO5 (344.37) mass spectrum: M* = 344 f. 2- [4- (N-benzyl-methylamino) -3-riitrc>-phenyl] -2-methyl-3-hy-ro y-l-pyrrol i di n-1-y1 -nror~an-1 -one Prepared analogously to Example ic from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Yield: 96% of theory, C22H2,N304 (397.48) mass spectrum: M' = 398 (M+Na)+ = 420 g. 2-[4-(N-benzyl-methy:Lamino)-3-nitro-phenyl]-2-methyl-3-me-thanPSUlphonylox~r-~ -~yrrolidin-~ -y1 -propan-1 -one A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-l-pyrrolidin-l-yl-propan-1-one in 20 ml tetrahydrofuran is mixed at ambient temperature with 1.3 ml (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 mmol) of inethanesu:Lphonyl chloride are added dropwise at 2-5 C. After 2 hours at ambient temperature the precipitate formed is suction filtered and the filtrate is concentrated by evaporation. The crude product is further reacted without: being purified.
Yield: 1.4 g(980 of theory) h. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-me-t-hy ami no-7 -pyrro1 i d; n-'=yl-pronan-1 -one A solution of 1.4 g(2.9 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-l-pyrrolidin-1-yl-propan-l-one in 10 ml dimethylformamide is combined with 20 ml of a 40% aqueous methylamine solution and heated to 100 C
for 70 minutes. After cooling the reaction mixture is combined with ice water and extracted with ethyl acetate. The organic phases are washed with water and with saline solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with ethyl acetate/ethanol (10:1, 9:1, 4:1 + lo conc. ammonia). The uni-form fractions are combined and concentrated by evaporation.
Yield: 740 mg (61% of theory), RF value: 0.45 (silica qel; methylene chloride/ethanol = 9:1 + lo conc. ammonia) i. 2-[4-(benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(N-me-thoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-l-yl-pro-r~an- l -onP
Prepared analogously to Example 7d from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3- methylamino-l-pyrrolidin-1-yl-propan-l-one and methyl malonate chloride.
Yield: 840 of theory, RF value: 0.65 (silica qel; ethyl acetate/ethanol = 9:1 + ammonia) C27H34N406 (510.60) mass spectrum: (M-H)- 509 (M+Na)' 533 j. 2-(4-methylamino-3-al:nino-phenyl)-2-methyl-3-(N-methoxycar-bonylmethylcarbonyl-methylamino)-i-pyrrolidin-l-yl-propari-l-one Prepared analogously to Example id from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethyl-carbonyl-methylamino)-i-pyrrolidin-l-yl-propan-l-one and hy-drogen/palladium on activated charcoal.
Yield: 1000 of theory, RF value: 0.40 (silica crel; ethyl acetate/ethanol = 9:1 + 1o conc. ammonia) CZOH30N404 (390.49) mass spectrum: M+ = 390 k. 4-[2-(3-(N-methoxyca:rbonylmethylcarbonyl-methylamino))-2-methyl-l-pyrrolidin-1-yl-propan-l-on-2-yl]-2-(4-cyano h nyl)-aminom_.hyl.on~rlamino-N-mPthyl-anilinP
Prepared analogously to Example le from 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-i-pyrrolid:in-l-yl-propan-l-one and 0-(benzotria-zol-1-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 951 of theory, RF value: 0.35 (silica gel; ethyl acetate/ethanol = 9:1 + lo conc. ammonia) 1. 2-(4-cyanophenylamin.omethyl)-1-methyl-5-[1-(N-ethoxycar-bonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)--prop-2-yl] -h _nzimid nl Prepared analogously to Example if from 4-[2-(3-(N-methoxycar-bonylmethylcarbonyl-methylamino))-2-methyl-i-pyrrolidin-l-yl-propan-l-on-2-yl]-2-(4-cyanophenyl)-aminomethylcarbonylarnino-N-methyl-aniline in glacial acetic acid.
Yield: 47 0 of theory, Rf value: 0.20 (silica (jel; ethyl acetate/ethanol = 9:1) C29H34N6Oy (530.63) mass spectrum: (M+H)` = 531 (M+Na)' = 553 m. 2-(4-amidinophenylam.inomethyl)-1-methyl-5-[1-(N-ethoxycar-bonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)--prop-2 -yl] -h .n .i mi dazol .-r~rdrochl nri dP
Prepared analogously to Example ig from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methyl-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 65 0 of theory, Rf value: 0.30 (silica gel; methylene chloride/methanol = 4:1 + glacial acetic acid) C30H39N7O4 x HC1 (561.69/598.19) mass spectrum: (M+H)+ -= 562 (M+C1)- 596/8 (Cl) The following compounds are obtained analogously to Example 15:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methoxy-carbonylmethyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-.2-yl]-benzimidazole-hydrochloride Yield: 89 0 of theory, R. value: 0.35 (Reverse(i phase RP 8; methanol/5o saline solu-tion = 3:2) C2BH37N7O3 x HC1 (519.66/556.11) mass spectrum: (M+H)' = 520 (M-H+HCl)- = 554/6 (Cl) (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycar-bonylmethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2--yl]-benzimidazole-acetate Yield: 451 of theory, R. value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 o ethyl acetate) C29H37N704 x CH3COOH (547.66/607.71) mass spectrum: (M+H)+ = 548 (M-H)- = 546 (M-H+CH3C(DOH) - = 606 (3) 2-(4-amidinophenyl.aminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(N-methyl-ethylamino-carbonyl)-prop-2-yl]-benzimidazole-hydrochloride (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethyl-methylamino)-2-(N-methyl-N-ethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylsulphonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methoxy-carbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-acetate Yield: 72% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 o glacial acetic acid) C29H37N7O9 x CH3COOH (547.66/607.71) mass spectrum: (M+H)' = 548 (M-H)- = 546 (8) 2- (4-amidinophenylaminomethyl) -i-methyl-5- [1- (2-etho}:y-carbonyl-ethylcarbonyl.amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (9) 2-(4-amidinophenyla,minomethyl)-1-methyl-5-[1-(ethoxyc:ar-bonylmethylsulphonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride Yield: 14 0 of theory, Rf value: 0.20 (silica qel; methylene chloride/ethanol = 8:2) C28H37N7O5S x HC1 (583.65/620.17) mass spectrum: (M+H)+ 584 (M+Na) * 606 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl)-methylcarbonylam.ino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochlo:ride (11) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(ethoxycar-bonylmethylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benz-imidazole-dihydrochloride Yield: 40 0 of theory, C26H37N703 x 2 HC1 ( 519 . 65/592 . 56 ) mass spectrum: (M+H)+ = 520 (M+Na) T = 542 (M+HCOO) - = 564 (M+C1)- = 554 Fxamr)l P

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyl-amino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]-benzimidazol.e-hydro_h1oride Prepared by hydrolysis of 2-(4-amidinophenylaminomethyl)-1-me-thyl-5-[1-(ethoxycarbonylmethylamino)-1-(isoxazolidin-1-yl-car-bonyl)-ethyl]-benzimidazole-hydrochloride with sodium hydroxide solution in ethanol.
Yield: 90 % of theory, Rf value: 0.65 (Reversed phase RP 8; methanol/5% saline solu-tion = 3:2) C24H29N,04 x HC1 (479.54/515.99) mass spectrum: (M+H)` = 480 The following compounds are prepared analogously to Example 16:
(1) 2- (4-amidinophenylarninomethyl) -1-methyl-5- [1- (2-carboxy-ethylamino)-1-(isoxazol_i.din-1-yl-carbonyl)-ethyl]-benzimida-zole-hydrochloride (2) 2 - ( 4 - amidinophenyl arninomethyl ) -1-methyl - 5 - [ 1- ( carboxyme -thylamino)-1-(N-methyl-N-ethylaminocarbonyl)-ethyl]-benzimida-zole-hydrochloride Yield: 930 of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5o saline solu-tion = 1:1) C24H31N703 x HCl (465.57/502.02) mass spectrum: (M+H)' = 466 (M+C1-H)- = 500/2 (Cl) (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimi-dazole-dihydrochloride Yield: 890 of theory, Rf value: 0.57 (Reversed phase RP 8; methanol/5% saline solu-tion = 4:3) C27H35N7O3 x 2 HCl (505.63/ 578.54) mass spectrum: (M+H)' = 506 (M+2H) = 253 (M+H+Na)'' = 264.5 (4) 2- (4-amidinophenylar.ninomethyl) -1-methyl--5- [1- (carboxyme-thylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimi-dazole-hydrochloride Yield: 900 of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5o saline solu-tion = 4:6) C27H33N7O4 x HC1 (519.61/556.06) mass spectrum: (M+H)+ = 520 (M-H)- = 518 (5) 2-(4-amidinophenylaminomethyl)-i-methyl-5-[1-(N-carboxy-methyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)-prop=-2-yl]-benzimidazole-hydrochloride (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methylcarbonyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (7) 2- (4-amidinophenyl.aminomethyl) -1-methyl-5- [1- (N-carboxy-methylcarbonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methylsulphonyl-methyl.amino)-2-(piperidinocarbonyl)-prop--2-yl]-benzimidazole-hydrochloride (9) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxj,rme-thylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole-hydro-chloride Yield: 81% of theory, Rf value: 0.40 (Reverseci phase RP 8; methanol/5% saline solu-tion = 1:1) C26H33N703 (491.60/528.05) mass spectrum: (M+H)+ = 492 (M-H) - = 490 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benz-imidazole-hydrochloride (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carbo>:y-methylsulphonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]--benzimidazole-hydrochloride (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(diethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 700 of theory, Rf value: 0.50 (Reversed. Phase RP 8; methanol/5% saline solu-tion = 1:1) C25H33N703 x HCl (479.59/516.05) mass spectrum: (M+H)' = 480 (M-H)- = 478 (M-H+HC1)- = 514/516 (Cl) (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxyme-thylamino)-2-(pyrrolidiriocarbonyl)-prop-2-yl]-benzimidazole-dihydrochloride Yield: 22 0 of theory, Rf value: 0.50 (Reversed Phase RP8; 5o saline solution/methanol = 1:1) C26H33N703 x 2 HC1 (491.60/564.51) mass spectrum: (M+H)' = 492 (M-H)- = 490 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carb-oxymethyl-methylamino)-1.-(pyrrolidinocarbonyl)-ethyl]-benz-imidazole-dihydrochloride Rf value: 0.48 (Reversed Phase RP8; 5o saline solution/metha-nol = 3:2) C26H33N7O3 x 2 HC1 (491.60/564.51) mass spectrum: (M+H)' = 492 (M-H)- = 490 (15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-carboxy-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 82 0 of theory, R. value: 0.73; (Reversed Phase; 51 saline solution/methanol = 1:1) C27H35N703 x 2 HC1 (505.63/578.54) mass spectrum: (M+H)' = 506 F,xamz l e 17 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl ]-b .n .; m' da .ol P
A suspension of 1.4 g (2.4 mmol) of 2-(4-amidinophenylami.no-methyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole-dihydrochloride in 5 ml of N-ethyl-diisopropylamine and 2 ml dimethylformamide is combined with 1.5 g (6 mmol) of 4-nitrophenyl benzoate, whilst a clear solution is formed by heating. After 2 hours at 120 C the so-lution is concentrated by evaporation in vacuo, after cooling the residue is dissolved in dichloromethane and purified on silica gel, eluting first with dichloromethane, later with dichloromethane/ethanol (50:1, 25:1, 18:1). The uniform frac-tions are combined, concentrated by evaporation, triturated with water, suction filtered and dried.
Yield: 0.7 g(490 of theory), E. value: 0.40 (silica gel; methylene chloride/ethanol =:19:1) C34H39N7O4 (609.73) mass spectrum: (M+H)' = 610 (M+Na)+ = 632 (M-H) 608 The following compounds are obtained analogously to Examples 14 and 17:
(1) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxyca:rbonylmethylamino)-1-(pyrrolidinocarbo-nyl)-ethyl]-benzimidazole Yield: 530 of theory, Rf value: 0.35 (silica cfel; methylene chloride/ethanol = 9:1) C34H47N7O5 (633.79) mass spectrum: (M+Na)+ = 656 (M-H)- = 632 (2) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinoc:arbo-nyl)-ethyl]-benzimidazole Yield: 46% of theory, Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1) C36HS1N7O5 (661.84) mass spectrum: (M+Na)' = 684 (M-H)- = 660 (3) 2-[4-(N-n-hexyloxycarbonyl-amidino)-phenylaminomethyl)-1-methyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidinocar-bonyl)-ethyl]-benzimidazole (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidinocar-bonyl) ethyl] -benzimidazole Yield: 32% of theory, Rf value: 0.27 (silica gel; methylene chloride/ethanol = 9:1) C35H49N705 (647.82) mass spectrum: (M+Na)' = 670 (M-H)- = 646 (5) 2-[4-(N-n-hexyloxvcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 520 of theorv, Rf value: 0.60 (silica qel; methylene chloride/ethanol = 9:1) C37H51N7O6 (689.85) mass spectrum: (M+H)* = 690 (M-H)- = 688) (M+Na)' = 712 (M+HCl-H)- = 724/26 (Cl) (6) 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl.)-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole (7) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 210 of theory, Rf value: 0.55 (silica crel; methylene chloride/ethanol = 9:1) C36H49N706 (675.83) mass spectrum: (M+H)' = 676 (M+Na)' = 698 (M+HC1-H;)- = 724/26 (Cl) (8) 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl)-1-methyl-5-[l-(N-methoxycarbonylmethylcarbonyl-methylamin.o)-2-(pyrrolidinocarbonyl)--prop-2-yl]-benzimidazole (9) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-m.ethyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 34a of theory.
Rf value: 0.55 (silica gel; methylene chloride/ethanol =
9:1 + 1 o ammonia) C33H37N7O4 (595.70) mass spectrum: (M-H)- = 594 ( M+Na ) ' _= 618 (10) 2-[4-(N-isopropyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-etho}:ycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 660 of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C34H45N.7O6 (647.77) mass spectrum: (M+H)* -= 648 (M-H) - 646 (M+Na) i 670 (11) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1--me-thyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-.(pyr-rolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 230 of theory, Rf value: 0.45 (silica qel; methylene chloride/ethanol = 9:1) C37H43N7O5 (665.79) mass spectrum: (M+H)+ = 666 (M-H)- = 664 (M+Na)' = 688 (M+H+Cl)' = 700/2 (Cl) (12) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-me-thyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyr-rolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 670 of theory, Rf value: 0.60 (silica qel; methylene chloride/ethanol = 9:1) C36H41N7O5 (G51.76) mass spectrum: (M+H)' 652 (M-H) - 650 (M+Na)+ 674 (13) 2-[4-(N-n-butyloxyz:arbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 450 of theory, Rf value: 0.50 (silica clel; methylene chloride/ethanol = 9:1) C34H45N706 (647.77) mass spectrum: (M+H)' = 648 (M-H)- = 646 (M+Na) ` = 670 (M-H+HCl)- = 682/4 (Cl) (14) 2-[4-(N-ethyloxyca:rbonylamidino)-phenylaminomethyl]-1-me-thyl-5-[1-(N-ethoxycarb(Dnylmethylcarbonyl-methylamino)-2-(pyr-rolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 540 of theory, Rf value: 0.40 (silica crel; methylene chloride/ethanol = 9:1) C33H43N7O6 (633 . 75) mass spectrum: (M+H)' = 634 (M-H)- = 632 (M+Na)+ = 656 (15) 2- [4- (N-ethyloxyca.~-bonylamidino) -phenylaminomethyl] -1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamin.o)-2-(pyrrolidinocarbonyl)--prop-2-yl]-benzimidazole Yield: 530 of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C32H41N7O6 (619.72) mass spectrum: (M+H)+ = 620 (M-H) = 618 (M+Na)' = 642 (16) 2-[4-(N-pyridin-3-yl-carbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxy(--arbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)--prop-2-yl]-benzimidazole Yield: 16% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C36H42NBO5 (6G6.78) mass spectrum: (M-H)- = 665 (M+Na)' = 689 (17) 2-[4-(N-n-butyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocar-bonyl)-ethyl]-benzimidazole Yield: 52% of theory, Rf value: 0.42 (silica qel; methylene chloride/ethanol = 9:1) C32H43N7O5 (605.74) mass spectrum: (M+H)' 606 (M+Na)' 628 (M-H) - 604 (18) 2-[4-(N-ethyloxyca:rbonylamidino)-phenylaminomethyl]--1-me-thyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 300 of theory, Rf value: 0.44 (silica qel; methylene chloride/ethanol = 9:1) C30H39N7O5 (577.68) mass spectrum: (M+H)+ 578 (M+Na) + 600 (M-H) - 576 (19) 2-[4-(N-benzyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxyca:rbonylmethylamino)-1-(pyrrolidinocarbo-nyl)-ethyl]-benzimidazole Yield: 51% of theory, Rf value: 0.50 (silica qel; methylene chloride/ethanol = 9:1) C35H41N705 (639.75) mass spectrum: (M+Na) + _662 (M-H) - _638 (20) 2-[4-(N-pyridin-3-yl-carbonylamidino)-phenylaminomethyl]-1-methyl-5- [1- (ethoxyca:rbonylmethylamino) -1- (pyrrolidinoc:arbo-nyl) -ethyl] -benzimidazo:Le Yield: 84 % of theory, Rf value: 0.20 (silica clel; ethyl acetate/ethanol = 4:1) C33H38N804 (610.72) mass spectrum: (M+H)' = 611 (M-H)- = 609 (M-HCOO) - = 611 (21) 2-[4-(N-acetoxymethyloxycarbonylamidino)-phenylaminome-thyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole Yield: 42% of theory, Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1) C31H39N7075 (621.09) mass spectrum: (M+Na)+ 644 (M-H)- 620 (22) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)-phenyl-aminomethyl]-i-methyl-5-[1-(ethoxycarbonylmethylamino)-1.-(pyr-rolidinocarbonyl)-ethyl]-benzimidazole Yield: 730 of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 9:1) C30H36C13N7o5 (681) mass spectrum: M+ = 679/81/3 (Cl3) (M+Na)` = 702/4/6 (C13) (M-H)- = 678/80/2 (C13) F,xami 1 a ~ g 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-rnethyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]--bP=.i mi c3a7c)1 P
A solution of 0.2 g (0.3 mmol) of 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl]-i-methyl-5-[1-(ethoxycarbonylme-thylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 3 ml tetrahydrofuran and 2.5 ml ethanol is mixed with 1.1 ml of iN
sodium hydroxide solution and stirred for 4 hours at ambient temperature. The reaction mixture is concentrated by evapora-tion and combined with 1 ml of iN hydrochloric acid. After 12 hours at ambient temperature (pH 4) 2 drops of ammonia (330) are added, whereupon a bright yellow precipitate is formed.
After the solid formed has been suction filtered the filtrate is combined with 1 ml of 1 N hydrochloric acid and concentrated by evaporation with the addition of toluene. The residue is triturated with acetone, suction filtered, washed with di-ethylether and dried.
Yield: 0.1 g(500 of theory), Rf value: 0.35 (Reversed phase RP 8; methanol/5% saline solu-tion = 2:1) C39Hq,N,OS (633. 79) mass spectrum: (M+H)' = 634 (M+H+Na)" = 328.5 Exam l P 19 2- [4- (N-hydroxyamidino) --phenylaminomethyl] -i-methyl-5- [1- (eth-oxycarbonylmethylamino)-----(pyrrolidinocarbonyl)-ethyl]-b .n .i mi da7.ol A suspension of 0.6 g(1.2 mmol) of 2-(4-cyanophenylaminome-thyl)-i-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-ber.izimidazole in 50 ml ethanol is mixed with 0.47 g (7.8 mmol) of hydroxylamine hydrochloride and.
0.35 g (3.5 mmol) of sodium carbonate and refluxed for 17 hours. After cooling, the residue is filtered off, the filtrate is concentrated by evapc>ration and taken up in water. After extracting twice with dichloromethane, the combined organic phases are dried and cor.Lc:entrated by evaporation. The crude product is purified on silica gel, eluting with dichlorome-thane/ethanol (19/1 and 7/1). The uniform fractions are com-bined, concentrated by evaporation, triturated with diisopro-pylether and dried.
Yield: 0.025 g (40 of thLeory), Rf value: 0.68 (silica gel; methylene chloride/ethanol = 4:1) CZ,H35N.,O4 (521.62) mass spectrum: (M-H)- = 520 (M+Na)+ = 544 Rxam le 20 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-i-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyi)_ ethyl 1-ben .i mi a.ol 4- (5-methyl -~ . 2, 4-ox d~ ol -~-~rl )-~ henyl ami no-ac~P a a. Ethyl Prepared analogously to Example 9a from 4-(5-methyl-1,2,4-oxa-diazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diiso-propylamine.
Yield: 780 of theory, Rf value: 0.60 (silica qel; ethyl acetate/petroleum ether =
1:1) b_ 4-(5-m _.hyl -1,2,4-oxa~jj a.ol --, -yl) -henylami_no- e.ic- acid Prepared analogously to Example 4 from ethyl 4-(5-methyl--1,2,4-oxadiazol-3-yl)-phenylamino-acetate and sodium hydroxide solu-tion in ethanol.
Yield: 750 of theorv, Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9:1) c. 2-[4-(5-methyl-1,2,4--oxadiazol-3-yl)-phenylaminomethyl.]-1-methyl-5- [1-amino- (py.-roli din-1-yl-carbonyl) -ethyl] -ber.Lz-~midazole Prepared analogously to Example le/f from 2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-amino-l-pyrrolidi.n-1-yl-propanone, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-acetic acid and carbony=_diimidazole in tetrahydrofuran and subsequent treatment with glacial acetic acid.
Yield: 34% of theory, Rf value: 0.10 (silica gel; methylene chloride/ethanol = 9:1) d. 2-[4-(5-methyl-1,2,4--oxadiazol-3-yl)-phenylaminomethyl]-i-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrro-1' di no . bonyl )-ethyl1 -benzi mi dazole Prepared analogously to Example 11 from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-l-(pyr-rolidinocarbonyl)-ethyl]-benzimidazole, isopropyl bromoacetate and potassium carbonate in isopropanol./methylene chloride.
Yield: 42% of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1) e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopropyloxy-carbonylmethylamino)-i.-(pyrrolidinocarbonyl)-ethyl]-benzi_mi-dazole-acetatP
Prepared analogously to Example id from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzi.mida-zole and hydrogen/palladium (10a on activated charcoal) in ethanol/glacial acetic acid.
Yield: 690 of theory, Rf value: 0.30 (silica gel; methylene chloride/ethanol = 7:3) f. 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-p-thyl ] -ben . i mi da .ol .
Prepared analogously to Example 17 from 2-(4-amidinophenylami-nomethyl)-1-methyl-5-[l-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate and 4-nitrophenyl benzoate in N-ethyl-diisopropylamine/dimethyl-formamide.
Yield: 26% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol =13:1) C35H41N704 (623.75) mass spectrum: (M+Na)' = 646 (M-H)- = 622 The following compounds are prepared analogously to Example 20:
(1) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole (2) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-phenylethyloxycarbonylmethylamino)-1-(pyrro-lidinocarbonyl)-ethyl]-benzimidazole (3) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropy:loxycarbonylmethylamino)-1-(pyrro-lidinocarbonyl)-ethyl]-benzimidazole Yield: 400 of theory, R. value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C35H49N7O5 (647.82) mass spectrum: (M+H)+ = 648 (M-H) = 646 (M+Na)' = 670 (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrro-lidinocarbonyl)-ethyl]-benzimidazole Yield: 31 % of theory, Rf value: 0.48 (silica gel; methylene chloride/ethanol = 9:1) C37H53N705 (675.88) mass spectrum: (M+H)' = 674 (M+Na) ` = 698 (5) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)-phenyl-aminomethyl]-1-methyl-5--[1-(isopropyloxycarbonylmethylami:no)-1-(pyrrolidinocarbonyl)--ethyl]-benzimidazole Yield: 43 0 of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1) C31H3BC13N?O5 (695.05) mass spectrum: (M-H)- = 692/694/696/698 (C13) (6) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 79 0 of theory, R. value: 0.35 (silica gel; ethyl acetate/ethanol = 9:1) C35H41N7O4 (623 . 76) mass spectrum: (M+H)' = 624 (M-H)- = 622 (M+HCOO) - = 668 (7) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole Yield: 53 0 of theory, Rf value: 0.39 (silica gel; ethyl acetate/ethanol = 9:1) C37H53N7O5 (675.88) mass spectrum: (M+H)' = 676 (M+Na)+ = 698 (M-H)- = 674 Fxa j~l a 21 (R) -2- (4-amidinophenylanlinomethyl) -1-methyl-5- [1- (carboxyme-thylamino)-1-(pyrrolidiriocarbonyl)-ethyl]-benzimidazole-hydro-chloridP
a. Rt-hyl ~-ami no-2- (4-r_.hl oro-~-ni t ro-nhanyl )-~ roi i ona _ A mixture of 28 g (0.11 mol) of 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid in 200 ml of 5.6N ethanolic hydrochloric acid is refluxed for 36 hours. After evaporation of the solvent the residue is suspended in 300 ml of ethyl acetate and mixed with 300 ml of saturated sodium hydrogen carbonate solution.
The organic phase is washed twice with saturated sodium hydro-gen carbonate solution and once with water. The obtained or-ganic phase is dried over sodium sulphate and evaporated.
Yield: 21.1 g(68% of theory) light brown oil.

h_ Rthyl ~~) -(+? -?-amino-~- (4- hlo o-~-ni ro- h~~~) -~rn~ ionafiP
17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3-nitro-phe-nyl)-propionate are dissolved in 247 ml of isopropanol und 207 ml of methanol and mixed with 9.54 g(63.6 mMol) of L-(+)-tartaric acid. The reaction mixture is heated up to 100 C, whereby a clear solution. is obtained. The solution is cooled within 3 hours up to 27"C and the obtained precipitate is suction filtered, washed with ethanol and dried. The formed precipitate (21.5 g) is suspended in 400 ml of ethyl acetate and mixed with 400 ml of saturated sodium hydrogen carboriate solution. After extraction and separation of the phases the organic phase is washed with water, dried and evaporated.
Yield: 7.68 g(44.40 of theory) light yellow oil, [a]20 = + 4.38 (ethyl acetate) HPLC-analysis: ee value >98.60 c_ (R)-(-)-2-amino- -(a=-chloro-3-nitro-=hPn~rl)-=ro=innir ?rid Prepared analogously to Example 4 from ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionate and sodium hydroxi_de solution in tetrahydrofurane.
Yield: 63% of theory, [a]2D = - 59.6 (methanol/water = 1:1) d. (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-enyl )-j~roz i on i c a ri d Prepared analogously to Example 5d from (R)-(-)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid and di-tert.butyl pyrocarbonate and triethylamine in dioxane.
Yield: 100% of theory, e. (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-ni.tro-Pnyl ) - ro7pionic acid Prepared analogously to Example lb from (R)-2-tert.butyloxy-carbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid and methylamine.
Yield: 69% of theory.

f . (R)-2-(4-methylamino--3-nitro-phenyl)-2-tert.butyloxyca.rbo-nyl ami o-I-j)yrrol i di n~-r)ropanone Prepared analogously to Example lc from (R)-2-tert.butyloxy-carbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionic acid, pyrrolidine and carbonyl diimidazole in tetrahydrofurane.
Yield: 96% of theory.
g. (R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbo-nylamino-I -~2yrrnlidinn-,nror)anonP
Prepared analogously to Example ic from (R)-2-(4-methylamino-3-nitro-phenyl)-2-tert..butyloxycarbonylamino-l-pyrrolidino-propanone and hydrogen/palladium on charcoal in methanol..
Yield: 990 of theory.

h. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.bu-tyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benz--imi a . 01 Prepared analogously to Example ic/if from (R)-2-(4-methyl-amino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-i-pyrro-lidino-propanone, 4-cyanophenylglycine, carbonyl diimidazole in tetrahydrofurane and subsequent cyclisation in glacial acetic acid.
Yield: 100% of theory.

i. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(I~yrrolidinoc,arbonyl)-5~thyll-b.n imida ol Prepared analogously to Example 6i from (R)-2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-(]\T-tert.butyloxycarbonylamino)-1-(pyr-rolidinocarbonyl)-ethyl:]-benzimidazole and 6N hydrochloric acid in dioxane.
Yield: 76% of theory.

k. (R)-2-(cyanophenylam:inomethyl)-1-methyl-5-[1-(ethoxycar-honyl methyl ami no) -i-1ny;rrnl i di nonarbonyl_ )Pt-hyl1 -b _n i mi daznl P
Prepared analogously to Example 6k from (R)-2-(4-cyanophenyl-aminomethyl)-1-methyl-5--[1-amino-l-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and ethyl jodoacetate/potassium carbonate in acetone.
Yield: 75% of theory.
1. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benz-im' da .ol e-h~rdro hl ori dP
Prepared analogously to Example ig from (R)-2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-((=_thoxycarbonylmethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 950 of theory.

m. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrroli(linocarbonyl)-ethyl]-benzimidazole-hydro .hl ori d Prepared analogously to Example 4 from (R)-2-(4-amidinoph.enyl-aminomethyl)-1-methyl-.5--[1-(ethoxycarbonylmethylamino)-1-(pyr-rolidinocarbonyl)-ethyl}-benzimidazole and sodium hydroxide solution in ethanol.
Yield: 1000 of theory.
C25H31N703 x 2HC1 (477. 57/550.5) mass spectrum: (M+H)+ = 478 (M-H+HC1)- = 512/514 (Cl) (M-H+2HC1)" = 448/550/552 (C12) Fx.am 1 . 22 Dry amr~oLl P _on i ni ng 'S mg of a.t i vP suhst-ancrP tz-~ -r 10 ml Composition:

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation:
Active substance and marinitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solu-tion ready for use, the product is dissolved in water for in-jections.
Rxamr 1 e 23 Dry amj:~oiil nn ai ni na 35 mg of active _quhqt-an lp.r 2 ml Composition:
Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.

RxamlplP 24 T bl _t _on a' ni ng 5 0 mg-of a.ti vP slihs an .
Composition:

(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mcs 215.0 mg Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4).. (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Rxam ltzp P 25 Tahlet .ontainin!Z 350 m.~ of ac iv? -,iibatanrp Preparation:

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg.
600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
F_xam li P 26 Car)sul PR .on i ni nZc7)0 mg a i v_ c;ubs anc .
Composition:
(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mcg 160.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

Rxami l e 27 ~~ su1 Ps cron ai ni ncl '~50 mQ of a_ i v. sihstanrP
Composition:

(1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine.

Exam l= ? 2 R

SuT2~ osi tori _s .ont i ni nc~ 7 00 mg of a. i v. subs n 1 suppository contains:
Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan rnonostearate 840.0 mg 2,000.0 mg Method:
The polyethyleneglycol is melted together with polyethylene sorbitan monostearate. At 40 C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38 'C and poured into slightly chilled suppository moulds.

Claims (31)

CLAIMS:
1. A benzimidazole of general formula wherein Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1-3-alkyl group, A denotes a C1-3-alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group wherein the alkyl moiety is optionally mono- or disubstituted by a carboxy group, R a denotes an R1-CO-C3-5-cycloalkyl group wherein R1 denotes a C1-3-alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group wherein each alkyl moiety is optionally substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which is optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups, wherein the alkyl substituent is optionally simultaneously substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl) -amino, carboxy-C1-3-alkylaminocarbonyl, N- (C1-3-alkyl) -N- (carboxy-C1-3-alkyl) -aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl) -aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1-3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R2-CX-C3-5-cycloalkyl group wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms wherein the alkyl substituent is optionally substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N- (C1-3-alkyl)-carboxy-C1-3-alkylamino group, and X denotes an oxygen atom, a C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di- (C1-3-alkyl) -hydrazino, C2-4-alkanoylhydrazino, N- (C1-3-alkyl) -C2-4-alkanoylhydrazino or C1-3-alkylidene group each of which is optionally substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C1-3- alkyl or C3-5-cycloalkyl group substituted by an imidazole or imidazolone group wherein the imidazole ring is optionally substituted by a phenyl or carboxy group and by one or two C1-3-alkyl groups or by one, two or three C1-3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents is optionally simultaneously substituted by a carboxy group or is optionally substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkylamino or di- (C1-3-alkyl)-amino group, and the imidazolone ring is optionally substituted by a C1-3-alkyl group, wherein the alkyl substituent is optionally substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N- (C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and additionally a phenyl or pyridine ring is optionally fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which is optionally substituted by one or two C1-3-alkyl groups, wherein at the same time an alkyl substituent is optionally substituted by a carboxy group, a C1-4-alkyl group which is substituted by a C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C1-3-alkyl group, by a pyrrolino-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-l-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein in the abovementioned groups the cycloalkyleneimino moiety is optionally substituted by one or two Cl-3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C1-3-alkylaminocarbonyl, di- (C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups is optionally substituted by a carboxy group, and the remaining hydrogen atoms of the C1-4-alkyl group are optionally wholly or partially replaced by fluorine atoms wherein R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH-group and Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R3NR4- group, and the imino groups occurring in the definition of the groups Y1 and Y2 is optionally each additionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group, a C1-3-alkyl or C3-5-cycloalkyl group substituted by an R5NR6- group wherein R5 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted by a C2-4-alkanoyl or C5-7-cycloalkanoyl group and by a C1-3-alkyl group substituted by a chlorine, bromine or iodine atom, R b denotes a hydrogen atom or a C1-3-alkyl group and R c denotes a cyano group or an amidino group optionally substituted by one or two C1-3-alkyl groups, wherein the carboxy groups mentioned in the definitions of the abovementioned groups are optionally replaced by a group which is convertable in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, or the amino and imino groups mentioned in the definitions of the abovementioned groups is optionally also substituted by a group which is cleavable in vivo, or a tautomer thereof, a stereoisomer thereof, a mixture thereof or a salt thereof.
2. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 1, wherein the group which is convertable in vivo into the carboxy group is a hydroxymethyl group or a carboxy group esterified with an alcohol.
3. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 2, wherein the alcohol moiety of the carboxy group esterified with the alcohol is a C1-6-alkanol; a phenyl-C1-3-alkanol; a C3-9-cycloalkanol; a C5-8-cycloalkanol substituted by one or two C1-3-alkyl groups;
a C5-8-cycloalkanol wherein a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group wherein the cycloalkanol moiety thereof is optionally additionally substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond; a C3-8-cycloalkyl-C1-3-alkanol; a bicycloalkanol with a total of 8 to 10 carbon atoms, which is optionally substituted in the bicycloalkyl moiety thereof by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula R d-CO-O- (R e CR f) -OH, wherein R d denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group, R e denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and R f denotes a hydrogen atom or a C1-3-alkyl group.
4. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 1, wherein the group which is negatively charged under physiological conditions is a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1-5-alkylsulphonylaminocarbonyl, phenylsulphonyl-aminocarbonyl, benzylsulphonylaminocarbonyl, or perfluoro-C1-6-alkylsulphonylaminocarbonyl group.
5. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 1 wherein the group which is cleavable in vivo from the imino group or the amino group is a hydroxy group, an acyl group, a pyridinoyl group, a C1-16-alkanoyl group, a 3,3,3-trichloropropionyl group, allyloxycarbonyl group, a C1-16-alkoxycarbonyl or C1-16-alkylcarbonyloxy group wherein hydrogen atoms are optionally wholly or partially replaced by fluorine or chlorine atoms, a phenyl-C1-6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono-or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and the substituents may be identical or different, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, R d-CO-O- (R d CR f) -O-CO-, C1-6-alkyl-CO-NH- (R g CR h) -O-CO- or C1-6-alkyl-CO-O-(R g CR h)-(R g CR h)-O-CO- group wherein R d to R f are as defined in claim 3 and wherein R g and R h, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups.
6. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 5, wherein the acyl group is a benzoyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl or C1-3-alkoxy groups, wherein the substituents may be identical or different.
7. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 5, wherein the C1-16-alkanoyl group is a formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group.
8. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 5, wherein the C1-16-alkoxycarbonyl or C1-16-alkylcarbonyloxy group wherein hydrogen atoms are optionally wholly or partially replaced by fluorine or chlorine atoms is a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert. butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group.
9. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 5, wherein the phenyl-C1-6-alkoxycarbonyl group is a benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group.
10. A benzimidazole of general formula wherein A denotes a C1-3-alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group wherein the alkyl moiety is optionally mono- or disubstituted by a carboxy group, R a denotes an R1-CO-C3-5-cycloalkyl group wherein R1 denotes a C1-3-alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group wherein each alkyl moiety is optionally substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which is optionally substituted by one or two C1-3-alkyl groups, wherein the one or two alkyl substituents are optionally simultaneously substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylamino-carbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1-3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C1-3-alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R2-CX-C3-5-cycloalkyl group wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms wherein the alkyl substituent is optionally substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and X denotes an oxygen atom, a C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-(C1-3-alkyl)-C2-4-alkanoylhydrazino or C1-3-alkylidene group each of which is optionally substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C1-3-alkyl or C3-5-cycloalkyl group substituted by an imidazole or imidazolone group wherein the imidazole ring is optionally substituted by a phenyl or carboxy group and by one or two C1-3-alkyl groups or by one, two or three C1-3-alkyl groups, wherein the substituents are identical or different and one of the abovementioned alkyl substituents is optionally simultaneously substituted by a carboxy group or is optionally substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and the imidazolone ring is optionally substituted by a C1-3-alkyl group, wherein the alkyl substituent is optionally substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and additionally a phenyl or pyridine ring may be fused to the imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which is optionally substituted by one or two C1-3-alkyl groups, wherein one of the one or two alkyl substituent is optionally substituted by a carboxy group, a C1-4-alkyl group which is substituted by a C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C1-3-alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein in the abovementioned groups the cycloalkyleneimino moiety is optionally substituted by one or two C1-3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C1-3-alkylaminocarbonyl, di- (C1-3-alkyl) -amino-carbonyl or cycloalkyleneiminocarbonyl groups is optionally substituted by a carboxy group, and the remaining hydrogen atoms of the C1-4-alkyl group are optionally wholly or partially replaced by fluorine atoms wherein R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH-group and Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R3NR4- group, and the imino groups occurring in the definition of the groups Y1 and Y2 are optionally each additionally substituted by a C1-3-alkyl or carboxy-C2-3-alkyl group, a C1-3-alkyl or C3-5-cycloalkyl group substituted by an R5NR6-group wherein R5 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted by a C2-4-alkanoyl or C5-7-cycloalkanoyl group and by a C1-3-alkyl group substituted by a chlorine, bromine or iodine atom, R b denotes a hydrogen atom or a C1-3-alkyl group and R c denotes a cyano group or an amidino group which is optionally substituted by a hydroxy group, by one or two C1-3-alkyl groups, or by one or two C1-8-alkoxycarbonyl groups, wherein the carboxy groups mentioned in the definitions of the above mentioned groups are optionally replaced by a group which is convertable in vivo into a carboxy group or by a group which is negatively changed under physiological conditions and the amino and imino groups mentioned in the definition of the abovementioned groups are optionally substituted by a group which is cleavable in vivo, or a C1-3-alkanol ester, tautomer, stereoisomer or salt thereof.
11. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 10, wherein the group which is convertable in vivo into the carboxy group is as defined in any one of claims 2 or 3.
12. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 10, wherein the group which is negatively charged under physiological conditions is as defined in claim 4.
13. A benzimidazole, tautomer, stereoisomer, mixture or salt according to claim 10, wherein the group which is cleavable in vivo is as defined in any one of claims 5 to 9.
14. A benzimidazole C1-C3-alkanol ester, tautomer, stereoisomer or salt according to claim 10, wherein A denotes a C1-3-alkylene group, B denotes an oxygen atom, a methylene, imino or N-(C1-3-alkyl)-imino group wherein the alkyl moiety is optionally substituted by a carboxy group, R a denotes a C3-5-cycloalkyl group substituted by the R1-CO
group in the 1 position wherein R1 denotes a C1-3-alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group wherein each alkyl moiety is optionally substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino group which is optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups, wherein the one or two alkyl substituents are optionally substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, N- (C1-3-alkyl) -N- (carboxy-C1-3-alkyl) -amino, carboxy-C1-3-alkylaminocarbonyl, N- (C1-3-alkyl) -N- (carboxy-C1-3-alkyl) -aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl) -aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1-3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, a C3-5-cycloalkyl group substituted in the 1 position by an R2-CX- group, wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group, wherein the 6-membered heteroaryl group comprises one, two or three nitrogen atoms and the 5-membered heteroaryl group comprises an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the alkyl substituent is optionally substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N- (C1-3-alkyl) -carboxy-C1-3-alkylamino group, and X denotes an oxygen atom, a C1-3-alkylimino, C1-3-alkoxyimino or C1-3-alkylidene group, each of which is optionally substituted in the alkyl or alkanoyl moiety by a carboxy group, a C1-3-alkyl group substituted in the 1 position by an imidazole or imidazolone group wherein the imidazole group is optionally substituted in the ring thereof by a phenyl or carboxy group and by one or two C1-3-alkyl groups or by one, two or three C1-3-alkyl groups, wherein the substituents are identical or different and one of the one or two alkyl substituents is optionally substituted by a carboxy group or is optionally substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N- (C2-4-alkanoyl) -C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and the imidazolone group is optionally substituted in the ring thereof by a C1-3-alkyl group, wherein the alkyl substituent is optionally substituted by a carboxy group or is optionally substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N- (C2-4-alkanoyl) -C1-3-alkylamino or di- (C1-3-alkyl) -amino group, and additionally a phenyl or pyridine ring is optionally fused to the imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which is optionally substituted by one or two C1-3-alkyl groups, whilst at the same time an alkyl substituent is optionally substituted by a carboxy group, a C1-4-alkyl group which is substituted in the 1 position by an R3NR4- or R3NR4-C1-3-alkyl group and by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di- (C1-3-alkyl) -aminocarbonyl, isoxazolidin-1-yl-carbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein the 4- to 7-membered cycloalkyleneiminocarbonyl group, the cycloalkyleneimino moiety is optionally substituted by one or two C1-3-alkyl groups and wherein each alkyl moiety or alkyl substituent in the C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups are optionally substituted by a carboxy group, and the remaining hydrogen atoms of the C1-3-alkyl group are optionally wholly or partially replaced by fluorine atoms, wherein R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom to which each is attached denote a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1 position by a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, wherein Y2 denotes a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R3NR4-group, and wherein the imino group of Y2 is optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group, a C1-3-alkyl or C3-5-cycloalkyl group substituted in the 1 position by an R5NR6-group wherein R5 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted by a C2-4-alkanoyl or C5-7-cycloalkanoyl group and by a C1-3-alkyl group substituted by a chlorine, bromine or iodine atom, R b denotes a C1-3-alkyl group and R c denotes an amidino group which is optionally substituted by a 2,2,2-trichloroethoxycarbonyl, C1-8-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, wherein the benzoyl group is optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl or C1-3-alkoxy groups and wherein the substituents may be identical or different.
15. A benzimidazole, C1-3-alkanoyl ester, tautomer, stereoisomer or salt according to claim 10, wherein A denotes a methylene group, B denotes an oxygen atom or an imino group, R a denotes a cyclopropyl group substituted by an R1-CO- group in the 1 position, wherein R1 denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl group is optionally substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl) -carboxy-C1-3-alkylamino group, a cyclopropyl group substituted in the 1 position by an R2-CX- group, wherein R2 denotes a phenyl, pyridyl or pyrazolyl group optionally substituted by a C1-3-alkyl group and X denotes an oxygen atom, a C1-3-alkoxyimino or C1-3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety thereof by a carboxy group, a C1-2-alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring is optionally substituted by a phenyl or carboxy group and by one or two C1-3-alkyl groups or by one, two or three C1-3-alkyl groups, wherein the substituents may be identical or different and one of the alkyl substituents is optionally substituted by a carboxy group or is optionally substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N- (C2-4-alkanoyl) -C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and wherein a phenyl or pyridine ring is optionally fused to the imidazole ring via two adjacent carbon atoms, a C1-2-alkyl substituted in the 1 position by a benzimidazolon-1-yl group, wherein the imidazolone ring thereof is optionally substituted by a methyl or ethyl group optionally substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position by an R3NR4 or R3NR4-C1-3-alkyl group and by a di-(C1-3-alkyl)-aminocarbonyl group, by a isoxazolidin-1-yl-carbonyl group, by a pyrrolidino-carbonyl or piperidino-carbonyl group substituted by a C1-3-alkyl group, wherein each alkyl moiety or alkyl substituent is optionally substituted by a carboxy group, wherein R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom to which they are both attached denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy group, wherein Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C1-3-alkyl group, a C1-2-alkyl group substituted in the 1 position by an R5NR6-group, wherein R5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and R6 denotes a C1-3-alkyl or carboxy-C1-3-alkyl group, an n-propyl group substituted in the 3 position by a chlorine atom, which is substituted in the 1 position by a cyclopentylcarbonyl group, a cyclopropyl group substituted in the 1 position by a cyclopentylamino group, which is substituted at the nitrogen atom by a carboxy-C1-3-alkylcarbonyl group, R b denotes a methyl group and R c denotes an amidino group which is optionally substituted by a C1-8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group.
16. A benzimidazole, C1-3-alkanol ester, tautomer, stereoisomer or salt according to claim 10, wherein A denotes a methylene group, B denotes an imino group, R a denotes a cyclopropyl group substituted by an R1-CO- group in the 1 position, wherein R1 denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl group is optionally substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, a cyclopropyl group substituted in the 1 position by an R2-CX
group, wherein R2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C1-3-alkyl group and X denotes an oxygen atom, a C1-3-alkoxyimino or C1-3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety thereof by a carboxy group, a C1-2-alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring thereof is optionally substituted by one to three methyl groups or by two methyl groups and an ethyl group, wherein one of the methyl or ethyl substituents is optionally substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position by an R3NR4- or R3NR4-CH2- group and by a di-(C1-3-alkyl)-aminocarbonyl, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by a C1-3-alkyl group, wherein each alkyl moiety or alkyl substituent is optionally substituted by a carboxy group, wherein R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R4 denotes a C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group wherein Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C1-3-alkyl group, Rb denotes a methyl group and R c denotes an amidino group which is optionally substituted by a C1-8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group.
17. A benzimidazole, tautomer, stereoisomer or salt according to any one of claims 1 to 16, wherein the group R a is in the 5 position.
18. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
19. (E/Z)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
20. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
21. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole, or a C1-3-alkanolester;
a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
22. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
23. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
24. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(N-methylcarboxymethylcarbonylaminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, or a C1-3-alkanolester; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
25. 2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, or a C1-3-alkanolester thereof; a N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl or N-benzoyl-amidine thereof; a tautomer thereof; a stereoisomer thereof or a salt thereof.
26. A physiologically acceptable salt of a benzimidazole according to any one of claims 1 to 17 wherein R c denotes one of the amidino groups defined in any one of claims 1 to 17 or a physiologically acceptable salt of a compound defined in any one of claims 18 to 25.
27. A pharmaceutical composition comprising a benzimidazole according to any one of claims 1 to 17 wherein R c denotes one of the amidino groups defined in any one of claims 1 to 17, or a salt according to claim 26, and one or more compounds selected from inert carriers and diluents.
28. Use of a benzimidazole according to any one of claims 1 to 17 wherein R c denotes one of the amidino groups defined in any one of claims 1 to 17, or a salt according to claim 26, in preparing a pharmaceutical composition with a thrombin time prolonging effect, a thrombin-inhibiting effect or an inhibiting effect on a related serine protease.
29. A pharmaceutical composition according to claim 27, with a thrombin time prolonging effect, a thrombin inhibiting effect or an inhibiting effect on a related serine protease.
30. A process for preparing a pharmaceutical composition according to claim 27 or 29, wherein a benzimidizole according to any one of claims 1 to 17 wherein R c denotes one of the amidino groups defined in any one of claims 1 to 17, or a salt according to claim 26, is admixed with one or more compounds selected from inert carriers and diluents.
31. A process for preparing a compound according to claim 1, wherein a) in order to prepare a compound of general formula I as defined in claim 1 wherein R c denotes a cyano group:

a compound of general formula optionally formed in the reaction mixture, wherein R a, R b, Ar, A and B are defined as in claim 1, Z1 and Z2, which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon atoms or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, is cyclised;

b) in order to prepare a compound of general formula I
wherein R a denotes a R2-CX'-C3-5-cycloalkylene group, wherein R2 is as defined in claim 1 and X' denotes one of the imino groups set out in the definition of X in claim 1:

a compound of general formula wherein R b, R c, Ar, A and B are defined as in claim 1 and R a' denotes an R2-CO-C3-5-cycloalkylene group, where R2 is defined as in claim 1, is reacted with an amine of general formula H2X' (V), wherein X' denotes one of the imino groups set out in the definition of X in claim 1;

c) in order to prepare a compound of general formula I
wherein R a denotes a R2-CX"-C3-5-cycloalkylene group, wherein R2 is as defined in claim 1 and X" denotes one of the alkylidene groups set out in the definition of X in claim 1, a compound of general formula wherein R b, R c, Ar, A and B are defined as in claim 1 and R a' denotes an R2-CO-C3-5-cycloalkylene group, where R2 is defined as in claim 1, is reacted with a phosphone of general formula Z3-HX" (VI), wherein X" denotes one of the alkylidene groups set out in the definition of X in claim 1, and Z3 denotes a triphenylphosphono or di-(C1-3-alkoxy)phosphono group;

d) in order to prepare a compound of general formula I
wherein R c denotes an amidino group which is optionally substituted by one or two C1-3-alkyl groups:

a compound of general formula optionally formed in the reaction mixture wherein R a, R b, Ar, A and B are defined as in claim 1 and Z4 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula:

H-R7NR8 (VIII), wherein R7 and R8, which are identical or different, each denote a hydrogen atom or a C1-3-alkyl group, with a salt thereof;
e) in order to prepare a compound of general formula I
wherein R a denotes an imidazolidin-2,4-dion-5-yl group which is optionally substituted by one or two C1-3-alkyl groups, wherein the one or two alkyl substituents are optionally substituted by a carboxy or C1-3-alkoxycarbonyl group:

a compound of general formula optionally formed in the reaction mixture wherein R b, Ar, A and B are defined as in claim 1 and R a" denotes an aminocarbonylamino group, substituted in the 3 position by a C1-3-alkoxycarbonyl-C1-3-alkyl group, is cyclised;

f) in order to prepare a compound of general formula I
wherein R c denotes a hydroxyamidino group:

a nitrile of general formula wherein R a, R b, Ar, A and B are defined as in claim 1, is reacted with hydroxylamine or a salt thereof;

g) in order to prepare a compound of general formula I
wherein R a contains a carboxy group and R c is defined as in claim 1 or R a is defined as in claim 1 and R c denotes an amidino group optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups:

a compound of general formula wherein R b, Ar, A and B are defined as in claim 1 and R a"' and R c' have the meanings given for R a and R c in claim 1, with the proviso that R a comprises a group which is convertable into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and R c is defined as in claim 1 or R c denotes a group which is convertable by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into an amidino group substituted by a hydroxy group or by one or two C1-3-alkyl groups and R a is defined as in claim 1, is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein R a contains a carboxy group and R c is defined as in claim 1 or R a is defined as in claim 1 and R c denotes an amidino group optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups; or h) in order to prepare a compound of general formula I
wherein R c denotes an amidino group which is substituted by one or two C1-8-alkoxycarbonyl groups or by a group which is cleavable in vivo:

a compound of general formula I

wherein R a, R b, Ar, A and B are defined as in claim 1 and R c" denotes an amidino group, is reacted with a compound of general formula Z5-R9 (XIII), wherein R9 denotes a C1-8-alkoxycarbonyl group or an acyl group of one of the groups which is cleavable in vivo and Z5 denotes a nucleofugic leaving group, and subsequently one or more of the following optional steps are performed:

(i) a compound of general formula I thus obtained which comprises an (R3NR4)-C1-3-alkyl group in which at least one of the groups R3 or R4 denotes a hydrogen atom, is converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of general formula I;

(ii) a compound of general formula I thus obtained which comprises a NH2-C1-3-alkyl group is converted with a corresponding acrylic acid ester into a corresponding 2-(C1-3-alkoxycarbonyl)-ethyl compound of general formula I;

(iii) a compound of general formula I thus obtained which comprises an (R3NR4)-C1-3-alkyl group in which R3 and R4 each denote a hydrogen atom is converted with a corresponding dihaloalkane into a corresponding compound of general formula I wherein R3 and R4 together with the nitrogen atom to which is attached denote a corresponding 4- to 7-membered cycloalkyleneimino group;

(iv) a compound of general formula I thus obtained wherein R c denotes an amidino group is converted with a haloacetic acid derivative and subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups;

(v) a compound of general formula I thus obtained wherein R c denotes a hydroxyamidino group is converted by a catalytic hydrogenation into a corresponding amidino compound;

(vi) a compound of general formula I thus obtained wherein R a comprises a carboxy group is converted by esterification into a corresponding ester;

(vii) a protecting grou0p used to protect a reactive group is cleaved;

(viii) a compound of general formula I thus obtained is resolved into its stereoisomers; and (ix) a compound of general formula I thus obtained is converted into a physiologically acceptable salt thereof with an inorganic or organic acid or base.
CA002337804A 1998-07-04 1999-07-01 Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions Expired - Fee Related CA2337804C (en)

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DE19829964.8 1998-07-04
DE1998129964 DE19829964A1 (en) 1998-07-04 1998-07-04 New benzimidazolyl amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates
DE19857202.6 1998-12-11
DE1998157202 DE19857202A1 (en) 1998-12-11 1998-12-11 New benzimidazolyl amidine or nitrile compounds, useful as thrombin inhibitors or antithrombotic agents, for treating deep leg vein thrombosis
DE19912690.9 1999-03-20
DE1999112690 DE19912690A1 (en) 1999-03-20 1999-03-20 New benzimidazolyl amidine or nitrile compounds, useful as thrombin inhibitors or antithrombotic agents, for treating deep leg vein thrombosis
PCT/EP1999/004531 WO2000001704A2 (en) 1998-07-04 1999-07-01 Benzimidazoles, production thereof and use thereof as medicaments

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