NZ509625A

NZ509625A - Benzimidazoles, production thereof and use thereof as medicaments

Info

Publication number: NZ509625A
Application number: NZ509625A
Authority: NZ
Inventors: Uwe Ries; Iris Kauffmann-Hefner; Norbert Hauel; Henning Priepke; Herbert Nar; Jean-Marie Stassen; Wolfgang Wienen
Original assignee: Boehringer Ingelheim Pharma
Priority date: 1998-07-04
Filing date: 1999-07-01
Publication date: 2003-08-29
Also published as: DE59903765D1; CA2337804C; CN1152866C; KR20010083087A; EA200100042A1; CN1308614A; AR019222A1; AU4903399A; JP2002519429A; AU763094B2; NO20010028D0; CO5080729A1; EA003947B1; CA2337804A1; ID26774A; EE04236B1; IL140060A0; HK1036976A1; WO2000001704A2; DK1095025T3

Abstract

Benzimidazoles of formula (I), 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 are disclosed, wherein Ra, Rb, Rc, A, Ar and B are as defined in the specification. Benzimidazoles of formula (I), wherein Rc represents a cyano group are useful intermediate products for the production of the other compounds of formula (I) and the compounds of formula (I) wherein Rc represents one of the amidino groups as defined in the specification have useful pharmacological properties, especially an antithrombotic effect.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 509625 WO 00/01704 - 1 - PCT/EP99/04531 S018842pct.203 Benzimidazoles, the preparation thereof and their use as The present invention relates to benzimidazoles of general formula their tautomers, their stereoisomers, 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 15 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 Rc 20 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 stereoisomers, the mixtures 25 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 thereof with inorganic or organic acids, and the 3 0 stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity. pharmaceutical compositions 5 (I) , 10 WO 00/01704 - 2 - PCT/EP99/04531 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 pharmacologically active compounds, the preparation and 5 use thereof. In the above general formula Ar denotes a phenylene or naphthylene group optionally 10 substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C^-alkyl or C1.3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally 15 substituted in the carbon skeleton by a C^-alkyl group, A denotes a C^-alkylene group, B denotes an oxygen or sulphur atom, a methylene, 2 0 carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C^-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 25 Ra denotes an R1-CO-C3.5-cycloalkyl group wherein Ri denotes a C^-alkoxy, amino, C^-alkylamino or di-(C!.,-alkyl) -amino group wherein each alkyl moiety may be substituted by a carboxy group, 30 a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two C^.j-alkyl groups, whilst an alkyl substituent may simultaneously be substituted 35 by a hydroxy, C-^-alkoxy, carboxy, carboxy-C1.3-alkoxy, carboxy-C^.j-alkylamino, N- (C^-alkyl) -N- (carboxy-Cx_3-alkyl) -amino, carboxy--alkylaminocarbonyl, WO 00/01704 - 3 - PCT/EP99/04531 N- (C^j-alkyl) -N- (carboxy-Cx.3-alkyl) -aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1- (C^-alkyl) -3- (carboxy-C^.,-alkyl) -aminocarbonylamino, 3- (C^-alkyl) -3-(carboxy-Cx.3-alkyl)-aminocarbonylamino or 1,3-di-5 -alkyl) - 3- (carboxy-C^-alkyl) -aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 10 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C^-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, 15 a morpholino, piperazino, N- (C^-alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R2-CX-C3_5-cycloalkyl group wherein 20 R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C^-j-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 25 optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C^-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-3 0 C1.3-alkoxy, carboxy-C^-alkylamino or N- (C^-alkyl) -carboxy-Cx.3-alkylamino group, and X denotes an oxygen atom, a -alkylimino, Ci.-j-alkoxyimino, C^-alkylhydrazino, di-(C^-alkyl) -35 hydrazino, C2_4-alkanoylhydrazino, N- (C^j-alkyl) - C2_4-alkanoylhydrazino or C^-alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety WO 00/01704 - 4 - PCT/EP99/04531 or in the alkyl and alkanoyl moieties by a carboxy group, a C^-alkyl or C3.5-cycloalkyl group substituted by an 5 imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C^j-alkyl groups or by one, two or three Ca_3-alkyl groups, wherein the 10 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, C^-alkylamino, N- (C2_4-alkanoyl) -C^-alkylamino or di-15 (Cx_ 3 - alkyl) -amino group, and the imidazolone ring may be substituted by a C-L^-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 20 amino, C2_4-alkanoylamino, C1_3-alkylamino, N- (C2_4-alkanoyl) -C^-alkylamino or di-(C^-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 25 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C^-alkyl groups, whilst at the 3 0 same time an alkyl substituent may be substituted by a carboxy group, a C^-alkyl group which is substituted 35 by a C^-alkyl-Yj-C^-j-alkyl, HOOC-C1_3-alkyl-Y1-C1_3-alkyl, tetrazolyl-C^-alkyl-Yj, R3NR4- or RjNR^CVa-alkyl group and WO 00/01704 - 5 - PCT/EP99/04531 by an isoxazolidinylcarbonyl group optionally substituted by a C^-alkyl group, by a pyrrolino-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-5 carbonyl, carboxy, aminocarbonyl, C-L.j-alkylaminocarbonyl, di-(C^-j-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or 10 two C1-3 — alkyl groups and at the same time each alkyl moiety or aikyl substituent in the abovementioned C^.j-alkylaminocarbonyl, di- (C^-alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the 15 C^-alkyl group may be wholly or partially replaced by fluorine atoms wherein R3 denotes a hydrogen atom or a C^- alkyl group optionally substituted by a carboxy group and 20 R4 denotes a hydrogen atom, a -alkyl - Yi -Ci.3- alkyl -Y2, carboxy-Cx.3 - alkyl -Y1-C1.3- alkyl -Y2, C^j-alkyl-Yj or carboxy-C^-alkyl-Y;, group or 25 R3 and R4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C^-alkyl or carboxy-C^-alkyl group wherein 30 Y-l 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, 35 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 WO 00/01704 - 6 - PCT/EP99/04 531 in the definition of the groups Yx and Y2 may each additionally be substituted by a C^-alkyl or carboxy-C1.3-alkyl group, 5 a C^-alkyl or C3_s-cycloalkyl group substituted by a RSNR6-group wherein R5 denotes a hydrogen atom, a C^-alkyl, C5_7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 10 R6 denotes a C^-alkyl, carboxy-C^-alkyl or carboxy-Ci.j-alkylcarbonyl group, a C^-alkyl group which is substituted by a C2_4-alkanoyl 15 or Cs_7-cycloalkanoyl group and by a C^-alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C^-alkyl group and 20 Rc denotes a cyano group or an amidino group optionally substituted by one or two C^-alkyl groups. The carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group 25 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 3 0 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 International Journal of Pharmaceutics 39, 75-85 (1987). WO 00/01704 - 7 - PCT/EP99/04531 A group which can be converted in vivo into a carboxy group may be, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, wherein the alcoholic moiety is preferably a C^g-alkanol, a phenyl - - alkanol, 5 a C3_9-cycloalkanol, whilst a Cs_8-cycloalkanol may additionally be substituted by one or two C^-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, 10 phenyl-Cx_3-alkyl, phenyl-C^-alkoxycarbonyl or C2_6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C^-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 15 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 may additionally be substituted in the bicycloalkyl moiety by one or two 20 C1.3-alkyl groups, a 1, 3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula Rd-C0-0- (ReCRf) -OH, 25 wherein Rd denotes a C^.g-alkyl, C5.7-cycloalkyl, phenyl or phenyl-C1-3 — alky 1 group, Re denotes a hydrogen atom, a C^-alkyl, C5„7-cycloalkyl or 3 0 phenyl group and Rf denotes a hydrogen atom or a C^-alkyl group, a group which is negatively charged under physiological 3 5 conditions may be a tetrazol-5-yl, phenylcarbonylamino-carbonyl, trifluormethylcarbonylaminocarbonyl, C^g-alkylsulphonylamino, phenylsulphonylamino, WO 00/01704 - 8 - PCT/EP99/04531 benzylsulphonylami.no, trifluoromethylsulphonylamino, Cj.g-alkylsulphonylaminocarbonyl, phenylsulphonylamino-carbonyl, benzylsulphonylaminocarbonyl or perfluoro-Cj.g-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 fluorine, chlorine, bromine or iodine atoms, by C^-alkyl or C1.3-alkoxy groups, wherein the substituents may be identical or different, a pyridinoyl group or a C^g-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a Ci_i6-alkoxycarbonyl or C^^-alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as the 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, a phenyl-C^.g-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C^.g-alkyl or C3_7-cycloalkyl groups and the substituents may be identical or different, a Ci^-alkylsulphonyl-C2_4-alkoxycarbonyl, C^-alkoxy-Cj^-alkoxy- C2.4-alkoxycarbonyl, Rd-C0-0-(RdCR£)-O-CO-, C^.g-alkyl-CO-NH- WO 00/01704 - 9 - PCT/EP99/04531 (RgCRh)-O-CO- or C^-alkyl-CO-O- (RgCRh) - (RgCRh) -O-CO- group wherein Rd to Rf are as hereinbefore defined, Rg and Rh, which may be identical or different, denote 5 hydrogen atoms or C1_3-alkyl groups. Moreover, the saturated alkyl and alkoxy moieties which contain more than 2 carbon atoms mentioned in the above definitions also include the branched isomers thereof, 10 such as, for example, the isopropyl, tert.butyl, isobutyl group etc. Preferred compounds are those of general formula A denotes a C^-alkylene group, 20 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 may be mono- or disubstituted by a carboxy group, 25 Ra denotes an R1-CO-C3.5-cycloalkyl group wherein Ri denotes a C^-alkoxy, amino, C^-alkylamino or di- (C^-alkyl) -amino group wherein each alkyl moiety may be 3 0 substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by WO 00/01704 - 10 - PCT/EP99/04531 one or two C^j-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, - alkoxy, carboxy, carboxy-C^- alkoxy, carboxy-C1_3-alkylamino, N- (C^-alkyl) -N- (carboxy-C^j-alkyl) -5 amino, carboxy--alkylaminocarbonyl, N-(C1.3-alkyl)-N- (carboxy-C^-alkyl) -aminocarbonyl, carboxy-Cj^.j-alkylaminocarbonylamino, 1- (C^-alkyl) -3- (carboxy-Ci.3-alkyl) -aminocarbonylamino, 3- (C^-alkyl) - 3- (carboxy-C1_3_alkyl) —aminocarbonylamino or 1, 3-di-(C1.3-alkyl)-10 3-(carboxy-C1_3-alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 15 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C^-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C-^-alkyl) -piperazino, 20 pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, an R2-CX-C3.5-cycloalkyl group wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 25 6-membered heteroaryl group optionally substituted by a Cx_3 — alky1 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 C^-alkyl group, an oxygen 3 0 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 alkyl substituent may be substituted by a carboxy, carboxy-C^-alkoxy, carboxy-C1_3-alkylamino or N- (C^.j-alkyl) -35 carboxy-C1_3-alkylamino group, and WO 00/01704 - 11 - PCT/EP99/04531 X denotes an oxygen atom, a C1_3-alkylimino, Cj.j-alkoxyimino, C^-alkylhydrazino, di- (C^-alkyl) -hydrazino, C2_4-alkanoylhydrazi.no, N- (C1_3-alkyl) -C2_4-alkanoylhydrazi.no or C1_3-alkylidene group each of 5 which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C^-alkyl or C3_5-cycloalkyl group substituted by an 10 imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C^.,-alkyl groups or by one, two or three C^-alkyl groups, wherein the 15 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2„4-alkanoylamino, C^-alkylamino, N- (C2_4-alkanoyl) -C^-alkylamino or di-20 (0^3—alkyl)-amino group, and the imidazolone ring may be substituted by a C^-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 25 amino, C2_4-alkanoylamino, C^-alkylamino, N- (C2_4-alkanoyl)-C^-alkylamino or di- (C^-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 30 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C^-alkyl groups, whilst at the 35 same time an alkyl substituent may be substituted by a carboxy group, WO 00/01704 - 12 - PCT/EP99/04531 a C^-alkyl group which is substituted by a C1_3-alkyl-Y1-C1_3-alkyl, HOOC-C1_3-alkyl-Y1-C1_3-alkyl, tetrazolyl-C^-alkyl-Y2, R3NR4- or R3NR4-C1.3-alkyl group 5 and by an isoxazolidinylcarbonyl group optionally substituted by a G^-alkyl group, by a pyrro-linocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-10 l-yl-carbonyl, carboxy, aminocarbonyl, C1.3-alkylaminocarbonyl, di-(C^-j-alkyl) -aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or 15 two C^-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C^.j-alkylaminocarbonyl, di-(C^-,-alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the 20 C^-alkyl group may be wholly or partially replaced by fluorine atoms wherein R3 denotes a hydrogen atom or a Cj^-alkyl group optionally substituted by a carboxy group and 25 R4 denotes a hydrogen atom, a C^- alkyl - - Cj.j - alkyl - Y2, carboxy- Cx.3 - alkyl - Y1 - - alkyl - Y2, C1_3-alkyl-Y2 or carboxy-C1_3-alkyl-Y2 group or 3 0 R3 and R4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C^-alkyl or carboxy-C^-alkyl group wherein 35 Yx denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and WO 00/01704 - 13 - PCT/EP99/04 531 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 5 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^-alkyl or carboxy-C^j-alkyl group, 10 a C1_3-alkyl or C3_s-cycloalkyl group substituted by a R5NR6-group wherein R5 denotes a hydrogen atom, a C^-alkyl, C5.7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 15 R6 denotes a C^-alkyl, carboxy-C^-alkyl or carboxy-C^j-alkylcarbonyl group, a C^-j-alkyl group which is substituted by a C2_4-alkanoyl 2 0 or C5_7-cycloalkanoyl group and by a C1.3-alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C^-alkyl group and 25 Rc denotes a cyano group or an amidino group which may be substituted by a hydroxy group, by one or two C^-alkyl groups, or by one or two C^g-alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in 30 the definition of the abovementioned groups may also be substituted by a group which can be cleaved in vivo, the tautomers, stereoisomers and salts thereof. 35 WO 00/01704 - 14 - PCT/EP99/04 531 Particularly preferred compounds of the above general formula la are those wherein A denotes a C^-alkylene group, 5 B denotes an oxygen atom, a methylene, imino or N- (C^.j-alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, 10 Ra denotes an C3.5-cycloalkyl group substituted by the R^CO group in the 1 position wherein R^^ denotes a C^-alkoxy, amino, C^-alkylamino or di-(C^-alkyl) -amino group wherein each alkyl moiety may be 15 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 C^-alkyl groups, whilst an alkyl substituent may 2 0 simultaneously be substituted by a hydroxy, -alkoxy, carboxy, carboxy-C^-alkoxy, carboxy-C-^-alkylamino, N- (C^-alkyl) -N- (carboxy-C^j-alkyl) -amino, carboxy-C^j-alkylaminocarbonyl, N- (C1_3-alkyl) -N- (carboxy-Ci.3-alkyl) -aminocarbonyl, carboxy-25 C-L.j-alkylaminocarbonylamino, 1-(C^-alkyl)-3- (carboxy- C1_3-alkyl) -aminocarbonylamino, 3- (C^-j-alkyl) -3- (carboxy-C^-alkyl) -aminocarbonylamino or 1, 3-di-(C^-alkyl) -3- (carboxy-alkyl) -aminocarbonylamino group, 3 0 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C^-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C^-alkyl)-piperazino, 35 pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, WO 00/01704 - 15 - PCT/EP99/04531 a C3.5-cycloalkyl group substituted in the 1 position by the R2-CX- group, wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 5 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 C^-alkyl group, an oxygen 10 or sulphur atom or an imino group optionally substituted i by a 0^3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-C1.3-alkoxy, carboxy-C^.j-alkylamino or N- (C^.j-alkyl) -15 carboxy-0^3-alkylamino group, and X denotes an oxygen atom, a C^-alkylimino, C^-alkoxyimino or C^-alkylidene group, each of which may be substituted in the alkyl or alkanoyl moiety by a 20 carboxy group, a C^-alkyl group substituted in the 1 position by an imidazole or imidazolone group wherein 25 the imidazole ring may be substituted by a phenyl or carboxy group and by one or two Cj.j-alkyl groups or by one, two or three Cx,3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously 30 be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino, CjL.j-alkylamino, N- (C2_4-alkanoyl) -C^-alkylamino or di-(^.3-alkyl)-amino group, and 35 the imidazolone ring may be substituted by a C^-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an WO 00/01704 - 16 - PCT/EP99/04531 amino, C2_4-alkanoylamino, C^-alkylamino, N-(C2.4-alkanoyl)-Ci^-alkylamino or di-(C^-alkyl) -amino group, and 5 additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be 10 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 15 by an R3NR4- or R3NR4-CX.3-alkyl group and by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, 20 C^-alkylaminocarbonyl, di-(C^-alkyl)-aminocarbonyl, isoxazolidin-l-ylcarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C^-alkyl groups and at the 25 same time each alkyl moiety or alkyl substituent in the abovementioned C^-alkylaminocarbonyl, di-(C^-alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C^-alkyl group may be wholly or 3 0 partially replaced by fluorine atoms, wherein R3 denotes a hydrogen atom or a C^-alkyl group optionally substituted by a carboxy group and 35 R4 denotes a hydrogen atom, a C1.3-alkyl-Y2 or carboxy- C1_3-alkyl-Y2 group or WO 00/01704 - 17 - PCT/EP99/04531 R3 and R4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1 position by a carboxy, C^j-alkyl or carboxy-C1.3-alkyl group, wherein 5 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 the imino group occurring in the 10 definition of the groups Y2 may additionally be substituted by a C^-alkyl or carboxy-C^-alkyl group, a Cj^-alkyl or C3_5-cycloalkyl group substituted in the 1 position by an R5NR6- group, wherein 15 R5 denotes a hydrogen atom, a C^-alkyl, C5_7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C^-alkyl, carboxy-C^-alkyl or carboxy-20 C^-alkylcarbonyl group, a C^-alkyl group which is substituted by a C2_4-alkanoyl or C5_7-cycloalkanoyl group and by a C^-j-alkyl group substituted by a chlorine, bromine or iodine atom, 25 Rb denotes a C^-j-alkyl group and Rc denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, 30 C^g-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C^-j-alkyl or C-^-alkoxy groups and the substituents may be identical or 35 different, WO 00/01704 - 18 - PCT/EP99/04531 the C1_3-alkanol esters, the tautomers, stereoisomers and salts thereof. Most particularly preferred compounds of general formula I 5 are those wherein A denotes a methylene group, B denotes an oxygen atom or an imino group, 10 Ra denotes a cyclopropyl group substituted by the R^CO-group in the 1 position, wherein Ri denotes a pyrrolidino or piperidino group optionally 15 substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C^-alkoxy, carboxy-C^-alkylamino or N- (^.3-alkyl) -carboxy--alkylamino group, 2 0 a cyclopropyl group substituted in the 1 position by the R2-CX- group, wherein R2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C^-alkyl group and 25 X denotes an oxygen atom, a C^-alkoxyimino or C^-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, 3 0 a C^-alkyl group substituted in the 1 position by an imidazole 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 C.^-alkyl groups, wherein the substituents may be identical or 35 different and one of the abovementioned alkyl substituents may simultaneously be substituted by a WO 00/01704 - 19 - PCT/EP99/04531 carboxy group or may be substituted in the 2 or 3 position by an amino, C2.4-alkanoylamino, C^-alkylamino, N- (C2_4-alkanoyl)-C1_3-alkylamino or di-(C1_3-alkyl)-amino group, whilst additionally a phenyl or pyridine ring may 5 be fused to the abovementioned imidazole rings via two adjacent carbon atoms, a C^-alkyl substituted in the 1 position by a benzimidazolon-l-yl group, whilst the imidazolone ring may 10 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 15 by an R3NR4- or R3NR4-C1.3-alkyl group and by a di - (C^-alkyl) -aminocarbonyl group, by an isoxazolidin-l-ylcarbonyl group, by a pyrrolidino- 2 0 carbonyl or piperidinocarbonyl group substituted by a C-^-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent in the abovementioned groups may be substituted by a carboxy group, wherein 25 R3 denotes a hydrogen atom or a C^.j-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C^-j-alkyl-Y2 or carboxy- 3 0 — 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 group, wherein 35 WO 00/01704 - 20 - PCT/EP99/04531 Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a -alkyl group, 5 a C^-alkyl group substituted in the 1 position by an R5NR6- group, wherein R5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and 10 R6 denotes a C^-alkyl or carboxy-C^-alkyl group, an n-propyl group substituted in the 3 position by a chlorine atom, which is substituted in the 1 position by a 15 cyclopentylcarbonyl group, a cyclopropyl group substituted in the 1 position by a cyclopentylamino group, which is substituted at the nitrogen atom by a carboxy-C^-alkylcarbonyl group, 20 Rb denotes a methyl group and Rc denotes an amidino group which may optionally be substituted by a C^g-alkoxycarbonyl, 25 acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, particularly those compounds of general formula la wherein 3 0 A denotes a methylene group, B denotes an imino group, Ra denotes a cyclopropyl group substituted by the R^CO-3 5 group in the 1 position, wherein WO 00/01704 - 21 - PCT/EP99/04531 Ri denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C^-alkoxy, carboxy-C^-alkylamino or 5 N-(C^-alkyl)-carboxy-C^-alkylamino group, a cyclopropyl group substituted in the 1 position by the R2-CX group, wherein 10 R2 denotes a' phenyl, pyridyl, pyrazolyl group optionally substituted by a C^-alkyl group and X denotes an oxygen atom, a C^-alkoxyimino or C^-alkylidene group, each of which is substituted in 15 the alkyl or alkoxy moiety by a carboxy group, a C^-alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring may be substituted by one to three methyl groups or by two 20 methyl groups and an ethyl group, whilst additionally one of the abovementioned methyl or ethyl substituents may simultaneously be substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 25 position by an R3NR4 - or R3NR4-CH2- group and by a di-(0^3-alkyl)-aminocarbonyl, by a pyrro-3 0 lidinocarbonyl or piperidinocarbonyl group optionally substituted by a C^-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent may be substituted by a carboxy group, wherein 35 R3 denotes a hydrogen atom or a C^-j-alkyl group optionally substituted by a carboxy group and WO 00/01704 - 22 - PCT/EP99/04531 10 15 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 C^j-alkyl group, Rb denotes a methyl group and Rc denotes an amidino group which may optionally be substituted by a C1.8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the abovementioned compounds in which the group Ra is in the 5 position are particularly preferred, the C^-alkanol esters, the tautomers, stereoisomers and 20 salts thereof. The following are mentioned as examples of particularly preferred compounds: 25 (a) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (pyrrolidin-l-yl-carbonyl)-cyclopropyl]-benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene] - 3 0 cyclopropyl]-benzimidazole, (c) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole, 35 WO 00/01704 - 23 - PCT/EP99/04531 (d) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [2- (2-carboxyethyl)-pyrrolidin-l-yl-carbonyl]cyclopropyl]-benzimidazole, (e) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2- (2-carboxyethyl)-4,5-dimethyl-imidazol-l-yl-methyl]-benzimidazole (f) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxy-methylamino)(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole and (g) 2-(4-amidinophenylaminomethyl) - l-methyl-5-[1-(N-methyl carboxymethylcarbonylaminomethyl)-1-methyl-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole and the C1_3-alkanol esters, the N- (C^.g-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 following methods: a) In order to prepare a compound of general formula I wherein Rc denotes a cyano group: cyclising a compound of general formula Z, Zp —NH C a—B—Ar — CN R= "NH (II) , Rv, WO 00/01704 - 24 - PCT/EP99/04531 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 5 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 10 alkylenedithio group with 2 or 3 carbon atoms. The cyclisation is expediently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, 15 glycol, glycol monomethyl ether, diethyleneglycol dimethylether, sulpholane, 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 2 0 example at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesulphonic 25 acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N-dicyclohexyl-carbodiimide or optionally in the presence of a base such as potassium ethoxide or potassium tert. butoxide. However, the cyclisation may also be 30 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 35 optionally in the presence of a carboxylic acid of general formula WO 00/01704 - 25 - PCT/EP99/04531 HO-CO—A—B—Ar CN (III), wherein Ar, A and B are as hereinbefore defined, by acylation of a corresponding amino compound optionally formed in the 5 reaction mixture. b) In order to prepare a compound of general formula I wherein Ra denotes an R2-CX'-C3.5-cycloalkylene group, wherein R2 is as hereinbefore defined and X' denotes one 10 of the imino groups mentioned for X hereinbefore: reacting a compound of general formula Rb 15 wherein Rb, Ar, A and B are as hereinbefore defined and Ra' denotes an R2-CO-C3_5-cycloalkylene group, where R2 is as hereinbefore defined, 20 with an amine of general formula H2X« (V), 25 wherein X' denotes one of the imino groups mentioned for X hereinbefore. The reaction is preferably carried out in a solvent such 30 as methanol/toluene, ethanol, isopropanol or xylene and expediently 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 WO 00/01704 - 26 - PCT/EP99/04531 at temperatures between 50 and 100°C, preferably at the boiling temperature of the reaction mixture. c) In order to prepare a compound of general formula I 5 wherein Ra denotes an 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 10 wherein Rb, Ar, A and B are as hereinbefore defined and Ra 1 denotes an R2-CO-C3_5-cycloalkylene group, where 15 R2 is as hereinbefore defined, with a phosphone of general formula 20 Z3-HX" (VI), wherein X" denotes one of the alkylidene groups mentioned for X hereinbefore and. 25 Z3 denotes a triphenylphosphono or di- (C-l.j-alkoxy) phosphono group such as the triethoxyphosphono group. The reaction is preferably carried out under protective 3 0 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 WO 00/01704 - 27 - PCT/EP99/04531 10 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 Rc denotes an amidino group which may be substituted by one or two C^.j-alkyl groups: reacting a compound of general formula (VII), Rb optionally formed in the reaction mixture wherein Ra, Rb, Ar, A and B are as hereinbefore defined and 15 Z4 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula 20 H - R7NR8 , (VIII) wherein R7 and Re, which may be identical or different, each 25 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 3 0 dioxane at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C, with an amine of general formula VIII or with a corresponding acid addition salt WO 00/01704 - 28 - PCT/EP99/04531 such as for example ammonium carbonate or ammonium acetate. A compound of general formula VII is obtained for example 5 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 trialkyloxonium salt such as 10 triethyloxonium-tetrafluoroborate in a solvent 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 15 dimethylformamide and in the presence of a base such as triethylamine and subsequently alkylating the thioamide formed with a corresponding alkyl or aralkyl halide. e) In order to prepare a compound of general formula I 20 wherein Ra denotes an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or C^-alkoxycarbonyl group: 25 cyclising a compound of general formula CN (IX) optionally formed in the reaction mixture 30 wherein Rb, Ar, A and B are as hereinbefore defined and WO 00/01704 - 29 - PCT/EP99/04531 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 5 as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at 2 0 °C. 10 f) In order tp prepare a compound of general formula I wherein Rc denotes a hydroxyamidino group: reacting a nitrile of general formula wherein Ra, Rb, Ar, A and B are as hereinbefore defined, with hydroxylamine or the salts thereof. 20 The reaction is expediently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran, tetrahydrofuran/water, dioxane or dioxane/water at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C. 25 g) In order to prepare a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined or Ra is as hereinbefore defined and Rc denotes an amidino group optionally substituted by a 30 hydroxy group or by one or two C1.3-alkyl groups: converting a compound of general formula WO 00/01704 - 30 - PCT/EP99/04531 wherein Rb, Ar, A and B are as hereinbefore defined and Ra' " and Rc' have the meanings given for Ra and Rc with the 5 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 Rc denotes a group which may optionally be converted by hydrolysis, treatment with an 10 acid or base, thermolysis or hydrogenolysis into an amidino group substituted by a hydroxy group or by one or two C-^-alkyl groups and Ra is as hereinbefore defined, is converted by hydrolysis, treatment with an acid or 15 base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined or Ra is as hereinbefore defined and Rc denotes an amidino group optionally substituted by a hydroxy group or by one or two C1.3-alkyl 20 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 25 thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters thereof which are expediently converted by hydrolysis into a carboxyl group, 3 0 the esters thereof with tertiary alcohols, e.g. the tert.butyl ester, which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and WO 00/01704 - 31 - PCT/EP99/04531 the esters thereof with aralkanols, e.g. the benzylester, which are expediently converted into a carboxyl group by hydrogenolysis. 5 The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or the mixtures thereof or in the 10 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/tetrahydrofuran or water/dioxane at temperatures 15 between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. If a compound of formula XI for example contains the 2 0 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 acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such 25 as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120°C, e.g. at temperatures between 0 and 60°C, or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, 30 toluene, tetrahydrofuran 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, preferably at the boiling temperature of the solvent used, e.g. at temperatures 35 between 4 0 and 120°C. WO 00/01704 - 32 - PCT/EP99/04531 If a compound of formula XI contains, for example, a benzyloxy or benzyloxycarbonyl group, these may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a 5 suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature, and at a hydrogen pressure of from 1 to 5 bar. 10 h) In order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by one or two C^g-alkoxycarbonyl groups or by a group which can be cleaved in vivo: 15 reacting a compound of general formula I wherein 20 Ra, Rb, Ar, A and B are as hereinbefore defined and Rc" denotes an amidino group, with a compound of general formula Z5 - R9 (XIII) , 25 wherein R9 denotes a C^g-alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned hereinbefore and 30 Z5 denotes a nucleofugic leaving group such as a halogenatom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group. WO 00/01704 - 33 - PCT/EP99/04531 The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulphoxide or dimethylformamide 5 optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 2 0°C and the boiling temperature of the solvent used. With a compound of general formula XIII wherein Z5 denotes 10 a nucleofugic,leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethyl sulphoxide, optionally in the presence of a base such as sodium hydride, potassium 15 carbonate, potassium tert. butoxide 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 2 0 group wherein at least one of the groups R3 or R4 denotes a hydrogen atom, this may subsequently be converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of general formula I and/or 25 if a compound of general formula I is obtained which contains an NH^C^-alkyl group, this may subsequently be converted with a corresponding acrylic acid ester into a corresponding 2-(C1.3-alkoxycarbonyl)-ethyl compound of general formula I and/or 30 if a compound of general formula I is obtained which contains an (R3NR4) -C^-,-alkyl group wherein R3 and R4 each denote a hydrogen atom, this may subsequently be converted with a corresponding dihaloalkane into a corresponding 35 compound of general formula I wherein R3 and R4 together with the nitrogen atom between them [denote] a WO 00/01704 - 34 - PCT/EP99/04531 corresponding 4- to 7-membered cycloalkyleneimino group and/or if a compound of general formula I is obtained wherein Rc 5 denotes an amidino group, this may subsequently be converted by reaction with a haloacetic acid derivative and subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and/or 10 if a compound of general formula I is obtained wherein Rc denotes a hydroxyamidino group, this may subsequently be converted into a corresponding amidino compound by catalytic hydrogenation and/or 15 if a compound of general formula I is obtained wherein Ra contains a carboxy group, this may subsequently be converted into a corresponding ester by esterification. 20 The subsequent preparation of a corresponding urea compound of general formula I is expediently carried out with a corresponding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such 25 as triethylamine at temperatures between 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 3 0 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. 35 The subsequent preparation of a corresponding 4- to 7- membered cycloalkyleneimino compound of general formula I is expediently carried out with a corresponding WO 00/01704 - 35 - PCT/EP99/04531 dihaloalkane, preferably in a solvent such as methanol, ethanol or isopropanol in the presence of a base such as sodium carbonate at temperatures between 50 and 100°C, preferably at the boiling temperature of the reaction 5 mixture. The subsequent alkylation is expediently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone 10 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 tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, 15 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. 2 0 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, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium 25 hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane and subsequent decarboxylation in the presence of an acid as hereinbefore 30 described at temperatures 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 3 5 corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, WO 00/01704 - 36 - PCT/EP99/04531 benzene/tetrahydrofuran or dioxan, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl 5 chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, 10 N,N1-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N1-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, 15 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, dimethylsulphoxide, 20 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 tertiary organic base such as N-ethyl-25 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. 30 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 35 conventional protecting groups which are cleaved again after the reaction. WO 00/01704 - 37 - PCT/EP99/04531 For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, 5 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 10 may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group. 15 Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid 20 or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. 25 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 solvent such as methanol, ethanol, 3 0 ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen 3 5 pressure of 1 to 7 bar, but preferably 3 to 5 bar. WO 00/01704 - 38 - PCT/EP99/04531 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 temperatures between 0 and 50°C, but 5 preferably at ambient temperature. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol. 10 A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether. 15 A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50°C. 20 An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as 25 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) 3 0 chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70°C. 3 5 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 WO 00/01704 - 39 - PCT/EP99/04531 literature and in addition their preparation is described in the Examples. The chemistry of the compounds of general formula III is 5 described, for example, by Jack Robinson in J. Chem. Soc. 1941, 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-10 Weyl), 4th edition, Verlag Thieme, Stuttgart 1993. Thus, for example, a compound of general formula II is obtained by acylating a corresponding o-diamino compound with a corresponding reactive derivative of a compound of 15 general formula III, a compound of general formulae IV, VII, IX, X, XI and XII is obtained by cyclisation of a corresponding substituted compound according to process a) and if necessary 20 subsequent reduction of any nitro group present in the phenyl moiety, followed by acylation, amidation and/or halogenation. Moreover, the compounds of general formula I obtained may 25 be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by 30 methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on 35 the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or WO 00/01704 - 40 - PCT/EP99/04531 fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above. 5 The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic 10 compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric 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 15 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, aspartic acid or 20 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 (-)-menthyloxycarbonyl. 25 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, 30 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 35 carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the WO 00/01704 - 41 - PCT/EP99/04531 physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanol-amine, diethanolamine and triethanolamine. 5 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 10 products for preparing the other compounds of general formula I, and the compounds of general formula I wherein Rc denotes one of the abovementioned amidino groups, and the tautomers, stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological 15 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 20 effect on related serine proteases such as, for example, trypsin, urokinase factor Vila, factor IX, factor XI and factor XII. For example, the compounds 25 A = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride, 30 B = (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole-hydrochloride, C = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-35 carboxyethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride, WO 00/01704 - 42 - PCT/EP99/04531 D = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-l-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride, E = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl-imidazol-l-yl-methyl]-benzimidazole-hydrochloride, F = 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]"benzimidazole -hydrochloride and G = 2-(4-amidinophenylaminomethyl)-l-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 human 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 WO 00/01704 - 43 - PCT/EP99/04 531 was started by the addition of 0.1 ml of calcium solution. Because of the design of the apparatus, 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 5 added were used as controls. According to the definition the effective concentration of substance at which the aPTT time was double that of the control was determined by means of a dosage/activity 10 curve. , The following Table contains the values found: 15 substance APTT time (ED2OO in 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. 20 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 thrombotic diseases, such as for example the 25 treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases WO 00/01704 - 44 - PCT/EP99/04531 such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic 5 support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary 10 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 15 to 3 0 mg/kg by oral route, in each case administered 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. 20 with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, 25 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 suppositories. 3 0 The Examples which follow are intended to illustrate the invention: WO 00/01704 - 45 - PCT/EP99/04531 Example 1 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-1-vl-carbonvl)cvclopropvll-benzimidazole-hydrochloride 5 a. 1-(4-chloro-3-nitro-phenvl)-1-cvclopropanecarboxvlic acid To 350 ml of fuming nitric acid are added, in batches, at -25°C, 50.0 g (0.21 mol) of 1-(4-chlorophenyl)-1-10 cyclopropanecarboxylic acid. The solution is stirred for 15 minutes at -25°C and subsequently poured onto ice water. The product precipitated is suction filtered, washed with water and dried. Yield: 58.5 g (95 % of theory), 15 Rf value: 0.45 (silica gel; methylene chloride/methanol = 9.5:0.5) b. 1-(4-methylamino-3-nitro-phenvl)-1-cvclopropanecarboxvlic acid 20 20.0 g (0.083 mol) of 1-(4-chloro-3-nitro-phenyl)-1-cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% 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 25 acetic acid. The product precipitated is suction filtered, washed with water and dried. Yield: 16.9 g (93 % of theory), Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) 30 c. 4-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-2-nitro-N- methvl-aniline 2.4 g (0.01 mol) of 1-(4-methylamino-3-nitro-phenyl)-1-cyclopropanecarboxylic acid are dissolved in 50 ml 35 dimethyIformamide and after the addition of 3.2 g (0.01 mol) of O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) of pyrrolidine and 1.1 WO 00/01704 - 46 - PCT/EP99/04531 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 fractions are concentrated 5 by evaporation, triturated with ether, suction filtered and dried. Yield: 1.8 g (61 % of theory), Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) 10 d. 4-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-2-amino-N-methvl-aniline 1.8 g (6.2 mmol) of 4-[1-(pyrrolidin-l-yl-15 carbonyl)cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 40 ml methanol and 4 0 ml methylene chloride and after the addition of 0.4 g of palladium on activated charcoal (10%) hydrogenated for 4 hours at ambient temperature. Then the catalyst is filtered off and the 2 0 residue is concentrated by evaporation. Yield: 1.6 g (100 % of theory), Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1) 25 e. 4-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-2-(4-cvanophenvl)aminomethvlcarbonvlamino-N-methvl-ani1ine Prepared analogously to Example lc from 4-[1-(pyrrolidin-l-yl-carbonyl) cyclopropyl] -2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N1,N'-tetramethyluronium 30 tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 66 % of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol = 9 :1) 35 f. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-1-vl-carbonyl)cvclopropvll -benzimidazole WO 00/01704 - 47 - PCT/EP99/04 531 1.7 g (0.004 mol) of 4-[1-(pyrrolidin-l-yl-carbonyl) cyclopropyl]-2-(4-cyanophenyl)- aminomethylcarbonylamino-N-methyl-aniline are refluxed in 7 ml of glacial acetic acid for 2 hours. The solvent is 5 distilled off, the residue dissolved in water and extracted with methylene chloride. The organic phase is dried, concentrated by evaporation and subsequently chromatographed on silica gel, eluting with methylene chloride + 2 to 3% methanol. 10 Yield: 1.0 g (62 % of theory), Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) g. 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-15 (pyrrolidin-l-yl-carbonyl)cyclopropyl] -benzimidazole- hydrochloride 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)cyclopropyl]-benzimidazole are dissolved in 50 ml saturated ethanolic hydrochloric 20 acid and stirred for 5 hours at ambient temperature. The solvent is distilled 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 25 chromatographed on silica gel, eluting with methylene chloride/methanol (7:1).' Yield: 700 mg (62 % of theory), Rf value: 0.61 (silica gel; methylene chloride/methanol = 4:1) 30 C24H28N60 x HCl (416.54/453.0) mass spectrum: (M+H)+ = 417 The following compounds are obtained analogously to Example 1: 35 WO 00/01704 - 48 - PCT/EP99/04531 (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3-methyl-piperidin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 45 % of theory, Rf value: 0.25 (silica gel; methylene chloride/methanol = 4:1) C26H32N60 x HCl (444.59/481.05) mass spectrum: (M+H)+ = 445 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(piperidin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 57 % of theory, Rf value: 0.23 (silica gel; methylene chloride/methanol = 4:1) C25H30N6O x HCl (430.56/467.93) mass spectrum: (M+H)+ = 431 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(4-methyl-piperazin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 32 % of theory, Rf value: 0.26 (silica gel; methylene chloride/methanol/- ammonia = 2:1:0.25) C25H31N70 x HCl (445.58/482.04) mass spectrum: (M+H)+ = 446 (4) 2 -(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2,3-dihydroindolin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 60 % of theory, Rf value: 0.34 (silica gel; methylene chloride/methanol = 4:1) C28H28N60 x HCl (464.58/501.04) mass spectrum: (M+H)+ = 465 WO 00/01704 - 49 - PCT/EP99/04531 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-((2-ethoxycarbonylethyl)-piperidin-l-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 85 % of theory, Rf value: 0.57 (silica gel; methylene chloride/methanol = 4:1) C3oH38N603 x HCl (530.67/567.13) mass spectrum: (M+H)+ = 531 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-((2-ethoxycarbonylethyl)-pyrrolidin-1-yl- carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 60 % of theory, C29H36N603 x HCl (516.64/553.10) mass spectrum: (M+H)+ = 517 (M+2H)++ = 259 (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(N- (2-ethoxycarbonylethyl)-N-methyl-aminomethyl)-pyrrolidin-l-yl-carbonyl] cyclopropyl]-benzimidazole-hydrochloride Yield: 65 % of theory, C31H41N703 x HCl (559.72/ 596.18) mass spectrum: (M+H)+ = 560 (M+2H)++ = 280.6 (8) 2 -(4 -amidinophenylaminomethyl)-1-methyl-5-[1-[(2 -ethoxycarbonylmethyloxymethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 61 % of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid) C29H36N604 x HCl (532.66/569.11) mass spectrum: (M+H)* = 533 (M+2H)++ = 267 WO 00/01704 - 50 - PCT/EP9 9/04 531 Example 2 2-(4-amidinophenylaminomethyl)-l-methyl-5-(1-cyclopentylcarbonyl-3-chloro-n-propyl)-benzimidazole-5 hydrochloride a. 4- l"l- (cvclopentvlcarbonvl) cvclopropvll -chlorobenzene 2.4 g (0.1 mol) of magnesium chips are suspended in 10 ml ether. After the addition of a spatula-tip of iodine, 10 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 3 0 minutes. Then a solution of 14.0 g (0.08 mol) of 1-(4-chlorophenyl)-1-15 cyclopropanecarbonitrile in 75 ml ether is added and refluxed for a further 3 hours. The reaction solution is poured onto ice water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is 20 chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1 and 15:1). Yield: 3.0 g (12 % of theory), Rf value: 0.58 (silica gel; petroleum ether/ethyl acetate = 4:1) 25 b. 4-Tl-(cvclopentvlcarbonvl)cvclopropvll -2-nitro-chlorobenzene Prepared analogously to Example la from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-chlorobenzene and fuming 30 nitric acid. Yield: 87 % of theory, Rf value: 0.60 (silica gel; petroleum ether/ethyl acetate = 9:1) WO 00/01704 - 51 - PCT/EP99/04531 c. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-N- methvl-aniline Prepared analogously to Example lb from 4-[1- (cyclopentylcarbonyl)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-(cyclgpentylcarbonyl)cyclopropyl]-2-amino-N- methvl-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 % of theory), Rf value: 0.15 (silica gel; methylene chloride/ethanol = 19 :1) e. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-(4-cvanophenvl-aminomethvlcarbonvlamino)-N-methvl-ani1ine Prepared analogously to Example lc from 4-[1- (cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methyl-aniline, 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumtetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 96 % of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) f. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- (cvclopentvlcarbonvl)-cvclopropvll -benzimidazole Prepared analogously to Example If from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-(4-cyanophenyl- WO 00/01704 - 52 - PCT/EP99/04531 aminomethylcarbonylamino)-N-methyl-aniline in glacial acetic acid. Yield: 53 % of theory, Rf value: 0.46 (silica gel; methylene chloride/ethanol = 5 19:1) g. 2-(4-amidinophenylaminomethyl)-l-methyl-5-(1-cyclopentyl-carbonyl-3-chloro-n-propyl)-benzimidazole hydrochloride 10 Prepared analogously to Example lg from 2-(4- cyanophenylaminomethyl)-l-methyl-5-(1-cyclopentylcarbonyl-3-chloro-n-propyl)-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 61 % of theory, 15 C25H30ClN5O x HCl (452.00/488.56) mass spectrum: (M+H)+ = 452/4 (Cl)) Example 3 20 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino)-methylene!cvclopropvll-benzimidazole-hydrochloride a. 1-1"(pvridin-3-vl)-carbonvllcyclopropyl-benzene 25 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 butyllithium (1.6 M in hexane) and then stirred for 20 minutes at -4 0°C. The mixture is then cooled to -60°C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane-30 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 20% hydrochloric acid and heated to 100°C for 30 minutes. After cooling, the mixture is 35 adjusted to pH 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The WO 00/01704 - 53 - PCT/EP99/04531 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 5 acetate =9:1) b. 4-F1-T(pvridin-3-vl)-carbonvll cvclopropvll-nitrobenzene Prepared analogously to Example la from 1-[(pyridin-3-yl)-carbonyl]cyclopropyl-benzene and fuming nitric acid. 10 Yield: 53.7 %,of theory, Rf value: 0.2^ (aluminium oxide; petroleum ether/ethyl acetate = 4:1) c. 4-Tl-T(pvridin-3-vl)-carbonvll cvclopropvll -aniline 15 Prepared analogously to Example 2d from 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-nitrobenzene and Raney nickel in ethyl acetate/ethanol. Yield: 94 % of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol = 20 19:1) d. 4-[1-t(pyridin-3-yl)-carbonyl]cyclopropyl]- trifluoroacetvlaniline 25 8.0 g (33.5 mmol) of 4-[l-[(pyridin-3-yl)- carbonyl]cyclopropyl]-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 30 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) 35 WO 00/01704 - 54 - PCT/EP99/04531 e. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-trifluoroacetvlaniline 1.7 g (5 mmol) of 4-[1-[(pyridin-3-yl)-5 carbonyl]cyclopropyl]-trifluoroacetylaniline are added batchwise to 13 ml of conc. sulphuric acid and 16 ml of 65% 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 10 dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (50:1 and 25:1). The desired fractions are concentrated by evaporation, triturated with ether/petroleum ether, suction filtered and dried. 15 Yield: 1.2 g (75 % of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1) f. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-2 0 trifluoroacetvl-N-methvl-aniline 1.15 g (3.0 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-trifluoroacetylaniline are dissolved in 50 ml acetone and after the addition of 25 2.0 g potassium carbonate and 0.8 ml methyl iodide refluxed for two hours. The insoluble matter is filtered off and the solution is evaporated down. The residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (1:1 and 1:4). 30 Yield: 0.88 g (75 % of theory), Rf value: 0.38 (silica gel; petroleum ether/ethyl acetate = 1:1) WO 00/01704 - 55 - PCT/EP99/04531 g. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-methvl-aniline 7.4 g (18.8 mmol) of 4-[1-[ (pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methyl-aniline are stirred in 200 ml of 20% potassium hydroxide solution for one hour at 30°C. Then the mixture is 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 chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (4:1 and 1:1). Yield: 2.6 g (47 % of theory), Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate = 1:1) h. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-N-methvl-aniline 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 % of theory, R£ value: 0.51 (silica gel; methylene chloride/ethanol = 19 :1) i . 4- l"l- T (pvridin-3-vl) -carbonvll cvclopropvll -2- (4-cvano-phenvl)-aminomethvlcarbonvlamino-N-methvl-aniline Prepared analogously to Example lc from 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline, 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 97 % of theory, Rf value: 0.48 (silica gel; methylene chloride/ethanol = 19 :1) WO 00/01704 - 56 - PCT/EP99/04531 k. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-vl)-carbonvll cvclopropvll-benzimidazole Prepared analogously to Example If from 4-(pyridin-3-yl-carbonyl)cyclopropyl-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid. Yield: 76 % of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol = 19 :1) 1. (E/Z)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-(carboxymethyloxyimino)methylene]-cvclopropvllbenzimidazole 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 triethylamine, 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 filtrate 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 chloride/ethanol/glacial acetic acid (25:1:0 and 8:2:0.2). Yield: 0.9 g (48 % of theory), Rf value: 0.34 (silica gel; methylene chloride/ethanol/-glacial acetic acid = 8:2:0.2) m. (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino)-methvlenelcvclopropvll-benzimidazole-hydrochloride Prepared analogously to Example lg from (E/Z)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)- WO 00/01704 - 57 - PCT/EP99/04531 (ethoxycarbonylmethyloxyimino)methylene]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 60 % of theory, Rf value: 0.28 (silica gel; methylene chloride/ethanol/-glacial acetic acid = 8:2:0.2) C29H31N703 x HCl (525.62/562.09) mass spectrum: (M+H)+ = 526 The following,compounds are obtained analogously to Example 3: (1) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[ (pyridine-2-yl)-(ethoxycarbonylmethyloxyimino)-methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 52 % of theory, Rf value: 0.21 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2) C29H31N703 x HCl (525.62/562.09) mass spectrum: (M+H)+ = 526 (2) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[phenyl-(ethoxycarbonylmethyloxyimino)-methylene]-cyclopropyl]-benzimidazole-hydrochloride Yield: 18 % of theory, C3oH32N603 x HCl (524.63/561.09) mass spectrum: (M+H)+ = 525 (M-H+HCl)~ = 559/61 (CI) (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(1-methyl-pyrazol-5-yl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 10 % of theory, C24H25N70 x HCl (427.51/ 463.97) mass spectrum: (M+H)+ = 428 (M+H+HCl)" = 464/6 (CI) WO 00/01704 - 58 - PCT/EP99/04 531 (4) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(1-methyl-pyrazol-5-yl-(ethoxycarbonylmethyloxyimino)-methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 80 % of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid) C28H32N803 x HCl (528.63/565.08) mass spectrum: (M+H)+ = 529 (5) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-[phenyl-(3-ethoxycarbonyl-n-propyloxyimino)methylene]-cyclopropyl]-benzimidazole-dihydrochloride Yield: 47 % of theory, Rf value: 0.06 (silica gel; methylene chloride/methanol = 9:1) C32H36N6°3 x 2 HC1 (552.69/625.60) mass spectrum: (M+H)+ = 553 Example 4 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridine-2-yl)-(carboxymethyloxyimino)methylene]-cvclopropvll-benzimidazole-hydrochloride 150 mg (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl-(ethoxycarbonylmethyloxyimino)-methylene]cyclopropyl]-benzimidazole-hydrochloride and 2.5 ml of 2N sodium hydroxide solution are stirred in 10 ml ethanol for 5 hours at ambient 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 % of theory, Rf value: 0.10 (silica gel; methylene chloride/ethanol/-glacial acetic acid = 8:2:0.1) C27H27N703 x HCl (497.58/534.05) WO 00/01704 - 59 - PCT/EP99/04 531 mass spectrum: (M+H)+ = 498 (M+Na)+ = 520 The following compounds are obtained analogously to 5 Example 4: (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[2-(2-carboxyethyl)-piperidin-l-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride 10 Yield: 94 % of theory, t Rf value: 0.57 (Reversed phase RP 18; methanol/5% sodium chloride solution = 3:2) C28H34N6°3 x HCl (502.62/539.08) mass spectrum: (M+H)+ = 503 15 (M+Na) + = 525 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride 20 Yield: 98 % of theory, Rf value: 0.73 (Reversed phase RP 8; methanol/5% sodium chloride solution = 1:2) C26H33N703 x HCl (491.60/564.54) mass spectrum: (M+H)+ = 492 25 (M+2H) ++ = 247 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3-carboxypropionylamino)-1-(ethoxycarbonyl)-ethyl]-benzimidazole-hydrochloride 30 Yield: 98 % of theory, Rf value: 0.70 (RP 8; methanol/5% sodium chloride solution = 1 :2) C25H3ON6°5 x hc1 (494.55/531.05) mass spectrum: (M+H)+ = 495 35 (2M+H)+ = 989 WO 00/01704 - 60 - PCT/EP99/04531 (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidin-l-yl-carbonyl)-methyl]-benzimidazole-hydrochloride Yield: 87 % of theory, C24H29N703 x HCl (463.54/500.04) mass spectrum: (M+H)+ = 464 (M+2H)+ = 232.6 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [2- (2-carboxyethyl)-pyrrolidin-l-yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 94 % of theory, C27H32N603 x HCl (488.59/525.05) mass spectrum: (M+H)+ = 489 (M+Na)+ = 511 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylcarbonylamino)-1-(pyrrolidin-l-yl-carbonyl)-methyl]-benzimidazole-hydrochloride Yield: 49 % of theory, C25H29N704 x HCl (491.55/528.01) mass spectrum: (M+H)+ = 492 (M+H+Na) ++ = 257.7 (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylcarbonylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 92 % of theory, C26H31N704 x HCl (505.58/542.04) mass spectrum: (M+H)+ = 506 (M+H+Na)++ = 264.7 (8) 2-(4-amidinophenylaminomethyl)-l-methyl-5-(5-methyl-3 -carboxymethyl-imidazolin-2,4-dion-5-yl)-benzimidazole-hydrochloride Yield: 88 % of theory, C22H23N704 x HCl (449.47/485.94) WO 00/01704 - 61 - PCT/EP99/04531 mass spectrum: (M+H)+ = 450 (M+2Na)++ = 247.7 (9) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-[(pyridin-3-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole-hydrochloride Yield: 54 % of theory, C27H27N703 x HCl (497.56/534.09) mass spectrum: (M+H)+ = 498 (M+Na)+ = 520 (10) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[2-(N-(2-carboxyethyl)-N-methyl-aminomethyl)-pyrrolidin-l-yl-carbonyl] cyclopropyl]-benzimidazole-hydrochloride Yield: 100 % of theory, C29H37N703 X HCl (531.66/568.12) mass spectrum: (M+H)+ = 532 (M-H)~ = 530 (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(2-carboxyethyl)-N-(2-pyridyl)-aminomethyl] -benzimidazole-hydrochloride Yield: 91 % of theory, C25H27N702 x HCl (457.54/493.96) mass spectrum: (M+H)+ = 458 (12) 2-(4-amidinophenylaminomethyl)-l-methyl-5-(N-benzenesulphonyl-N-carboxymethyl-aminomethyl)-benzimidazole-hydrochloride 30 Yield: 84 % of theory, C25H26N604S x HCl (506.59/543.06) mass spectrum: (M+H)+ = 507 (13) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2-(2- 35 carboxy-ethyl)-benzimidazole-l-yl-methyl] -benzimidazole-hydrochloride Yield: 76% of theory, 5 10 15 20 25 WO 00/01704 - 62 - PCT/EP99/04531 C27H27N702 x HCl (481.56/518.05) mass spectrum: (M+H)+ = 482 (M+2H) 2+ = 242 (M+Na)+ = 504 5 (M+H+Na)2+ = 253 (M-H+2Na)+ = 526 (M+2Na)2+ = 264 (14) 2-(4-amidinophenylaminomethyl)-l-methyl-5-(2-methyl-10 4-carboxy-imidazol-1-yl-methyl)-benzimidazole- hydrochloride Yield: 61% of theory, C22H23N7O2 x HCl (417.47/453.92) mass spectrum: (M+H)+ = 418 15 (15) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[3-(3-carboxy-n-propyl)-benzimidazol-2-on-l-yl-methyl]-benzimidazole-hydrochloride Yield: 86% of theory, 20 C28H29N703 x HCl (511.59/548.04) mass spectrum: (M+H)+ = 512 (M+Na)+ = 534 (M+H+Na) 2+ = 267.7 (M+2Na)2+ = 278.8 25 (16) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[3-(2-carboxy-ethyl)-imidazo[4,5-b]pyridin-2-on-l-yl-methyl]-benzimidazole-hydrochloride Yield: 83% of theory, 30 C26H2SN803 x HCl (498.55/535) mass spectrum: (M+H)+ = 499 (M+Na)+ = 521 (M-H)~ = 497 (2M-H) ' = 995 35 WO 00/01704 - 63 - PCT/EP99/04531 (17) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl-imidazol-l-yl-methyl]-benzimidazole-hydrochloride Yield: 68% of theory, 5 Rf value: 0.70 (Reversed phase RP 8; methanol/5% sodium chloride solution = 6:4) C25H29N702 x HCl (459.56/496.01) mass spectrum: (M+H)+ = 460 (M+Na)+ = 482 10 , (M+H+Na)2+ = 241 (18) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[phenyl-(carboxymethyloxyimino)methylene]cyclopropyl]-benzimidazole-dihydrochloride Yield: 70% of theory, C28H2eN6°3 X 2HC1 (496.57/569.5) mass spectrum: (M+H)+ = 497 (M-H) * = 495 (19) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-(carboxymethylidene)-methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 37% of theory Rf value: 0.45 (Reversed phase RP 8; methanol/5% sodium chloride solution = 6:4) C27H26N602 x HCl (466.55/503.0) mass spectrum: (M+H)+ = 467 (20) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-30 [(1-methyl-pyrazol-5-yl)-(carboxymethyloxyimino)- methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 30% of theory, Rf value: 0.25 (Reversed phase RP 8; (5% saline solution/methanol = 1:1) 35 C26H28N803 x HCl (500.58/537.03) 15 20 25 WO 00/01704 - 64 - PCT/EP99/04531 mass spectrum: (M+H)* = 501 (M-H)~ = 499 (M+Cl)+ = 535/537 (CI) 5 (21) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[phenyl-(3-carboxy-n-propyloxyimino)methylene]-cyclopropyl]-benzimidazole-dihydrochloride Yield: 37 % of theory, Rf value: 0.35 (Reversed phase RP 8; 5% saline 10 solution/methanol = 3:2) C30H32N6O3 x 2 HCl (524.64/597.55) mass spectrum: (M+H)+ = 525 Example 5 15 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-1-vl-carbonyl)-aminomethvll -benzimidazole-hydrochloride a. 5-(4-chlorophenvl)-imidazolidin-2,4-dione 20 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 25 ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. Yield: 8.6 g (38 % of theory), melting point: 215°C 3 0 b. 5-(4-chloro-3-nitro-phenvl)-imidazolidin-2.4-dione Prepared analogously to Example la from 5-(4-chlorophenyl)-imidazolidin-2,4-dione and fuming nitric acid. Yield: 52 % of theory, 3 5 Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1) WO 00/01704 - 65 - PCT/EP99/04531 c. 4-chloro-3-nitro-phenvlalanine-hvdrochloride 560 rag (2.2 mmol) of 5-(4-chloro-3-nitro-phenyl)-imidazolidin-2,4-dione are refluxed for 24 hours in 20 ml of semiconc. hydrochloric acid. The solvent is distilled 5 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. 10 Yield: 380 mg,(65 % of theory), melting point: 186°C d. 4-chloro-3-nitro-N-tert.butvloxvcarbonvl-phenylalanine 5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine-hydro- 15 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 20 sulphate solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporat ion. Yield: 6.3 g (100 % of theory), Rf value: 0.20 (silica gel; methylene chloride/methanol = 25 9:1) e. 2-(4-chloro-3-nitro-phenyl)-2- tert.butvloxvcarbonvlamino-l-(pyrrolidin-l-vl)-ethanone 3 0 Prepared analogously to Example lc from 4-chloro-3-nitro-N-tert.butyloxycarbonyl-phenylalanine, 0-(benzotriazol-1-yl)-N,N,N1,N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-diisopropylamine in tetrahydrofuran. 35 Yield: 68 % of theory, melting point: 203°C WO 00/01704 - 66 - PCT/EP99/04531 f. 2-(4-methylamino-3-nitro-phenyl)-2- tert.butvloxvcarbonvlamino-1-(pyrrolidin-l-vl)-ethanone Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-ethanone and methylamine solution. Yield: 76 % of theory, Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate = g. 2-(4-methylamino-3-amino-phenyl)-2- tert.butvloxvcarbonvlamino-1-pyrrolidin-1-vl-ethanone Prepared analogously to Example Id from 2-(4-methylamino-3-nit ro-phenyl)-2-tert.butyloxycarbony1amino-1-(pyrrolidin-1-yl)-ethanone and palladium on activated charcoal in methylene chloride/ethanol. Yield: 100 % of theory, Rf value: 0.12 (silica gel; cyclohexane/ethyl acetate = 1:1) h. 2-[4-methylamino-3-(4- cyanophenylaminomethylcarbonylamino)-phenyl] -2- tert.butvloxvcarbonvlamino-1-(pyrrolidin-l-vl)-ethanone Prepared analogously to Example lc from 2-(4-methylamino-3-aminophenyl)-2 -tert.butyloxycarbonylamino-1-(pyrrolidin-l-yl) -ethanone, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in tetrahydrofuran. Yield: 100 % of theory, Rf value: 0.50 (silica gel; methylene chloride/methanol = 9:1) 1:1) WO 00/01704 - 67 - PCT/EP99/04531 i. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-1-vl-carbonvl)-aminomethvll-benzimidazole Prepared analogously to Example If from 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-(pyrrolidin-l-yl)-ethanone in glacial acetic acid. Yield: 30 % of theory, Rf value: 0.19 (silica gel; methylene chloride/methanol = 9.5:0.5) k. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)-aminomethyl]-benzimidazole- hydrochloride Prepared analogously to Example lg from 2- (4- cyanophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl- carbonyl) -aminomethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 27 % of theory, C22H27N70 x HCl (405.50/441.96) mass spectrum: (M+H)+ = 406 The following compounds are obtained analogously to Example 5: (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-(pyrrolidin-l-yl-carbonyl)-N-acetyl-aminomethyl]-benzimidazole-hydrochloride Yield: 29 % of theory, C24H29N702 X HCl (447.54/484.54) mass spectrum: (M+H)+ = 448 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-N-methyl-aminomethyl]-benzimidazole-hydrochloride Yield: 74 % of theory, C28H37N703 x HCl (519.65/556.11) WO 00/01704 - 68 - PCT/EP99/04531 mass spectrum: (M+H)+ = 520 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (pyrrolidin-l-yl-carbonyl)-N-(ethoxycarbonylmethyl)-aminomethyl]-benzimidazole-hydrochloride Yield: 76 % of theory, C26H33N703 x HCl (491.59/528.05) mass spectrum: (M+H)+ = 492 (M+2H)++ = 246.7 (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)-N,N-di-(ethoxycarbonylmethyl)-aminomethyl]-benzimidazole-hydrochloride Yield: 51 % of theory, C30H39N7O5 x HCl (577.68/614.14) mass spectrum: (M+H)+ = 578 (M+Na)+ = 600 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin-l-yl-carbonyl)-N- (ethoxycarbonylmethylcarbonyl)-aminomethyl]-benzimidazole-hydrochloride Yield: 29 % of theory, C27H33N704 x HCl (519.60/556.06) mass spectrum: (M+H)+ = 520 (M+2 H)++ = 260.7 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (pyrrolidin-l-yl-carbonyl)-N-(2-ethoxycarbonylethyl)- aminomethyl]-benzimidazole-hydrochloride Yield: 84 % of theory, C27H35N703 x HCl (505.62/542.62) mass spectrum: (M+H)+ = 506 (M+2H)++ = 253.7 WO 00/01704 - 69 - PCT/EP99/04 531 Example 6 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-(2-ethoxy-carbonylethyl)-amino]-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-5 benzimidazole-hydrochloride a. 5-(4-chloro-3-nitro-phenvl)-5-methyl-imidazolidin-2.4-dione To 50 ml of fuming nitric acid are added batchwise at 10 -25°C to -35° p 10.0 g (4.45 mmol) of 5-(4-chloro-phenyl)-5-methyl-imidazolidin-2,4-dione. After 45 minutes at -25 to -20°C the reaction mixture is poured onto ice water. The crystalline product is suction filtered, washed with water and dried. 15 Yield: 10.5 g (100 % of theory), melting point: 173-178°C Rf value: 0.3 0 (silica gel; cyclohexane/ethyl acetate = 1:1) 2 0 b. 2-amino-2-(4-chloro-3-nitro-phenvl)-propionic acid 10.5 g (0.044 mol) of 5-(4-chloro-3-nitro-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 25 taken up in water and extracted with ethyl acetate. The aqueous phase is concentrated by evaporation, mixed with toluene and evaporated to dryness. The residue is triturated with ether, suction filtered and dried. Yield: 6.8 g (63 % of theory), 30 Rf value: 0.24 (Reversed phase RP8, 5% saline solution/methanol = 1:1) c. 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenvl)-propionic acid 35 Prepared analogously to Example 5d from 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid, di-tert.butyl WO 00/01704 - 70 - PCT/EP99/04531 pyrocarbonate and triethylamine in dioxane. Yield: 9.6 g (100 % of theory), Rf value: 0.31 (Reversed phase RP8, 5% saline solution/methanol = 1:2) d. 2-(4-chloro-3-nitro-phenyl)-2- tert.butvloxvcarbonvlamino-1-(pyrrolidin-l-vl)-propanone Prepared analogously to Example lc from 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid, 0-(benzotriazol-l-yl)-N,N,N1,N1 -tetramethyluronium tetrafluoroborate, pyrrolidine and N-methylmorpholine in dimethylformamide. Yield: 94 % of theory, Rf value: 0.11 (silica gel; cyclohexane/ethyl acetate = 1:1) e. 2-(4-methylamino-3-nitro-phenyl)-2- tert.butvloxvcarbonvlamino-1-(pyrrolidin-1-vl)-propanone Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone and methylamine solution in dimethylformamide at 160°C. Rf value: 0.79 (silica gel; ethyl acetate/ethanol = 9:1) f. 2-(4-methylamino-3-amino-phenyl)-2- tert.butvloxvcarbonvlamino-1-pyrrolidin-1-vl-propanone 30 Prepared analogously to Example Id from 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-l-yl)-propanone and palladium on activated charcoal/hydrogen in methanol. Yield: 100 % of theory, 35 Rf value: 0.63 (silica gel; ethyl acetate/ethanol = 9:1) 10 15 WO 00/01704 - 71 - PCT/EP99/04 531 cr. 2- -met hvl amino-3 - (4-cvanophenvlaminomethvl-carbonvlamino)-phenyl]-2-tert.butvloxvcarbonvlamino-1-(pyrrolidin-1-vl)-propanone Prepared analogously to Example lc from 2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-l-yl)-propanone, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and N-methylmorpholine in dimethylformamide. Yield: 37 % of theory, Rf value: 0.47 (silica gel; ethyl acetate) h. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- (N-tert.butyloxycarbonylamino)-1-(pyrrolidin-l-yl-carbonvl)-ethvll-benzimidazole Prepared analogously to Example If from 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-(pyrrolidin-l-yl)-propanone and glacial acetic acid. Yield: 60 % of theory, Rf value: 0.37 (silica gel; ethyl acetate) i. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-amino-l-(pvrrolidin-l-vl-carbonvl)-ethvll -benzimidazole 1.3 g (2.3 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole 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 solution is mixed with ice, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporat ion. Yield: 0.9 g (98 % of theory), Rf value: 0.14 (silica gel; ethyl acetate/ethanol = 9:1) WO 00/01704 - 72 - PCT/EP99/04531 k. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-l-yl-carbonyl)-ethvll-benzimidazole 0.4 g (1.04 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-l-(pyrrolidin-l-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 % of theory), Rf value: 0.26 (silica gel; ethyl acetate/ethanol = 9:1) 1. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-l-yl-carbonyl)-ethyl1-benz imidazole-hydrochloride Prepared analogously to Example lg from 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 96 % of theory, C28H37N703' X HCl (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)-l-methyl-5-[1-(3- ethoxycarbonylpropionylamino)-1-ethoxycarbonyl-ethyl]- benzimidazole-hydrochloride Yield: 69 % of theory, C27H34N6Os x HCl (522.62/555.08) WO 00/01704 - 73 - PCT/EP99/04 531 mass spectrum: (M+H)+ = 523 (M+H+Na)++ = 273 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- 5 (ethoxycarbonylmethylcarbonylamino)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole-hydrochloride Yield: 95 % of theory, C28H35N7°4 x HCl (533.64/570.10) mass spectrum: (M+H)+ = 534 10 ( (M+Na)+ = 556 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3-ethoxycarbonylpropionylamino)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole-hydrochloride 15 Yield: 20 % of theory, C29H37N704 x HCl (547.66/584.12) mass spectrum: (M+H)+ = 548 (M+H+Na)++ = 285.7 20 (4) 2-[4-amidinophenyl-N-(2-ethoxycarbonylethyl)- aminomethyl]-l-methyl-5-[1-dimethylamino-l-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole-hydrochloride Yield: 91 % of theory, C30H41N7O3 x HCl (547.71/584.17) 25 mass spectrum: (M+H)+ = 548 (M-H)~ = 546 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-ethoxycarbonylethylamino)-1-(dimethylaminocarbonyl)-30 ethyl]-benzimidazole-hydrochloride Yield: 40 % of theory, R£ value: 0.60 (Reversed phase RP 8; 5% saline solution/methanol = 1/1) C26H35N703 x HCl (493.63/530.08) 35 mass spectrum: (M+H)+ = 494 (M-H+2HC1)" = 564/566/568 (Cl2) WO 00/01704 - 74 - PCT/EP99/04531 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 77 % of theory, 5 Rf value: 0.4 0 (silica gel; methylene chloride/methanol = 4:1+1% glacial acetic acid) C27H35N703 x HCl (505.63/542.08) mass spectrum: (M+H)+ = 506 10 (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-ethoxycarbonylethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl] -benzimidazole-hydrochloride Yield: 85 % of theory, RF value: 0.44 (silica gel; methylene chloride/ethanol = 15 9:1) C27H37N703 x HCl (507.64/544.14) mass spectrum: (M+H)+ = 508 (M+C1)" = 542/4 (CI) 20 (8) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 99 % of theory, Rf value: 0.21 (silica gel; methylene chloride/methanol 25 4:1 + 1 % glacial acetic acid) C26H33N7°3 x hc1 (491.60/528.05) mass spectrum: (M+H)+ = 492 (M-H+HCl)" = 526/8 (CI) (M-H+2HC1) " = 562/4/8 (Cl2) 30 (9) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N,N-bis(ethoxycarbonylmethyl)amino)-1-(pyrrolidinocarbonyl) ethyl]-benz imidazole-hydrochloride Yield: 65 % of theory, 35 Rf value: 0.35 (silica gel; methylene chloride/methanol 4:1 + 1 % glacial acetic acid) C31H41N7°5 x hc1 (591.72/628.17) WO 00/01704 - 75 - PCT/EP99/04531 mass spectrum: (M+H)+ = 592 (M-H+HCl)" = 626/8 (Cl) (M-H+2HC1) " = 662/4/6 (Cl2) 5 (10) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(isoxazolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 9% of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline 10 solution = 3:2) C26H33N704 x HCl (507.60/544.05) mass spectrum: (M+H)+ = 508 (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2- 15 ethoxycarbonyl-ethylamino)-1-(isoxazolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride (12) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(N-methyl-N- 20 ethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 58% of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/5% saline solution = 3:2) C26H35N703 x 2 HCl (493.62/566.52) 25 mass spectrum: (M+H)+ = 494 (M+HC1-H)" = 528/30 (Cl) (13) 2-(4-amidinophenylaminomethyl)-l-methyl-5 - [1-( (N,N-di-(ethoxycarbonylmethyl)-amino)-1-(N-methyl-N- 30 ethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 3 0% of theory, Rf value: 0.4 0 (Reversed phase RP 8; methanol/5% saline solution = 3:2) C30H41N7O5 x 2 HCl (579.71/652.62) 35 mass spectrum: (M+H)+ = 580 (M-H)" = 578 WO 00/01704 - 76 - PCT/EP99/04531 (14) 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1- (ethoxycarbonylmethylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 82% of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5% saline solution = 3:2) C28H37N703 x 2 HCl (519.65/592.75) mass spectrum: (M+H)+ = 520 (M-H+HCl)" = 534/6 (Cl) (M-H+2HC1)" = 590/2/4 (C12) (15) 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-(ethoxycarbonylmethylamino)-1-(diethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 88% of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5% saline solution = 3:2) C27H37 N7 03 x 2 HCl (507.64/580.56) Mass spectrum: (M+H) + = 508 (M-H+2HC1)~ = 578/580/582 (Cl2) (16) 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1-(ethoxycarbonylmethyl-methylamino)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole-dihydrochloride Yield: 46 % of theory, Rf value: 0.43 (silica gel; methylene chloride/methanol = 4:1 + 1% glacial acetic acid) C28H37N703 x 2 HCl (519.65/592.56) mass spectrum: (M+H)+ = 520 (M+Cl)" = 554/6 (Cl) (17) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benz imidazole-dihydrochloride WO 00/01704 - 77 - PCT/EP99/04531 (18) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3-ethoxycarbonyl-propylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 95 % of theory, 5 Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline solution = 1:1) C29H39N703 x 2 HCl (533.68/606.58) mass spectrum: (M+H)+ = 534 10 Example 7 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-15 amino]cyclopropyl]-benzimidazole-hydrochloride a. 4-((1-tert.butyloxycarbonylamino)cyclopropyl)-2-nitro-N-methvl-aniline 20 15.0 g (63.5 mmol) of 4-((1-carboxy)cyclopropyl)-2-nitro-N-methyl-aniline and 17.6 ml (127 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and 8.3 g (76 mmol) of ethyl chloroformate are added at 0°C. After one hour at ambient temperature 0.75 g tetrabutylammonium 25 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 extracts are dried and concentrated by evaporation. The residue is 30 dissolved in 200 ml tert.butanol and refluxed for two hours. The solvent is concentrated by evaporation, the residue chromatographed on silica gel and eluted with methylene chloride. Yield: 15.5 g (77 % of theory), 35 Rf value: 0.83 (silica gel; methylene chloride/methanol = 9.5:0.5) WO 00/01704 - 78 - PCT/EP99/04531 b. 4-((1-araino)cyclopropyl)-2-nitro-N-methyl-aniline-hvdrochloride 15.5 g (0.05 mol) of 4-[ (1-tert.butyloxycarbonylamino)-5 cyclopropyl]-2-nitro-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. 10 Yield: 98 % of theory, Rf value: 0.44 (silica gel; methylene chloride/methanol = 9.5:0.5) c. 4-[N-(1-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl-15 aniline 12.0 g (0.05 mol) of 4-[(1-amino)cyclopropyl]-2-nitro-N-methyl-aniline-hydrochloride are dissolved in 500 ml of tetrahydrofuran and after the addition of 4.1 g (0.05 mol) 20 of eye1opentanone and 3.2 ml of glacial acetic acid, 13.6 g (0.064 mol) of sodium triacetoxyborohydride are added batchwise under a nitrogen atmosphere. After 16 hours at ambient temperature, the mixture is diluted with sodium hydrogen carbonate solution and extracted with ethyl 25 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 % of theory) Rf value: 0.56 (silica gel; methylene chloride/methanol = 30 9.5:0.5) d. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cvclopropvll-2-nitro-N-methvl-aniline 35 1.0 g (3.6 mmol) of 4-[(1-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 3 0 ml tetrahydrofuran and after the addition of 0.45 g (4.4 WO 00/01704 - 79 - PCT/EP99/04531 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 temperature. Then it is diluted with ethyl acetate and sodium hydrogen carbonate solution, the organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1:1) . Yield: 1.3 g (90 % of theory), Rf value: 0.46 (silica gel; ethyl acetate/cyclohexane = 1:1) e. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cvclopropvll-2-amino-N-methvl-aniline Prepared analogously to Example Id 4-[l-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-nitro-N-methyl-aniline and palladium on activated charcoal/hydrogen in methylene chloride/ethanol. Yield: 100 % 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)- aminomethvlcarbonvlamino-N-methvl-aniline Prepared analogously to Example lc 4-[1-(N-(3 -ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 96 % of theory, Rf value: 0.54 (silica gel; methylene chloride/methanol = 9.5:0.5) WO 00/01704 - 80 - PCT/EP99/04 531 g. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino]-cvclopropvll-benzimidazole Prepared analogously to Example If from 4-[l-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid. Yield: 52 % of theory, Rf value: 0.81 (silica gel; methylene chloride/methanol = 9:1) h. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)- amino]cvclopropvll-benzimidazole-hydrochloride Prepared analogously to Example lg from 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[N-cyclopentyl-N- (3-ethoxycarbonylpropionyl)-amino]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 36 % of theory, C30H38N6O3 X HCl (530.68/567.14) mass spectrum: (M+H)+ = 531 Example 8 2-(4-amidinophenylaminomethyl)-l-methyl-5-(5-methyl-3- ethoxycarbonylmethyl-imidazolin-2,4-dion- 5-vl)benzimidazole-hydrochloride a. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-1-yl-carbonvl)-ethvll-benzimidazole 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-l-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole are dissolved in 10 ml dimethylformamide and WO 00/01704 - 81 - PCT/EP99/04 531 10 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) I b. 2-(4-amidinophenylaminomethyl)-l-methyl-5-(5-methyl-3-ethoxycarbonylmethyl-imidazolin-2,4-dion-5-yl)-benzimidazole-hydrochloride 15 Prepared analogously to Example lg from 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- (ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. 20 Yield: 68 % of theory, C24H27N704 x HCl (477.52/513.99) mass spectrum: (M+H)+ = 478 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole-hydrochloride 30 a. 4-(2-tert.butyloxycarbonylethyl)-2- (pyridvlaminomethvl)-2-nit ro-chlorobenzene 13.4 g (0.053 mol) of 4-chloro-3-nitro-benzylbromide and 11.8 g (0.053 mol) of 2-tert.butyloxycarbonylethylamino-3 5 pyridine are stirred in 80 ml of N-ethyl-diisopropylamine for 3 hours at 90° C. The solution is concentrated by WO 00/01704 - 82 - PCT/EP99/04531 evaporation, the residue chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (8:2 and 7:3). Yield: 8.2 g (40 % of theory), Rf value: 0.64 (silica gel; petroleum ether/ethyl acetate 5 =8:2) b. 4-(2-tert.butyloxycarbonylethyl) - 2 - (pyridvlaminomethvl)-2-nitro-N-methvl-aniline 10 Prepared analogously to Example lb from 4-(2- tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nitro-chlorobenzene and methylamine solution. Yield: 20 % of theory, Rf value: 0.65 (silica gel; methylene chloride/ethanol = 15 9:1) c. 4-(2-tert.butyloxycarbonylethyl)-2- (pyridvlaminomethvl)-2-amino-N-methvl-aniline 20 1.6 g (4 mmol) of 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nitro-N-methyl-aniline are dissolved in 200 ml methanol and, after the addition of 2 g of Raney nickel, combined with 1 ml of hydrazine hydrate. The solution is stirred for 3 0 minutes at ambient 25 temperature and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (95:5). Yield: 1.2 g (82 % of theory), Rf value: 0.33 (silica gel; methylene chloride/ethanol = 30 9:1) d. 2 -(4 -cyanophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxvcarbonvlethvl)-aminomethvll-benzimidazole 35 Prepared analogously to Example lc from 4-(2- tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'- WO 00/01704 - 83 - PCT/EP99/04531 tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine in tetrahydrofuran and glacial acetic acid. Yield: 72 % of theory, Rf value: 0.36 (silica gel; methylene chloride/ethanol = 9:1) e. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole-hydrochloride / Prepared analogously to Example lg from 4-[(5-(2- tert.butyloxycarbonylethyl)-2-pyridylaminomethyl-1-methyl- benzimidazole-2-yl)-methylamino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol. Yield: 59 % of theory, C27H31N702 x HCl (485.59/522.1) mass spectrum: (M+H)+ = 486 The following compounds are obtained analogously to Example 9: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5- [N-(ethoxycarbonylmethyl)-benzenesulphonylaminomethyl]-benz imidazole-hydrochloride Yield: 53 % of theory, C27H30N6O4S x HCl (534.64/571.1) mass spectrum: (M+H)+ = 535 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-(N-methyl-phenylcarbonylaminomethyl)]-benzimidazole-hydrochloride Yield: 42 % of theory, C25H26N60 x HCl (426.53/462.96) mass spectrum: (M+H)+ = 427 WO 00/01704 - 84 - PCT/EP99/04531 Example 10 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-methyl-benzimidazol-l-vl)methyl1-benzimidazole-hydrochloride 5 a. 1-(4-chloro-3-nitrobenzyl)-2-methvl-benzimidazole Prepared analogously to Example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide. 10 Yield: 78% of theory, C15H12C1N302 (3 01.7) mass spectrum: M+ = 301/303 b. 1-(4-methvlamino-3-nitrobenzyl)-2-methvl-benzimidazole 15 Prepared analogously to Example lb from 1-(4-chloro-3- nitrobenzyl)-2-methyl-benzimidazole and methylamine. Yield: 96% of theory, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 19 :1) 20 c. 1-(4-methvlamino-3-aminobenzvl)-2-methvl-benzimidazole Prepared analogously to Example lc from 1-(4-methylamino- 3-nitrobenzyl)-2-methyl-benzimidazole and hydrogen/Raney nickel. 25 Yield: 100% of theory, Rf value: 0.34 (silica gel; methylene chloride/ethanol = 19:1) d. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[(2-methyl- 3 0 benzimidazol-l-vl)methyl 1 -benzimidazole 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 tetrahydrofuran for 15 35 minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4-methylamino-3-aminobenzyl)-2-methyl-benzimidazole the mixture is refluxed for a further 16 hours. Then the WO 00/01704 - 85 - PCT/EP99/04531 solution is evaporated to dryness, the residue is mixed with 80 ml glacial acetic acid and refluxed 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 5 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 (96% of theory), Rf value: 0.30 (silica gel; methylene chloride/ethanol = 10 19:1) C25H22N6 (406.5) mass spectrum: M+ = 4 06 e. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-methyl-15 benzimidazol-l-vl)methyl1-benzimidazole-hydrochloride Prepared analogously to Example lg from 2-(4-cyanophenylaminomethyl)-l-methyl-5-[(2-methyl-benzimidazol-l-yl)methyl]-benzimidazole hydrochloric 2 0 acid/ammonium carbonate. Yield: 59% of theory, C25H25N7 x HCl (423.5/459.9) mass spectrum: (M+H)+ = 424 (M+2H) 2+ = 217.7 25 The following compounds are obtained analogously to Example 10: (1) 2-(4-amidinophenyloxymethyl)-l-methyl-5-[(imidazol-1-30 yl)-methyl]-benzimidazole-hydrochloride Yield: 30% of theory, C2oH2oN60 x HCl (360.4/396.9) mass spectrum: (M+H)+ = 361 (M+2H) 2+ = 181 35 (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (imidazol-l-yl)-ethyl]-benzimidazole-hydrochloride WO 00/01704 - 86 - PCT/EP99/04531 Yield: 70% of theory, C21H23N7 x HCl (373.46/410) mass spectrum: (M+H)+ = 374 (M+2H)2+ = 187.6 5 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-ethyl-4-methyl-imidazol-1-yl)-ethyl]-benzimidazole-dihydrochloride Yield: 18% of theory, 10 C24H29N7 x 2HC1 (415.55/488.46) mass spectrum: (M+H)+ = 416 (M+2H) 2+ = 208.7 (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-ethyl-4-15 methyl-imidazol-1-yl)-methyl]-benzimidazole- dihydrochloride Yield: 36% of theory, C23H27N7 x 2Hc1 (401.52/437.97) mass spectrum: (M+H)+ = 402 20 (M+2H) 2+ = 201.7 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(pyridin-2-yl)-N-methyl-aminomethyl] -benzimidazole-dihydrochloride Yield: 78% of theory, 25 C23H25N7 x 2HC1 (399.5/435.95) mass spectrum: (M+H)+ = 400 (M+2H) 2+ = 200.6 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-(2-30 ethoxycarbonyl-ethyl)-benzimidazol-l-yl)-methyl]- benzimidazole-dihydrochloride Yield: 61% of theory, C29H31N702 x HCl (509.62/546.07) mass spectrum: (M+H)+ = 510 35 (M+2H) 2+ = 255.7 (M+H+Na) 2+ = 266.7 WO 00/01704 - 87 - PCT/EP99/04531 (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(imidazol-1-yl)-methyl]-benzimidazole-hydrochloride Yield: 35% of theory, C20H21N7 x HCl (359.44/395.89) 5 mass spectrum: (M+H) + = 360 (M+2H)2+ = 180.6 (8) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-(2-acetylamino-ethyl)-4,5-dimethyl-imidazol-l-yl)-methyl]- 10 benzimidazole-dihydrochloride Yield: 42% of" theory, C26H32N80 x 2HC1 (472.6/545.51) mass spectrum: (M+H)+ = 473 (M+2H)2+ = 237 15 (M+H+Na)2+ = 248 (9) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-(2-aminocarbonyl-ethyl)-4,5-dimethyl-imidazol-l-yl)-methyl]-benzimidazole-dihydrochloride 20 Yield: 68% of theory, C25H30NbO x 2HC1 (458.6/531.51) mass spectrum: (M+H)+ . = 459 (M+2H)2+ = 230 25 (10) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-methyl-4-ethoxycarbonyl-imidazol-1-yl)-methyl] -benzimidazole-hydrochloride Yield: 34% of theory, C24H27N702 x HCl (445.53/481.98) 30 mass spectrum: (M+H)+ = 446 (M+2H) 2+ = 223.5 (M+H+Na)2+ = 234.5 (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(3-(3-35 ethoxycarbonyl-n-propyl)-benzimidazol-2-on-l-yl)-methyl]-benzimidazole-hydrochloride Yield: 58% of theory, WO 00/01704 - 88 - PCT/EP99/04531 C30H33N7O3 x HCl (539.64/576.09) mass spectrum: (M+H)+ = 540 (M+H+Na)2+ = 281.7 5 (12) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(3-(2-ethoxycarbonyl-ethyl)-imidazo[4,5-b]pyridin-2-on-l-yl)-methyl]-benzimidazole-hydrochloride Yield: 29% of theory, C2eH3oN803 x HCl (526.6/563.05) 10 mass spectrum: (M+H)+ = 527 (M+2H)2+ = 264 (M+H+Na)2+ = 275 (13) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-phenyl-15 imidazol-l-yl)-methyl]-benzimidazole-hydrochloride Yield: 58% of theory, C26H25N7 x HCl (435.54/472) mass spectrum: (M+H)+ = 436 (M+Na)+ = 218.6 20 (14) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(4,5-dimethyl-2-(2-ethoxycarbonylethyl)-imidazol-l-yl)-methyl]-benzimidazole-dihydrochloride Yield: 52% of theory, 25 C27H33N702 x 2HC1 (487.61/560.52) mass spectrum: (M+H)+ = 488 (M+2H)2+ = 244.6 30 35 Example 11 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-ethoxycarbonyl-azetidin-l-yl)-1-(pyrrolidin-l-yl-carbonyl) -ethyl]-benzimidazole-hydrochloride a. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(2-tert.butyloxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-l-yl- WO 00/01704 - 89 - PCT/EP99/04531 carbonyl)-ethvll-benzimidazole 0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-5 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 mmol) 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. 10 The filtrate |s concentrated by evaporation, 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 concentrated by evaporation. 15 Yield: 0.44 g (44% of theory) as a mixture of diastereomers, C31H38N603 (542.69) mass spectrum: (M+H)+ = 543 20 b. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-ethoxycarbonyl-azetidin-l-yl)-1-(pyrrolidin-l-yl-carbonyl ) -ethyl] -benzimidazole-hydrochloride (mixture of diastereomers) Prepared analogously to Example lg from 2-(4- 25 cyanophenylaminomethyl)-l-methyl-5-[1-(2- tert.butyloxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 12 % of theory, 3 0 C29H37N703 X HCl (531.66/568.12) mass spectrum: (M+H)+ = 532 (M+H+HC1)2+ = 568/70 (Cl) WO 00/01704 - 90 - PCT/EP99/04531 10 Example 12 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methvlenelcvclopropvll-benzimidazole-hydrochloride a. (E/Z)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methvlenelcvclopropvll-benzimidazole 8 97 mg (4.0 mmol) of triethyl phosphonoacetate are dissolved in 30 ml tetrahydrofuran under argon. At -15°C 449 mg (4.0 mmol) of potassium tert. butoxide are added. After 30 minutes 815 mg (2.0 mmol) of 2-(4-15 cyanophenylaminomethyl)-l-methyl-5-[1-(pyridin-3-yl- carbonyl)cyclopropyl]-benzimidazole are added batchwise and the mixture is stirred overnight at ambient temperature. Then the solution is refluxed for a further 6 hours and concentrated by evaporation. The residue is 2 0 mixed with sodium chloride solution and extracted 3x with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in dichloromethane and chromatographed on silica gel, eluting with 25 dichloromethane containing 5% ethanol. The desired fractions are concentrated by evaporation, the residue is triturated with ether, suction filtered and dried. Yield: 365 mg (38% of theory). 30 b. ((E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methvlenelcvclopropvll -benzimidazole-hydrochloride Prepared analogously to Example lg from (E/Z)-2-(4-35 cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl]- WO 00/01704 - 91 - PCT/EP99/04531 benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 58 % of theory, C2gH30N6O2 x HCl (494.60/531.05) 5 mass spectrum: (M+H)+ = 495 The following compound is obtained analogously to Example 12 : 10 (1) (E/Z)-2-(£-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-2-yi)-ethoxycarbonylmethylidene)-methylene]-cyclopropyl]-benzimidazole-hydrochloride Yield: 72 % of theory, C29H30N6O2 x HCl (494.60/531.05) 15 mass spectrum: (M+H)+ =495 Example 13 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxy-20 azetidin-l-yl)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]- benzimidazole-hydrochloride (mixture of diastereomers) 200 mg (0.35 mmol) of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycarbonyl-azetidin-l-yl)-1-25 (pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole- hydrochloride are dissolved in 3 0 ml of 6N hydrochloric acid and stirred for 13 hours at ambient temperature. The reaction mixture is concentrated by evaporation with the addition of toluene, the residue is triturated with 30 acetone/ether, suction filtered, washed with ether and dried. Yield: 200 mg (>100 % of theory, contains ammonium chloride), C27H33N703 x HCl (503.62/540.07) 35 mass spectrum: (M+H)+ = 504 WO 00/01704 - 92 - PCT/EP99/04531 The following compounds are obtained analogously to Example 13: (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 91% of theory, Rf value: 0.75 (Reversed phase; 5% saline solution/methanol = 1:1) C24H3iN7°3 x hc1 (465.56/502.01) mass spectrum: (M+H)+ = 466 (M-H+2HC1) " = 537/539 C12) (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 70 % of theory, Rf value: 0.51 (Reversed phase; 5% saline solution/methanol = 3:2) C25H31N703 x 2 HCl (477.57/550.48) mass spectrum: (M+H)+ = 478 (3) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[(pyridin-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+C1)+ = 501/503 (Cl) (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-me t hy1-carboxymethy1carbony1amino)-2- (pyrrolidinocarbonyl)-prop-2-yl] -benzimidazole-dihydrochloride Yield: 99 % of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution = 1:1) WO 00/01704 - 93 - PCT/EP99/04531 C28H35N704 x 2 HCl (533.64/606.64) mass spectrum: (M+H)+ = 534 (M-H)~ = 532 (M-H+HCl)" = 568/70 (Cl) 5 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 75 % of theory, 10 Rf value: 0.54; (Reversed phase RP 8; methanol/5% saline solution = 1:1) C25H33N703 x 2 HCl (479.59/552.59) mass spectrum: (M+H)+ = 480 15 Example 14 2-[4-(N-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-ethoxycarbonylethylamino)-1-(dimethvlaminocarbonvl)-ethvll-benzimidazole 20 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, 25 mixed with 2.0 g potassium carbonate 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 30 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 7.5% ethanol. The uniform fractions are combined, concentrated by evaporation, dissolved in a 35 little ethyl acetate and mixed with petroleum ether. The solid form is suction filtered, washed with petroleum ether and dried. WO 00/01704 - 94 - PCT/EP99/04531 Yield: 0.8 g (43 % of theory), C33H47N705 (621.79) Rf value: 0.50 (silica gel; methylene chloride/ethanol = 19:1) 5 mass spectrum: (M+H)+ = 622 (M+Na)+ = 644 Example 15 10 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride 15 a. Methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl- propionate 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 20 diisopropylamine (85 mmol) in 20 ml tetrahydrofuran at -78°C. Then a solution of 10.0 g (50 mmol) of methyl 2-(4-chloro-phenyl)-propionate in 3 0 ml tetrahydrofuran is added dropwise at -78°C. Formaldehyde gas is then piped into the reaction mixture at -20°C for 30 minutes. After 25 the addition of 5% citric acid and glacial acetic acid the mixture is extracted with ethyl acetate. The organic phases are washed with IN sulphuric acid, water, saturated sodium bicarbonate solution and saline solution and dried over magnesium sulphate. The crude product is purified on 30 silica gel, eluting with cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1 and 0:1). The uniform fractions are combined and concentrated by evaporation. Yield: 9.7 g (84% of theory) yellow oil, RF value: 0.25 (silica gel; petroleum ether/ethyl acetate 35 4:1) WO 00/01704 - 95 - PCT/EP99/04531 b. 2-(4-chloro-phenvl)-3-hydroxy-2-methyl-propionic acid Prepared analogously to Example 4 from methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxide solution in ethanol. 5 Yield: 83% of theory, Rf value: 0.55 (silica gel; ethyl acetate/cyclohexane 2:1 + glacial acetic acid) c. 2-(4-chloro-3-nitro-phenvl)-2-methvl-3-nitroxv-10 propionic acid Prepared analogously to Example la from 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid. Yield: 90% of theory, melting point: 129-132°C 15 C10H9ClN2O7 (304.64) d. 2-(4-chloro-3-nitro-phenvl)-2-methyl-3-hydroxy-propionic acid Prepared analogously to Example 6 from 2-(4-chloro-3-20 nitro-phenyl)-3-nitrooxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane. Yield: 98% of theory, C10H10ClNO5 (259.65) mass spectrum: (M-H)" = 258/60 (Cl) 25 (2M-H)" = 517/9 (C12) e. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hvdroxv-propionic acid 30 Prepared analogously to Example lb from 2-(4-chloro-3-nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and time thy 1 -benzylamine. Yield: 81% of theory, C18H20ClN2O5 (344.37) 3 5 mass spectrum: M+ = 344 WO 00/01704 - 96 - PCT/EP99/04531 f. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hvdroxv-1-pyrrolidin-1-vl-propan-1-one Prepared analogously to Example lc from 2-[4-(N-benzyl-5 methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine. Yield: 96% of theory, C22H27N304 (3 97.48) mass spectrum: M+ = 398 10 (M+Na)+ = 420 g. 2- [4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonvloxv-1-pyrrolidin-1-vl-propan-1-one 15 A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino) -3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-l-yl-propan-l-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 methanesulphonyl 20 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. 25 Yield: 1.4 g (98% of theory) h. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methylamino-1-pyrrolidin-1-vl-propan-1-one 3 0 A solution of 1.4 g (2.9 mmol) of 2-[4-(N-benzyl-methylamino) -3-nitro-phenyl]-2-methyl-3- methanesulphonyloxy-l-pyrrolidin-l-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 35 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 WO 00/01704 - 97 - PCT/EP99/04531 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 + 1% conc. ammonia). The uniform fractions are combined and 5 concentrated by evaporation. Yield: 740 mg (61% of theory), RF value: 0.45 (silica gel; methylene chloride/ethanol 9:1 + 1% conc. ammonia) 10 i. 2-[4-(benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-vl-propan-1-one Prepared analogously to Example 7d from 2-[4-(N-benzyl-15 methylamino)-3-nitro-phenyl]-2-methyl-3- methylamino-1- pyrrolidin-1-yl-propan-1-one and methyl malonate chloride. Yield: 84% of theory, RF value: 0.65 (silica gel; ethyl acetate/ethanol 9:1 + ammonia) 20 C27H34N4Os (510.60) mass spectrum: (M-H) ~ = 509 (M+Na)+ = 533 j. 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N-25 methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-l-vl-propan-1-one Prepared analogously to Example Id from 2-[4-(N-benzyl-methylamino) -3-nitro-phenyl]-2-methyl-3-(N-30 methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-l-yl-propan-1-one and hydrogen/palladium on activated charcoal. Yield: 100% of theory, Rp value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 +1% 35 conc. ammonia) C20H30N4O4 (390.49) mass spectrum: M+ = 390 WO 00/01704 - 98 - PCT/EP99/04 531 k. 4-[2-(3-(N-raethoxycarbonylmethylcarbonyl-methylamino))- 2-methyl-l-pyrrolidin-l-yl-propan-l-on-2-yl]-2-(4-cyano-phenvl)-aminomet hvlcarbonylamino-N-me thvl-aniline Prepared analogously to Example le from 2-(4-methylamino- 3-amino-phenyl)-2-methyl-3-(N- methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and 0-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 95% of theory, RF value: 0.35 (silica gel; ethyl acetate/ethanol 9:1 + 1% conc. ammonia) 1. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2 -(pyrrolidinocarbonyl)-prop-2-vll-benzimidazole Prepared analogously to Example If from 4-[2-(3-(N-methoxycarbonylmethylcarbonyl-methylamino))-2-methyl-l-pyrrolidin-l-yl-propan-l-on-2-yl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid. Yield: 47 % of theory, Rf value: 0.20 (silica gel; ethyl acetate/ethanol = 9:1) C29H34N604 (530.63) mass spectrum: (M+H)+ = 531 (M+Na)+ = 553 m. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-e t hoxyc arbonylme t hy1carbony1-methy1amino)-2 -(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole- hvdrochloride Prepared analogously to Example lg from 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2- WO 00/01704 - 99 - PCT/EP99/04 531 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 65 % of theory, Rf value: 0.3 0 (silica gel; methylene chloride/methanol = 5 4:1 + glacial acetic acid) C30H39N7O4 x HCl (561.69/598.19) mass spectrum: (M+H)+ = 562 (M+Cl)" = 596/8 (Cl) 10 The following,compounds are obtained analogously to Example 15: (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-methoxycarbonylmethyl-methylamino)-2- 15 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride Yield: 89 % of theory, Rf value: 0.35 (Reversed phase RP 8; methanol/5% saline solution = 3:2) 20 C28H37N703 x HCl (519.66/556.11) mass spectrum: (M+H)+ = 520 (M-H+HC1) " = 554/6 (Cl) (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-25 ethoxycarbonylmethylcarbonylamino)-2- (pyrrolidinocarbonyl)-prop-2-yl] -benzimidazole-acetate Yield: 45% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % ethyl acetate) 30 C29H37N704 x CH3COOH (547.66/607.71) mass spectrum: (M+H)+ = 548 (M-H)" = 546 (M-H+CH3COOH)" = 606 35 (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(N-methyl-ethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride WO 00/01704 - 100 - PCT/EP99/04531 (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5 - [1-(N-ethoxycarbonylmethyl-methylamino)-2-(N-methyl-N-ethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbony1methy1carbony1-me t hy1amino)-2-(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylsulphonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2 -(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-acetate Yield: 72% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid) C29H37N704 x CHjCOOH (547.66/607.71) mass spectrum: (M+H)+ = 548 (M-H)" = 546 (8) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-e thoxycarbonyl-e thylcarbonylamino)-2 -(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (9) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylsulphonylamino)-2 -(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride Yield: 14% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2) WO 00/01704 - 101 - PCT/EP99/04531 C28H37N705S X HCl mass spectrum: (583.65/620.17) (M+H)+ = 584 (M+Na)+ = 606 10 (10) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(1H-tetrazol-5-yl)-methylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-dihydrochloride Yield: 40% of theory, 15 C28H37N703 X 2 HCl (519.65/592.56) mass spectrum: (M+H)+ = 520 (M+Na)+ = 542 (M+HCOO)" = 564 (M+Cl)" = 554 20 Example 16 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-25 (carboxymethylamino)-1-(isoxazolidin-l-yl-carbonyl)- ethvll-benzimidazole-hydrochloride Prepared by hydrolysis of 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(isoxazolidin-30 1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride with sodium hydroxide solution in ethanol. Yield: 90 % of theory, Rf value: 0.65 (Reversed phase RP 8; methanol/5% saline solution = 3:2) 35 C24H29N704 x HCl (479.54/515.99) mass spectrum: (M+H)+ = 480 WO 00/01704 - 102 - PCT/EP99/04531 The following compounds are prepared analogously to Example 16: (1) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyethylamino)-1-(isoxazolidin-l-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride (2) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylamino)-1-(N-methyl-N-ethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 93% of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5% saline solution = 1:1) C24H31N703 x HCl (465.57/502.02) mass spectrum: (M+H)+ = 466 (M+Cl-H)" = 500/2 (Cl) (3) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-carboxymethyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-dihydrochloride Yield: 89% of theory, Rf value: 0.57 (Reversed phase RP 8; methanol/5% saline solution = 4:3) C27H35N703 x 2 HCl (505.63/578.54) mass spectrum: (M+H)+ = 506 (M+2H)++ = 253 (M+H+Na)++ = 264.5 (4) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride Yield: 90% of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution = 4:6) C27H33N704 x HCl (519.61/556.06) mass spectrum: (M+H)+ = 520 (M-H)~ = 518 WO 00/01704 - 103 - PCT/EP99/04531 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-carboxymethyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5 - [1-(N-carboxymethylcarbonyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride , (7) 2-(4-amidinophenylaminomethyl)-l-methyl-5 - [1-(N-carboxymethylcarbonyl-methylamino)-2 -(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (8) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-carboxymethylsulphonyl-methylamino)-2 -(piperidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride (9) 2-(4-amidinophenylaminomethyl)-l-methyl-5 - [1- (carboxymethylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 81% of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5% saline solution = 1:1) C26H33N7°3 (491.60/528.05) mass spectrum: (M+H)+ = 492 (M-H)" = 490 (10) 2-(4-amidinophenylaminomethyl)-l-methyl-5- [1- (2-carboxyethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] -benzimidazole-hydrochloride WO 00/01704 - 104 - PCT/EP99/04531 (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylsulphonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride 5 (12) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (carboxymethylamino)-1-(diethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 70% of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline 10 solution = 1:1) C25H33N703 (479:59/516.05) mass spectrum: (M+H)+ = 480 (M-H)" = 478 (M-H+HC1)" = 514/516 (Cl) 15 (13) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(carboxymethylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-dihydrochloride 20 Yield: 22 % of theory, Rf value: 0.50 (Reversed phase RP 8; 5% saline solution/ methanol = 1:1) C26H33N703 x 2 HCl (491.60/564.51) mass spectrum: (M+H)+ = 492 25 (M-H)" = 490 (14) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N-carb-oxymethyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-30 benzimidazole-dihydrochloride Rf value: 0.48 (Reversed phase RP 8; 5% saline solution/ methanol = 3:2) C26H33N703 X 2 HCl (491.60/564.51) mass spectrum: (M+H)+ = 492 35 (M-H)" = 490 WO 00/01704 - 105 - PCT/EP99/04531 (15) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3-carboxy-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride 5 Yield: 82 % of theory, Rf value: 0.73 (Reversed phase; 5% sodium chloride solution/ methanol = 1:1) C27H35N703 x 2 HCl (505.63/578.54) mass spectrum: (M+H)+ = 506 10 Example 17 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-15 (pyrrolidinocarbonyl)-ethvll -benzimidazole A suspension of 1.4 g (2.4 mmol) of 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-20 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 solution is concentrated by evaporation in 25 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 fractions are combined, concentrated by evaporation, triturated with water, 30 suction filtered and dried. Yield: 0.7 g (49% of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1) C34H39N704 (609.73) 35 mass spectrum: (M+H) + = 610 (M+Na)+ = 632 WO 00/01704 - 106 - PCT/EP99/04 531 (M-H)■ = 608 The following compounds are obtained analogously to Examples 14 and 17: (1) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 53% of theory, Rf value: 0.35( (silica gel; methylene chloride/ethanol = 9:1) C34H47N705 (633.79) mass spectrum: (M+Na)+ = 656 (M-H)" = 632 (2) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 46% of theory, Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1) C36H51N705 (661.84) mass spectrum: (M+Na)+ = 684 (M-H)" = 660 (3) 2-[4-(N-n-hexyloxycarbonyl-amidino)-phenylaminomethyl)-l-methyl-5-[1- (methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(methoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)ethyl]-benzimidazole Yield: 32% of theory, Rf value: 0.27 (silica gel; methylene chloride/ethanol = 9:1) WO 00/01704 - 107 - PCT/EP99/04531 C35H49N705 (647.82) mass spectrum: (M+Na)+ = 670 (M-H)" = 646 (5) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]- 1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 52% of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1) C37H51N706 (689.85) mass spectrum: (M+H)+ = 690 (M-H)" = 688) (M+Na)+ = 712 (M+HC1-H) " = 724/26 (Cl) (6) 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl)-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)- 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole (7) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 21% of theory, Rf value: 0.55 (silica gel; 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)-l-methyl-5-[1- (N- WO 00/01704 - 108 - PCT/EP99/04531 methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole (9) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-5 methyl-5-[1-(methoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 34% of theory. Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1 + 1 % ammonia) 10 C33H37N704 (595.70) mass spectrum": (M-H) " = 594 (M+Na)+ = 618 (10) 2-[4-(N-isopropyloxycarbonylamidino)-15 phenylaminomethyl]-l-methyl-5-[1-(N- e t hoxyc arbonylme t hy1carbony1-methy1amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 66% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 20 9:1) C34H45N706 (64 7.77) mass spectrum: (M+H)+ = 648 (M-H)" = 646 (M+Na)+ = 670 25 (11) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)■ 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 23% of theory, 30 Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C37H43N705 (665.79) mass spectrum: (M+H)+ = 666 (M-H)" = 664 35 (M+Na)+ = 688 (M+H+Cl)+ = 700/2 (Cl) WO 00/01704 - 109 - PCT/EP99/04531 (12) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]- 1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 67% of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1) C36H41N705 (651.76) mass spectrum: (M+H)+ = 652 (M-H)" = 650 (M+Na)+ = 674 (13) 2-[4-(N-n-butyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)- 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 45% of theory, Rf value: 0.50 (silica gel; 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-ethyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 54% of theory, Rf value: 0.40 (silica gel; methylene chloride/ethanol = 9:1) C33H43N706 (633.75) mass spectrum: (M+H)+ = 634 (M-H)" = 632 (M+Na)+ = 656 WO 00/01704 - 110 - PCT/EP99/04 531 (15) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]- 5 benzimidazole Yield: 53% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1) C32H4iN706 (619.72) 10 mass spectrum; (M+H)+ = 620 (M-H)~ = 618 (M+Na) + = 642 (16) 2-[4-(N-pyridin-3-yl-carbonylamidino)-15 phenylaminomethyl]-l-methyl-5-[1-(N- e t hoxycarbony1methy1carbony1-methy1amino)- 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 16% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 20 9:1) C3GH42N805 (666.78) mass spectrum: (M-H)" = 665 (M+Na)+ = 689 25 (17) 2 -[4 -(N-n-butyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 52% of theory, 3 0 Rf value: 0.42 (silica gel; methylene chloride/ethanol = 9:1) C32H43N705 (605.74) mass spectrum: (M+H)+ = 606 (M+Na)+ =628 35 (M-H)" = 604 WO 00/01704 - Ill - PCT/EP99/04 531 (18) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 30% of theory, Rf value: 0.44 (silica gel; 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]-l-methyl-5 - [1-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 51% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1) C35H41N705 (63 9.75) mass spectrum: (M+Na)+ = 662 (M-H)" = 638 (20) 2-[4-(N-pyridin-3-yl-carbonylamidino)-phenylaminomethyl]-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 84% of theory, Rf value: 0.2 0 (silica gel; ethyl acetate/ethanol = 4:1) C33H38N804 (610.72) mass spectrum: (M+H)+ = 611 (M-H)" = 609 (M-HCOO)" = 611 (21) 2-[4-(N-acetoxymethyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 42% of theory, WO 00/01704 - 112 - PCT/EP9 9/04 531 Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1) C31H39N7075 (621.09) mass spectrum: (M+Na)+ = 644 5 (M-H)" = 620 (22) 2 -[4 -(N-(2,2,2 -trichloroethyloxycarbonyl)-amidino)-phenylaminomethyl]-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-10 ethyl]-benzimidazole Yield: 73% of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 9:1) C30H36Cl3N7O5 (681) 15 mass spectrum: M+ = 679/81/3 (Cl3) (M+Na)+ = 702/4/6 (Cl3) (M-H)" = 678/80/2 (Cl3) Example 18 20 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole 25 A solution of 0.2 g (0.3 mmol) of 2-[4-(N-n- octyloxycarbonylamidino) -phenylaminomethyl]-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 3 ml tetrahydrofuran and 2.5 ml ethanol is mixed with 1.1 ml of IN sodium hydroxide 30 solution and stirred for 4 hours at ambient temperature. The reaction mixture is concentrated by evaporation and combined with 1 ml of IN hydrochloric acid. After 12 hours at ambient temperature (pH 4) 2 drops of ammonia (33%) are added, whereupon a bright yellow precipitate is formed. 35 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 WO 00/01704 - 113 - PCT/EP99/04531 toluene. The residue is triturated with acetone, suction filtered, washed with diethylether and dried. Yield: 0.1 g (50% of theory), Rf value: 0.3 5 (Reversed phase RP 8; methanol/5% saline 5 solution = 2:1) C34H47N705 (633.79) mass spectrum: (M+H)+ = 634 (M+H+Na)++ = 328.5 10 Example 19 2-[4-(N-hydroxyamidino)-phenylaminomethyl]-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole 15 A suspension of 0.6 g (1.2 mmol) of 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 50 ml ethanol is mixed with 0.47 g 2 0 (7.8 mmol) of hydroxylamine hydrochloride and 0.3 5 g (3.5 mmol) of sodium carbonate and refluxed for 17 hours. After cooling, the residue is filtered off, the filtrate is concentrated by evaporation and taken up in water. After extracting twice with dichloromethane, the combined 25 organic phases are dried and concentrated by evaporation. The crude product is purified on silica gel, eluting with dichloromethane/ethanol (19/1 and 7/1). The uniform fractions are combined, concentrated by evaporation, triturated with diisopropylether and dried. 30 Yield: 0.025 g (4% of theory), Rf value: 0.68 (silica gel; methylene chloride/ethanol = 4:1) C27H35N704 (521.62) mass spectrum: (M-H)" = 520 35 (M+Na) + = 544 WO 00/01704 - 114 - PCT/EP99/04 531 Example 2 0 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-5 (pyrrolidinocarbonyl)-ethvll-benzimidazole a. Ethyl 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-acetate 10 Prepared analogously to Example 9a from 4-(5-methyl-l,2,4- / oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine. Yield: 78% of theory, Rf value: 0.60 (silica gel; ethyl acetate/petroleum ether 15 = 1:1) b. 4-(5-methvl-l.2,4-oxadiazol-3-vl)-phenvlamino-acetic acid Prepared analogously to Example 4 from ethyl 4-(5-methyl-20 1, 2, 4-oxadiazol-3-yl)-phenylamino-acetate and sodium hydroxide solution in ethanol. Yield: 75% of theory, Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9:1) c . 2-[4-(5-methyl-l,2,4-oxadiazol-3-yl)- phenylaminomethyl]-l-methyl-5-[1-amino-(pyrrolidin-l-yl-carbonvl)-ethvll-benzimidazole 30 Prepared analogously to Example le/f from 2-(4- methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-amino-1-pyrrolidin-l-yl-propanone, 4-(5-methyl-l,2,4-oxadiazol-3-yl)-phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran and subsequent treatment with glacial 35 acetic acid. Yield: 34% of theory. WO 00/01704 - 115 - PCT/EP99/04 531 Rf value: 0.10 (silica gel; methylene chloride/ethanol = 9:1) d. 2 -[4 -(5-methyl-l,2,4-oxadiazol-3-yl)-phenylaminomethyl]-l-methyl-5-[1- (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)- ethvll-benzimidazole Prepared analogously to Example 11 from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-l-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-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)-l-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate Prepared analogously to Example Id from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-l-methyl-5- [1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and hydrogen/palladium (10% on activated charcoal) in ethanol/glacial acetic acid. Yield: 69% 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)-ethyl]-benzimidazole Prepared analogously to Example 17 from 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)- WO 00/01704 - 116 - PCT/EP99/04531 ethyl]-benzimidazole-acetate and 4-nitrophenyl benzoate in N-ethyl-diisopropylamine/dimethylformamide. Yield: 26% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1) C35H41N704 (623.75) mass spectrum: (M+Na) + = 646 (M-H)" = 622 The following compounds are prepared analogously to I Example 20: 4 (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- (pyrrolidinocarbonyl)-ethyl]-benzimidazole (3) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) -ethyl]-benzimidazole Yield: 40 % of theory, Rf value: 0.45 (silica gel: methylene chloride/ethanol = 9:1) C3SH49N705 (647.82) mass spectrum: (M+H)+ = 648 (M-H)" = 646 (M+Na)+ = 670 (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-l-methyl-5- [1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) -ethyl]-benzimidazole Yield: 31% of theory, Rf value: 0.48 (silica gel: methylene chloride/ethanol = 9:1) WO 00/01704 - 117 - PCT/EP99/04531 C37H53N705 (675.88) mass spectrum: (M+H)+ = 674 (M+Na)+ = 698 (5) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)-phenylaminomethyl]-l-methyl-5-[1-(isopropyloxycarbonyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 43% of theory, Rf value: 0.50 (silica gel: methylene chloride/ethanol = 9:1) C31H38C13N705 (695.05) mass spectrum: (M-H)" = 692/694/696/698 (Cl3) (6) 2- [4-(N-phenylcarbonylamidino)- phenylaminomethyl]-l-methyl-5- [1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) -ethyl]-benzimidazole Yield: 79% of theory Rf value: 0.35 (silica gel; ethyl acetate/ethanol = 9:1) C35H41N704 (623.76) mass spectrum: (M+H) + = 624 (M-H)" = 622 (M+HCOO)" = 668 (7) 2-[4-(N-n-octyloxycarbonylamidino)- phenylaminomethyl]-l-methyl-5-[1-(n-propyloxycarbonyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 53% of theory Rf value: 0.3 9 (silica gel; ethyl acetate/ethanol = 9:1) C37H53N705 (675.88) mass spectrum: (M+H)+ = 676 (M+Na)+ = 698 (M-H)" = 674 WO 00/01704 - 118 - PCT/EP99/04531 Example 21 (R)-2-(4-Amidinophenylaminomethyl)-l-methyl-5-fl-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethvll-5 benzimidazole hydrochloride a. Ethyl 2-amino-2-(4-chloro-3-nitrophenvl)-propionate A mixture of 28 g (0.11 mol) of 2-amin-2-(4-chloro-3-nitrophenyl)-propionic acid in 200 ml of 5.6 N ethanolic 10 hydrochloric acid is refluxed for 36 hours. After the I solvent has been evaporated off the residue is suspended in 300 ml of ethyl acetate and combined with 300 ml of saturated sodium hydrogen carbonate solution. The organic phase is washed twice with saturated sodium hydrogen 15 carbonate solution and once with water, dried over sodium sulphate and evaporated down. Yield: 21.1 g (68% of theory) of light brown oil. b. ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitrophenvl)-2 0 propionate 17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3-nitrophenyl)-propionate are dissolved in 247 ml of isopropanol and 207 ml of methanol and mixed with 9.54 g 25 (63.6 mmol) of L-(+)-tartaric acid. The reaction mixture is heated to 100°C, whereupon a clear solution is formed. The solution is cooled to 27°C within 3 hours, the precipitate formed is suction filtered, washed with ethanol and dried. Then the solid formed (21.5 g) is 30 suspended in 400 ml of ethyl acetate and combined with 400 ml of saturated sodium hydrogen carbonate solution. After extraction and phase separation, the organic phase is washed with water, dried and evaporated down. Yield: 7.68 g (44.4% of theory) of light yellow oil, 35 [a] 20 = +4.38° (ethyl acetate) HPLC analysis: ee value > 98.6% WO 00/01704 - 119 - PCT/EP99/04531 c. (R)-(-)-2-amino-2-(4-chloro-3-nitrophenvl)-propionic acid 5 Prepared analogously to Example 4 from ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitrophenyl)-propionate and sodium hydroxide solution in tetrahydrofuran. Yield: 63% of theory, [a] 20 = -59.6° (methanol/water 1:1) 10 d . (R)- 2-tert.butyloxycarbonylamino-2-(4-chloro-3- nitrophenyl)-propionic acid Prepared analogously to Example 5d from (R)-(-)-2-amino-2-15 (4-chloro-3-nitrophenyl)-propionic acid and pyrocarbonic acid di-tert.butyldicarbonate and triethylamine in dioxan. Yield: 100% of theory. e . (R)-2-tert.butyloxvcarbonvlamino-2-(4-methylamino-3- 20 nitrophenyl)-propionic acid Prepared analogously to Example lb from (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitrophenyl)-propionic acid and methylamine. 25 Yield: 69% of theory. f. (R)-2-(4-methylamino-3-nitrophenvl)-2-tert.butvloxvcarbonvlamino-1-pyrrolidino-propanone 3 0 Prepared analogously to Example lc from (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitrophenyl)-propionic acid, pyrrolidine and carbonyldiimidazole in tetrahydrofuran. Yield: 96% of theory. WO 00/01704 - 120 - PCT/EP99/04531 q. (R)-2-(4-methylamino-3-aminophenvl)-2- tert.butvloxvcarbonvlamino-1-pyrrolidino-propanone Prepared analogously to Example lc from (R)-2-(4-5 methylamino-3-nitrophenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone and hydrogen/palladium on activated charcoal in methanol. Yield: 99% of theory. 10 h. (R) -2- (4Tcvanophenvlaminomethyl) -l-methvl-5- ["1- (N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole Prepared analogously to Example lc/lf from (R)-2-(4-15 methylamino-3-aminophenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone, 4-cyanophenylglycine, carbonyldiimidazole in tetrahydrofuran and subsequent cyclisation in glacial acetic acid. Yield: 100% of theory. 20 i. (R)-2-(4-cyanophenylaminomethyl)-l-methvl-5-ri-amino-1-(pyrrolidinocarbonyl)-ethvll -benzimidazole Prepared analogously to Example 6i from (R)-2-(4- 2 5 cyanophenylaminomethyl)-l-methyl-5-[1-(N- tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and 6N hydrochloric acid in dioxan. Yield: 76% of theory. 3 0 k. (R)-2-(4-cyanophenylaminomethyl)-l-methvl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole Prepared analogously to Example 6k from (R)-2-(4-3 5 cyanophenylaminomethyl)-l-methyl-5-[1-amino-1- (pyrrolidino-carbonyl)-ethyl]-benzimidazole and ethyl iodoacetate/potassium carbonate in acetone. WO 00/01704 121 PCT/EP9 9/04 531 Yield: 75% of theory. 1. (R) -2- (4-amidinophenylaminomethyl) -l-methvl-5- ["1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole hydrochloride Prepared analogously to Example lg from (R)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 95% of theory. m. (R) -2- (4-amidinophenylaminomethyl) -l-methvl-5- ["1- (carbonvlmethvlamino)-1-(pyrrolidinocarbonyl)-ethvll-benzimidazole hydrochloride Prepared analogously to Example 4 from (R)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(ethoxycarbonylmethylamino) -1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and sodium hydroxide solution in ethanol. Yield: 100% of theory, C25H31N703 x 2HC1 (477.57/550.5) Mass spectrum: (M+H)+ = 478 Example 2 2 Dry ampoule containing 75 mg of active substance per 10 ml Composition: (M-H+HC1)" = 512/514 (Cl) (M-H+2HC1)~ = 448/550/552 (Cl2) Active substance Mannitol water for injections 75.0 mg 50.0 mg ad 10.0 ml WO 00/01704 - 122 - PCT/EP99/04 531 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 5 water for injections. Example 23 Dry ampoule containing 3 5 mg of active substance per 2 ml 10 / Composition: Active substance 35.0 mg Mannitol 100.0 mg 15 water for injections ad 2.0 ml Preparation: Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. 20 To produce the solution ready for use, the product is dissolved in water for injections. 25 Example 24 Tablet containing 50 mg of active substance Composition: 3 0 (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 mg 3 5 215.0 mg WO 00/01704 - 123 - PCT/EP99/04531 Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried 5 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. 10 Example 25 Tablet containing 3 50 mg of active substance 15 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 mq 600 . . 0 mg (1), (2) and (3) are mixed together and granulated with an 2 5 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. 30 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/01704 124 PCT/EP99/04 531 Example 2 6 Capsules containing 50 mg of active substance 5 Composition: (1) Active substance (2) Dried maize starch (3) Powdered lactose 50.0 mg 58.0 mg 50.0 mg 2 . 0 mg 160.0 mg 10 (4) Magnesium/stearate Preparation: (1) is triturated with (3). This trituration is added to 15 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. 2 0 Example 2 7 Capsules containing 350 mg of active substance Composition: Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. 25 (1) Active substance (2) Dried maize starch (3) Powdered lactose (4) Magnesium stearate 35 0.0 mg 4 6.0 mg 3 0.0 mg 4 . 0 mq 43 0.0 mg 30 35 WO 00/01704 - 125 - PCT/EP99/04 531 This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine. Example 28 5 Suppositories containing 100 mg of active substance 1 suppository contains: 10 Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 84 0.0 ma 2,000.0 mg 15 Method: The polyethyleneglycol is melted together with polyethylene sorbitan monostearate. At 4 0°C the ground active substance is homogeneously dispersed in the melt. 20 It is cooled to 38°C and poured into slightly chilled suppository moulds. 50962 WO 00/01704 126 PCT/EP99/04531 Patent Claims

1. Benzimidazoles of general formula R. •a ■A—B—Ar Rc (I) , wherein. Ar denotes a-phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, Ci-3-alkyl or Ci_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a Ci_3-alkyl group, A denotes a Ci-3-alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a Ci_3-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, Ra denotes an Ri-CO-C3_5-cycloalkyl group wherein 2 6 MAY 2C03 WO 00/01704 - 127 - 50962 PCT/EP99/04531 R denotes a Ci _3-alkoxy, amino, Ci-4-alkylamino or di- (Ci-4-alkyl) -amino group wherein each alkyl moiety may be substituted by a carboxy group, 5 a 4- to '7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two Ci-3-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, Ci-3-alkoxy, carboxy, carboxy-Ci-3-alkoxy, 10 carboxy-Ci-3-alkylamino, N-(Ci-3-alkyl)-N-(carboxy-Ci_3-alkyl) -amino, carboxy-Ci-3-alkylaminocarbonyl, N- (Ci-3-alkyl) -N- (carboxy-Ci_3-alkyl) -aminocarbonyl, carboxy-Ci-3-alkylaminocarbonylamino, 1- (Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino, 3- (Ci-3-alkyl) -15 3-(carboxy-Ci-3-alkyl) -aminocarbonylamino or 1,3-di-(Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group 20 substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a Ci-3-alkyl group, to which a phenyl ring is fused via two adiacent carbon atoms. 25 30 a morpholino, piperazino, N- (Ci_3-alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-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 IPONZ 2 6 MAY 2003 50962 WO 00/01704 - 128 - PCT/EP99/04531 ) Ci-3-alkyi 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 Ci_3-alkyl group, an oxygen 5 or sulphur atom or:an imino group optionally substituted by a Ci-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-Ci_3-alkoxy, carboxy-Ci-3-alkylamino or N-(Ci-3-alkyl) -10 carboxy-Ci-3-alkylamino group, and X denotes an oxygen atom, a Ci_3-alkylimino, Cx-3-alkoxyimino, Ci_3-alkylhydrazino, di-(Ci-3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-(Ci_3-alkyl)-15 C2-4-alkanoylhydrazino or Ci-3-alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, 20 a Ci-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 Ci_3-alkyl groups or by 25 one, two or three Ci_3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2-4~alkanoylamino,-30 . Ci-3-alkylamino, N-(C2-4~alkanoyl)-Ci_3-alkyiamino or di-(Ci_3-alkyl)-amino group, and r1PONZ 2 6 MAY WO 00/01704 - 129 - 509625 PCT/EP99/04531 the imidazolone ring may be substituted by a Ci-3-aikyi group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoylarru.no, Ci-3-alkylamino, 5 N-(C2-4~alkanoyl)-Ci-3-alkylamino or di- (Ci^-alkyl) -amino group, and additionally a .phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via 10 two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two Ci-3-alkyl groups, whilst at the ■same time an alkyl substituent may be substituted by a 15 carboxy group, a Ci-4-alkyl group which is substituted by a Ci_3-alkyl-Yi-Ci_3-alkyl, HOOC-Ci_3-alkyl-Yi-Ci_3-al-20. kyl, tetrazolyl-Ci-3-alkyl-Y2, R3NR4- or R3NR4-Ci-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a Ci_3-alkyl group, by a pyrrolino-25 carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-l-yl-carbonyl, carboxy, aminocarbonyl, Ci-3-alkylaminocarbonyl, di- (Ci_3-alkyl) -aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the 3 0 cycloalkyleneimino moiety may be substituted by one or two Ci-3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned iponz 2 6 mat 2003 5096 «-J! WO 00/01704 - 130 - PCT/EP99/04 531 Ci-3-alkylaminocarbonyl, di- (Ci-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the Ci-4-alkyl group may be wholly or partially replaced by 5 fluorine atoms wherein R3 denotes a hydrogen atom or a Ci-3-alkyl group optionally substituted by a carboxy group and •10 R4 denotes a hydrogen atom, a Ci-3-alkyl- Yi-Ci-3-alkyl-Y2, carboxy-Ci-3-alkyl-Yi-Ci-3-alkyl-Y2, Ci_3-alkyl-Y2 or carboxy-Ci-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them 15 denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, Ci_3-alkyl or carboxy-Ci-3-alkyl group wherein Yi denotes a carbon-carbon bond, an oxygen atom, a 20 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 2 5 carbonylgroup 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 Yi and Y2 may each additionally be substituted by a Ci-3-alkyl or carboxy-Ci-3-alkyl group, 30 a Ci-3-alkyl or C3_5-cycloalkyl group substituted by a R5NR6- group wherein IPONZ 26 MAY 2003 50 9 625 WO 00/01704 - 131 - PCT/EP99/04531 Rs denotes a hydrogen atom, a Ci-3-alkyl, Cs-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 5 Rg denotes a Ci-3-alkyl, carboxy-Ci-3-alkyl or carboxy- Ci_3-alkylcarbonyl group, a Ci-3-alkyl group which is substituted by a C2-4~alkanoyl or C5-7~cycloalkanoyl group and by a Ci_3-alkyl group 10 substituted by a chlorine,'bromine or iodine atom, Rb denotes a hydrogen atom or a Ci-3-alkyl group and Rc denotes a cyano group or an amidino group optionally 15 substituted by one or two Ci-3-alkyl groups, wherein the carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group which can be converted in vivo into a carboxy group or by 20 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 25 group which can be cleaved in vivo, wherein a group which can be converted in vivo into a carboxy group denotes a hydroxme'thyl group or a carboxy group 'esterified with an alcohol, wherein the alcoholic moiety is a Ci-g-alkanol, a phenyl-Ci-3-alkanol, a C3_9-cycloalkanol, whilst a 30 Cs-s-cycloalkanol may additionally be substituted by one or two Ci-3-alkyl groups, a Cs-s-cycloalkanol wherein a methylene group in the 3- or 4-position is replaced 2 6 MAT 2003 50 1 5 WO 00/01704 132 PCT/EP99/04 531 oxygen atom or by an imino group optionally substituted by a Ci-3-alkyl, phenyl-Ci_3-alkyl, phenyl-Ci-3-alkoxycarbonyl or C2-6_alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two Ci-3-alkyl 5 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-Ci_3-alkanol, a bicycloalkanol with a total 10 of 8 to 10 carbon atoms, which may additionally be substituted in- the bicycloalkyl moiety by one or two Ci-3-alkyl groups, a 1, 3-dihydro-3-oxo-l-isobenzofuranol or an alcohol of formula 15 Rd-C0-0- (ReCRf) -OH, wherein Rd denotes a Ci-a-alkyl, Cs-7-cycloalkyl, phenyl or phenyl-Ci-3-alkyl group, Re .denotes a hydrogen atom, a Ci_3-alkyl, C5-7-cycloalkyl or phenyl group and Rf denotes a hydrogen atom or a Ci_3-alkyl group, a group which is negatively charged under physiological conditions denotes a tetrazol-5-yl, phenylcarbonylamino-carbonyl, trifluoromethylcarbonylaminocarbonyl, Ci-6-alkyl sulphonyl amino, phenyl sulphonyl amino, 30 benzylsulphonylaird.no, trif luoromethylsulphonylamino, Ci-6-alkylsulphonylaminocarbonyl, phenylsulphonylamino- 20 25 iponz 26 may 2003 50 Z WO 00/01704 133 PCT/EP99/04531 carbonyl, benzylsulphonylaminocarbonyl or perfluoro-Ci_6-alkylsulphonylaminocarbonyl group and a group which can be cleaved in vivo from an imino or 5 amino group denotes a hydroxy group or an acyl group selected from a benzoyl group, optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by Ci_3-alkyl or Ci-3-alkoxy groups, wherein, the substituents may be identical or different, a pyridinoyl 10 group or a Ci-ig-alkanoyl group, a 3, 3, 3-trichloropropionyl or allyloxycarbonyl group, a Ci_i6-alkoxycarbonyl or Ci-i6-alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, a phenyl-Ci-6-alkoxycarbonyl group, a 3-amino-15 propionyl group wherein the amino group may be mono- or disubstituted by Ci_6-alkyl or C3_7-cycloalkyl groups and the substituents may be identical or different, a Ci-3-alkylsulphonyl-C2-4-alkoxycarbonyl, Ci-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, Rd-C0-0- (RdCRf) -O-CO-, 20 Ci-6-alkyl-CO-NH-(RgCRh)-O-CO- or Ci-5-alkyl-C0-0-(RgCRh)-(RgCRh)-O-CO- group wherein Rd to Rf are as hereinbefore defined, and •25 Rg and Rh, which may be identical or different, denote hydrogen atoms or Ci_3-alkyl groups, the tautomers, stereoisomers, mixtures and salts thereof. 30 2. Benzimidazoles of general formula iponz 26 mai 2003 WO 00/01704 - 134 - PCT/EP99/04 531 A denotes a Ci-3-alkylene group, 5 B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a Ci-3-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy 10 group, Ra denotes an Ri-CO-C3-5-cycloalkyl group wherein Rx denotes a Ci_3-alkoxy, amino, Ci-4-alkylamino or di-15 (Ci-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 20 one or two Ci-3-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, Ci-3-alkoxy, carboxy, carboxy-Ci-3-alkoxy, carboxy-Ci-3-alkylamino,- N- (Ci_3-alkyl) -N- (carboxy-Ci-3-alkyl) -amino, carboxy-Ci-3-alkylaminocarbonyl, N-(Ci-3-alkyl) -25 ' N-(carboxy-Ci-3-alkyl)-aminocarbonyl, carboxy- Ci-3-alkylaminocarbonylamino, 1- (Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino, 3- (Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino or 1, 3-di- (Ci_3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino group, IPONZ 2 6 MAr 2ii23 WO 00/01704 - 135 - PCT/EP99/04 531 a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a Ci-3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (Ci-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 Ci_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 Ci-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a Ci-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-Ci-3-alkoxy, carboxy-Ci-3-alkylamino or N-(Ci-3-alkyl)-carboxy-Ci-3-alkylamino group, and X denotes an oxygen' atom, a Ci-3-alkylimino, Ci-3-alkoxyimino, Ci-3-alkylhydrazino, di-(Ci-3-alkyl)-; hydrazino, C2-4_alkanoylhydrazino, N- (Ci-3-alkyl) - C2-4-alkanoylhydrazino or Ci-3-alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety IPONZ 26 MAi WO 00/01704 - 136 - CWEra997T)4 5jl or in the alkyl and alkanoyl moieties by a carboxy group, a Ci-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 Ci-3-alkyl' groups or by one, two or three Ci_3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, Ci-3-alkylamino,' N- (C2-4-alkanoyl) -Ci-3-alkylamino or di-(Ci-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-alkanoylamino, Ci-3-alkylamino, N-(C2-4-alkanoyl)-Ci-3-alkylamino or di-(Ci-3-alkyl)-amino group, and ' additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be .substituted by one or two Ci_3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, iponz 26 MAY 2003 WO 00/01704 - 137 - a Ci-4-alkyl group which is substituted by a Ci-s-alkyl-Yi-Ci-a-alkyl, HOOC-Ci-3~alkyl-Yi-Ci-3-al-kyl, tetrazolyl-Ci_3-alkyl-Y2, R3NR4- or R3NR4-Ci-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a Ci-3-alkyl group, by a pyrro-linocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, Ci-3-alkylaminocarbonyl, di-(Ci-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 Ci-3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned Ci-3-alkylaminocarbonyl, di- (Ci-3-alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the Ci-4-alkyl group may be wholly or partially replaced by fluorine atoms wherein R3 denotes- a hydrogen atom or a Ci-3-alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a Ci_3-alkyl-Yi-Ci-3-alkyl-Y2, carboxy-Ci-3-alkyl-Yi-Ci-3-alkyl-Y2, Ci-3-alkyl-Y2 or carboxy-Ci_3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group IPONZ

2 E Mai a*i3;WO 00/01704;- 138 -;PCT/EP99/04531;optionally substituted by a carboxy, Ci_3-alkyl or carboxy-Ci_3-alkyl group wherein;Yi 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 Yi and Y2 may each additionally be substituted by a Ci-3-alkyl or carboxy-Ci-3-alkyl group,;a Ci-3-alkyl or C3-5-cycloalkyl group substituted by a R5NR6- group wherein;R5 denotes a hydrogen atom, a Ci-3-alkyl, Cs-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and;Rs denotes a Ci-3-alkyl, carboxy-Ci-3-alkyl or carboxy-Ci-3-alkylcarbonyl group,;a Ci-3-alkyl group which is substituted by a C2-4~alkanoyl or Cs-7-cycloalkanoyl group and by a Ci-3-alkyl group substituted by a chlorine, bromine or iodine atom,;-Rb denotes a" hydrogen atom or a Ci-3-alkyl group and tiponz;26 MAr m;WO 00/01704;- 139 -;PCT/EP99/04531;Rc denotes a cyano group or an amidino group which may be substituted by a hydroxy group, by one or two Ci-3-alkyl groups, or by one or two Ci-g-alkoxycarbonyl groups,;wherein the carboxy, amino and imino groups mentioned in the definition of the abovementioned groups may also be substituted by a group as defined in claim 1 which can be converted in vivo into a carboxy group or cleaved in vivo from an amino or imino group,;the tautomers, stereoisomers and salts thereof.;

3. Benzimidazoles of general formula la according to claim 2, wherein;A denotes a Ci-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,;Ra denotes an C3_5-cycloalkyl group substituted by the Ri-CO group in the 1 position wherein;R denotes a Ci-3-alkoxy, amino, Ci-4-alkylamino or di-;(Ci-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 Ci-3-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, Ci-3-alkoxy,;IPONZ;2 6 MAY 2003;WO 00/01704;- 140 -;PCT/EP99/04531;carboxy, carboxy-Ci_3-alkoxy, carboxy-Ci-3-alkyiamino, N- (Ci-3-alkyl) -N- (carboxy-Ci-3-alkyl) -amino, carboxy-Ci-3-alkylaminocarbonyl, N- (Ci-3-alkyl) -N- (carboxy- . C1-3-alkyl) -aminocarbonyl, carboxy-;Ci-3-alkylaminocarbonylamino, 1- (Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino, 3- (Ci-3-alkyl) -3- (carboxy-Ci-3-alkyl) -aminocarbonylamino or 1, 3-di-(Ci_3-alkyl) -3-(carboxy-Ci-3-alkyl)-aminocarbonylamino group,;a 5- to 7-membered cycloalkyleneimino group optionally substituted by a Ci_3-alkyl group, to which a phenyl ring is fused via two adjacent -carbon atoms,;a morpholino, piperazino, ■ N- (Ci-3-alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group,;a C3-5-cycloalkyl group substituted in the 1 position by the R2-CX- group, wherein;R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a Ci-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 Ci-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a Ci-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-Ci-3-alkoxy, carboxy-Ci-3-alkylamino -or N- (Ci-3-alkyl) -carboxy-Ci-3-alkylamino group, and;'IPONZ;26 may 2003;WO 00/01704;- 141 -;PCT/EP99/0 4 531;X denotes an oxygen atom, a Ci-3-alkylimino,;Ci-3-alkoxyimino or Ci-3-alkylidene group, each of which may be substituted in the alkyl or alkanoyl moiety by a carboxy group,;a Ci-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 Ci_3-alkyl groups or by one, two or three Ci_3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, Ci-3-alkylamino, N-(C2-4-alkanoyl)-Ci-3-alkylamirio or di-(Ci_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-alkanoylamino, Ci-3-alkylamino, N-(C2-4-alkanoyl)-Ci_3-alkylamino or di- (Ci-3-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms,;an .imidazolidine-2,4-dion-5-yl group which may be substituted by one or two Ci-3-alkyl groups, whilst at the;IPONZ;26 MAT 2093;WO 00/01704;- 142 -;PCT/EP997 04531;same time'an alkyl substituent may be substituted by a carboxy group,;a Ci-4-alkyl group which is substituted in the 1 position by an R3NR4- or R3NR4-Ci-3-alkyl group and by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-l-yl-carbonyl, carboxy, aminocarbonyl, Ci-3-alkylaminocarbonyl, di- (Ci-3-alkyl) -aminocarbonyl, isoxazolidin-l-ylcarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two Ci-3-alkyl groups and at the same time each alkyl moiety or alkyl substituent- in the abovementioned Ci-3-alkylaminocarbonyl, di-(Ci-3-alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the Ci-4-alkyl group may be wholly or partially replaced by fluorine atoms, wherein;R3 denotes a hydrogen atom or a Ci-3-alkyl group optionally substituted by a carboxy group and;R4 denotes a hydrogen atom, a Ci_3-alkyl-Y2 or carboxy- Ci-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 in the 1 position by a carboxy, Ci-3-alkyl or carboxy-Ci-3-alkyl group, wherein;1PONZ;2 6 MAi 2003;WO 00/01704;- 143 -;PCT/EP99/0 4531;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 the imino group occurring in the 5 definition of the groups Y2 may additionally be substituted by a Ci-3-alkyl or carboxy-Ci-3-alkyl group,;a Ci-3-alkyl or C3-5-cycloalkyl group substituted in the 1 position by an R5NRS- group, wherein;■10;Rs denotes a hydrogen atom, a Ci_3-alkyl, C5_7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and;R6 denotes a Ci-3-alkyl, carboxy-Ci-3-alkyl or carboxy-15 Ci-3-alkylcarbonyl group,;a Ci-3-alkyl group which is substituted by a C2-4~alkanoyl or C5-7-cycloalkanoyl group and by a Ci-3-alkyl group substituted by a chlorine, bromine- or iodine atom, 20 ... ';Rb denotes a Ci-3-alkyl group and;Rc denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, 2 5 Ci-g-alkoxycarbonyl, acetoxymethyloxycarbonyl,;benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine,;chlorine, bromine or iodine atoms, by Ci_3-alkyl or Ci-3-alkoxy groups and the substituents may be Identical or 30 different,;iponz;2 6 mai itwwj;509625;WO 00/01704 - 144 - PCT/EP99/04531;the Ci-3-alkanol esters, the tautomers, stereoisomers and salts thereof.;

4. Benzimidazoles of general formula la according to claim 5 2, wherein;A denotes a methylene group,;B denotes an oxygen atom or an imino group,;1-0;Ra denotes a cyclopropyl group substituted by the Ri-CO-group in the 1 position, wherein;Rx denotes a pyrrolidino or piperidino group optionally 15 substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-Ci-3-alkoxy, carboxy-Ci-3-alkylamino or N- (Ci-3-alkyl) -carboxy-Ci-3-alkylamino group,;20 a cyclopropyl group substituted in the 1 position by the R2-CX- group, wherein;R2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a Ci-3-alkyl group and;25;X denotes an oxygen atom, a Ci-3-alkoxyimino or Ci-3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group,;30 a Ci-2-alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring may be substituted by a phenyl or carboxy aroup and by one or;IPONZ;2 6 MAT 2G03;509625;WO 00/01704 - 145 - PCT/EP99/04531;two Ci-3-aikyi groups or by one, two or three Ci-3-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a 5 ■carboxy group or may be substituted in the 2 or 3;position by an amino, C2_4-alkanoylamino, Ci-3-alkylamino, N-(C2-4-alkanoyl)-Ci-3-alkylamino or di- (Ci-3-alkyl) -amino group, whilst additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole rings via two 10 adjacent carbon atoms,;a Ci-2-alkyl substituted in the 1 position by a benzimidazolon-l-yl group, whilst the imidazolone ring may be substituted by a methyl or ethyl group optionally 15 substituted by a carboxy group,;■ a methyl or ethyl group which is substituted in the 1 position;2 0 by an R3NR4 or R3NR4-Ci-3-alkyl group and by a di-(Ci-3-alkyl)-aminocarbonyl group, by a isoxazolidin-l-ylcarbonyl group, by a pyrrolidinocarbonyl or piperidinocarbonyl group substituted by a 2 5 Ci-3-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent in the abovementioned groups may be substituted by a carboxy group, wherein;30 R3 denotes a hydrogen atom or a Ci-3-alkyl group optionally substituted by a carboxy group and iponz;2 E mai 2003;WO 00/01704;- 146 -;PCT/EP99/04531;R4 .denotes a hydrogen atom, a Ci-3-aikyi-Y2 or carboxy- Ci-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 group, wherein;Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a Ci_3-alkyl group,;a Ci_2-alkyl group substituted in the 1 position by an R5NR6- group, wherein;Rs denotes a pyridinyl, phenylcarbonyl or phenyl;sulphonyl group and;R6. denotes a Ci-3-alkyl or carboxy-Ci-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-Ci-3-alkylcarbonyl group,;Rb denotes a methyl group and;Rc denotes an amidino group which may optionally be substituted by a Ci_8-alkoxycarbonyl,;iponz;26 may 2003;WO 00/01704;- 147 -;PCT/EP99/04 531;acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group,;the Ci-3-alkanol esters thereof, the tautomers,;stereoisomers and salts thereof.;

5. Benzimidazoles of general formula la according to claim 2, wherein;A denotes a methylene group,;B denotes an imino group,;Ra denotes a cyclopropyl group substituted by the Ri-CO-group in the 1 position, wherein;Rx denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-Ci-3-alkoxy, carbcxy-Ci_3-alkylamino or N- (Ci-3-alkyl) -carboxy-Ci-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 substituted by a Ci-3-a.lkyl group and;X denotes an oxygen atom, a Ci-3-alkoxyimino or Ci-3-alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy- group,;iponz;2 6 may 2003;509625;WO 00/01704 - 148 - PCT/EP99/04531;a Ci-2-alkyl group substituted in the 1 position by an imidazole 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 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-(Ci_3-alkyl)-aminocarbonyl, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by a Ci-3-alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent may be substituted by a carboxy group, wherein;R3 denotes a hydrogen atom or a Ci_3-alkyl group optionally substituted by a carboxy group and;R4 denotes a Ci-3-alkyl-Y2 or carboxy- Ci-3-alkyl-Y2;ffv*pii-!t\ wnfiroi n Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a Ci-3-alkyl group, Rb denotes a methyl group and 1ponz 26 mat 2003 509625 WO 00/01704 - 149 - PCT/EP99/04531 Rc denotes an amidino group which may optionally be substituted by a Ci-g-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, the Ci-3-alkanol esters thereof, the tautomers, stereoisomers and salts thereof.

6. Benzimidazoles of general formula I according to at least one of claims 1 to 5 wherein the group Ra is in the 5 position, the tautomers/ stereoisomers and salts thereof.

7. The following compounds of general formula la: (a) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 1-(pyrrolidin-l-yl-carbonyl)cyclopropyl] -benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 1-[ (pyridin-2-yl)-(carboxymethyloxyimino)methylene] -cyclopropyl] -benzimidazole, (c) 2-(4 — amidinophenylaminomethyl)—1—methyl — 5— [ 1—(2 — carboxyethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl] -benzimidazole, (d) 2-( 4-amidinophenylaminomethyl) -l-methyl-5-[ l-[ 2-(2-carboxyethyl)-pyrrolidin-l-yl-carbonyl] cyclopropyl] -benzimidazole, ' IPONZ 26 MAi 2u03 WO 00/01704 - 150 - PCT/EP99/04 531 (e) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 2-(2-carboxyethyl)-4,5-dimethyl-imidazol-l-yl-methyl] -benzimidazole 5 (f) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 1-(carboxymethylamino) -1-(pyrrolidin-l-yl-carbonyl)-ethyl] -benzimidazole and (g) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[ l-.(N-methyl 10 carboxymethylcarbonylaminomethyl)-1-methyl-l-(pyrrolidin-l-yl-carbonyl) -ethyl] -benzimidazole and the Ci-3-alkanolesters, the N-(Ci-8-alkoxycarbonyl) , N-benzyloxycarbonyl and N-benzoyl-amidines thereof, the 15 tautomers, stereoisomers and salts thereof.

8. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 1- (carboxymethylamino)-1-(pyrrolidin-l-yl-carbonyl)-ethyl] -benzimidazole, the Ci-3-alkanolesters thereof, and their 20 N-(Ci-8-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines, tautomers, stereoisomers and salts.

9. R-2-(4-amidinophenylaminomethyl)-l-methyl-5-[ 1- (carboxymethylamino-1-(pyrrolidinocarbonyl)-ethyl] -25 benzimidazole, the Ci-3-alkanolesters thereof and their N-(Ci-g-alkoxycarbonyl, N-benzyloxycarbonyl and N-benzoylamidines, tautomers, stereoisomers and salts.

10. Physiologically acceptable salts of the compounds 30 according to claims 1 to 8 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9. IPO NZ - 4 JUN 2003 509625 WO 00/01704 - 151 - PCT/EP99/0 4 531

11. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10, optionally together 5 with one or more inert carriers and/or diluents.

12. Use of a compound according to at least one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10 10, for preparing a pharmaceutical composition with a thrombin time prolonging effect, a thrombin-inhibiting effect and an inhibiting effect on related serine proteases. 15

13. Process for preparing a pharmaceutical composition according to claim 11, wherein a compound according to at least one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10, is incorporated in one or more 20 inert carriers and/or diluents by a non-chemical method.

14. Process for preparing the compounds according to claims 1 to 10, wherein 2 5 a) in order to prepare a compound of general formula I wherein Rc denotes a cyano group: a compound of general formula iponz 2 6 mat 2003 WO 00/01704 - 152 - PCT/EP99/04531 Rb optionally formed in the reaction mixture, wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 8, Zi 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 Zi 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 in a solvent or mixture of solvents in an excess of the acylating agent used to prepare the compound of general formula II, at temperatures between 0 and 250°C, to form a benzimidazole of general formula I wherein Rc denotes a cyano group, or b) in order to prepare a compound of general formula I wherein Ra denotes an R2-CX'-C3-5-cycloalkylene group, wherein R2 is defined as in claims 1 to 8 and X' denotes one of the imino groups mentioned for X in claims 1 to 8: a compound of general formula iponz 26 mai 2003 WO 00/01704 - 153 - PCT/EP99/04531 ^>—A—B —Ar— Rc (IV) , N Rb wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra' denotes an R2-C0-C3-5-cycloalkylene group, where 5 R2 is defined as in claims 1 to 8, is reacted with an amine of general formula 10 H2X' (V), wherein ' X' denotes one of the imino groups' mentioned for X in claims 1 to 8, or 15 c) in order to prepare a compound of general formula I wherein Ra denotes an R2-CX"-C3-5-cycloalkylene group, wherein R2 is defined as in claims 1 to 8 and X" denotes one of the alkylidene groups mentioned for X in claims 1 20 to 8, a. compound of general formula 25 R= :iv), wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra' denotes an R2-CO-C3-5-cycloalkylene group, where 1ponz 2 6 mat 2003 WO 00/01704 154 PCT/EP9 9/0 4 531 R2 is defined as in claims 1 to 8 is reacted with a phosphone of general formula 5 Z3-X"H (VI) , wherein X" denotes one of the alkylidene groups mentioned for X in claims 1 to 8 and 10 Z3 denotes a triphenylphosphono or di-(Ci-3-alkoxy) phosphono group, or d) in order to prepare a compound of general formula I wherein Rc denotes an amidino group which may be 15 substituted by one or two Ci-3-alkyl groups: , a compound of general formula 2 0 optionally formed in the reaction mixture wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 8 and Z4 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio 25 group, is reacted with an amine of general formula R •a C=(NH)Z4 (VII), wherein H - R7NR8 ,(VIII) iponz 26 mar 2003 WO 00/01704 - 155 - 509625 PCT/EP99/04 531 R7 and Rg, which.may be identical or different, each denote a hydrogen atom or a Ci-3-alkyl group, or with the salts thereof, or 5 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 Ci-3-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or Ci-3-alkoxycarbonyl group: 10 a compound of general formula (IX) , Rv 15 optionally formed in the reaction mixture wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra" denotes an aminocarbonylamino group, substituted in 20 the 3 position by a Ci^3-alkoxycarbonyl-Ci-3-alkyl group, is cyclised in a solvent in the presence of an acid at temperatures between 0 and 50°C to form said imidazolidin-2,4-dion-5-yl compound, or 25 f) in order to prepare a compound of general formula I wherein Rc denotes a hydroxyamidino group: IPONZ a nitrile of general formula 2g WO 00/01704 - 156 - PCT/EP99/04531 N y—A—B—Ar CN . (X), N Rb wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 8, is reacted with hydroxylamine or the salts thereof, or g) in order to prepare a compound of general formula .1 wherein Ra contains a carboxy group and Rc is defined as in claims 1 to 8 or Ra is defined as in claims 1 to 8 and Rc denotes an amidino group optionally substituted by a hydroxy group or by one or two Ci-3-alkyl groups: a compound of general formula R= Rv -B—Ar- R, (XI) , wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra'" and Rc' have the meanings given for Ra and Rc respectively in claims 1 to 8, 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 defined as in claims 1 to 8 - or Rc denotes a group which may optionally be converted 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 Ci-3-alkyl IPONZ groups and Ra is defined as in claims 1 to 8, 26 MAY 2003 509625 WO 00/01704 157 PCT/EP99/0 4 531 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 5 Rc is defined as in claims 1 to 8 or Ra is defined as in claims 1 to 8 and Rc denotes an amidino group optionally substituted by a hydroxy group or by one or two Ci-3-alkyl groups, or 10 h) in order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by one or two Ci-8-alkoxycarbonyl groups or by a group which can be cleaved in vivo: 15 a compound of general formula I wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 8 and 2 0 Rc" denotes an amidino group, is reacted with a compound of general formula 2 5 wherein R9 denotes a Ci-8-alkoxycarbonyl group or an acyl group selected from a benzoyl group, optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by Ci-3-alkyi or Ci_3-alkoxy groups, wherein the (XII), Z5 - Rg (XIII), iponz 2 6 mar 2003 509625 WO 00/01704 - 158 - PCT/EP99/04531 substituents may be identical or different, a pyridinoyl group or a Ci-i6-alkanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a Ci-i6~alkoxycarbonyl or Ci-i6-alkylcarbonyloxy group wherein hydrogen atoms may be 5 wholly or partially replaced, by fluorine or chlorine atoms, a phenyl-Ci_6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by Ci-s-alkyl or C3-7-cycloalkyl groups and the substituents may be identical or different, a 1.0 Ci_3-alkylsulphonyl-C2-4-alkoxycarbonyl, Ci-3-alkoxy- C2-4~alkoxy-C2-4-alkoxycarbonyl, Rd-C0-0- (RdCRf) -O-CO-, Ci-6-alkyl-CO-NH-(RgCRh)-O-CO- or Ci_6-alkyl-C0-0-(RgCRh) -(RgCRh) -O-CO- group wherein Rd to Rf are as hereinbefore defined, and 15 Rg and Rh, which may be identical or different, denote hydrogen atoms or Ci-3-alkyl groups which can be cleaved in vivo and Z5 denotes a nucleofugic leaving group, and 20 subsequently if desired a compound of general formula I thus obtained which contains an (R3NR4) -Ci-3-alkyl group in which at least one of the groups R3 or R4 denotes a hydrogen atom, is converted with a corresponding 25 isocyanate or carbamoyl halide into a corresponding urea compound of general formula I, and/or a compound of general formula I thus obtained which contains a NH2-Ci-3-alkyl group is converted with a 30 corresponding acrylic acid ester into a corresponding 2-(Ci-3-alkoxycarbonyl)-ethyl compound of general formula I and/or IPONZ 2 6 Mat 2003 50 9625 WO 00/01704 - 159 - PCT/EP99/04531 a compound of general formula I thus obtained which contains an (R3NR4) -Ci-3-alkyl group in which R3 and R4 each denote a hydrogen atom is converted with a corresponding 5 dihaloalkane into 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 cycloalkyleneimino group and/or 10 a compound of general formula I thus obtained wherein Rc 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 and/or 15 a compound of gener-al formula I thus obtained wherein Rc denotes a hydroxyamidino group is converted by catalytic hydrogenation into a corresponding amidino compound and/or 20 a compound of general formula I thus obtained wherein Ra contains a carboxy group is converted by esterification into a corresponding ester and/or a orotectino orouD used to orotect reactive orouDS durino 25 the reactions is cleaved and/or a compound of general formula I thus obtained is resolved into its stereoisomers and/or 30 a compound of general formula I thus obtained is converted into the salts thereof, more particularly for iponz 26 mat 2003 WO 00/01704 - 160 - 509625 PCT/EP99/0 4 531 pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.

15. A benzimidazole of general formula (I) as defined in 5 claim 1 or a physiologically acceptable salt thereof, substantially as herein described with reference to any one of the Examples.

16. A benzimidazole according to any one of claims 1 to 9 ■ 10 . or a salt according to claim 10, substantially as herein described.

17. A pharmaceutical composition according to claim 11, substantially as herein described with reference to any 15 one of Examples 22 to 28. j

18. A pharmaceutical composition according to claim 11, substantially as herein described. 20

19. Use according to claim'12, substantially as herein described with reference to any one of Examples 22 to 28.

20. Use according to claim 12, substantially as herein described. 25

21. Process according to claim 13, substantially as herein described with reference to any one of Examples 22 to 28.

22. Process according to claim 13, substantially as herein 30 described. iponz 2 6 MAi m 509625 WO 00/01704 - 161 - PCT/EP99/0 4 531

23. Process according to claim 14, substantially as herein described with reference to any one of Examples 1 to 21.

24. Process according to 'claim 14, substantially as herein 5 described. IPONZ 26 MAi 2bu3 Abstract 5 The present invention relates to new benzimidazoles of general formula Rb 10 wherein Ra to Rc, A, Ar and B are defined as in claim 1, the tautomers, the stereoisomers, the mixtures thereof the prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological 15 conditions, instead 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. 20 The compounds of the above general formula I wherein Rc 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 amidino groups mentioned in claim 1 25 which have valuable pharmacological properties, particularly an antithrombotic activity. </div>